Publikationen

Publikationen zum Thema Long COVID

Die folgende Auflistung bietet einen Übersicht zu ausgewählten Studien und Veröffentlichung aus der medizinischen Forschung, verschiedenen Fachbereichen sowie partizipativen Vorhaben, die sich mit den Post-Acute Sequelae of SARS-CoV-2 (PASC) (sog. Post-COVID-19-Syndrom), diversen Folgeerkrankungen nach einer SARS-CoV-2-Infektion und den unterschiedlichen Aspekten von Long COVID befassen.

Folgende Plattformen und Tools bieten die Möglichkeiten für eine gezielte Suche nach wissenschaftlichen Publikationen zum Thema Long COVID:

NIH National Library of Medicine – pubmed.gov
ZB MED preprint Viewer – preVIEW: COVID-19
Association COVID Long France – Resources Long COVID &
ApresJ20
Corona Central – Long Haul
Research-Aid Network – Long COVID Library


The Prevalence, Severity, and Impact of Post-COVID Persistent Fatigue, Post-Exertional Malaise, and Chronic Fatigue Syndrome
November 2022
Overall, 5515 individuals participated in this study (response rate 70.7%), with 5406 participants at 6 months or more after their test date. A total of 1497 (27.7%) participants had a documented positive SARS-CoV-2 test and were ultimately included in the study. The median time for follow-up was 225 days (interquartile range 207–398). Respectively, fatigue was reported by 17.2%, post-exertional malaise by 8.2%, and the presence of criteria for chronic fatigue syndrome by 1.1% of SARS-CoV-2-positive individuals, compared to 8.9%, 3.5%, and 0.5% of SARS-CoV-2-negative individuals.


Cognitive Deficits in Long Covid-19
November 2022
Some patients who have recovered from an infection have reported transient or even lasting cognitive dysfunction. This includes patients who have been infected with SARS-CoV-2, many of whom, including those with mild disease, have reported deficits in attention, executive functioning, language, processing speed, and memory — symptoms collectively referred to as “brain fog.” Together with increased incidence of anxiety, depression, sleep disorder, and fatigue, this syndrome of cognitive impairment contributes substantially to the morbidity of post–Covid-19 conditions (also called “long Covid”).


Post-COVID-19-associated morbidity in children, adolescents, and adults: A matched cohort study including more than 157,000 individuals with COVID-19 in Germany
November 2022
We used routine data from German statutory health insurance organizations covering the period between January 1, 2019 and December 31, 2020. The base population included all individuals insured for at least 1 day in 2020. Based on documented diagnoses, we identified individuals with polymerase chain reaction (PCR)-confirmed COVID-19 through June 30, 2020. A control cohort was assigned using 1:5 exact matching on age and sex, and propensity score matching on preexisting medical conditions. The date of COVID-19 diagnosis was used as index date for both cohorts, which were followed for incident morbidity outcomes documented in the second quarter after index date or later.Overall, 96 prespecified outcomes were aggregated into 13 diagnosis/symptom complexes and 3 domains (physical health, mental health, and physical/mental overlap domain). In this retrospective matched cohort study, we observed significant new onset morbidity in children, adolescents, and adults across 13 prespecified diagnosis/symptom complexes, following COVID-19 infection. These findings expand the existing available evidence on post-COVID-19 conditions in younger age groups and confirm previous findings in adults.


Acute and postacute sequelae associated with SARS-CoV-2 reinfection
November 2022
Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n?=?443,588), reinfection (two or more infections, n?=?40,947) and a noninfected control (n?=?5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR)?=?2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR?=?3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.


Long COVID: long-term health outcomes and implications for policy and research
November 2022
More than two years into the pandemic, we still do not have systems that enable the assessment of the toll of long COVID and its myriad complications, including kidney disease. Current surveillance systems capture acute effects of infectious disease but do not account for their post-acute and long-term effects. This gap needs to be urgently addressed and thus governments and health systems must develop adequate data systems that can capture this missing information. These data will be vital to inform health system planning for post-COVID-19 care. Of note, the effects of SARS-CoV-2 infection and, more broadly, of the pandemic on the rates of non-communicable diseases, life expectancy and economic indicators should also be evaluated. The development of large-scale clinical trial programmes to test therapeutics for long COVID is another urgent need. Experimental studies using organoid and animal models have potential to clarify the mechanisms of injury that underlie long COVID and to inform therapeutic strategies. Moreover, given that currently approved SARS-CoV-2 vaccines are limited in their ability to reduce the risk of viral transmission and of developing long COVID, vaccine strategies that can address these shortcomings are also urgently required. Finally, comparative studies that can examine differences and similarities in the biology and clinical features of long COVID and other infection-associated illnesses (for example, ‘long flu’ following influenza infection, and myalgic encephalomyelitis or chronic fatigue syndrome) are also urgently needed.


Post-acute sequelae of covid-19 six to 12 months after infection: population based study
Oktober 2022
50457 patients were invited to participate in the study, of whom 12053 (24%) responded and 11710 (58.8% (n=6881) female; mean age 44.1 years; 3.6% (412/11602) previously admitted with covid-19; mean follow-up time 8.5 months) could be included in the analyses. Symptom frequencies (six to 12 months after versus before acute infection), symptom severity and clustering, risk factors, and associations with general health recovery and working capacity. The symptom clusters fatigue (37.2% (4213/11312), 95% confidence interval 36.4% to 38.1%) and neurocognitive impairment (31.3% (3561/11361), 30.5% to 32.2%) contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness, and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. Considering new symptoms with at least moderate impairment of daily life and ?80% recovered general health or working capacity, the overall estimate for post-covid syndrome was 28.5% (3289/11536, 27.7% to 29.3%) among participants or at least 6.5% (3289/50457) in the infected adult population (assuming that all non-responders had completely recovered). The true value is likely to be between these estimates.


Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study
Oktober 2022
A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.


Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021
Oktober 2022
This observational analysis involved bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. The modeled estimated proportion with at least 1 of the 3 self-reported Long COVID symptom clusters 3 months after symptomatic SARS-CoV-2 infection was 6.2%, including 3.7% for ongoing respiratory problems, 3.2% for persistent fatigue with bodily pain or mood swings, and 2.2% for cognitive problems after adjusting for health status before COVID-19.


The Neurobiology of Long COVID
Oktober 2022
We highlight a number of possible underlying disease mechanisms that could contribute to CNS dysfunction, including neuroinflammatory effects of distal inflammation, autoimmunity, direct CNS infection, herpesvirus reactivation, neurovascular injury, and hypoxia. What accounts for the persistent nature of cognitive dysfunction in neuro-COVID remains to be fully elucidated. Continuing neuro-inflammation could reflect a lasting state change in CNS immune and glial cells that perpetuates neural pathophysiology, ongoing endotheliopathy with microvascular disruption and blood-brain-barrier breakdown, autoimmunity, response to ongoing peripheral inflammation – attributable to latent herpesvirus reactivation, possible persistent reservoirs of SARS-CoV2 infection outside of the nervous system, or persistent circulating spike protein – or a combination of these possibilities. A deeper mechanistic understanding of Journal Pre-proof the pathophysiology of long COVID in general and neuro-COVID in particular will be required to develop effective therapies to ease the suffering of millions of people affected by the often-debilitating long-term consequences of COVID-19.


Long-term neurological sequelae of SARS-CoV-2 infection
Oktober 2022
In the post-acute phase, patients with COVID-19 had an increased risk of a wide range of incident neurological disorders, including cerebrovascular disorders, cognition and memory disorders (memory problems and Alzheimer’s disease), peripheral nervous system disorders, episodic disorders, extrapyramidal and movement disorders, musculoskeletal disorders, sensory disorders, other neurological or related disorders, and any neurological outcome (a composite outcome of any of the neurological outcomes we studied) (Fig. 1; see the associated paper for the full list of conditions assessed). Overall, we estimate that patients with COVID-19 have a 42% increased risk of developing a neurological sequela in the year after infection, translating to a burden of 7% of infected people. The risks were evident in subgroups based on age, race, sex, obesity, smoking, measures of socioeconomic deprivation, diabetes, chronic kidney disease, hyperlipidaemia, hypertension and immune dysfunction. The risks were evident even among patients who had mild acute COVID-19 that did not necessitate hospitalization, but were higher among people who were hospitalized and the highest risks were among patients who needed intensive care during the acute phase of COVID-19. The results were consistent in analyses involving the COVID-19 group versus either the contemporary or the historical control cohorts as the referent category.


A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
August 2022
In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.


The chronification of post-COVID condition associated with neurocognitive symptoms, functional impairment and increased healthcare utilization
August 2022
In this study, follow-up was conducted at 7 and 15 months after testing at the outpatient SARS-CoV-2 testing center of the Geneva University Hospitals. The chronification of symptoms was defined as the continuous presence of symptoms at each evaluation timepoint (7 and 15 months). Adjusted estimates of healthcare utilization, treatment, functional impairment and quality of life were calculated. Logistic regression models were used to evaluate the associations between the chronification of symptoms and predictors. Overall 1383 participants were included, with a mean age of 44.3 years, standard deviation (SD) 13.4 years, 61.4% were women and 54.5% did not have any comorbidities. Out of SARS-CoV-2 positive participants (n?=?767), 37.0% still had symptoms 7 months after their test of which 47.9% had a resolution of symptoms at the second follow-up (15 months after the infection), and 52.1% had persistent symptoms and were considered to have a chronification of their post-COVID condition. Having several symptoms at testing and difficulty concentrating at 7 months were associated with a chronification of symptoms.


Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity
August 2022
Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.


Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1.284.437 patients
August 202
We identified 1.487.712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1.284.437 (185.748 children, 856.588 adults, and 242.101 older adults; overall mean age 42·5 years [SD 21·9]; 741.806 [57·8%] were female and 542.192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47.675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44.835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39.845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar.


Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study
August 2022
76.422 participants (mean age 53·7 years [SD 12·9], 46.329 [60·8%] were female) completed a total of 883.973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint.


Long COVID symptomatology after twelve months and its impact on quality of life according to initial COVID-19 disease severity 
August 2022
Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least one symptom with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently one or more symptoms (82.6% vs 38.6%, p<0.001) and had on average 6.8 more symptoms (CI 95% [4.18; 9.38]) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, like neurological and cardiovascular symptoms, but also less frequent such as gastrointestinal symptoms, tended to cluster.


Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro
August 2022
Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive. Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro. PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay. While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients. Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers. PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups. Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation. Overall, PCS and PCS/CFS patients? sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients.


Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection
Juli 2022
This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls. This cohort study found that, although 10% of children hospitalized with acute SARS-CoV-2 infections and 5% of those discharged from the ED reported PCCs at 90 days, these rates were only slightly higher than the rates among SARS-CoV-2–negative controls. Risk factors for reporting PCCs included the number of acute symptoms, length of hospitalization, and older age. These findings can inform public health policy decisions regarding COVID-19 mitigation strategies for children and screening approaches for PCCs among those with severe infections.


How COVID-19 affects microvessels in the brain 
Juli 2022
Early studies described signs of vascular abnormalities in the brains of severely ill COVID-19 patients that were verified by immunohistology in post-mortem tissue. With increasing evidence, it is now accepted that infection with SARS-CoV-2 affects the vasculature of various organs and that these effects may contribute to organ dysfunction. However, it is still unclear exactly what happens to the brain microvessels and which mechanisms are involved. An activated endothelium and more permeable blood–brain barrier could result in infiltration of immune cells as seen in other neurological diseases. Indeed, the authors showed data supporting the infiltration of CD3- or CD8-positive T cells and CD68-positive macrophages. These infiltrates were present almost exclusively in the perivascular space and not in the brain parenchyma, indicating indirect effects, if any, on cells like neurons and glia.


Symptoms and risk factors for long COVID in non-hospitalized adults
Juli 2022
We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.


Autoimmunity and SARS-CoV-2 infection: unraveling the link in neurological disorders
Juli 2022
Although the underpinning pathophysiological mechanisms remain elusive, a growing body of evidence suggests that SARS-CoV-2 infection may trigger an autoimmune response, which could potentially contribute to the establishment and/or exacerbation of neurological disorders in COVID-19 patients. Shedding light on this aspect is urgently needed for the development of effective therapeutic intervention. This review highlights the current knowledge of the immune responses occurring in Neuro-COVID patients and discusses potential immune-mediated mechanisms by which SARS-CoV-2 infection may trigger neurological complications.


Post-COVID-Syndrom mit Fatigue und Belastungsintoleranz: Myalgische Enzephalomyelitis bzw. Chronisches Fatigue-Syndrom
Juli 2022
Bei ME/CFS handelt es sich um eine zumeist infektinduzierte, in der Regel lebenslang persistierende neuroimmunologische Erkrankung mit mindestens 6 Monate anhaltender Fatigue und dem definierenden Kernmerkmal der Belastungsintoleranz („post-exertional malaise“ [PEM]). Darunter versteht man eine nach (auch leichter) Alltagsanstrengung auftretende Verschlechterung der Beschwerden, die meist erst nach mehreren Stunden oder am Folgetag einsetzt, mindestens 14h nach Belastung noch spürbar ist und oft mehrere Tage (bis Wochen oder länger) anhält. Des Weiteren bestehen bei ME/CFS Schmerzen, Störungen von Schlaf, Denk- und Merkfähigkeit sowie Fehlregulationen von Kreislauf, Hormon- und Immunsystem. Als eigenständige klinische Entität ist ME/CFS von der chronischen Fatigue abzugrenzen, die als Symptom bei ganz unterschiedlichen Erkrankungen auftritt. Die Diagnose ME/CFS wird anhand etablierter internationaler Diagnosekriterien klinisch gestellt und erfordert zum Ausschluss anderer Diagnosen eine sorgfältige Stufendiagnostik. Eine kausale Therapie für ME/CFS ist nicht etabliert, im Vordergrund steht die Linderung der Beschwerden, die Behandlung der oft begleitenden orthostatischen Intoleranz sowie die Unterstützung beim vorausschauenden Energiemanagement („pacing“).


Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial
Juli 2022
This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection. Seventy-three patients were randomized to receive daily 40 session of HBOT (n=37) or sham (n=36). Follow-up assessments were performed at baseline and 1–3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d=0.495, p=0.038; d=0.477, p=0.04 and d=0.463, p=0.05 respectively). Significant improvement was also demonstrated in the energy domain (d=0.522, p=0.029), sleep (d=-0.48, p=0.042), psychiatric symptoms (d=0.636, p=0.008), and pain interference (d=0.737, p=0.001). Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.


SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death
Juni 2022
Here, we reported that SARS-CoV-2 can directly infect human microglia, eliciting M1-like proinflammatory responses, followed by cytopathic effects. Specifically, SARS-CoV-2 infected human microglial clone 3 (HMC3), leading to inflammatory activation and cell death. RNA sequencing (RNA-seq) analysis also revealed that endoplasmic reticulum (ER) stress and immune responses were induced in the early, and apoptotic processes in the late phases of viral infection. SARS-CoV-2-infected HMC3 showed the M1 phenotype and produced proinflammatory cytokines, such as interleukin (IL)-1?, IL-6, and tumor necrosis factor ? (TNF-?), but not the anti-inflammatory cytokine IL-10. After this proinflammatory activation, SARS-CoV-2 infection promoted both intrinsic and extrinsic death receptor-mediated apoptosis in HMC3. Using K18-hACE2 transgenic mice, murine microglia were also infected by intranasal inoculation of SARS-CoV-2. This infection induced the acute production of proinflammatory microglial IL-6 and TNF-? and provoked a chronic loss of microglia. Our findings suggest that microglia are potential mediators of SARS-CoV-2-induced neurological problems and, consequently, can be targets of therapeutic strategies against neurological diseases in patients with COVID-19.


The impact of Long COVID on the UK workforce
Juli 2022
Using estimates of cumulative prevalence of Long COVID, activity-limiting Long COVID in the working-age population and of economic inactivity and job loss resulting from Long COVID, we provide evidence of the profound impact of Long COVID on national labour supply. Since the start of the pandemic, cumulatively 2.9 million people of working age (7% of the total) in the UK have had, or still have, Long COVID. This figure will continue to rise due to very high infection rates in the Omicron wave. Since the beginning of the pandemic, economic inactivity due to long-term sickness has risen by 120,900 among the working-age population, fuelling the UK’s current labour shortage. An estimated 80,000 people have left employment due to Long COVID. We argue that governments need to tackle the twin challenges to public health and labour supply and provide employment protection and financial support for individuals and firms affected by Long COVID.


Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records
Juni 2022
To elucidate the burden and possible causes of long COVID in the community, we coordinated analyses of survey data from 6907 individuals with self-reported COVID-19 from 10 UK longitudinal study (LS) samples and 1.1 million individuals with COVID-19 diagnostic codes in electronic healthcare records (EHR) collected by spring 2021. Proportions of presumed COVID-19 cases in LS reporting any symptoms for 12+ weeks ranged from 7.8% and 17% (with 1.2 to 4.8% reporting debilitating symptoms). Increasing age, female sex, white ethnicity, poor pre-pandemic general and mental health, overweight/obesity, and asthma were associated with prolonged symptoms in both LS and EHR data, but findings for other factors, such as cardio-metabolic parameters, were inconclusive.


Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID
Juni 2022
A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022. Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS. The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.


Long COVID symptoms in SARS-CoV-2-positive children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study
Juni 2022
After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0–14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. Compared with controls, children aged 0–14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial.


Long-COVID in children and adolescents: a systematic review and meta-analyses
Juni 2022
The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (??12 weeks) symptoms. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.


Call for action: Health services in the European region must adopt integrated care models to manage Post-Covid-19 Condition
Juni 2022
As Post-Covid-19 Condition is now getting recognised as a new long-term condition, it is clear that health systems worldwide will be facing a significant pressure on the services they provide for patients with this condition, including their morbidity and the healthcare costs to manage these individuals optimally. Traditionally, health services in most countries have operated largely on a single organ system model (such as Cardiology or Gastroenterology) providing highly specialist care at a single point of access to the service. There are some notable exceptions in elderly care, pain, rehabilitation and cancer services, where there is cross-specialty and interdisciplinary working. Standalone super-specialty driven care models will struggle to manage Post-Covid-19 Condition comprehensively and effectively. There is a risk to patient safety that arises from inappropriately lengthy or unidisciplinary traditional pathways that do not have the skill mix to manage this complex and multisystem condition.


The IL-1ß, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19
Juni 2022
Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1ß, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop.

What SARS-CoV-2 does to our brains
Juni 2022
In theory, the neurological symptoms observed after SARS-CoV-2 infection could be (i) directly caused by the virus infecting brain cells, (ii) indirectly by our body’s local or systemic immune response towards the virus, (iii) by co-incidental phenomena or (iv) a combination of these factors. As indisputable evidence of intact and replicating SARS-CoV-2 particles in the central nervous system (CNS) is currently lacking, we suggest focusing on the host’s immune reaction when trying to understand the neurocognitive symptoms associated with SARS-CoV-2 infection. In this Perspective, we discuss the possible immune-mediated mechanisms causing functional or structural CNS alterations during acute infection as well as in the post-infectious context. We also review the available literature on CNS affection in the context of COVID-19 infection, as well as observations from animal studies on the molecular pathways involved in sickness behavior.


Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infection
Juni 2022
SARS-CoV-2 infection is known to result in a range of symptoms with varying degrees of acute-phase severity. In a subset of individuals, an equally diverse collection of long-term sequelae has been reported after convalescence. As survivorship and therefore the number of individuals with ‘long-COVID’ continues to grow, an understanding of the prevalence, origins, and mechanisms of post-acute sequelae manifestation is critically needed. Here, we will explore proposed roles of the anti-SARS-CoV-2 immune response in the onset, severity, and persistence of SARS-CoV-2 post-acute sequelae. We discuss the potential roles of persistent virus and autoantigens in this syndrome, as well as the contributions of unresolved inflammation and tissue injury. Furthermore, we highlight recent evidence demonstrating the potential benefits of vaccination and immunity in the resolution of post-acute symptoms.


Versorgungsbedarfe zu Long-COVID aus Sicht von Betroffenen und Hausärzt*innen – eine Mixed-Methods-Studie aus Baden-Württemberg
Juni 2022
Die vorliegende Arbeit zeigt erste Einblicke in Versorgungsbedarfe und Inanspruchnahmeverhalten bei Long-COVID in Deutschland. Die Ergebnisse stützen ein interdisziplinäres, intersektorales und interprofessionelles gestuftes Versorgungskonzept für Long-COVID in Deutschland mit Hausärzt*innen als ersten Ansprechpartner*innen, Einbezug von Spezialanlaufstellen und Wissenstransfer. Die Etablierung regionaler Netzwerke mit Verknüpfung der regionalen ambulanten Versorgungsstrukturen und dem universitären medizinischen Sektor erscheint hierfür sinnvoll und wichtig.


Is ‘Long Covid’ similar to ‘Long SARS’?
Juni 2022
It is clear that Long SARS (post SARS ongoing symptomatology) exists, persists (apparently permanently) and can be devastatingly life-changing for some. Sufficient similarities exist between Long SARS and Long Covid (PASC) in symptoms, findings and course over time (so far) that one can predict that it is very highly likely that some Long Covid disability will persist permanently. For those interested in rehabilitation, it is once more noted that the peer group support was very highly valued by the patients. Those wishing to treat Long Covid remotely (such as with telehealth) should consider this. All of the foregoing information is provided as a personal opinion to help guide treatment and counseling, so as to provide hope but not false hope for those affected by Long Covid.


Is post-COVID syndrome an autoimmune disease?
Juni 2022
An autoimmune phenomenon plays a major role in most causative theories explaining PCS. There is a need for both PCS definition and classification criteria (including severity scores). Longitudinal and controlled studies are necessary to better understand this new entity, and to find what additional factors participate into its development. With the high prevalence of COVID-19 cases worldwide, together with the current evidence on latent autoimmunity in PCS, we may observe an increase of autoimmune diseases (ADs) in the coming years. Vaccination’s effect on the development of PCS and ADs will also receive attention in the future. Health and social care services need to develop a new framework to deal with PCS.


Fatigue and quality-of-life in the year following SARS-Cov2 infection
Juni 2022
120 patients completed both follow-up consultations. Overall, about 40% of the patients presented dyspnoea symptoms. The median mMRC score was 1 Interquartile ranges (IQR)=[0–2] at the two assessment. Concerning FSS scores, 35% and 44% of patients experienced fatigue at both follow-ups. The two scores of SF12 were lower than the general population standard scores. The mean PCS12 score was 42.85 (95% confidence interval (95% CI [41.05–44.65])) and mean MCS12 score of 46.70 (95% CI [45.34–48.06]) at 6 months. At 12 months, the mean PCS12 score was 42.18 (95% confidence interval (95% CI [40.46–43.89])) and mean MCS12 score of 47.13 (95% CI [45.98–48.28]). No difference was found between SF12 scores at 6 and 12 months. This study pinpoints the persistence of fatigue and a low mental and physical QOL compared to population norms even after 1 year following infection. It also supports the claims of mental or psychological alterations due to infection by this new virus, hence a lower overall QOL in patients.


Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Juni 2022
COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.


Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID
Juni 2022
Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness. Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.


Long COVID after breakthrough SARS-CoV-2 infection
Mai 2022
At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with breakthrough infection (BTI) exhibited a higher risk of death (hazard ratio (HR)=1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR=1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n=113,474), people with BTI exhibited lower risks of death (HR=0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR=0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.


Pathophysiology and mechanism of long COVID: a comprehensive review
Mai 2022
A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far.


Impact of Long Covid on workers and workplaces and the role of OSH
Mai 2022
For some sufferers, COVID-19 can trigger symptoms that last for weeks or even months after the original infection has passed. This phenomenon, known as Long Covid, has had a significant effect on workers and workplaces with implications for occupational safety and health (OSH). This discussion paper outlines challenges for preventing and managing OSH related risks and explores measures that can be taken at the policy, research, and implementation level to reduce the impact of Long Covid. It also highlights the importance of addressing these issues to protect against potential future pandemics.


Unexplained post-acute infection syndromes
Mai 2022
SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.


Self-reported long COVID after infection with the Omicron variant in the UK: 6 May 2022
Mai 2022
The odds of reporting long COVID symptoms four to eight weeks after a first coronavirus (COVID-19) infection were 49.7% lower in infections compatible with the Omicron BA.1 variant than those compatible with the Delta variant among adults who were double-vaccinated when infected; this was after adjusting for socio-demographic characteristics. However, there was no statistical evidence of a difference in risk between first infections compatible with the Delta and Omicron BA.1 variants among triple-vaccinated adults; the socio-demographically adjusted prevalence of self-reported long COVID was 8.5% for Delta and 8.0% for Omicron BA.1. There was also no statistical evidence of a difference in risk between first infections compatible with the Delta and Omicron BA.2 variants among triple-vaccinated adults; the socio-demographically adjusted prevalence of self-reported long COVID was 7.4% for Delta and 9.1% for Omicron BA.2. The odds of reporting long COVID symptoms four to eight weeks after a first COVID-19 infection were 21.8% higher after an infection compatible with Omicron BA.2 than Omicron BA.1 among adults who were triple-vaccinated when infected; this was after adjusting for socio-demographic characteristics and time since last COVID-19 vaccination.


Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases
Mai 2022
We report expression of SARS-CoV-2 RNA in the gut mucosa 7 months after mild acute COVID-19 in 32 of 46 patients with IBD. Viral nucleocapsid protein persisted in 24 of 46 patients in gut epithelium and CD8+ T cells. Expression of SARS-CoV-2 antigens was not detectable in stool and viral antigen persistence was unrelated to severity of acute COVID-19, immunosuppressive therapy and gut inflammation. We were unable to culture SARS-CoV-2 from gut tissue of patients with viral antigen persistence. Post-acute sequelae of COVID-19 were reported from the majority of patients with viral antigen persistence, but not from patients without viral antigen persistence. Our results indicate that SARS-CoV-2 antigen persistence in infected tissues serves as a basis for post-acute COVID-19. The concept that viral antigen persistence instigates immune perturbation and post-acute COVID-19 requires validation in controlled clinical trials.


Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients
April 2022
The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.


SARS-CoV-2 triggering autoimmune diseases
April 2022
It seems that viruses cause autoimmunity with mechanisms such as molecular mimicry, bystander activation of T cells, transient immunosuppression, and inflammation, which has also been seen in post-Covid-19 autoimmunity. Infection of respiratory epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates the immune response, triggers both innate and acquired immunity that led to the immune system’s hyperactivation, excessive cytokine secretion known as “cytokine storm,” and finally acute respiratory distress syndrome (ARDS) associated with high mortality. Any factor in the body that triggers chronic inflammation can contribute to autoimmune disease, which has been documented during the Covid-19 pandemic. It has been observed that some patients produce autoantibody and autoreactive CD4+ and CD8+ T cells, leading to the loss of self-tolerance. However, there is a scarcity of evidence defining the precise molecular interaction between the virus and the immune system to elicit autoreactivity. Here, we present a review of the relevant immunological findings in Covid-19 and the current reports of autoimmune disease associated with the disease.


The Relationship between Physical Activity and Long COVID: A Cross-Sectional Study
April 2022
The relationship between Long Covid (LC) symptoms and physical activity (PA) levels are unclear. In this cross-sectional study, we examined this association, and the advice that individuals with LC received on PA. Adults with LC were recruited via social media. The New Zealand physical activity questionnaire short form (NZPAQ-SF) was adapted to capture current and pre-COVID-19 PA levels and activities of daily living (ADLs). Participants reported how PA affected their symptoms, and what PA recommendations they had received from healthcare professionals and other resources; 477 participants completed the survey. Mean age (SD) was 45.69 (10.02) years, 89.1% female, 92.7% white, and median LC duration was 383.5 days (IQR: 168.25,427). Participants were less active than pre-COVID-19 (26.88 ± 74.85 vs. 361.68 ± 396.29 min per week, p < 0.001) and required more assistance with ADLs in a 7-day period compared to pre-COVID-19 (2.23 ± 2.83 vs. 0.11 ± 0.74 days requiring assistance, p < 0.001). No differences were found between the number of days of assistance required with ADLs, or the amount of PA, and the different durations of LC illness (p > 0.05). Participants reported the effect of PA on LC symptoms as: worsened (74.84%), improved (0.84%), mixed effect (20.96%), or no effect (28.72%). Participants received contradictory advice on whether to be physically active in LC. LC is associated with a reduction in PA and a loss of independence, with most participants reporting PA worsened LC symptoms. PA level reduction is independent of duration of LC. Research is needed to understand how to safely return to PA without worsening LC symptoms.


Persistent COVID-19 symptoms in a community study of 606,434 people in England
April 2022
We have identified a substantial proportion of people who experience persistent symptoms lasting 12 weeks or more post COVID-19. After the initial decline in symptom prevalence between 4 and 12 weeks the prevalence of persistent symptoms plateaued indicating that large numbers of people may have chronic symptoms requiring investigation and intervention including rehabilitation. We show here that economically disadvantaged people and those in deprived areas appear to have a higher burden of persistent symptoms post COVID-19, compounding the excess burden of severe illness and mortality from COVID-19 experienced by these groups. In conclusion, the scale of morbidity identified in this study post COVID-19 presents significant challenges for the affected individuals and their families, and indicates a high potential population health burden. Managing the long-term sequelae of COVID-19 will remain a major challenge for affected individuals and their families and for health services.


Updated ME/CFS prevalence estimates reflecting post-COVID increases and associated economic costs and funding implications
April 2022
Prior to the COVID pandemic, we estimated a United States ME/CFS prevalence of 1.5 million and an annual economic impact of $36–51 billion. Now, due to COVID and its resulting post-acute sequalae, we estimate total ME/CFS prevalence could rise to between five and nine million. This would incur an annual U.S. economic impact of $149 to $362 billion in medical expenses and lost income, exclusive of other costs, such as disability benefits, social services, and lost wages of caretakers. NIH funding for ME/CFS research would need to expand from the current amount of $15 million per year to approximately $472–$600 million annually, up to a 40-fold increase, to be commensurate with that of similarly burdensome diseases.


Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort
April 2022
We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients’ responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients’ lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.


Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19
April 2022
We performed a prospective, observational evaluation of patients with PASC complaining of poor exertional tolerance, tachycardia with minimal activity or positional change, and palpitations. Exclusion criteria included pregnancy, pre-PASC autonomic dysfunction or syncope, or another potential explanation of PASC symptoms. All subjects underwent HUTT. Twenty-four patients with the described PASC symptoms were included. HUTT was performed a mean of 5.8 ± 3.5 months after symptom onset. Twenty-three of the 24 had orthostatic intolerance on HUTT, with 4 demonstrating POTS, 15 provoked orthostatic intolerance (POI) after nitroglycerin, 3 neurocardiogenic syncope, and one orthostatic hypotension. Compared to those with POTS, patients with POI described significantly earlier improvement of symptoms. This prospective evaluation of HUTT in PASC patients revealed orthostatic intolerance on HUTT suggestive of autonomic dysfunction in nearly all subjects. Those with POI may be further along the path of clinical recovery than those demonstrating POTS.


Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates
April 2022
Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.


Dysfunctional breathing diagnosed by cardiopulmonary exercise testing in ‘long COVID’ patients with persistent dyspnoea
März 2022
Cardiopulmonary exercise testing (CPET) was performed in 51 SARS-CoV-2 patients (median age, 64 years (IQR, 15)); male, 66.7%) living with ‘long COVID’ and persistent dyspnoea. CPET was classified into three dominant patterns: respiratory limitation with gas exchange abnormalities (RL); normal CPET or O2 delivery/utilisation impairment (D); and DB. Non-parametric and ?2 tests were applied to analyse the association between CPET dominant patterns and demographics, pulmonary function tests and SARS-CoV-2 severity. Among 51 patients, DB mostly without hyperventilation was found in 29.4% (n=15), RL in 54.9% (n=28) and D in 15.7% (n=8). When compared with RL individuals, patients with DB were younger, had significantly less severe initial infection, a better transfer capacity for carbon monoxide (median 85% (IQR, 28)), higher oxygen consumption (22.9 mL/min/kg (IQR, 5.5)), a better ventilatory efficiency slope (31.6 (IQR, 12.8)), and a higher SpO2 (95% (IQR, 3)). Our findings suggest that DB without hyperventilation could be an important pathophysiological mechanism of disabling dyspnoea in younger outpatients following SARS-CoV-2 infection, which appears to be a feature of COVID-19 not described in other viral diseases.


Clinical characteristics, activity levels and mental health problems in children with long coronavirus disease: a survey of 510 children
März 2022
We described a cluster of the most frequent symptoms and their dynamics in children with long COVID in a large cohort of children. Symptoms such as fatigue, headache, muscle and joint pain, rashes and heart palpitations and mental health issues such as lack of concentration and short-term memory problems were particularly frequent and confirmed previous observations, suggesting that they may characterize this condition. A better comprehension of long COVID is urgently needed, especially considering that at the moment there are no therapeutic options for these children who, months after COVID-19, struggle to come back to a normal life.


Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)
März 2022
As reported in our previous study, we found elevated levels of the pro-inflammatory mediator IL-8 in approximately 60% of PCS patients. As IL-8 is rapidly degraded in serum, its concentration was determined in lysed erythrocytes, which bind IL-8 via a Duffy antigen receptor. Endothelial cells and monocytes are the main producers of IL-8. IL-8 promotes endothelial cell migration and proliferation as well as survival and endothelial permeability. Elevated IL-8 levels were described in patients with severe as well as mild COVID-19 and correlated with disease prognosis. Therefore, IL-8 might indicate ongoing endothelial inflammation in our PCS patients. In conclusion, our study found that a subset of PCS patients had a diminished RHI, indicating peripheral ED. A limitation of our study is the lack of a reconvalescent cohort for RHI assessment; thus, we do not know whether a diminished RHI is associated with PCS symptoms. Elevated ET-1 levels were, however, found in PCS patients only, indicating that endothelial hypoperfusion plays a role in PCS and providing a rationale for therapeutic targeting. The paradoxical association of RHI with age, blood pressure and BMI as well as diminished Ang-2 may indicate a distinct pathomechanism in the non-ME/CFS PCS subgroup.


Changes in cognitive functioning after COVID-19: A systematic review and meta-analysis
März 2022
We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment.. Of 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients.  The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = 0.94, 95% confidence interval [CI] 1.59, 0.29; P = .0049). Patients recovered from COVID-19 have lower general cognition compared to healthy controls up to 7 months post-infection.


Quantitative Chest CT Assessment of Small Airways Disease in Post-Acute SARS-CoV-2 Infection
März 2022
100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls. Sixty-seven percent (67/100) of the participants with PASC were classified as ambulatory, 17% (17/100) wer e hospitalized and 16% (16/100) required care in the ICU. Among the hospitalized and ICU groups, the mean percent of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than in the ambulatory group (3.7%, p<.001 for both comparisons). The mean percentage of total lung affected by air trapping was 25.4%, 34.6%, and 27.3% in the ambulatory, hospitalized, and ICU groups and 7.2% in healthy controls (p<.001). Air trapping correlated with the residual volume to total lung capacity rati o (RV/TLC; r=0.6, p<.001).


The immunology and immunopathology of COVID-19
März 2022
Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need.


COVCOG 2: Cognitive and Memory Deficits in Long COVID: A Second Publication From the COVID and Cognition Study
März 2022
In this second investigation of the first baseline session of the COVID and Cognition study, we explored whether those who had experienced the COVID-19 infection showed measurable differences in assessments of cognitive performance. We found a consistent association between the COVID-19 infection and reduced memory performance, with those with ongoing symptoms being less accurate and slower in a test of verbal memory, but (once demographics and multiple comparisons were accounted for) there were no significant group effects in any other cognitive domain. When considering the nature of symptoms experienced, Fatigue/Mixed and Dermatological symptoms during the initial 3 weeks of illness were associated with reduced memory performance and slower reaction times on Executive Function Performance and Reaction Time tasks, respectively. Neurological symptoms during the ongoing illness were associated with performance in the Executive Function tasks, while the same symptoms experienced at the time of test predicted variance in memory. These were the most robust findings, with a conservative correction for multiple comparisons, suggesting that other identified associations may be worthy of further investigation.


Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach
März 2022
Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium–proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium–calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.


Long COVID-19 and Postural Orthostatic Tachycardia Syndrome- Is Dysautonomia to Be Blamed?
März 2022
A recent hypothesis is that long COVID symptoms could be attributed to dysautonomia, defined as malfunction of the autonomic nervous system (ANS). The most prevalent cardiovascular dysautonomia amongst young people is postural orthostatic tachycardia syndrome (POTS). Numerous reports have described the development of POTS as part of long COVID. Possible underlying mechanisms, although not mutually exclusive or exhaustive, include hypovolaemia, neurotropism, inflammation and autoimmunity. Treatment options for POTS and other long COVID symptoms are currently limited. Future research studies should aim to elucidate the underlying mechanisms of dysautonomia to enable the development of targeted therapies. Furthermore, it is important to educate healthcare professionals to recognise complications and conditions arising from COVID-19, such as POTS, to allow prompt diagnosis and access to early treatment.


Autoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity
März 2022
Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.


Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS
März 2022
Emerging data confirm that prolonged symptoms can develop following even mild or asymptomatic initial SARS-CoV-2 infection. The most common symptoms are fatigue, cognitive dysfunction, and headaches. As ascertainment for orthostatic intolerance in these patients improves, lightheadedness is becoming more commonly recognized. A proportion of long COVID patients meet the criteria for ME/CFS at 6 months. At present, management of post-COVID conditions focuses primarily on addressing symptoms, borrowing management strategies from conditions like OI and ME/CFS.


Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection
März 2022
We enrolled a total of 64 study participants, including 9 hospitalized patients with COVID-19 encephalopathy (CE), 9 posthospitalization neuro-PASC (PNP) patients, 38 nonhospitalized neuro-PASC (NNP) patients, and 8 HC subjects. Patients with CE were older, had higher pNfL and pGFAP concentrations, and more frequent pN Ag detection than all neuro-PASC groups. PNP and NNP patients exhibited similar PASC symptoms, decreased quality-of-life measures, and cognitive dysfunction, and 1 of the 38 (2.6%) NNP patients had pN Ag detectable 3 weeks postsymptoms onset. Patients with neuro-PASC presenting with anxiety/depression had higher neuroglial scores, which were correlated with increased anxiety on quality-of-life measures. These data shed new light on SARS-Cov-2 neuropathogenesis and demonstrate the value of plasma biomarkers across the COVID-19 disease spectrum.


Long-term health-related quality of life in non-hospitalised COVID-19 cases with confirmed SARS-CoV-2 infection in England: Longitudinal analysis and cross-sectional comparison with controls
März 2022
Of 548 cases (mean age 41.1 years; 61.5% female), 16.8% reported physical symptoms at month 6 (most frequently extreme tiredness, headache, loss of taste and/or smell, and shortness of breath). Cases reported more limitations with doing usual activities than controls. Almost half of cases spent a mean of £18.1 on non-prescription drugs (median: £10.0), and 52.7% missed work or school for a mean of 12 days (median: 10). On average, all cases lost 13.7 (95%-CI: 9.7, 17.7) QALDs, while those reporting symptoms at month 6 lost 32.9 (24.5, 37.6) QALDs. Losses also increased with older age. Cumulatively, the health loss from morbidity contributes at least 18% of the total COVID-19-related disease burden in England.


Neurological outcomes one year after COVID-19 diagnosis: a prospective longitudinal cohort study
März 2022
Symptoms at 1-year follow-up were reported by 48/81 (59%) patients, including fatigue (38%), concentration difficulties (25%), forgetfulness (25%), sleep disturbances (22%), myalgia (17%), limb weakness (17%), headache (16%), impaired sensation (16%), and hyposmia (15%). Neurological examination revealed findings in 52/81 (64%) patients without improvement over time (3-months: 61%, p=0.230) including hyposmia (SS-16<13; 51%). Cognitive deficits were apparent in 18%, whereas depression, anxiety, and post-traumatic stress disorders were diagnosed in 6%, 29%, and 10% one year after infection, respectively. These mental and cognitive disorders did not improve since 3-month follow-up (all p>0.05). Our data indicate that a significant patient number still suffer from neurological sequelae including neuropsychiatric symptoms one year after COVID-19 calling for interdisciplinary management of these patients.


Multiple early factors anticipate post-acute COVID-19 sequelae
März 2022
We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2–3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.


Current Insights Into Complex Post-infection Fatigue Syndromes With Unknown Aetiology: The Case of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Beyond
Februar 2022
In conclusion, this Research Topic collects further pieces of evidence about how various viruses including SARS-CoV-2 can trigger ME/CFS. The neglect of research in ME/CFS during the last decades has left patients, carers, and clinicians alike adrift without a licensed drug to use in the disease. On the one hand, the COVID-19 pandemic will result in an unprecedented explosion of ME/CFS cases. At the same time, this pandemic is the perfect storm that can motivate different stakeholders, including funders and clinicians, to take the necessary steps to accelerate research on ME/CFS and other post-infectious syndromes. If taken, these steps will bring hope to all those outstanding patients who have been homebound or even bedridden for many years but neglected by national health authorities.


A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications
Februar 2022
A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other ?-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.


Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID?
Februar 2022
Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery. Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.


Pathological sequelae of long-haul COVID
Februar 2022
This Review details organ-specific sequelae of post-COVID-19 syndromes and examines the underlying pathophysiological mechanisms available so far, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs. Finally, we propose diagnostic strategies to better understand this heterogeneous disorder that continues to afflict millions of people worldwide.


Long-term cardiovascular outcomes of COVID-19
Februar 2022
Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.


Estimating total morbidity burden of COVID-19: relative importance of death and disability
Februar 2022
In all models, acute mortality was only a small share of total morbidity. For lifelong moderate symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of morbidity; if survivors’ later mortality increased, morbidity increased most in young people of both sexes. Under most conditions most COVID-19 morbidity was in survivors. Future research should investigate incidence, risk factors, and clinical course of long-COVID to elucidate total disease burden, and decisionmakers should allocate scarce resources to minimize total morbidity.


Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects

Januar 2022
The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.


Lessons from Long COVID: working with patients to design better research
Januar 2022
When ‘Long COVID’ emerged as a concept in Spring 2020, it was those with lived experience of the disease who gave it its name and characterized it to the world, initially through use of social media1. Even though chronic illness induced by viral infection is not a new phenomenon, awareness of this potential outcome of the COVID-19 pandemic was entirely absent from public messaging, even at a time when large numbers of people were becoming infected with SARS-CoV-2. In summary, people with lived experience of chronic conditions from diverse backgrounds and characteristics must have a central role in conceptualizing and phrasing the research question, shaping the study design, and co-producing innovative ways to capture real-life experiences, as well as defining and labelling their conditions in a way that serves their wellbeing. Scientific research sets the medical and care agenda for patients with chronic illnesses. It also influences the wider social and economic agenda for people living with these conditions. The more socially and economically disadvantaged people are, the greater the potential influence on their lives.


Persistent Autoimmune Activation and Proinflammatory State in Post-COVID Syndrome 
Januar 2022
Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by upregulated IFN-?, TNF-?, G-CSF, IL-17A, IL-6, IL-1, and IL-13, whereas IP-10 was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of IgG S1-SARS-CoV-2 antibodies remained elevated over time. The clinical manifestations of PCS are associated with the persistence of a proinflammatory, and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.


Post-acute COVID-19 syndrome in patients after 12 months from COVID-19 infection in Korea
Januar 2022
The median period from the date of the first symptom onset or COVID-19 diagnosis to the time of the survey was 454 (interquartile range [IQR] 451–458) days. The median age of the responders was 37 (IQR 26.0–51.0) years, and 164 (68.0%) responders were women. Altogether, 11 (4.6%) responders were asymptomatic, and 194 (80.5%), 30 (12.4%), and 6 (2.5%) responders had mild, moderate, and severe illness, respectively. Overall, 127 (52.7%) responders still experienced COVID-19-related persistent symptoms and 12 (5.0%) were receiving outpatient treatment for such symptoms. The main symptoms were difficulty in concentration, cognitive dysfunction, amnesia, depression, fatigue, and anxiety. Considering the EQ5D index scores, only 59.3% of the responders did not have anxiety or depression. Older age, female sex, and disease severity were identified as risk factors for persistent neuropsychiatric symptoms.


Health Status, Persistent Symptoms, and Effort Intolerance One Year After Acute COVID-19 Infection
Januar 2022
In summary, declined cognitive function, psychiatric morbidity and low QoL are prevalent in moderate to severe COVID-19 survivors 1 year after hospital discharge. These data await confirmation by further prospective studies in other regions. Meanwhile, health policies should be designed to address these long-term problems. A multidisciplinary approach that includes neurocognitive rehabilitation and psychiatric evaluation and treatments should be offered to indicated patients.


Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVD-19 respiratory disease
Januar 2022
We delineated the immune-proteomic landscape in the airway and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. 1 year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.


Long COVID-19: Objectifying most self-reported neurological symptoms
Januar 2022
ifty patients with persisting symptoms for at least 4?weeks were included and classified by initial hospitalization status. Median time from SARS-CoV-2 detection to investigation was 29.3?weeks (range 3.3–57.9). Although individual cognitive performance was generally within the normative range in both groups, mostly mild deficits were found in attention, executive functions, and memory. Hospitalized patients performed worse in global cognition, logical reasoning, and processes of verbal memory. In both groups, fatigue severity was associated with reduced performance in attention and psychomotor speed tasks (rs?=??0.40, p?<?0.05) and reduced quality of life (EQ5D, rs?=?0.57, p?<?0.001) and with more persisting symptoms (median 3 vs. 6, p?<?0.01). PROMs identified fatigue, reduced sleep quality, and increased anxiety and depression in both groups but more pronounced in non-hospitalized patients. Brain MRI revealed microbleeds exclusively in hospitalized patients (n?=?5).


Chronic Fatigue and Postexertional Malaise in People Living with Long COVID: An Observational Study
Januar 2022
Long COVID is characterized by chronic fatigue that is clinically relevant and at least as severe as fatigue in several other clinical conditions. PEM is a significant challenge for this patient group. Because of the potential for setbacks and deteriorated function following overexertion, fatigue and postexertional symptom exacerbation must be monitored and reported in clinical practice and in studies involving interventions for people with long COVID. Physical therapists working with people with long COVID should measure and validate the patient’s experience. Postexertional symptom exacerbation must be considered, and rehabilitation needs to be carefully designed based on individual presentation. Beneficial interventions might first ensure symptom stabilization via pacing, a self-management strategy for the activity that helps minimize postexertional malaise.


Abnormality Pattern of F-18 FDG PET Whole Body with Functional MRI Brain in Post-Acute COVID-19
Januar 2022
Among the 13 patients, 8 (61.5%) had myositis, followed by 8 (61.5%) with vasculitis (mainly in the thoracic aorta), and 7 (53.8%) with lung abnormalities.. Interestingly, one patient with a very high serum RBD IgG antibody demonstrated diffuse myositis throughout the body which potentially associated with immune-mediated myositis. One patient experienced psoriasis exacerbation with autoimmune-mediated after COVID-19. Most patients had multiple areas of abnormal brain connectivity involving the frontal and parieto-temporo-occipital lobes, as well as the thalamus. The whole body F-18 FDG PET can be a potential tool to assess inflammatory process and support the hyperinflammatory etiology, mainly for lesions in skeletal muscle, vascular wall, and lung, as well as, multiple brain abnormalities in post-acute COVID-19. Nonetheless, further studies are recommended to confirm the results.


Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome
Januar 2022
At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months.


Self-reported long COVID after two doses of a coronavirus (COVID-19) vaccine in the UK: 26 January 2022
Januar 2022
In a sample of UK adults aged 18 to 69 years, receiving two doses of a coronavirus (COVID-19) vaccine at least two weeks before a first test-confirmed COVID-19 infection was associated with a 41.1% decrease in the odds of self-reported long COVID at least 12 weeks later, relative to socio-demographically similar study participants who were not vaccinated when infected. This analysis was based on data to 30 November 2021, and longer follow-up time is needed to assess the impact of booster doses and the Omicron variant; furthermore, the observational nature of the analysis means that we cannot say whether COVID-19 vaccination caused subsequent changes in the likelihood of self-reported long COVID. Long COVID symptoms of any severity were reported by 9.5% of double-vaccinated study participants, compared with 14.6% of socio-demographically similar participants who were unvaccinated when infected; the corresponding estimates for long COVID symptoms severe enough to result in limitation to day-to-day activities were 5.5% and 8.7% respectively.


Small Fiber Neuropathy and SARS-CoV-2 Infection. Another piece in the long COVID puzzle?
Januar 2022
It is likely that management of long COVID will remain a challenge for the next several years, particularly considering that vaccination, although very effective in preventing severe forms of SARS, does not eliminate subclinical and minimally symptomatic infections, potentially leading to long-term manifestations. Long COVID is a complex condition, mechanistically heterogeneous, and with protean manifestations, so its management needs to be considered holistically. On the other hand, different phenotypes of long COVID may be identified, which may be an important precondition for more focused treatment options. A subgroup of long COVID patients could be characterized by a predominant SFN phenotype, indicating the need for investigation of potential COVID-incident SFN. Accurate phenotypic characterization of long COVID patients is useful to inform symptomatic treatment, but also may provide clues to underlying pathogenic mechanisms; better insight into apparently unexplained symptoms also can result in psychological support. 


Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae
Januar 2022
We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.


Long COVID and self-management
Januar 2022
People with long COVID reported turning to a vast range of over-the-counter medicines, remedies, supplements, other therapies, and dietary changes to manage relapsing and remitting symptoms. Individuals have expressed a willingness to try anything because symptoms have substantial effects on quality of life and work capability.There are potential risks of self-prescription, such as harmful drug–drug interactions and use of inappropriate treatments.5 Medicines can be used off label, in unsafe doses, and sometimes purchased in an unregulated manner overseas. Harmful drug–drug interactions are enhanced due to the complexity and multiple symptoms of long COVID leading to use of multiple treatments.


Do vaccines protect from long COVID?
Januar 2022
The data on long COVID are worrying, particularly during the current increase in global cases of COVID-19 infection. There are, however, encouraging emerging data that individuals who are vaccinated against COVID-19 are less likely to report long COVID symptoms. For example, a case-control study of 1·2 million users of a COVID symptom tracker app in the UK showed that there were lower odds of symptoms lasting 28 days or more in individuals who had received two vaccine doses (odds ratio 0·51 [95% CI 0·32–0·82]; p=0·0060)—ie, the risk of developing long COVID was reduced by around 50% in those who were double vaccinated. 


Nervous system consequences of COVID-19
Januar 2022
Since early in the COVID-19 pandemic, patients have described lingering syndromes following acute infection, now called Long Covid. These syndromes often include predominant neurologic and psychiatric symptoms, such as difficulty with memory, concentration, and ability to accomplish everyday tasks, frequent headaches, alterations in skin sensation, autonomic dysfunction, intractable fatigue, and in severe cases, delusions and paranoia. Many people who experience neurologic symptoms that linger after acute COVID-19 are less than 50 years old and were healthy and active prior to infection. Notably, the majority were never hospitalized during their acute COVID-19 illness, reflecting mild initial disease. Many of the symptoms experienced by individuals with Long Covid are similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is also considered to be a postinfectious syndrome caused by a variety of infectious agents. Because the pathophysiology of ME/CFS is poorly understood and there are no effective disease-modifying therapies available, it is likely that the study of Long Covid may benefit ME/CFS patients as well. There is also overlap in symptoms of post–Lyme disease, suggesting that there may be common host susceptibility factors that underlie these illnesses.


Covid-19: How Europe is approaching long covid
Januar 2022
A World Health Organization policy brief published earlier this year found that surveillance of long covid was not happening routinely in European countries. There are few specialist clinics for the condition—access to such a service largely depends on where you live—and in many countries action seems to be limited to guidance and monitoring. Carmen Scheibenbogen, professor of immunology at Charité University in Berlin, says she currently has two or three patient enquiries for every appointment available at her clinic. “We need to put more effort into research,” she says. “In Germany, at least, we don’t have much funding at the moment for these post-covid syndromes.” The German Ministry of Education and Research has allocated €6.5m to 10 projects investigating the condition. The French government’s budget for long covid research is €2.2m, according to France24. In contrast, the UK has allocated nearly £20m in funding to research the condition.


Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19
Januar 2022
Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p?=?0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p?=?0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.


Rapid vigilance and episodic memory decrements in COVID-19 survivors 
Januar 2022
Here, we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial–visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation. However, they displayed significantly worse episodic memory (up to 6 months post-infection) and greater decline in vigilance with time on task (for up to 9 months). Overall, the results show that specific chronic cognitive changes following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after 6–9 months, demonstrating evidence of recovery over time.


Healthcare use in 700.000 children and adolescents for six months after covid-19: before and after register based cohort study
Januar 2022
A substantial short term relative increase in primary care use was observed for participants during the first month after a positive SARS-CoV-2 test result compared with those who tested negative (age 1-5 years: 339%, 95% confidence interval 308% to 369%; 6-15 years: 471%, 450% to 491%; 16-19 years: 401%, 380% to 422%). Use of primary care for the younger age groups was still increased at two months (1-5 years: 22%, 4% to 40%; 6-15 years: 14%, 2% to 26%) and three months (1-5 years: 26%, 7% to 46%, 6-15 years: 15%, 3% to 28%), but not for the oldest group (16-19 years: 11%, ?2% to 24% and 6%, ?7% to 19%, respectively). Children aged 1-5 years who tested positive also showed a minor long term (?6 months) relative increase in primary care use (13%, ?0% to 26%) that was not observed for the older age groups, compared with same aged children who tested negative. Results were similar yet the age differences less pronounced compared with untested controls. For all age groups, the increase in primary care visits was due to respiratory and general or unspecified conditions. No increased use of specialist care was observed.


Endothelial dysfunction is the key of long COVID-19 symptoms: The results of TUN-EndCOV study
Januar 2022
A total of 798 patients were included in this study. Patients were included at an average time of 68.93 ± 43.1 days. The mean EQI was 2.02 ± 0.99 [0–5]. A total of 397 (49.7%) patients had poor or very poor EQI and 211 (26.4%) patients had very poor EQI. The median age was 49.94 ± 14.2 (18–80) years. A total of 618 patients (77.4%) had long COVID-19 symptoms. Patients with long COVID-19 symptoms had a reduced EQI (1.99 ± 0.97 vs. 2.09 ± 1.05, P = 0.24). Among long COVID-19 symptoms, fatigue was the most common symptom reported in 42.2%. Fatigue and chest pain were significantly associated to the endothelial dysfunction (P = 0.04 and 0.001 respectively). Patients with chest pain had significantly lower EQI (1.74 ± 1.0 vs. 2.09 ± 0.9, P ? 10?3) and LVGLS (?16.35 ± 3.0 vs. ?17.16 ± 2.5, P = 0.04).


Return to work after COVID-19 infection – A Danish nationwide registry study
Januar 2022
Among the 7466 patients included in the study, 81.9% (6119/7466) and 98.4% (7344/7466) returned to work within 4 weeks and 6 months, respectively, with 1.5% (109/7466) not returning. Of the patients admitted, 72.1% (627/870) and 92.6% (805/870) returned 1 month and 6 months after admission to the hospital, with 6.6% (58/870) not returning within 6 months. Of patients admitted to the ICU, 36% (9/25) did not return within 6 months. Patients with an admission had a lower chance of return to work 3 months from positive test (relative risk [RR] 0.95, 95% confidence interval [CI] 0.94-0.96), with the lowest chance in patients admitted to an ICU department (RR 0.54, 95% CI 0.35-0.72). Female sex, older age, and comorbidity were associated with a lower chance of returning to work.


Experiences of living with long COVID and of accessing healthcare services: a qualitative systematic review
Januar 2022
People experience long COVID as a heterogeneous condition, with a variety of physical and emotional consequences. It appears that greater knowledge of long COVID is required by a number of stakeholders and that the design of emerging long COVID services or adaptation of existing services for long COVID patients should take account of patients’ experiences in their design.


Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection
Januar 2022
A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-?) and type III IFN (IFN-?1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-?, PTX3, IFN-?, IFN-?2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.


Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme
Januar 2022
Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management.


Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19
Januar 2022
Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.


Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Januar 2022
Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 PASC patients contained ddPCR+ peripheral blood mononuclear cells, however, only fragmented SARS-CoV-2 RNA was found in PASC patients. No full length sequences were identified, and no sequences that could account for the observed S1 protein were identified in any patient. That non-classical monocytes may be a source of inflammation in PASC warrants further study.


Long-term outcomes after NeuroCOVID: A 6-month follow-up study on 60 patients
Januar 2022
We obtained data on 60 patients. NeuroCOVID had a negative impact on the quality of life (QoL) of 49% of patients. Age was a predictor of residual QoL impairment (OR: 1.06, 95% CI: 1.01–1.13, p = 0.026). At six months, a significant residual disability was found in 51.7% of patients, and impaired cognition in 68.9% of cases. The main persistent neuropsychiatric manifestations were a persistent smell/taste disorder in 45% of patients, memory complaints in 34% of patients, anxiety or depression in 32% of patients. NeuroCOVID likely carries a high risk of long-term neuropsychiatric disability. Long-term care and special attention should be given to COVID-19 patients, especially if they had neurological manifestations during acute infection.


Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome
Januar 2022
Our data suggest abnormally low FATox and altered lactate production by skeletal muscle as a putative cause of—or contributor to—the functional limitation of patients with PASC. Normally, as glycolysis increases with exercise intensity, lactate is oxidized for fuel in mitochondria, mainly in adjacent slow-twitch muscle fibers. Like FATox, lactate clearance capacity is a useful surrogate for mitochondrial function. In patients with PASC, even in those with normal pre–COVID-19 physical fitness and free of comorbidities, the metabolic disturbances of the skeletal muscle during exercise may be worse than those reported in moderately active individuals or in individuals with metabolic syndrome. Whereas rising blood lactate levels are expected during high exercise intensity (as glycolytic flux exceeds the rate of mitochondrial pyruvate oxidation), a high blood lactate at lower exercise levels indicates mitochondrial dysfunction. The inappropriately high arterial lactate levels at relatively low exercise intensity (e.g., >9 mM at 150 W) in patients with PASC indicate that the transition from FATox to CHOox occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.


Postural tachycardia syndrome and long COVID: an update
Januar 2022
The precise pathophysiology of PoTS is not fully understood. It is not a unique disease entity. As with heart failure, it is a syndrome and there is evidence that several mechanisms are involved in PoTS including hypovolaemia, autonomic denervation, hyperadrenergic stimulation, and autoimmune pathology. More than one mechanism can occur in an individual. It is not yet known whether the pathophysiologies of PoTS prior to the pandemic are the same as those found in patients with long COVID and PoTS; further research in this area is necessary. However, to date, the symptom profile of PoTS and response to treatments appear to mirror those of non-COVID PoTS. There is a growing concern that, in addition to long COVID, we may now also be facing an epidemic of PoTS.


Long COVID in children
Januar 2022
Recent analysis of Zoe application (app) data (launched jointly by Zoe Limited and King’s College London) by Erika Molteni and colleagues assessed the symptom profile and duration in children with a confirmed positive SARS-CoV-2 test. Due to the methods used, the study probably underestimates the actual prevalence of the disease in children. Understanding the true prevalence of long COVID in children is of crucial importance because many governments are using this data to define policies, from school safety measures to research funding.


Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease
Dezember 2021
Acute neurological disorders affecting patients with COVID-19 range widely from anosmia, stroke, encephalopathy/encephalitis, and seizures to Guillain–Barré syndrome. Chronic neurological sequelae are less well defined although exercise intolerance, dysautonomia, pain, as well as neurocognitive and psychiatric dysfunctions are commonly reported. Molecular analyses of CSF and neuropathological studies highlight both vascular and immunologic perturbations. Low levels of viral RNA have been detected in the brains of few acutely ill individuals. Potential pathogenic mechanisms in the acute phase include coagulopathies with associated cerebral hypoxic-ischaemic injury, blood–brain barrier abnormalities with endotheliopathy and possibly viral neuroinvasion accompanied by neuro-immune responses. Established diagnostic tools are limited by a lack of clearly defined COVID-19 specific neurological syndromes. Future interventions will require delineation of specific neurological syndromes, diagnostic algorithm development and uncovering the underlying disease mechanisms that will guide effective therapies.


Fatigue and Cognitive Impairment in Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis
Dezember 2021
The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2=99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2=98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.


Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection
Dezember 2021
In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.


Aortic 18F-FDG PET/CT hypermetabolism in patients with long COVID: a retrospective study
Dezember 2021
In summary, we retrospectively found aortic hypermetabolism in ten out of 47 patients with long COVID who had an 18F-FDG PET/CT scan, with more frequent chest pain in this group (6/10; 60% vs. 7/37; 19%, p 0.017). The high proportion of aortic hypermetabolism in our cohort (21%) makes us think that this phenomenon is not incidental. To have an idea of the prevalence of an incidental finding of thoracic aortic hypermetabolism, we compared thoracic aortic uptakes between our long COVID patients, and a non-COVID-19 control group of 20 randomly selected patients with negative SARS-CoV-2 RT-PCR and serology, who had an 18F-FDG PET/CT scan for oncological indications. No patients in this control group had visually detected aortic hypermetabolism and comparative analysis with a non-parametric Kruskall–Wallis test showed significant differences in mean aortic SUVmax between our ten patients with aortic hypermetabolism and the non-COVID-19 control group (3.36, (SD 0.63) and 2.15 (SD 0.59), respectively; p < .0001). Supported by the SARS-CoV-2 pathophysiological mechanism of entry, which uses the ACE2 receptor present on endothelial cells, evidence of SARS-CoV2 virions inside vascular tissues is now emerging. Nonetheless, it is still not clear whether this FDG/PET inflammation means active endothelial viral replication, passive viral persistence without endothelial damage, post-infectious aortic inflammation mechanism or sequelae. 18F-FDG PET/CT thoracic aortic hypermetabolism found in primary syphilitic infection, long before the development of aortic aneurysm, looks very similar to the images we found in COVID-19-infected patients, suggesting similar pathogenesis.


Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Dezember 2021
There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.


Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC)
Dezember 2021
This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. PASC following mild COVID-19 infection is associated with multisystem involvement including: 1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; 2) small fiber neuropathy and related dysautonomia; 3) respiratory dysregulation; 4) chronic inflammation.


A clinical case definition of post-COVID-19 condition by a Delphi consensus
Dezember 2021
Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on everyday functioning. Symptoms might be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms might also fluctuate or relapse over time. A separate definition might be applicable for children. Although the consensus definition is likely to change as knowledge increases, this common framework provides a foundation for ongoing and future studies of epidemiology, risk factors, clinical characteristics, and therapy.


In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19
Dezember 2021
The population was comprised by 3 groups: patients investigated during acute COVID-19 (group 1), patients investigated during past COVID-19 (group 2), and controls 1:1 matched to COVID-19 patients by demographics and cardiovascular risk factors (group 3). The natural logarithmic scaled reactive hyperemia index (LnRHI), a measure of endothelium-mediated dilation of peripheral arteries, was obtained in all the participants and compared between study groups.144 participants were enrolled (72 COVID-19 patients and 72 matched controls). Median time from COVID-19 symptoms to PAT assessment was 9.5 and 101.5 days in groups 1 and 2, respectively. LnRHI was significantly lower in group 2 compared to both group 1 and controls (0.53 ± 0.23 group 2 vs. 0.72 ± 0.26 group 1, p = 0.0043; and 0.79 ± 0.23 in group 3, p < 0.0001). In addition, within group 1, it was observed a markedly decrease in LnRHI from acute COVID-19 to post infection stage (0.73 ± 0.23 vs. 0.42 ± 0.26, p = 0.0042). This study suggests a deleterious effect of SARS-CoV-2 infection on systemic vascular endothelial function. These findings open new venues to investigate the clinical implication and prognostic role of vascular endothelial dysfunction in COVID-19 patients and post-COVID syndrome using non-invasive techniques.


Cognitive sequelae of long COVID may not be permanent. A prospective study
Dezember 2021
The study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant – likely age-related – decline in MoCA scores between the two pre-pandemic tests (?: -1.53; 95% C.I.: -2.14 to -0.92; p<0.001), which did not differ across individuals who later developed COVID-19 when compared to non-infected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (?: -1.37; 95% C.I.: -2.14 to -0.61; p<0.001), which reversed after one additional year of follow-up (?: 0.66; 95% C.I.: -0.11 to 1.42; p=0.092). No differences were noticed among non-infected individuals when both post-pandemic MoCA scores were compared. Study results suggest that long COVID-related cognitive decline may spontaneously improve over time.


Long COVID: The long-term health effects of COVID-19
Dezember 2021
There are still a series of unknowns related to Long COVID that need to be addressed to adequately shape a public health response. The main recommendations for research following the latest NICE review focused on a better understanding of interventions (e.g., medical treatments; social prescribing and community support; effectiveness of different interventions for specific population groups and the role of exercise) and of prevalence (especially in the vaccinated population). Other recommendations for research included the development of tools able to identify Long COVID and predict its emergence, better understand of the biological mechanisms and further study of this condition in children, young people, pregnant women and older people. There are different mechanisms that could probably explain the variety of symptoms. These could be different in different people or could co-exist in individuals. These mechanisms include the possibility that SARS-CoV-2 persist in reservoirs in the body; defects in the immune response (including autoimmunity) and presence of microscopic blood clots.


Promotion of non-evidence-based therapeutics within patient-led Long COVID support groups
Dezember 2021
Long COVID support groups play an essential role in advocacy, patient support and research development. However, patient-led support groups are vulnerable to people joining the group who then use their access to promote experimental, unproven or ineffective therapeutics and treatments. The combination of potential adverse effects and the often false hope offered by these non-evidence-based therapeutics can be damaging to patient health and wellbeing. The promotion of these therapeutics also suggests that there are existing treatment options for Long COVID patients, diminishing the ability of groups to advocate for new Long COVID research that may lead to actual evidence-based therapeutics.


Models of Care for Postacute COVID-19 Clinics: Experiences and a Practical Framework for Outpatient Physiatry Settings
Dezember 2021
The frequency and heterogeneity of persistent post-COVID conditions have created challenges in care. Specialty clinics are being established in response to an increasing need to care for patients with postacute sequelae of SARS-CoV-2 or long COVID syndrome. Although many post-COVID conditions can be bettered through a comprehensive rehabilitation plan, various clinical settings may benefit from differing models of coordinated care. We present five models of care in varying degrees of development and compare processes and adaptations to address the unique needs of each center and their unique patient populations. Forging a path to recovery will necessitate a multidisciplinary team with physiatry involvement to meet the distinctive needs of patients with postacute sequelae of SARS-CoV-2. 


Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies
Dezember 2021
Depending on the study referred, about 10%–30% (or more) of COVID-19 survivors may develop long-COVID or post-COVID-19 syndrome (PCS), characterised by persistent symptoms (most commonly fatigue, dyspnoea, and cognitive impairments) lasting for 3 months or more after acute COVID-19. While the pathophysiological mechanisms of PCS have been extensively described elsewhere, the subtypes of PCS have not. Owing to its highly multifaceted nature, this review proposes and characterises six subtypes of PCS based on the existing literature. The subtypes are non-severe COVID-19 multi-organ sequelae (NSC-MOS), pulmonary fibrosis sequelae (PFS), myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), post-intensive care syndrome (PICS) and medical or clinical sequelae (MCS).


Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease
Dezember 2021
Eighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO2 averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO2). VE/VCO2 slope was 30 ± 7. PetCO2 at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n = 3) or dysfunctional breathing (n = 12). For the whole cohort, 88% of patients (n = 36) had ventilatory abnormalities with dysfunctional breathing (n = 26), increased VE/VCO2 (n = 17), and/or hypocapnia PetCO2 <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS. Circulatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.


Long COVID in Children: Observations From a Designated Pediatric Clinic
Dezember 2021
This prospective cohort preliminary study provides a detailed description of the continuum of persisting symptoms in children with long COVID and the results of their medical investigation at a designated pediatric clinic. Despite a mild acute disease and lack of background illness in the vast majority, for nearly 60%, symptoms were associated with functional impairment at 1–7 months after the onset of infection. The 2 most common symptoms were fatigue and dyspnea, as has been described in adults. However, obstructive sleep apnea and developmental regression were not previously described and warrant further research. Interestingly, several symptoms were more common among older children. In contrast to reports in adults in which females were at greater risk for long COVID, our cohort showed a minor male predominance.


COVID-19 Post-acute Sequelae Among Adults: 12 Month Mortality Risk
Dezember 2021
There are concerns regarding post-acute sequelae of COVID-19, but it is unclear whether COVID-19 poses a significant downstream mortality risk. The objective was to determine the relationship between COVID-19 infection and 12-month mortality after recovery from the initial episode of COVID-19 in adult patients. An analysis of electronic health records (EHR) was performed for a cohort of 13,638 patients, including COVID-19 positive and a comparison group of COVID-19 negative patients, who were followed for 12 months post COVID-19 episode at one health system. Patients with a COVID-19 hospitalization were at significantly increased risk for future mortality. In a time when nearly all COVID-19 hospitalizations are preventable this study points to an important and under-investigated sequela of COVID-19 and the corresponding need for prevention.


Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study
November 2021
This is the largest and the first study up to date that focused on the non-invasive evaluation of endothelial function by FTM during the long COVID-19. An important finding is the probable association of “non-respiratory” long COVID-19 symptoms especially chest pain, fatigue, and neuro-cognitive difficulties to endothelial dysfunction, highlighting the importance of an early evaluation of the endothelium quality for appropriate management. Understanding the pathophysiology and underlying mechanisms of persistent symptoms in long COVID-19 patients is required to guide investigations, management and improve patient prognosis.


Long Covid: Online patient narratives, public health communication and vaccine hesitancy
November 2021
Results indicate that the negative impacts arise mostly from conflicting definitions of Covid-19 and fears around the Covid-19 vaccine for Long Covid sufferers. Key areas of concern are: time/duration; symptoms/testing; emotional impact; lack of support and resources. Whilst Covid-19 is a global issue, specific sociocultural, political and economic contexts mean patients experience Long Covid at a localised level, needing appropriate localised responses. This can only happen if we build a knowledge base that begins with the patient, ultimately informing treatment and rehabilitation strategies for Long Covid.


Associations of Post-Acute COVID syndrome with physiological and clinical measures 10 months after hospitalization in patients of the first wave
November 2021
Median age was 60 years, 42% were female, 76% had at least one comorbidity, the median length of the hospital stay was 8 days, 19% had been on the ICU. The most prevalent symptoms included shortness of breath (49%), fatigue (49%) and cognitive impairment (39%). Signs of major depression (PHQ-9-D ? 10) occurred in 28%/2% (p < 0.05) of patients with/without self-reported cognitive impairment, with median total SGRQ score being 25.4/5.3 (p < 0.05). There were associations between shortness of breath and BMI, SGRQ and hemoglobin levels; between fatigue, SGRQ and PHQ-9-D; and between cognitive impairment and PHQ-9-D (p < 0.05 each) but not with lung function or physical capacity. Characteristics of the acute disease were not related to symptoms.


Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome
November 2021
Nearly two years into the worldwide COVID-19 pandemic, post COVID-19 condition syndrome has proven to be a serious and lingering problem for many recovering patients. This multifactorial illness is characterised by a variety of debilitating symptoms, including fatigue, brain fog, and post-exertional malaise. Many of the pathological observations of post COVID-19 condition, including changes in immune, cardiovascular, metabolic, gastrointestinal, nervous and autonomic systems, are shared with or similar to the symptoms described in ME/CFS patients. Considering the current evidence presented in this study, it is possible that large groups of post COVID-19 condition patients may eventually meet the criteria for ME/CFS diagnosis. Comprehensive longitudinal symptom monitoring is required to confirm this diagnosis, uncover the mechanisms of post-COVID-19 -associated ME/CFS development, and design or develop relevant prevention and treatment measures. Current absence of the effective treatment reflects the unclear causes of the post COVID-19 conditions which cannot be targeted properly until the mechanism is established and confirmed.


Mast cell activation is associated with post-acute COVID-19 syndrome
November 2021
Taken together, our findings support a potential role for immune dysfunction associated with MC activation in a subgroup of patients with PASC. Findings from this study also suggest that MCs are differentially activated in acute SARS-CoV-2 infection compared to PASC. Additional studies are needed to determine if these differences are based on distinct populations of activated MCs or local environmental cues. Interestingly, IL-6 has been shown to increase MC proliferation and induce a more reactive phenotype providing a possible link between elevated IL-6 levels and MC activation in PASC. While it remains unclear if MC activation is causative in PASC or simply a consequence, larger longitudinal studies to validate our findings and assess the natural history are critical.


Navigating the social identity of long covid
November 2021
Due to the nature of the condition, people living with long covid are additionally at risk of experiencing isolation. The most prevalent symptom of long covid, debilitating fatigue, reduces patients’ access to social contact and connection with their communities, and thereby their access to social support. Also, people living with long covid may experience some degree of identity loss. Many people with long covid were previously active, and the illness has unavoidably affected their ability to work, exercise, care for their families, and relate to others. This likely has a huge impact on their professional identity, abled identity, and identity as an active member of society, whether a child or adult. It is crucial to understand how stigma, isolation, and social identity shape people’s experiences of long covid, and their recovery or disease progression journeys.


A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination
November 2021
The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is incompletely understood, with its effects on multiple organ systems and the syndrome of “long Covid” occurring long after the resolution of infection. The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated.


Do vaccines protect against long COVID? What the data say
November 2021
At present, public-health officials are flying blind when it comes to long COVID and vaccination. Although vaccines greatly reduce the rates of serious illness and death caused by COVID-19, they are not as effective at completely preventing the disease, and long COVID can arise even after a mild or asymptomatic coronavirus infection. Countries with high infection rates could still end up with many cases of long COVID, even if nations have high rates of vaccination.


Counting the neurological cost of COVID-19
November 2021
In conclusion, the accumulating evidence on neurological sequelae in patients with COVID-19 is a cause for concern. Without proper care and treatment, patients with these neurological manifestations might be permanently debilitated. Moreover, the continuation of neurological symptoms in long COVID could overwhelm already fractured health-care systems. Consequently, we urgently need to understand and respond to the covert yet potentially incapacitating neurological consequences of COVID-19 in the acute and chronic phases of the disease.


Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection
November 2021
In conclusion, here, we report a remarkable reversal of an LCS with a variety of characteristics in a patient with seropositivity for GPRC-AAbs by neutralization of these GPCR-AAbs with the aptamer, BC 007. The specific neutralization of the latter improved the impaired retinal capillary microcirculation and chronic fatigue symptoms, arose from LCS. In parallel, loss of taste, imbalances, and brain fog disappeared, and IOP and blood pressure (diastolic) could be lowered.


Post-Acute Sequelae of COVID-19 and Cardiovascular Autonomic Dysfunction: What Do We Know?
November 2021
Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.





PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response
November 2021
We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared to healthy controls. Plasma levels of IL-1ß, IL-1RA and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1 as well as of PD1 promoter methylation and PD1-targeting miR-15-5p in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection.


Post-COVID syndrome: the aftershock of SARS-CoV-2
November 2021
Due to the accumulating evidence of persistent post-infectious symptoms reported by numerous recovered patients, the focus of the medical and research communities might need to start shifting focus from the acute phase of COVID-19 to the chronic manifestations of the SARS-CoV-2 infection, referred to as by “post-COVID syndrome”. Post-COVID syndrome presents as non-specific symptoms, most commonly fatigue, headache, dyspnea, anosmia, and memory complaint, which is suspiciously similar to the infection-induced myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. As current studies suggest an involvement of immune-related dysfunction in the development of post-COVID syndrome, immunosuppressive therapeutic options could be beneficial in parallel to heist SARS-CoV-2 vaccination of the population.


Post-COVID Syndrome symptoms, functional disability and clinical severity phenotypes in hospitalised and non-hospitalised individuals: a cross-sectional evaluation from a community COVID rehabilitation service
November 2021
This is the first study reporting on severity phenotypes in a largely non-hospitalised PCS cohort. Severity phenotypes might help stratify patients for targeted interventions and planning of care pathways. Mean age was 47 years, with 237 (64%) female. Median duration of symptoms was 211 days (interquartile range 143 to 353). Half (49%) of patients were still employed or studying on the same hours as before infection with COVID-19, and 41 (11%) in their same role as homemaker, still on maternity leave, retired or unemployed. However, 144 (40%) had reduced their work hours, were still on sick leave, or had stopped work altogether because of ill health


Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status
November 2021
In conclusion, we estimate that the burden of PASC is around 7%; while the burden of PASC increased according to the severity of the care setting of the acute COVID-19 infection, it was not trivial (4.4%) among those who were not hospitalized for acute COVID-19. Our results also show that PASC is not monolithic; the burden of its individual components may be differentially expressed in various population groups. Together, the estimates provided here suggest that the toll of morbidity of COVID-19 extends well beyond the acute phase of the disease. While optimism is rising that—as vaccine availability increases—the pandemic may soon be behind us, the focus on the immediate health effects of COVID-19 allows visibility of the tip of the iceberg. The long-term consequences of COVID-19—as evidenced in our work—are substantial and will reverberate for a long time after the surges in acute infections abate. Long covid (or as we refer to it in this work PASC) is a complex multifaceted non-monolithic post-viral syndrome; it demands greater attention and a coordinated long-term global response strategy.


Global surveillance, research, and collaboration needed to improve understanding and management of long COVID
November 2021
A hidden epidemic of long COVID is possible given the challenges in access to care and uncertainty about diagnostic criteria—factors that will differ in their importance between low-income and high-income settings. Patients report not being taken seriously by medical practitioners or refused referral to long COVID services. These services remain limited and where they exist vary in scope, quality, and access to some therapeutic options. In the absence of diagnostic tests, long COVID is partly a diagnosis of exclusion, creating challenges for patients and carers. Previous diagnoses of exclusion, such as chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome, are now better defined than in the past, meaning patients are more able to obtain acknowledgment, treatment, sick pay, or insurance.


Evidence for impaired chronotropic responses to and recovery from 6-minute walk test in women with post-acute COVID-19 syndrome
November 2021
Compared to controls, the increase in heart rate was attenuated and recovery was delayed following a 6MWT in SARS-CoV-2 participants. Women reporting specific symptoms at time of testing had greater impairments compared with controls and SARS-CoV-2 participants not actively experiencing these symptoms. Such alterations have potential to constrain not only exercise tolerance but participation in free-living physical activity in women during post-acute recovery from COVID-19.


Retrospective diagnosis of SARS-CoV-2 infection in patients with Long COVID by measuring specific T cell mediated IL-2 release
November 2021
Long COVID is as yet poorly understood and difficult to diagnose. The diagnostic complexity of Long COVID is compounded in many patients who were infected with SARS-CoV-2 but not tested at acute presentation and are antibody negative. Given the diagnostic conundrum of Long COVID, we set out to design a SARS-CoV-2 specific T cell assay, to follow up a cohort of undifferentiated mostly non-hospitalised patients with Long COVID for up to 13 months. Here, we show that IL-2 release from SARS-CoV-2-specific memory T cells shows >75% sensitivity and >88% specificity in identifying individuals with confirmed SARS-CoV-2 infection >6 months after a positive PCR test.


Lasting Changes to Circulating Leukocytes in People with Mild SARS-CoV-2 Infections
November 2021
Individuals who had experienced mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1–3 months after symptom onset, and changes in phenotype and function of circulating T-cells that were not apparent in individuals 6–9 months post-symptom onset. Markers of monocyte activation, and expression of adherence and chemokine receptors indicative of altered migratory capacity, were also higher at 1–3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6–9 months post-infection. Perhaps most surprisingly, significantly more T-cells could be activated by polyclonal stimulation in individuals who had recently experienced a mild SARS-CoV-2, infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for at least three months after mild or asymptomatic SARS-CoV-2 infections.


The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study
November 2021
Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51–70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06–13.77]; p?<?0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, ??0.19 [??0.28 to ??0.10]; p?<?0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning.


Long covid: new wine in need of new bottles
November 2021
When it comes to long covid, traditional models of care and research need to move pragmatically, adaptively, iteratively, and rapidly, considering dissemination and implementation in parallel – otherwise, we risk finding the answers after the train has left the station. It is not hard to see why we have not always been successful in responding to long covid. From HIV/AIDS to Ebola, emerging disease threats with coordinated international responses are usually acute and infectious. A new chronic condition, albeit as a post-acute complication of SARS-CoV-2 infection, requires new ways of thinking across clinical, public health, policy, and academic disciplines. Whether it be the World Health Organisation (WHO), governments, or research funders, emergency preparedness has tended to exclude chronic and post-infectious disease management, but long covid must change that.


Patient symptoms and experience following COVID-19: results from a UK-wide survey
November 2021
The ongoing symptoms most frequently reported were: breathing problems (92.1%), fatigue (83.3%), muscle weakness or joint stiffness (50.6%), sleep disturbances (46.2%), problems with mental abilities (45.9%), changes in mood, including anxiety and depression (43.1%) and cough (42.3%). Symptoms did not appear to be related to the severity of the acute illness or to the presence of pre-existing medical conditions. Analysis of free-text responses revealed three main themes: (1) experience of living with COVID-19: physical and psychological symptoms that fluctuate unpredictably; (2) interactions with healthcare that were unsatisfactory; (3) implications for the future: their own condition, society and the healthcare system, and the need for research. Consideration of patient perspectives and experiences will assist in the planning of services to address problems persisting in people who remain symptomatic after the acute phase of COVID-19.


Long COVID care pathways: a systematic review
November 2021
Due to the expected growing number of long COVID cases and the associated increasing average sick leave durations, it not only places a burden on the patients and their families but also the wider economy, in particular, the workforce. The present systematic review aimed to support preparations and adjustments in the long COVID care planning in Austria by giving (1) an overview of recommendations about long COVID care pathways for adult patients as well as (2) examples of already existing care structures in selected European countries. Overall, multidisciplinarity, a personalised approach and shared decision-making have been named as key factors for successful long COVID care. For that matter, good communication between healthcare professionals and the patients, including inclusive communication (e.g. by offering translated materials) and the right balance in the detail of provided information to avoid unnecessary uncertainty, is crucial.


Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY
November 2021
Current recording of long COVID in primary care is very low, and variable between practices. This may reflect patients not presenting; clinicians and patients holding different diagnostic thresholds; or challenges with the design and communication of diagnostic codes. Increased awareness of diagnostic codes is recommended to facilitate research and planning of services, and also surveys with qualitative work to better evaluate clinicians’ understanding of the diagnosis.


CSF analysis in post-COVID-19 is not suggestive of persistent CNS infection
November 2021
Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome.


Mechanisms of exercise intolerance after COVID-19: new perspectives beyond physical deconditioning
November 2021
Considering the current pathophysiological knowledge of intolerance mechanisms and the range of systemic manifestations of the acute phase of COVID-19 infection, it would be simplistic for us to consider that all chronic symptoms of the long-COVID-19 syndrome are due to physical deconditioning by inactivity or prolonged hospitalization. The physical deconditioning theory does not explain the presence of persistent symptoms in patients who were affected by mild forms of the disease, many of whom did not even require hospitalization. Similarly, this theory does not explain the dissociation between the severity of hospitalization and the reduction in peak VO2 reported so far, nor does it explain the antagonism of the persistence of symptoms in patients with preserved peak VO2. In light of the potential complexity and the lack of knowledge on the post-COVID-19 syndrome, it is unacceptable to be simplistic when attempting to unravel the post-COVID-19 syndrome exercise intolerance mechanisms. More robust scientific evidence is needed before drawing simple conclusions.


Limited recovery from post-acute sequelae of SARS-CoV-2 at 8 months in a prospective cohort
November 2021
A total of 99 patients underwent 8-month assessment at a median of 240?days (IQR 227–256) after positive SARS-CoV-2 PCR. Of these, 66 patients were diagnosed at St Vincent’s Hospital testing clinics and 33 patients were self-referred following external diagnosis. 15 patients originally enrolled in ADAPT did not attend (n=6), were lost to follow-up (n=7), or withdrew consent (n=2). The majority (87%) of patients were managed in the community. Median age was 47?years (IQR 35–58), with 61% males. 92 participants completed a study assessment at both 4 and 8?months. There was no significant difference in the proportion of patients reporting symptoms at 4?months (41/92, 45%) and 8?months (47/92, 51%) (p=0.47). There was no significant difference in the proportion of patients with Long COVID at 4?months (27/92, 29%) compared with 8?months (32/92, 35%) (p=0.53).


Long-lasting immune response to a mild course of PCR-confirmed SARS-CoV-2 infection: A cohort study
November 2021
Taken together, our results indicate a strong and persistent immune response against SARS-CoV-2 infection in individuals who recovered from a mild course of COVID-19 for up to 8 months post infection. Importantly, our findings are in line with a recent study10 that used the very same quantitative anti-RBD antibody assay as we did and reported a robust and persistent antibody response after six months post infection. The titre at the baseline visit and its change through time was modulated by the time lag between infection and sampling. In line with Wells et al., we found that individuals without core symptoms developed immunity against COVID-19, although to a lower degree than individuals showing core symptoms, and it persisted through time.


Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children
Oktober 2021
We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group’s inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery.


COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis
Oktober 2021
In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1? and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons. Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.


Late Onset Hematological Complications post COVID-19: An Emerging Medical Problem for the Hematologist
Oktober 2021
Coronavirus disease 19 (COVID-19) is considered as a multisystemic disease. Several studies have reported persistent symptoms or late-onset complications after acute COVID-19, including post-COVID-19 hematologic disorders. COVID-19- induced coagulopathy, an immunothrombotic state, has been linked to thromboembolic and hemorrhagic events. Late onset thrombocytopenia related to immune system dysregulation has been also reported as a rare manifestation post COVID-19. Close monitoring of laboratory dynamics is considered essential to identify timely abnormal values that need further investigation providing supportive care whenever indicated. The role of hematologists is essential in terms of the multidisciplinary approach of long COVID-19. This review summarizes all the available evidence on post-acute COVID-19 hematological complications.


Long-term outcome after SARS-CoV-2 infection in healthcare workers: a single centre cohort study
Oktober 2021
We assessed frequency and risk factors of persisting symptoms in a retrospective cohort of healthcare workers infected with SARS-CoV-2. Persistent symptoms at 3 and 12 months were reported by 26.5% and 13.5% of participants, respectively. Most commonly reported symptoms were fatigue, impaired sense of taste or smell and general weakness. A history of depression or state of exhaustion, pre-existing lung disease and older age were associated with persisting symptoms. Our study shows that a relevant proportion of healthcare workers with mild COVID-19 report persisting symptoms over 3 and 12 months. Although in the majority of cases symptoms are mild, this study highlights the need for further research into causes and therapy.


Assessment of Cognitive Function in Patients After COVID-19 Infection
Oktober 2021
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-19 and has considerable implications for occupational, psychological, and functional outcomes. It is well known that certain populations (eg, older adults) may be particularly susceptible to cognitive impairment after critical illness; however, in the relatively young cohort in the present study, a substantial proportion exhibited cognitive dysfunction several months after recovering from COVID-19. The findings of this study are generally consistent with those of research on other viruses (eg, influenza).


Post-acute COVID-19 syndrome negatively impacts physical function, cognitive function, health-related quality of life and participation
Oktober 2021
A total of 156 patients completed the survey, at a median (range) time of 351 (82 to 457) days post COVID-19 infection. All patients were pre-vaccination. The most common persistent symptoms reported were fatigue (n = 128, 82%), brain fog (n = 105, 67%) and headache (n = 94, 60%). The most common triggers of symptom exacerbation were physical exertion (n = 134, 86%), stress (n = 107, 69%) and dehydration (n = 77, 49%). Increased levels of fatigue (Fatigue Severity Scale) and dyspnea (Medical Research Council) were reported, alongside reductions in levels of regularly completed physical activity. Ninety-eight (63%) patients scored for at least mild cognitive impairment (Neuro-Qol), and the domain of the EQ-5D-5 L most impacted was Self-care, Anxiety/Depression and Usual Activities. Persistent symptoms associated with PACS appear to impact physical and cognitive function, health-related quality of life and participation in society. More research is needed to further clarify the relationship between COVID-19 infection and PACS symptoms, the underlying mechanisms, and treatment options.


The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells
Oktober 2021
In many patients with COVID-19, neurological and psychiatric symptoms occur during the acute disease and determine the post-acute syndrome. Here, we show microvascular pathology in the brains of SARS-CoV-2-infected patients that likely explains signs and symptoms, although systemic effects, including respiratory failure and cytokine release, may contribute to CNS symptoms. Furthermore, we propose a mechanism by which SARS-CoV-2 infection compromises brain endothelial function, damages the BBB and reduces CNS perfusion. Mpro-mediated damage of brain endothelial cells suggests that inhibitors of Mpro may prevent neurological complications of the SARS-CoV-2 infection. Another therapeutic approach may arise from the observation that deletion of Ripk3 or inhibition of RIPK1 profoundly improved the microvascular pathology. RIPK1 inhibitors are available and have already entered clinical testing suggesting potential therapeutic options for COVID-19 as well as for incontinentia pigmenti.


Neuropsychological profiles and cerebral glucose metabolism in neurocognitive Long COVID-syndrome
Oktober 2021
Patients self-reported impaired attention, memory, and multitasking abilities (31/31), word-finding difficulties (27/31), and fatigue (24/31). Twelve of 31 patients could not return to the previous level of independence/employment. For all cognitive domains, average group results of the neuropsychological test-battery showed no impairment, but deficits (z-score<-1.5) were present on single-patient level mainly in the domain of visual memory (in 7/31; other domains ?2/31). Mean MoCA performance (27/30 points) was above the cutoff-value for detection of cognitive impairment (< 26 points), although 9/31 patients performed slightly below this level (23-25 points). In the subgroup of patients who underwent F-FDG PET, we found no significant changes of regional cerebral glucose metabolism. Long COVID patients self-report uniform symptoms hampering their ability to work in a relevant fraction. However, cognitive testing showed minor impairments only on single-patient level approximately six months after the infection, whereas functional imaging revealed no distinct pathological changes. This clearly deviates from previous findings in subacute COVID-19 patients, suggesting that underlying neuronal causes are different and possibly related to the high prevalence of fatigue.


Evaluation of Endothelial Dysfunction and Inflammatory Vasculopathy After SARS-CoV-2 Infection—A Cross-Sectional Study
Oktober 2021
Post-COVID-19 patients had higher values of PWV, augmentation index, IMT, asymmetric and symmetric dimethylarginine, vWF, homocysteine, CD31+/CD42b– EMP, C-reactive protein, erythrocyte sedimentation rate, interleukin-6, and ?-2-glycoprotein antibodies as well as lower levels of homoarginine and tryptophan compared to healthy controls (all with p < 0.05). A higher total number of pathologically altered inflammatory conditions and higher rates of capillary ramifications, loss, caliber variability, elongations and bushy capillaries with an overall higher microangiopathy evolution score were also observed in post-COVID-19 patients (all with p < 0.05). Most parameters of endothelial dysfunction and inflammation were comparably altered in post-COVID-19 patients and patients with ASCVD, including FMD and NMD. COVID-19 may affect arterial stiffness, capillary morphology, EMP and selected parameters of arginine, kynurenine and homocysteine metabolism as well as of inflammation contributing to COVID-19-associated endothelial dysfunction and inflammatory vasculopathy.


Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection – A Systematic Review
Oktober 2021
In this systematic review of 57 studies comprising more than 250?000 survivors of COVID-19, most sequelae included mental health, pulmonary, and neurologic disorders, which were prevalent longer than 6 months after SARS-CoV-2 exposure. These findings suggest that long-term PASC must be factored into existing health care systems, especially in low- and middle-income countries. In this systematic review, more than half of COVID-19 survivors experienced PASC 6 months after recovery. The most common PASC involved functional mobility impairments, pulmonary abnormalities, and mental health disorders. These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries.


Autoimmune Encephalitis Post-SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes
Oktober 2021
Residual sera from 556 consecutive Mayo Clinic Rochester patients (laboratory cohort) who underwent autoimmune encephalopathy neural IgG evaluation were tested for total antibodies against the SARS-CoV-2 spike glycoprotein using an FDA-authorized chemiluminescence assay (October 2019-December 2020). Clinical records from patients with a positive SARS-CoV-2 antibody result and available research consent were reviewed. This laboratory cohort was cross-referenced with the Department of Neurology’s COVID-related consultative experience (encephalopathy cohort, n=31). We encountered occasional cases of AE in our 2020 COVID-19 experience. Consistent with sporadic reports and small case series during the COVID-19 pandemic, and prior experience of postinfectious AE, our cases had diverse clinical presentations and were neural IgG and CSF viral particle negative. Application of diagnostic criteria assists in differentiation of AE from toxic-metabolic causes arising in the setting of systemic infection.


Acute disseminated encephalomyelitis and COVID-19: A systematic synthesis of worldwide cases
Oktober 2021
Acute disseminated encephalomyelitis (ADEM) has been reported after coronavirus disease 2019 (COVID-19). In this review, we systematically included worldwide reported cases on this association. We included 30 case reports (pediatric and adults) and explored epidemiological and clinical evidence. We described time to diagnosis, clinical, imaging, and laboratory features, response to treatment regimens, and differences regarding severity. Also, an original case report was presented. Neurologists must be alert to the occurrence of multifocal neurological symptoms with or without encephalopathy in patients recovered from COVID-19. Timely MRI studies should be performed to establish the diagnosis and to consider early corticosteroid-based treatment.

Neurological outcome and quality of life 3 months after COVID-19: A prospective observational cohort study
Oktober 2021
Of 135 consecutive COVID-19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3-month follow-up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID-19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain-Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3-month follow-up. Self-reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow-up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively. Despite recovery from the acute infection, neurological symptoms were prevalent at the 3-month follow-up. Above all, smelling disorders were persistent in a large proportion of patients.


Long-COVID following mild SARS CoV-2 infection: characteristic T cell alterations and response to antihistamines
Oktober 2021
Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.


Recommendations for the recognition, diagnosis, and management of long COVID: a Delphi study
Oktober 2021
Thirty-three clinicians representing 14 specialties reached consensus on 35 recommendations. Chiefly, GPs should consider long COVID in the presence of a wide range of presenting features (not limited to fatigue and breathlessness) and exclude differential diagnoses where appropriate. Detailed history and examination with baseline investigations should be conducted in primary care. Indications for further investigation and specific therapies (for myocarditis, postural tachycardia syndrome, mast cell disorder) include hypoxia/desaturation, chest pain, palpitations, and histamine-related symptoms. Rehabilitation should be individualised, with careful activity pacing (to avoid relapse) and multidisciplinary support. Long COVID clinics should operate as part of an integrated care system, with GPs playing a key role in the multidisciplinary team. Holistic care pathways, investigation of specific complications, management of potential symptom clusters, and tailored rehabilitation are needed.


Central Nervous System Outcomes of COVID-19
September 2021
Although COVID-19, the disease caused by the SARS-CoV-2 virus, is primarily a respiratory disease, an increasing number of neurologic symptoms have been reported. Some of these symptoms, such as loss of smell or taste, are mild and non-life threatening, while others, such as stroke or seizure, are more critical. Many of these symptoms remain long after the acute illness has passed, a phenomenon known as „long COVID“ or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Neurological symptoms can be difficult to study due to the complexity of the central and peripheral nervous system. These neurologic symptoms can be difficult to identify and quantitate. This narrative review will describe approaches for assessing neurologic manifestations of COVID-19, with examples of the data they provide, as well as some directions for future research to aid in understanding the pathophysiology of COVID-19 related neurological implications.


Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France
September 2021
In total, 455 patients were allocated to the vaccination group and 455 to the control group; 545 (60·1%) had confirmed infections, and 81 (8·9%) had been hospitalized during their acute COVID-19. By 120 days, vaccination reduced the long COVID symptoms (mean (SD) ST score in the vaccination group 13·0 (9·4) vs. 14·8 (9·8) in the control group; mean difference: -1·8, 95% CI -2·5 to -1·0) and doubled the rate of patients in complete remission (remission rate 16·6% vs 7·5%, HR: 1·97, 95% CI 1·23 to 3·15). Furthermore, vaccination reduced both disease impact on patients’ lives (mean (SD) IT score 24.3 (16·7) vs 27·6 (16·7); mean difference: -3·3, 95% CI -6·2 to -0·5) and the proportion of patients with an unacceptable symptom state (38.9% vs 46.4%, risk difference -7·5%, 95% CI -14·4 to -0·5). In the vaccination group, two (0·4%) patients reported serious adverse events leading to hospitalisation. COVID-19 vaccination lowers the severity and life impact of long COVID at 120 days among patients with persistent symptoms.


Symptoms and Health Outcomes Among Survivors of COVID-19 Infection 1 Year After Discharge From Hospitals in Wuhan, China
September 2021
In this cohort study of 2433 patients who had been hospitalized with COVID-19, the most common symptoms at 1 year after discharge were fatigue, sweating, chest tightness, anxiety, and myalgia. Patients with severe disease had more postinfection symptoms and higher chronic obstructive pulmonary disease assessment test scores. This study reported prolonged symptoms of COVID-19 and found that severe disease during hospitalization was a risk factor for more symptoms and higher chronic obstructive pulmonary disease assessment test scores.


Characterising long COVID: a living systematic review
September 2021
A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10?951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95%?CI 25% to 59%), general malaise (33%; 95%?CI 15% to 57%), fatigue (31%; 95%?CI 24% to 39%), concentration impairment (26%; 95%?CI 21% to 32%) and breathlessness (25%; 95%?CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function. Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings.


Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19
September 2021
Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%). All 9 features were more frequently reported after COVID-19 than after influenza (with an overall excess incidence of 16.60% and hazard ratios between 1.44 and 2.04, all p < 0.001), co-occurred more commonly, and formed a more interconnected network. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity.


Biomarkers of Post-COVID Depression
September 2021
In our work, we focused on the search for major depressive disorder (MDD) biomarkers, which are also present in COVID-19 patients and may influence the development of post-COVID depression. For this purpose, we searched PubMed, Scopus and Google Scholar scientific literature databases using keywords such as ‘COVID-19’, ‘SARS-CoV-2’, ‘depression’, ‘post-COVID’, ‘biomarkers’ and others. Among the biomarkers found, the most important that were frequently described are increased levels of interleukin 6 (IL-6), soluble interleukin 6 receptor (sIL-6R), interleukin 1 ? (IL-1?), tumor necrosis factor ? (TNF-?), interferon gamma (IFN-?), interleukin 10 (IL-10), interleukin 2 (IL-2), soluble interleukin 2 receptor (sIL-2R), C-reactive protein (CRP), Monocyte Chemoattractant Protein-1 (MCP-1), serum amyloid a (SAA1) and metabolites of the kynurenine pathway, as well as decreased brain derived neurotrophic factor (BDNF) and tryptophan (TRP). The biomarkers identified by us indicate the etiopathogenesis of post-COVID depression analogous to the leading inflammatory hypothesis of MDD.


Mast cell activation symptoms are prevalent in Long-COVID
September 2021
There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.


SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism
September 2021
In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients. Healthy control and recovered patients had similar B-cell populations at the resting and stimulated state. However, the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation, and the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. More interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. CD19 is one of the members of the B-cell receptor co-complex, consisting of CD19, CD81, CD21, and CD225, which effectively amplifies antigenic signaling via the B-cell receptor (BCR). Thus, although the CD19 expression in recovered COVID-19 patients was mildly reduced within a range of about 10% probably, BCR signaling was largely decreased in B cells from recovered patients upon BCR activation. CD19 is a critical regulator of BCR signaling, B-cell development, and humoral immune response.


Conceptualising Long COVID as an episodic health condition
September 2021
Long COVID may be conceptualised as an episodic illness, characterised by health-related challenges (or disability) that may be multidimensional, episodic and unpredictable in nature. It is essential to better understand and define episodic disability experienced by people living with Long COVID and establish tools to measure the presence, severity and episodic nature of disability, in order to target timely and appropriate rehabilitation interventions and mitigate disability to enhance health outcomes for people living with Long COVID. The role for safe and effective rehabilitation is emerging in the context of Long COVID. While evidence continues to develop, rehabilitation professionals are well positioned to address episodic disability in Long COVID. Opportunities exist to build on successful disability and rehabilitation models from other chronic and episodic illnesses in the context of Long COVID.


A Neurological Outpatient Clinic for Patients With Post-COVID-19 Syndrome — A Report on the Clinical Presentations of the First 100 Patients
September 2021
A total of 89% of the patients presenting to the Neurology outpatient clinic had an initially mild course of COVID-19 and had not been hospitalized. The majority of the patients were female (67 vs. 33% male). The most frequent symptom reported was cognitive impairment (72%). There were 30% of patients who reported cognitive deficits and scored below 26 points on the Montreal Cognitive Assessment Scale. Fatigue (67%), headache (36%), and persisting hyposmia (36%) were also frequently reported; 5.5% of all patients showed signs of severe depression. To our knowledge, this is the first report of patient data of a PCS Neurology outpatient clinic. Neurological sequelae also exist for more than 3 months after mainly mild SARS-CoV-2 acute infections. The reported symptoms are in accordance with recently published data of hospitalized patients.


How Common Is Long COVID in Children and Adolescents?
September 2021
In light of the large number of children and adolescents infected with SARS-CoV-2, the impact of even a low prevalence of persisting symptoms will be considerable. However, in the majority of studies, symptoms did not persist longer than 12 weeks. Consistent with this, 1 study that did find a difference between cases and controls in persisting symptoms (at 4 weeks post COVID) reported that by 8 weeks, most symptoms had resolved, suggesting long COVID might be less of a concern in children and adolescents than in adults. Interestingly in one study, more than half of adolescents in the uninfected control group reported symptoms at 12 weeks despite only 8% reporting symptoms at the time of testing for SARS-CoV-2. The relative scarcity of studies of long COVID and the limitations of those reported to date mean the true incidence of this syndrome in children and adolescents remains uncertain. The impact of age, disease severity and duration, virus strain, and other factors on the risk of long COVID in this age group also remains to be determined.


New-onset IgG autoantibodies in hospitalized patients with COVID-19
September 2021
Our studies have begun to quantify the impact of SARS-CoV-2 on autoimmunity, identifying which antigens and specific autoimmune diseases to surveil in patients who have been infected, and contributing to our mechanistic understanding of COVID-19 pathogenesis. These studies provide a starting point for large-scale epidemiology studies to determine the extent of autoimmunity that results from SARS-CoV-2 infection, and its long-term impacts on the health care system and the economy. While the COVID-19 pandemic is leaving a wake of destruction as it progresses, it also provides an unprecedented opportunity to understand how exposure to a new virus could potentially break tolerance to self, potentially giving rise to autoimmunity and other chronic, immune-mediated, diseases.


Post-COVID syndrome. A case series and comprehensive review
September 2021
A total of 40 articles (11,196 patients) were included in the meta-analysis. Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients reported. In conclusion, PCS is mainly characterized by musculoskeletal, pulmonary, digestive and neurological involvement including depression. PCS is independent of severity of acute illness and humoral response. Long-term antibody responses to SARS-CoV-2 infection and a high inter-individual variability were confirmed. Future studies should evaluate the mechanisms by which SARS-CoV-2 may cause PCS and the best therapeutic options.


Long-term side effects and lingering symptoms post COVID-19 recovery
September 2021
Despite predilection of COVID-19 for lungs, multiple extra-pulmonary manifestations appear in multiple organs and biological systems and with continued infection and recovery worldwide. It is necessary that clinicians provide patients with previous SARS-CoV-2 infection with expectations of long-term effects during or after recovery from COVID-19. Herein, we review the long-term impact of COVID-19 on different organ systems reported from different clinical studies. Understanding risk factors and signs and symptoms of long-term consequences after recovery from COVID-19 will allow for proper follow-up and management of the disease post recovery.


Long COVID and post-infective fatigue syndrome – a review
September 2021
Fatigue is a dominant feature of both acute and convalescent COVID-19 (sometimes termed ‘long-COVID’), with up to 46% of patients reporting fatigue lasting weeks to months. The investigators of the international Collaborative on Fatigue Following Infection (COFFI) conducted a systematic review of post-COVID fatigue, a narrative review on fatigue after other infections and made recommendations for clinical and research approaches to assessment of fatigue following COVID-19. In the majority of COVID-19 cohort studies, persistent fatigue was reported by a significant minority of patients, ranging from 13-33% at 16-20 weeks post symptom onset. Data from the prospective cohort studies in COFFI and others, indicate that fatigue is also a prevalent outcome from many acute systemic infections notably infectious mononucleosis, with a case rate for clinically-significant post-infective fatigue after exclusion of recognized medical and psychiatric causes, of 10-35% at 6 months. To better characterize post-COVID fatigue, the COFFI investigators recommend: application of validated screening questionnaires for case detection, standardized interviews encompassing fatigue, mood, and other symptoms, and investigative approaches to identify end-organ damage and mental health conditions.


Gut Microbiome Alterations in COVID-19
September 2021
Accumulating evidence is unveiling that the gut microbiome is broadly altered in COVID-19, including the bacterial microbiome, mycobiome, and virome. Overall, the gut microbial ecological network is significantly weakened and becomes sparse in patients with COVID-19, together with a decrease in gut microbiome diversity. Beyond the existence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome of patients with COVID-19 is also characterized by enrichment of opportunistic bacteria, fungi, and eukaryotic viruses, which are also associated with disease severity and presentation. Meanwhile, a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19. Such gut microbiome features persist in a significant subset of patients with COVID-19 even after disease resolution, coinciding with ‚long COVID‘ (also known as post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely a consequence of SARS-CoV-2 infection and its downstream detrimental effects on the systemic host immunity and the gut milieu. The impaired host immunity and distorted gut microbial ecology, particularly loss of low-abundance beneficial bacteria and blooms of opportunistic fungi including Candida, may hinder the re-assembly of the gut microbiome post COVID-19. Future investigation is necessary to fully understand the role of the gut microbiome in host immunity against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the gut microbiome in relation to the host health after the pandemic.


Platelets amplify endotheliopathy in COVID-19
September 2021
We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients. Last, we present evidence that targeting platelet P2Y12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.


Psychiatric symptoms and cognitive impairment in “Long COVID”: the relevance of immunopsychiatry
September 2021
The development of depression and anxiety symptoms and of cognitive impairment after COVID-19 may partly be the result of somatic, functional or psychosocial consequences of the disease. Coronaviruses can also induce cognitive, emotional, neurovegetative and behavioral dysregulation due to direct neurological injury through hypoxic damage and neuroinvasion. In addition to this, the systemic immune activation seen in COVID-19 can contribute significantly to the mental health toll even months after the initial disease. For fatigue, illustration of immune system involvement comes most strongly from studies of chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), a condition characterized by persistent, unexplained fatigue that is not alleviated by rest. Although CFS/ME has long been indicated as a mystery illness, recent studies suggest that inflammation is central to its pathogenesis in at least a considerable proportion of patients, as suggested by higher levels of inflammatory markers that show a dose-response relationship to disease severity. If even low-grade systemic immune activity increases the risk of depression, cognitive impairment and fatigue, it is obvious that we need to be aware of the role that immune activation can play in the mental health consequences of COVID-19, which involves a massive cytokine storm.


SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration
September 2021
SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood–brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.


Long-Term Symptoms Among Adults Tested for SARS-CoV-2
September 2021
In this convenience sample of U.S. adults, the prevalence of long-term symptoms often associated with SARS-CoV-2 infection was higher among respondents who ever received a positive test result than among those who always received a negative test result, and symptoms in these persons tended to persist for >4 weeks. Previous studies have found that nonhospitalized persons with SARS-CoV-2 infection have higher prevalence of some long-term symptoms or conditions than nonhospitalized persons with negative SARS-CoV-2 test results (2–5). Similarly, in this investigation, more respondents who received a positive test result (65.9%) than those who received a negative test result (42.9%) experienced any long-term symptoms, and approximately one half of these symptoms were more likely to be reported among those who received a positive test result.


Development of ACE2 autoantibodies after SARS-CoV-2 infection
September 2021
Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.

Kidney Outcomes in Long COVID
September 2021
Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR=1.94 (95%CI: 1.86,2.04)), eGFR decline ?30% (1.25 (1.14,1.37)), eGFR decline ?40% (1.44 (1.37,1.51)), eGFR decline ?50% (1.62 (1.51,1.74)), ESKD (2.96 (2.49-3.51)), and MAKE (1.66 (1.58,1.74)). There was a graded increase in risks of post-acute kidney outcomes according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared to non-infected controls, 30-day COVID-19 survivors exhibited excess eGFR decline of -3.26 (-3.58, -2.94), -5.20 (-6.24, -4.16), and -7.69 (-8.27, -7.12) mL/min/1.73m2/year in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. COVID-19 survivors exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should involve attention to kidney disease.

Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study
September 2021
Individuals with COVID-19 have differing symptoms and clinical needs. Elucidating symptom profiles in individuals with COVID-19 after vaccination has clinical utility, facilitating the identification of risk groups for intervention, predicting medical resource requirements, and informing appropriate testing guidelines. Additionally, some unvaccinated individuals with COVID-19 have prolonged illness duration (so-called long COVID), and whether vaccination reduces the risk of long COVID is currently unknown. We found that the odds of having symptoms for 28 days or more after post-vaccination infection were approximately halved by having two vaccine doses. This result suggests that the risk of long COVID is reduced in individuals who have received double vaccination, when additionally considering the already documented reduced risk of infection overall.

Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL) – A systematic review and meta-analysis
August 2021
Our study concludes that PCS is associated with poor quality of life, persistent symptoms including fatigue, dyspnea, anosmia, sleep disturbances, and worse mental health. This suggests that we need more research on PCS patients to understand the risk factors causing it and eventually leading to poor quality of life.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
August 2021
Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.

Understanding long COVID: a modern medical challenge
August 2021
Tedros Adhanom Ghebreyesus, WHO’s Director-General, has called on countries to prioritise recognition, rehabilitation, and research for the long-term consequences of COVID-19, as well as collection of data for long COVID. A cohesive research agenda is needed to prevent research waste and improve outcomes for patients. The scientific and medical communities must collaborate to explore the mechanism and pathogenesis of long COVID, estimate the global and regional disease burdens, better delineate who is most at risk, understand how vaccines might affect the condition, and find effective treatments via randomised controlled trials. At the same time, health-care providers must acknowledge and validate the toll of the persistent symptoms of long COVID on patients, and health systems need to be prepared to meet individualised, patient-oriented goals, with an appropriately trained workforce involving physical, cognitive, social, and occupational elements.

Cardiac Manifestations in Children with SARS-COV-2 Infection: 1-Year Pediatric Multicenter Experience
August 2021
Between March 2020 and March 2021, we performed a cardiac evaluation in 294 children (mean age 9 ± 5.9 years, male 60%) with active or previous SARS-COV-2 infection. Twenty-six showed ECG abnormalities: 63 repolarization anomalies, 13 Long QTc, five premature ventricular beats, two non-sustained ventricular tachycardia, and one atrial fibrillation. In total, 146 patients underwent cardiac biomarkers: NT-proBNP was elevated in 57, troponin in 34. An echocardiogram was performed in 98, showing 54 cardiac anomalies: 27 left-ventricular dysfunction, 42 pericarditis, 16 coronaritis. MIS-C was documented in 46 patients (mean age 9 ± 4.8 years, male 61%) with cardiac manifestations in 97.8%: 27 ventricular dysfunctions, 32 pericarditis, 15 coronaritis, 3 arrhythmias. All patients recovered, and during follow-up, no cardiac anomalies were recorded. Our experience showed that cardiac involvement is not rare in children with SARS-COV-2, and occurred in almost all patients with MIS-C. However, patients’ recovery is satisfactory and no additional events were reported during FU.


Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis Following COVID-19
August 2021
Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors‘ hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ?4 in 64% of patients with adequate follow-up information, including 32% who died.


1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study
August 2021
1276 COVID-19 survivors completed both visits. The median age of patients was 59·0 years (IQR 49·0–67·0) and 681 (53%) were men. The median follow-up time was 185·0 days (IQR 175·0–198·0) for the 6-month visit and 349·0 days (337·0–361·0) for the 12-month visit after symptom onset. The proportion of patients with at least one sequelae symptom decreased from 68% (831/1227) at 6 months to 49% (620/1272) at 12 months (p<0·0001). The proportion of patients with dyspnoea, characterised by mMRC score of 1 or more, slightly increased from 26% (313/1185) at 6-month visit to 30% (380/1271) at 12-month visit (p=0·014). Additionally, more patients had anxiety or depression at 12-month visit (26% [331/1271] at 12-month visit vs 23% [274/1187] at 6-month visit; p=0·015). No significant difference on 6MWD was observed between 6 months and 12 months. 88% (422/479) of patients who were employed before COVID-19 had returned to their original work at 12 months. Compared with men, women had an odds ratio of 1·43 (95% CI 1·04–1·96) for fatigue or muscle weakness, 2·00 (1·48–2·69) for anxiety or depression, and 2·97 (1·50–5·88) for diffusion impairment. Matched COVID-19 survivors at 12 months had more problems with mobility, pain or discomfort, and anxiety or depression, and had more prevalent symptoms than did controls. Most COVID-19 survivors had a good physical and functional recovery during 1-year follow-up, and had returned to their original work and life. The health status in our cohort of COVID-19 survivors at 12 months was still lower than that in the control population.

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology
August 2021
Long COVID defines a series of chronic symptoms that patients may experience after resolution of acute COVID-19. Early reports from studies with patients with long COVID suggests a constellation of symptoms with similarities to another chronic medical illness—myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A review study comparing and contrasting ME/CFS with reported symptoms of long COVID may yield mutualistic insight into the characterization and management of both conditions. A systemic literature search was conducted in MEDLINE and PsycInfo through to 31 January 2021 for studies related to long COVID symptomatology. The literature search was conducted in accordance with PRISMA methodology. Twenty-one studies were included in the qualitative analysis. Long COVID symptoms reported by the included studies were compared to a list of ME/CFS symptoms compiled from multiple case definitions. Twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study. Early studies into long COVID symptomatology suggest many overlaps with clinical presentation of ME/CFS. The need for monitoring and treatment for patients post-COVID is evident. Advancements and standardization of long COVID research methodologies would improve the quality of future research, and may allow further investigations into the similarities and differences between long COVID and ME/CFS.


Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
August 2021
We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in ?(2)-antiplasmin (?2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.


Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19
August 2021
Here, in 284 patients with COVID-19, we found type I IFN-specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non-COVID-19 controls revealed a lack of type I IFN-stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN-specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.

Redox imbalance links COVID-19 and myalgic encephalomyelitis/ chronic fatigue syndrome
August 2021
People with acute COVID-19 and people with ME/CFS share redox imbalance, systemic inflammation and neuroinflammation, impaired production of ATP and other abnormalities in common, abnormalities that have bidirectional connections. The syndrome of long COVID-19 that can develop in some COVID-19 survivors (people called “long haulers”) is very similar to ME/CFS, so it may well be that the group of abnormalities seen in acute COVID-19 and in ME/CFS also will be seen in long COVID-19. Presumably, redox abnormalities in COVID-19 are secondary to the infection with SARS-CoV-2. The same may be true among those ME/CFS patients whose illness began with an “infectious-like” illness. Clearly, COVID-19–induced permanent damage to the lungs (chronic hypoxia), heart (congestive failure), and kidneys (fluid and acid-base abnormalities) could cause some of the persisting symptoms seen in long COVID-19. In both long COVID-19 and ME/CFS other symptoms (e.g., fatigue, brain fog) may be generated by neuroinflammation, reduced cerebral perfusion due to autonomic dysfunction, and autoantibodies directed at neural targets, as summarized elsewhere.

Similar patterns of [18F]-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series
August 2021
Despite lower initial severity at the acute stage of the infection, paediatric patients demonstrated on average 5 months later a similar brain hypometabolic pattern as that found in adult long COVID patients, involving bilateral medial temporal lobes, brainstem and cerebellum (p-voxel?<?0.001, p-cluster?<?0.05 FWE-corrected), and also the right olfactory gyrus after small volume correction (p-voxel?=?0.010 FWE-corrected), with partial PET recovery in two children at follow-up. These results provide arguments in favour of possible long COVID in children, with a similar functional brain involvement to those found in adults, regardless of age and initial severity.


Clinical characteristics of paediatric COVID-19 patients followed for up to 13 months
August 2021
We report the first 201 paediatric patients under 16 years old that were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Marseille public hospitals during the first wave of the COVID-19 pandemic in France. Most of the children presented as outpatients after household exposure and had mild symptoms.There were no significant viral load differences by age group and severity. And the vast majority had favourable outcomes with no viral fatalities. About a sixth had persistent and/or recurrent symptoms after COVID-19, but had no inflammatory complications. Asthenia was the most common persisting symptom. Children with symptomatic acute COVID-19 were significatively more susceptible to develop long-term symptoms. In conclusion, open screening helped to detect asymptomatic carriers and moderately ill paediatric patients, especially when there were family clusters. This approach is enabling us to provide better clinical follow-up, including appropriate counselling and household isolation, especially if children have inflammatory complications or long COVID.

The long-term sequelae of COVID-19: an international consensus on research priorities for patients with pre-existing and new-onset airways disease
August 2021
We undertook an international consensus exercise to identify research priorities with the aim of understanding the long-term effects of acute COVID-19, with a focus on people with pre-existing airways disease and the occurrence of new-onset airways disease and associated symptoms. 202 international experts were invited to submit a minimum of three research ideas. After a two-phase internal review process, a final list of 98 research topics was scored by 48 experts. Patients with pre-existing or post-COVID-19 airways disease contributed to the exercise by weighting selected criteria. The highest-ranked research idea focused on investigation of the relationship between prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge in patients with and without pre-existing airways disease. High priority was also assigned to comparisons of the prevalence and severity of post-COVID-19 fatigue, sarcopenia, anxiety, depression, and risk of future cardiovascular complications in patients with and without pre-existing airways disease. Our approach has enabled development of a set of priorities that could inform future research studies and funding decisions. This prioritisation process could also be adapted to other, non-respiratory aspects of long COVID.

Musculoskeletal Symptoms and Related Factors in Post Acute COVID-19 Patients
August 2021
Most of the patients had fatigue (71.8%), spine pain (70.7%) and myalgia (60.7%). The most common pain region was the back (30.4%). The frequency of dyspnea was 30%, of cough 18.5%, and of chest pain 10.7%. Having any chronic disease (p=0.031), the duration of hospital stay (p=0.016), frequency of back pain during acute COVID-19 (p=0.018), tomography findings and D-dimer (p=0.035) levels were significantly higher, and lymphocyte (p=0.024) levels were significantly lower in the patients whose symptoms began with or were aggravated by COVID-19. Back pain was the most frequent symptom on admission.


Post-Covid-19 Tachycardia Syndrome: A distinct phenotype of Post-acute Covid-19 Syndrome
August 2021
We highlight the phenomenon of abnormal sinus tachycardia in patients with post-acute Covid-19 syndrome. We propose that Post-Covid-19 tachycardia syndrome should be considered a phenotype or sub-syndrome of Post-acute Covid-19 syndrome. This provides a safety net for those who have multiple symptoms besides the tachycardia and subsequently may not even mention this to their healthcare provider.Post-Covid-19 tachycardia syndrome may present as postural orthostatic tachycardia syndrome or inappropriate sinus tachycardia and likely contributes to several symptoms and the physical and mental disabilities in Post-acute Covid-19 syndrome. Future studies should focus on biological and clinical characterization of this novel clinical syndrome and interventional studies, testing established and novel pharmacological approaches.


Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing
August 2021
Some Coronavirus disease 2019 (COVID-19) patients who have recovered from their acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that is often unexplained by conventional investigative studies. Post-COVID-19 patients without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit along with an exaggerated hyper-ventilatory response during exercise.

More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis
August 2021
Fatigue (58%) is the most common symptom of long and acute COVID-19. It is present even after 100 days of the first symptom of acute COVID-19. In addition, there are syndromes such as acute respiratory distress syndrome (ARDS), in which it has been observed that after a year, more than two-thirds of patients reported clinically significant fatigue symptoms. The symptoms observed in post-COVID-19 patients, resemble in part the chronic fatigue syndrome (CFS), which includes the presence of severe incapacitating fatigue, pain, neurocognitive disability, compromised sleep, symptoms suggestive of autonomic dysfunction, and worsening of global symptoms following minor increases in physical and/or cognitive activity. Myalgic encephalomyelitis (ME) or CFS is a complex and controversial clinical condition without established causative factors, and 90% of ME/CFS has not been diagnosed. Possible causes of CFS include viruses, immune dysfunction, endocrine-metabolic dysfunction, and neuropsychiatric factors. The infectious agents related to CFS have been Epstein-Barr virus, cytomegalovirus, enterovirus, and herpesvirus. It is tempting to speculate that SARS-CoV-2 can be added to the viral agents‘ list causing ME/CFS.

Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections
August 2021
Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.


Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial deformation 4 months after infection
August 2021
Twenty-four patients (34.28%) were diagnosed with mild disease and were not subsequently hospitalized at any time of the course of the disease. Furthermore, 23 (32.85%) patients were diagnosed to have moderate and 23 (32.85%) severe disease at initial clinical assessment and thus were admitted to hospital. None of the examined patients required mechanical ventilation and none required hospitalization for a period of more than 15?days. Twenty-six patients (37.87%) presented with post-infection symptoms 4 months after COVID-19 disease. Among the symptoms, fatigue was the most common and it was present in 11 patients (15.71%), followed by dyspnoea in 9 (12.8%) cough in 3 (4.3%) and chest pain in 3 (4.3%). There was no significant difference among patients with or without post-infection symptoms regarding clinical characteristics (age, body mass index; data not shown). The mean age of participants was 54.59?±?8.85?years and there was no significant difference among the three groups regarding age (P = 0.991) and sex (44 males per group, P = 1).


Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome
August 2021
Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI -2.57– -1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID-19 patients. These pro-thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID-19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID-19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6-minute walk tests. Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID-19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.

6-month mortality and readmissions of hospitalized COVID-19 patients: A nationwide cohort study of 8,679 patients in Germany
August 2021
Of the 8,679 patients with a median age of 72 years, 2,161 (24.9%) died during the index hospitalization. The 30-day all-cause mortality rate was 23.9% (2,073/8,679), the 90-day rate was 27.9% (2,425/8,679), and the 180-day rate, 29.6% (2,566/8,679). The latter was 52.3% (1,472/2,817) for patients aged ?80 years 23.6% (1,621/6,865) if not ventilated during index hospitalization, but 53.0% in case of those ventilated invasively (853/1,608). Risk factors for the 180-day all-cause mortality included coagulopathy, BMI ? 40, and age, while the female sex was a protective factor beyond a fewer prevalence of comorbidities. Of the 6,235 patients discharged alive, 1,668 were readmitted a total of 2,551 times within 180 days, resulting in an overall readmission rate of 26.8%.

Persistierende Beschwerden nach akuter COVID-19-Erkrankung: „Long-COVID“?
August 2021
Die Pathogenese ist nicht geklärt. Ebenso unbekannt ist die Prognose über den Verlauf der Beschwerden. Wichtig erscheint ein symptomgeleiteter Ausschluss von behandlungsbedürftigen Alternativdiagnosen. Für den Beschwerdekomplex gibt es bislang weder einen einheitlichen Begriff („Long-COVID“) noch eine einheitliche Definition. Häufig wird die Definition des NICE verwendet, das zwischen anhaltendem COVID-19 bei Beschwerden 4–12 Wochen bzw. einem Post-COVID-19-Syndrom mehr als 12 Wochen nach Akuterkrankung unterscheidet. Eine verzögerte Rekonvaleszenz oder persistierende Beschwerden scheinen nach COVID-19 häufiger als nach anderen akuten Infektionskrankheiten aufzutreten und beinhalten vor allem ein Erschöpfungssyndrom mit Belastungsintoleranz, Brustschmerzen/Belastungsdyspnoe und verschiedene neurologische bzw. neuropsychiatrische Symptome. Diagnostik und Therapie?Diagnostik und Therapie sollten interdisziplinär erfolgen. Physiotherapie, psychologische/psychosomatische Anbindung und Möglichkeiten der Rehabilitation sollten erwogen werden. Insbesondere bei persistierender pulmonaler Symptomatik können Patienten von einer Rehabilitationsmaßnahme profitieren.

Descriptive analysis of long COVID sequelae identified in a multidisciplinary clinic serving hospitalised and non-hospitalised patients
August 2021
Three months after COVID-19 infection, patients were still symptomatic and demonstrated objective respiratory, functional, radiological and cognitive abnormalities, which were more prominent in hospitalised patients. Our study underlines the importance of multidimensional management strategies in these patients.

Multi-Disciplinary Collaborative Consensus Guidance Statement on the Assessment and Treatment of Fatigue in Post-Acute Sequelae of SARS-CoV-2 infection (PASC) Patients
August 2021
PASC-related fatigue affects individuals physically, emotionally, and cognitively. Individuals with PASC-related can experience severe disability and frustration. The pathophysiology causing fatigue after COVID-19 still warrants ongoing detailed research to better understand this constellation of symptoms, while acknowledging the cause of fatigue is likely multifactorial and may be specific to the individual. The goal of this PASC Collaborative Consensus Guidance Statement is to create a coordinated and systematic approach to the evaluation and treatment of patients presenting with PASC. The recommendations above represent a consensus of large national multidisciplinary collaborative of centers focused on the treatment of individuals with PASC. The recommendations are based on the most current available data, extrapolation from evidence in similar conditions, and the combined clinical experience of treating thousands of patients with PASC-related fatigue.


Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19
August 2021
We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a „cytokine storm“. We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.

Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT
August 2021
Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30-250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1-20). Amongst 157 participants with longer follow-up (?60 days), PASC prevalence was 77.1%.

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol
August 2021
Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.

Illness duration and symptom profile in symptomatic UK school-aged children tested for SARS-CoV-2
August 2021
Only 25 (1·8%) of 1379 children experienced symptoms for at least 56 days. Few children (15 children, 0·9%) in the negatively tested cohort had symptoms for at least 28 days; however, these children experienced greater symptom burden throughout their illness (9 symptoms, IQR 7·7–11·0 vs 8, 6–9) and after day 28 (5 symptoms, IQR 1·5–6·5 vs 2, 1–4) than did children who tested positive for SARS-CoV-2. Although COVID-19 in children is usually of short duration with low symptom burden, some children with COVID-19 experience prolonged illness duration. Reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. A holistic approach for all children with persistent illness during the pandemic is appropriate.

Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans
August 2021
Government, healthcare workers, and survivor groups should collaborate to establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recommendations for follow-up and rehabilitations details have been explored to cope with the tremendous Long COVID-19 Syndrome patients.

A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS
August 2021
It is proposed that inflammatory mediators, released at the site of COVID-19 infection, would be transmitted as stress-signals, via humoral and neural pathways, which overwhelm this stress-center. In genetically susceptible people, an intrinsic stress-threshold is suggested to be exceeded causing ongoing dysfunction to the hypothalamic PVN’s complex neurological circuitry. In this compromised state, the hypothalamic PVN might then be hyper-sensitive to a wide range of life’s ongoing physiological stressors. This could result in the reported post-exertional malaise episodes and more severe relapses, in common with ME/CFS, that perpetuate an ongoing disease state. When a certain stress-tolerance-level is exceeded, the hypothalamic PVN can become an epicenter for microglia-induced activation and neuroinflammation, affecting the hypothalamus and its proximal limbic system, which would account for the range of reported ME/CFS-like symptoms. A model for Post-COVID-19 Fatigue Syndrome is provided to stimulate discussion and critical evaluation. Brain-scanning studies, incorporating increasingly sophisticated imaging technology should enable chronic neuroinflammation to be detected, even at a low level, in the finite detail required, thus helping to test this model, while advancing our understanding of Post-COVID-19 Fatigue Syndrome pathophysiology.

A cardiovascular magnetic resonance imaging-based pilot study to assess coronary microvascular disease in COVID-19 patients
August 2021
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is primarily characterised by a respiratory disease. However, SARS-CoV-2 can directly infect vascular endothelium and subsequently cause vascular inflammation, atherosclerotic plaque instability and thereby result in both endothelial dysfunction and myocardial inflammation/infarction. Interestingly, up to 50% of patients suffer from persistent exercise dyspnoea and a post-viral fatigue syndrome (PVFS) after having overcome an acute COVID-19 infection. In the present study, we assessed the presence of coronary microvascular disease (CMD) by cardiovascular magnetic resonance (CMR) in post-COVID-19 patients still suffering from exercise dyspnoea and PVFS.

SARS-CoV-2 and the Brain: What Do We Know about the Causality of ‚Cognitive COVID?
August 2021
The second year of the COVID-19 (coronavirus disease) pandemic has seen the need to identify and assess the long-term consequences of a SARS-CoV-2 infection on an individual’s overall wellbeing, including adequate cognitive functioning. ‚Cognitive COVID‘ is an informal term coined to interchangeably refer to acute changes in cognition during COVID-19 and/or cognitive sequelae with various deficits following the infection. These may manifest as altered levels of consciousness, encephalopathy-like symptoms, delirium, and loss of various memory domains. Dysexecutive syndrome is a peculiar manifestation of ‚Cognitive COVID‘ as well. In the previous major outbreaks of viruses like SARS-CoV, MERS-CoV and Influenza. There have been attempts to understand the underlying mechanisms describing the causality of similar symptoms following SARS-CoV-2 infection. This review, therefore, is attempting to highlight the current understanding of the various direct and indirect mechanisms, focusing on the role of neurotropism of SARS-CoV-2, the general pro-inflammatory state, and the pandemic-associated psychosocial stressors in the causality of ‚Cognitive COVID.‘

Post-viral effects of COVID-19 in the olfactory system and their implications
August 2021
Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

Evidence of lung perfusion defects and ongoing inflammation in an adolescent with post-acute sequelae of SARS-CoV-2 infection
Juli 2021
In conclusion, in this report we present the first detailed evaluation of PASC in an adolescent, providing evidence of pulmonary circulation dysfunction with possible lung microvascular or endothelial damage as detected by CPET and chest SPECT/CT. Currently, most attention has been focused on long COVID in adults, with few studies including children, resulting in a lack of case definitions and management guidelines for this population. This report supports the emerging evidence on long COVID in children and highlights that, although children generally present with mild, acute COVID-19, they are at risk of prolonged organ damage, similar to what has been identified in adults. This report highlights the importance of doing a robust assessment of children presenting with PASC. SPECT/CT is useful to detect microvascular damage in patients with more severe and persisting symptoms. We urge clinicians and policy makers to not underestimate the risk of and consequences of long-term COVID-19 sequelae in children. We also call for urgent studies aiming for a better understanding of the PASC burden, with a particular focus on investigation of chronic organ damage to inform treatment and improve long-term COVID-19 outcomes in children. These data are urgently needed to identify risk factors for targeted prevention and support, inform management guidelines, and also provide indirect benefits to the understanding of other post-infectious conditions.

Psychiatric and neuropsychiatric sequelae of COVID-19 – a systematic review
Juli 2021
1725 unique studies were identified. Of these, 66 met the inclusion criteria and were included. Time to follow-up ranged from immediately after hospital discharge up to 7 months after discharge, and the number of participants spanned 3 to 266586 participants. Forty studies reported anxiety and/or depression, 20 studies reported symptoms- or diagnoses of post-traumatic stress disorder (PTSD), 27 studies reported cognitive deficits, 32 articles found fatigue at follow-up, and sleep disturbances were found in 23 studies. Highlighted risk factors were disease severity, duration of symptoms, and female sex. One study showed brain abnormalities correlating with cognitive deficits, and several studies report inflammatory markers to correlate with symptoms. Overall, the results from this review suggest that survivors of COVID-19 are at risk of psychiatric sequelae but that symptoms generally improve over time.

Post-COVID-19 acute sarcopenia: physiopathology and management
Juli 2021
This paper gathers the information about how the SARS-CoV-2 hyper-inflammatory involvement exacerbates the immunosenescence process, enhances the endothelial damage, and due to mitochondrial dysfunction and autophagy, induces myofibrillar breakdown and muscle degradation. The aftermath of these acute and complex immunological SARS-CoV-2-related phenomena, augmented by anosmia, ageusia and altered microbiota may lead to decreased food intake and exacerbated catabolism. Moreover, the imposed physical inactivity, lock-down, quarantine or acute hospitalization with bedrest would intensify the acute sarcopenia process. All these deleterious mechanisms must be swiftly put to a check by a multidisciplinary approach including nutritional support, early physical as well cardio-pulmonary rehabilitation, and psychological support and cognitive training. The proposed holistic and early management of COVID-19 patients appears essential to minimize the disastrous functional outcomes of this disease and allow avoiding the long COVID-19 syndrome.

Long-Term Impact of COVID-19: A Systematic Review of the Literature and Meta-Analysis
Juli 2021
This study aimed to explore post COVID-19 effects on patients chest computed tomography (CT), lung function, respiratory symptoms, fatigue, functional capacity, health-related quality of life (HRQoL), and the ability to return to work beyond 3 months post infection. Methods: A systematic search was performed on PubMed, Web of Science, and Ovid MEDLINE on 22 May 2021, to identify studies that reported persistent effects of COVID-19 beyond 3 months follow-up. Data on the proportion of patients who had the outcome were collected and analyzed using a one-group meta-analysis. Decreased functional capacity and HRQoL were found in 36% (95% CI 22–49, I2 = 97%) and 52% (95% CI 33–71, I2 = 94%), respectively. On average, 8 out of 10 of the patients had returned to work or reported no work impairment. Conclusion: Post-COVID-19 patients may experience persistent respiratory symptoms, fatigue, decreased functional capacity and decreased quality of life up to 6 months after infection. Further studies are needed to establish the extent to which post-COVID-19 effects continue beyond 6 months, how they interact with each other, and to clarify their causes and their effective management. 

COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis
Juli 2021
Penile tissue was collected from patients undergoing surgery for penile prosthesis for severe ED. Specimens were obtained from two men with a history of COVID-19 infection and two men with no history of infection. Specimens were imaged with TEM and H&E staining. RT-PCR was performed from corpus cavernosum biopsies. The tissues collected were analyzed for endothelial Nitric Oxide Synthase (eNOS, a marker of endothelial function) and COVID-19 spike-protein expression. Endothelial progenitor cell (EPC) function was assessed from blood samples collected from COVID-19 (+) and COVID-19 (?) men. TEM showed extracellular viral particles ~100 nm in diameter with peplomers (spikes) near penile vascular endothelial cells of the COVID-19 (+) patients and absence of viral particles in controls. PCR showed presence of viral RNA in COVID-19 (+) specimens. eNOS expression in the corpus cavernosum of COVID-19 (+) men was decreased compared to COVID-19 (?) men. Mean EPC levels from the COVID-19 (+) patients were substantially lower compared to mean EPCs from men with severe ED and no history of COVID-19. Our study is the first to demonstrate the presence of the COVID-19 virus in the penis long after the initial infection in humans. Our results also suggest that widespread endothelial cell dysfunction from COVID-19 infection can contribute to ED. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED.

Long COVID, a comprehensive systematic scoping review
Juli 2021
Of 120 papers, we found only one randomized clinical trial. Of the 67 original studies, 22 were cohort, and 28 were cross-sectional studies. Of the total 120 publications, 49.1% focused on signs and symptoms, 23.3% on management, and 10.8% on pathophysiology. Ten publications focused on imaging studies. The results are also presented extensively in a narrative synthesis in separated sections (nomenclature, diagnosis, pathophysiology, risk factors, signs/symptoms, management). The controversies in its definition have impaired proper recognition and management. The predominant symptoms were: fatigue, breathlessness, arthralgia, sleep difficulties, and chest pain. Recent reports also point to the risk of long-term sequela with cutaneous, respiratory, cardiovascular, musculoskeletal, mental health, neurologic, and renal involvement in those who survive the acute phase of the illness.

The road to addressing Long Covid
Juli 2021
To move forward to a more systematic response to the crisis of Long Covid, better reporting, recognition, and research are needed. Reporting involves systems that can measure Long Covid. This can be achieved through agreeing on specific diagnostic criteria, establishing disease registers, and following up those with acute infection or a positive test using contact tracing infrastructures. It is unknown if or when many of those with Long Covid will recover, particularly given the relapsing nature of the illness. Surveillance systems must start assessing recovery and medium-term survival (1, 2, and 5 years after SARS-CoV-2 infection). Without knowing how many people remain ill following acute infection, the pandemic and postpandemic responses will always be deficient because they will not account for the full impact of COVID-19. Rigorous research to understand the mechanisms, risk factors, prognosis, and subgroup characteristics, and to identify potential therapeutics for Long Covid, is desperately needed. Other chronic conditions, such as ME/CFS, fibromyalgia, and some connective tissue disorders, are largely under-researched in terms of underlying mechanisms, diagnostics, therapeutics, and management options. The understanding of Long Covid offers an opportunity to pave the way toward better outcomes for all patients experiencing similar conditions.

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers
Juli 2021
In this study, we characterized all Covid-19 breakthrough infections among 39 (of 1497) fully vaccinated health care workers during the 4-month period after the second vaccine dose and compared the peri-infection humoral response in these workers with the response in matched controls. We found a low rate of breakthrough infection (0.4%). Among the 39 workers who tested positive for Covid-19, most had few symptoms, yet 19% had long Covid-19 symptoms (>6 weeks). The most common symptom that was reported was upper respiratory congestion (36% of all cases), followed by myalgia (28%) and loss of smell or taste (28%); fever or rigors were reported in 21%. On follow-up questioning, 31% of all infected workers reported having residual symptoms 14 days after their diagnosis. At 6 weeks after their diagnosis, 19% reported having “long Covid-19” symptoms, which included a prolonged loss of smell, persistent cough, fatigue, weakness, dyspnea, or myalgia. Nine workers (23%) took a leave of absence from work beyond the 10 days of required quarantine; of these workers, 4 returned to work within 2 weeks. One worker had not yet returned after 6 weeks.

Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID 
Juli 2021
The mean time after the diagnosis of COVID-19 was 3.7±1.5 months. Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p=0.032), CNBD (p=0.020), and CNFL (p=0.012), and increased DC density (p=0.046) compared with controls, while patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p=0.003). There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (?=?0.436; p=0.005, ?=?0.387; p=0.038, respectively) and CNFL (?=?0.404; p=0.010, ?=?0.412; p=0.026, respectively). Corneal confocal microscopy identifies corneal small nerve fibre loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID.

Long covid – mechanisms, risk factors, and management
Juli 2021
With many people having been infected and continuing to be infected with covid-19, the long term implications are of increasing concern. Here, we have reviewed the studies that have explored the persisting symptoms of long covid, and have addressed the possible risk factors associated with developing long covid and the treatment options that may be useful in alleviating its symptoms. Currently, long covid remains enigmatic and, with the question of the impact that new variants of covid-19 will have on the incidence and severity of long covid still looming large, it is important that research continues to explore post-covid-19 syndrome. Greater understanding of the pathogenesis, risk factors, symptoms, and methods of treating long covid is required to reduce the strain and demand on people with the condition and the healthcare systems that will endeavor to support them.

The prolonged effects of COVID-19. A new „threat“?
Juli 2021
Coronavirus ‚long-haulers“ currently represent a significant public health concern. Recent reports suggest that persistent effects of COVID-19, such as fatigue, dyspnea, chest pain, anxiety, depression, arthralgia, may last for months and lead to a decline in quality of life. Risk factors for long COVID are still not very well understood. Survivors suffer from ongoing symptoms. This new entity highlights the need for a multidisciplinary approach that would enable closer monitoring of affected patients and implementation of measures that could reduce the impact of the pandemic on the overall patient wellbeing after the resolution of acute symptoms.

Cognitive deficits in people who have recovered from COVID-19
Juli 2021
People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition.

COVID-19 long haulers
Juli 2021
Now long-COVID is the focus of growing attention. In February, the US National Institutes of Health announced a $1.15 billion initiative to identify the causes of long-COVID and find ways of preventing and treating the condition. With no effective treatment and a potentially large untapped market, a scattering of trials of repurposed and repositioned drugs have been initiated for long-COVID sufferers. But with the prevalence of the condition unclear—and a unifying diagnosis or even an agreed-upon definition that explains the condition’s widely varying symptoms completely lacking—drug development for long-COVID is even more of a shot in the dark than usual.

A role for T-cell exhaustion in Long COVID-19 and severe outcomes for several categories of COVID-19 patients
Juli 2021
Active brain infections by protozoan parasite T. gondii can cause neuroinflammations, activation of microglia, astrocytes and complement, major neurotransmitter disruptions. Furthermore, some long duration active or latent infections by T. gondii can cause immune dysfunctions, including CD8 T-cell exhaustion. T. gondii infections have an extensively documented involvement in some schizophrenia cases. A statistically increased mortality rate for COVID-19 schizophrenia patients could be logically explained by a subset of schizophrenia patients having long duration T. gondii brain infections that cause immune dysfunctions, such as CD8 T-cell exhaustion. This could cause more severe outcomes for these COVID-19 patients. More importantly, the matches in corresponding patient categories between the OR of COVID-19 mortality and T. gondii infection suggest T. gondii in certain cases, especially in cases without early protozoan parasite drug treatments, can induce immune dysfunctions which cause more severe outcomes for these COVID-19 patient categories. In addition, some cancers and pathogens which also induce T-cell exhaustion can explain the more severe outcomes of COVID-19 patients experiencing certain cancer or disease comorbidities. Furthermore, latent pathogen infections that are partially or fully reactivated for any reason could explain why certain post-COVID-19 individuals experience the long duration symptoms of Long COVID-19.

Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study
Juli 2021
Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2 months and 6 months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct = 38) and 3% (median Ct = 36) patients at 2 months and 6 months, respectively, but no reinfections were demonstrated. Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66-0.94]) and higher WHO severity score (2.57 [1.20-5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79-0.99]) and female sex (2.41 [1.20-4.82]); no association was found with prolonged viral RNA shedding.

Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review
Juli 2021
In total, nine articles were included in this literature review. The frequency of persistent symptoms in patients after mild COVID-19 infection ranged between 10% and 35%. Symptoms persisting after a mild COVID-19 infection can be distinguished into physical, mental and social symptoms. Fatigue was the most frequently described persistent symptom. Other frequently occurring persistent symptoms were dyspnoea, cough, chest pain, headache, decreased mental and cognitive status and olfactory dysfunction. In addition, it was found that persisting symptoms after a mild COVID-19 infection can have major consequences for work and daily functioning.


Symptoms, complications and management of long COVID: a review
Juli 2021
Patients with ‚long COVID‘ experience a wide range of physical and mental/psychological symptoms. Pooled prevalence data showed the 10 most prevalent reported symptoms were fatigue, shortness of breath, muscle pain, joint pain, headache, cough, chest pain, altered smell, altered taste and diarrhoea. Other common symptoms were cognitive impairment, memory loss, anxiety and sleep disorders. Beyond symptoms and complications, people with long COVID often reported impaired quality of life, mental health and employment issues. These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health and social services support. Resilient healthcare systems are needed to ensure efficient and effective responses to future health challenges.

Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact
Juli 2021
For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden.

A longitudinal SARS-CoV-2 biorepository for COVID-19 survivors with and without post-acute sequelae
Juli 2021
We have enrolled and collected samples from 119 adults since July 2020, with 66% follow-up rate. Forty-nine percent of participants assessed with a symptom surveillance questionnaire (N = 37 of 75) had PASC at any time during follow-up (up to 8 months post infection). Ninety-three percent of hospitalized participants developed PASC, while 23% of those not requiring hospitalization developed PASC. At 90-174 days post SARS-CoV-2 diagnosis, 67% of all participants had persistent symptoms (N = 37 of 55), and 85% percent of participants who required hospitalization during initial infection (N = 20) still had symptoms. The most common symptoms reported after 15 days of infection were fatigue, loss of smell, loss of taste, exercise intolerance, and cognitive dysfunction.

A Molecular Basis of Long COVID-19
Juli 2021 (vorläufig)
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found capable of inducing long term effects commonly referred to as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. To define the molecular basis of this condition, we compared the short- and long-term responses to influenza A virus and SARSCoV-2 in the golden hamster model. These data demonstrated that SARS-CoV-2 resulted in sustained changes to lung, kidney, and brain. The most significant change in response to SARS-CoV-2 was observed in the olfactory bulb, where persistent inflammation was visible beyond one month post infection. This was characterized by microglial activation, pro-inflammatory cytokine production, and a Type I interferon (IFN-I) response in the absence of detectable virus. Given the connection between olfactory bulb injury and neurological disorders, we postulate that this prolonged inflammation is an underlying cause of long COVID.

Evolving Phenotypes of non-hospitalized Patients that Indicate Long Covid
Juli 2021 (vorläufig)
In this retrospective electronic health records (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3-6 and 6-9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston metropolitan area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized. We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records two months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR: 2.60, 95% CI [1.94 – 3.46]), alopecia (OR: 3.09, 95% CI [2.53 – 3.76]), chest pain (OR: 1.27, 95% CI [1.09 – 1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22-2.10]), shortness of breath (OR 1.41, 95% CI [1.22 – 1.64]), pneumonia (OR 1.66, 95% CI [1.28 – 2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22 – 1.64]) are some of the most significant indicators of a past COVID-19 infection.

Post-covid Syndrome: A Single-Center Questionnaire Study On 1007 Participants Recovered from COVID-19
Juli 2021
A total of 1007 participants, 39.0% had at least one comorbidity, and 47.5% had persistent symptoms. Fatigue/easy fatigability, myalgia, and loss of weight were the most frequent persistent symptoms (overall 29.3%) and followed by respiratory symptoms (25.4%). A total of 235 participants had visited outpatient clinics due to several reasons during the post-COVID-19 period, 17 of them were hospitalized. Severe acute COVID-19, hospitalization, and presence of comorbidity were independent factors for the development of persistent symptoms. Fully understanding the spectrum of post-covid syndrome is essential for appropriate management of all its long-term effects. Our study once again underlined that the prevalence of post-covid syndrome is higher than expected and concerns many systems, and a multidisciplinary follow-up should be provided to COVID-19 survivors in the post-recovery period.

Long-term Symptoms After SARS-CoV-2 Infection in Children and Adolescents
Juli 2021
Between October and November 2020 and March and April 2021, 4 of 109 seropositive children (4%) vs 28 of 1246 seronegative ones (2%) reported at least 1 symptom lasting beyond 12 weeks. The most frequently reported symptoms lasting more than 12 weeks among seropositive children were tiredness (3/109, 3%), difficulty concentrating (2/109, 2%), and increased need for sleep (2/109, 2%). None of the seropositive children reported hospitalization after October 2020. Similar proportions of seropositive and seronegative children reported excellent or good health. This study found a low prevalence of symptoms compatible with long COVID in a randomly selected cohort of children assessed 6 months after serologic testing.

Markers of immune activation and inflammation in individuals with post-acute sequelae of SARS-CoV-2 infection
Juli 2021
During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including TNF-alpha (1.14-fold higher mean ratio, 95%CI 1.01-1.28, p=0.028) and IP-10 (1.28-fold higher mean ratio, 95%CI 1.01-1.62, p=0.038). Among those with PASC, there was a trend toward higher IL-6 levels during early recovery (1.28-fold higher mean ratio, 95%CI 0.98- 1.70, p=0.07) which became more pronounced in late recovery (1.44-fold higher mean ratio, 95%CI: 1.11-1.86, p<0.001). These differences were more pronounced among those with a greater number of PASC symptoms. Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

Outcomes Among Patients Referred to Outpatient Rehabilitation Clinics After COVID-19 diagnosis 
Juli 2021
Using data acquired during January 2020–March 2021 from Select Medical outpatient rehabilitation clinics, CDC compared patient-reported measures of health, physical endurance, and health care use between patients who had recovered from COVID-19 (post–COVID-19 patients) and patients needing rehabilitation because of a current or previous diagnosis of a neoplasm (cancer) who had not experienced COVID-19 (control patients). All patients had been referred to outpatient rehabilitation. Compared with control patients, post–COVID-19 patients had higher age- and sex-adjusted odds of reporting worse physical health (adjusted odds ratio [aOR] = 1.8), pain (aOR = 2.3), and difficulty with physical activities (aOR = 1.6). Post–COVID-19 patients also had worse physical endurance, measured by the 6-minute walk test (6MWT) (p<0.001) compared with control patients. Among patients referred to outpatient rehabilitation, those recovering from COVID-19 had poorer physical health and functional status than those who had cancer, or were recovering from cancer but not COVID-19. Patients recovering from COVID-19 might need additional clinical support, including tailored physical and mental health rehabilitation services.

Burden of post-COVID-19 syndrome and implications for healthcare service planning: A population-based cohort study
Juli 2021
Symptoms were present in 385 (89%) participants at diagnosis and 81 (19%) were initially hospitalized. At six to eight months, 111 (26%) reported not having fully recovered. 233 (55%) participants reported symptoms of fatigue, 96 (25%) had at least grade 1 dyspnea, and 111 (26%) had DASS-21 scores indicating symptoms of depression. 170 (40%) participants reported at least one general practitioner visit related to COVID-19 after acute illness, and 10% (8/81) of initially hospitalized individuals were rehospitalized. Individuals that have not fully recovered or suffer from fatigue, dyspnea or depression were more likely to have further healthcare contacts. However, a third of individuals (37/111) that have not fully recovered did not seek further care. In this population-based study, a relevant proportion of participants suffered from longer-term consequences after SARS-CoV-2 infection. With millions infected across the world, our findings emphasize the need for the timely planning of resources and patient-centered services for post-COVID-19 care.


Long-term clinical follow-up of patients suffering from moderate-to-severe COVID-19 infection: a monocentric prospective observational cohort study
Juli 2021
In total, 199 individuals were included in the analysis. Most patients received oxygen supplementation (80.4%). Six months after discharge, 47% and 32% of patients still had exertional dyspnoea and fatigue. PFTs at 3-month follow-up revealed a reduced diffusion capacity of carbon monoxide (mean 71.6 ± 18.6%), and this increased significantly at 6-month follow-up (P<0.0001). Chest CT scans showed a high prevalence (68.9% of the cohort) of persistent abnormalities, mainly ground glass opacities. Duration of hospitalization, intensive care unit admission and mechanical ventilation were not associated with the persistence of symptoms 3 months after discharge.


The kids are not alright: A preliminary report of Post-COVID syndrome in university students
Juli 2021
51% of COVID-19 positive participants were classified with post-COVID syndrome. During acute illness, those with post-COVID syndrome experienced more chest pain, fatigue, fever, olfactory impairment, headaches, and diarrhea compared to fully recovered participants. They also reported more current exercise intolerance, dyspnea, chest pain, olfactory impairment, lymphadenopathy, gustatory impairment, and appetite loss than students who never contracted COVID-19. Our results contradict the perception that this yet to be defined post-COVID syndrome predominantly affects middle-aged adults. Student health centers should closely monitor those who contract COVID-19 for lingering effects.

Long COVID also possible after a mild case: interim research results
Juli 2021
More than 95% of the 1,741 participants in RIVM National Institute for Public Health and the Environment’s LongCOVID study, who reported long-term symptoms after COVID-19, had mild symptoms during the acute phase of the infection. This is evident from the initial results of the RIVM LongCOVID study. Only 5% of the people participating in the study who reported long-term symptoms were admitted to hospital due to COVID-19. The symptoms reported most frequently among the participants were tiredness (90%), concentration problems (74%) and shortness of breath (70%). The average duration of these symptoms among the participants was 7 months at the time they signed up for the study. It is not yet known whether the delta variant causes different long-term symptoms, and whether children have the same long-term symptoms as adults. 

Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection
Juli 2021
We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus. Symptom data were collected only during the acute phase of infection, which limited our ability to compare long-term physiological and behavioral changes with long-term symptoms. In the future, with larger sample sizes and more comprehensive participant-reported outcomes, it will be possible to better understand factors associated with interindividualized variability in COVID-19 recovery.

COVID and the brain: researchers zero in on how damage occurs
Juli 2021
New evidence suggests that the coronavirus’s assault on the brain could be multipronged: it might attack certain brain cells directly, reduce blood flow to brain tissue or trigger production of immune molecules that can harm brain cells. Infection with the coronavirus SARS-CoV-2 can cause memory loss, strokes and other effects on the brain. It has also accumulated that SARS-CoV-2 can affect the brain by reducing blood flow to it — impairing neurons’ function and ultimately killing them. There is also growing evidence that some neurological symptoms and damage are the result of the body’s own immune system overreacting and even misfiring after encountering the coronavirus. These pathways — astrocytes, pericytes and autoantibodies — are not mutually exclusive, and are probably not the only ones: it is likely that people with COVID-19 experience neurological symptoms for a range of reasons. A key question is what proportion of cases is caused by each of the pathways.

Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting
Juli 2021
Of the 629 participants in the study who completed the baseline interviews, 410 completed follow-up at 7 to 9 months after COVID-19 diagnosis; 39.0% reported residual symptoms. Fatigue (20.7%) was the most common symptom reported, followed by loss of taste or smell (16.8%), dyspnea (11.7%), and headache (10.0%).

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study
Juli 2021
At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titres were ?1:160 in 43.6% of patients at 12 months post COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titre ?1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one long COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2-antibody levels, but had a significantly reduced physical and mental life quality compared to patients without symptoms. Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.

Retinal Microcirculation as a Correlate of a Systemic Capillary Impairment After Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Juli 2021
Retinal microcirculation may offer a window to the systemic micro-vessel system. We found a remarkable duration of the changed VD in patients who had suffered at COVID-19 infection. The retinal micro-vascular layer in OCT-A imaging (ICP), correlating with the inner nuclear and inner plexiform layers, showed significantly lower microcirculation parameters after SARS-CoV-2 infection compared with healthy eyes, correlating with clinical marker of severity of COVID-19 disease. Future studies regarding the impact of baseline thrombosis prophylaxis might show a clinical impact of these data.

Sustained prothrombotic changes in convalescent patients with COVID-19
Juli 2021
We recently showed elevated thrombin-generating capacity and a hypofibrinolytic state in patients that predominantly had moderate disease (stage 2) 4 months after hospital discharge. Importantly, ex vivo hypercoagulability and hypofibrinolysis are associated with an increased risk of thrombotic events in the general population. It is tempting to speculate that a persistent hypercoagulable state contributes to the post-acute sequelae of SARS-CoV-2 infection (PASC; also known as long COVID) by facilitating formation of microthrombi in the pulmonary vasculature, similar to the thrombotic events proposed in stage 1 disease. In this scenario, post-discharge thromboprophylaxis might benefit some convalescent patients with COVID-19, and larger controlled trials, such as the ACTIV-4 trial, will provide important information on this matter. We feel that studies investigating underlying mechanisms and potential clinical consequences of sustained prothrombotic changes in convalescent patients with COVID-19 are needed, because they might have therapeutic implications.

Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study
Juli 2021
518 of 853 (61%) of eligible children were available for the follow-up assessment and included in the study. Median age was 10.4?years (IQR, 3–15.2) and 270 (52.1%) were girls; median follow-up since hospital discharge was 256 (223–271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%,) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: older age “6–11 years” (odds ratio 2.74 (95% confidence interval 1.37 to 5.75) and “12–18 years” (2.68, 1.41 to 5.4); and a history of allergic diseases (1.67, 1.04 to 2.67).

Prevalence of, and factors associated with, long-term COVID-19 sick leave in working-age patients followed in general practices in Germany
Juli 2021
The prevalence of long-term sick leave was 5.8% in this sample of approximately 31 000 COVID-19 patients followed in general practices in Germany. Long-term sick leave was defined as sick leave of at least 4 weeks. Sex, age, and several disorders (noninfective enteritis and colitis; reaction to severe stress, and adjustment disorders; atopic dermatitis; mononeuropathies; reflux diseases; diabetes mellitus; and hypertension) were significantly associated with the risk of long-term sick leave. Further research is warranted to corroborate or invalidate the study results in other settings and countries.

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY
Juni 2021
Working on behalf of NHS England, we used OpenSAFELY data encompassing 96% of the English population between 2020-02-01 and 2021-04-25. We measured the proportion of people with a recorded code for long COVID, overall and by demographic factors, electronic health record software system (EMIS or TPP), and week. Results: Long COVID was recorded for 23,273 people. Coding was unevenly distributed amongst practices, with 26.7% of practices having never used the codes. Long COVID coding in primary care is low compared with early reports of long COVID prevalence. This may reflect under-coding, sub-optimal communication of clinical terms, under-diagnosis, a true low prevalence of long COVID diagnosed by clinicians, or a combination of factors. We recommend increased awareness of diagnostic codes, to facilitate research and planning of services; and surveys of clinicians’ experiences, to complement ongoing patient surveys.

Getting to grips with long covid
Juni 2021
More than a million people in the UK are living with long covid, according to the UK’s Office for National Statistics (ONS). And while global figures vary, it is thought that about 14 per cent of people who catch covid-19 end up with lasting symptoms – which is some 25 million people worldwide. This could be a big underestimate, though, because less than 10 per cent of infections are thought to be detected, so the true figure could be nearer 250 million. What is clear is that even after the pandemic is brought under control, millions of people will be left with lingering symptoms that prevent them from working and enjoying life.

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Juni 2021
In conclusion, we developed a bioinformatics pipeline that analyzed cytokines of the immunological landscape of COVID-19 using machine learning methods to discriminate between PASC and Severe individuals from other classes. The implementation of random forest classifiers allowed for the identification of the critical cytokines for this discrimination, which in turn was used to calculate highly sensitive heuristics for PASC and Severe individuals. These models, which can be incorporated into clinical laboratory information systems, enabled a highly accurate, immune-based classification of severe COVID-19 infection and PASC. This workflow could greatly aid the triage, treatment, and prognosis of those affected. An interesting caveat affecting the specificity of the PASC classification was that 7 Severe COVID-19 patients classified as PASC that, while affecting the specificity of PASC classification, may represent a subset of acute COVID-19 patients destined to become affected by PASC.


Post-Acute COVID Syndrome (PACS): Definition, Impact and Management
Juni 2021
We propose a clear set of case definitions of PACS and its clinical scenarios. We recommend standardization and adequate coding of these case definitions to foster comparability, better estimates of the magnitude of the problem at the international level, and the establishment of national disease registries. We also recommend a comprehensive medical examination to characterise the clinical features and complications when assessing PACS. Data on the evolution and resolution dynamics of PACS remain scarce to date. Clear and functional referral circuits connecting primary care and hospitals are necessary to guarantee adequate management of these patients, with the development of multidisciplinary units that could offer a comprehensive and complete management of the patient. Persistent COVID symptoms can have a serious impact on people’s ability to return to work, with significant psychological, social and economic consequences for themselves, their families and society. It is now time to establish the appropriate strategies to tackle this second added burden of COVID in order to minimise its impact.

Chronic fatigue and post-exertional malaise in people living with long COVID
Juni 2021 (vorläufig)
Long COVID is characterized by chronic fatigue that is clinically relevant and is at least as severe as fatigue in several other clinical conditions, including cancer. PEM appears to be a common and significant challenge for the majority of this patient group. Patients, researchers, and allied health professionals are seeking information on safe rehabilitation for people living with long COVID, particularly regarding exercise. Fatigue and post-exertional symptom exacerbation must be monitored and reported in studies involving interventions for people with long COVID.


Post-Acute COVID-19 Syndrome and the cardiovascular system: What is known?
Juni 2021
Cardiovascular symptoms such as chest pain and palpitations commonly occur in PACS, but the underlying cause of symptoms is infrequently known. While autopsy studies have shown that the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) rarely causes direct myocardial injury, several syndromes such as myocarditis, pericarditis, and Postural Orthostatic Tachycardia Syndrome have been implicated in PACS. Additionally, patients hospitalized with acute COVID-19 who display biomarker evidence of myocardial injury may have underlying coronary artery disease revealed by the physiological stress of SARS-CoV-2 infection and may benefit from medical optimization. We review what is known about PACS and the cardiovascular system and propose a framework for evaluation and management of related symptoms.

Chronic fatigue syndrome and long covid: moving beyond the controversy
Juni 2021
Patients with long covid are a diverse group, and it’s hard to know what treatment path to put them on. Finding the right balance between gentle activity to avoid deconditioning and not triggering post-exercise malaise is important in each patient. BMJ has spoken to clinicians and academics who have been challenged over their views on treatment of long covid, or their research intentions, where “exercise” has become a toxic term for some. Clinicians working with long covid patients have also told The BMJ that, despite the challenges, long covid provides an opportunity to progress the understanding of postviral syndromes and to acknowledge that they are a very real condition.

The Impact of COVID Vaccination on Symptoms of Long COVID. An International Survey of People with Lived Experience of Long COVID
Juni 2021 (vorläufig)
900 people participated in the questionnaire, of whom 45 had pre-existing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) but no evidence of COVID infection and a further 43 did not complete the survey in full. The demographics and symptomology of the remaining 812 people were similar to Office of National Statistics. Following vaccination, 57.9% of participants reported improvements in symptoms, 17.9% reported deterioration and the remainder no change. There was considerable individual variation in responses. Larger improvements in symptom severity scores were seen in those receiving the mRNA vaccines compared to adenoviral vector vaccines. Our survey suggests COVID-19 vaccination may improve long COVID patients on average. The observational nature of the survey limits drawing direct causal inference, but demands validation with a randomised controlled trial.


Whole of population-based cohort study of recovery time from COVID-19 in New South Wales Australia
Juni 2021
In analyses 2904 cases were followed for recovery (median follow-up time 16 days, range 1-122, IQR 11-24).There were 2572 (88.6%) who reported resolution of symptoms (262/2572 were also hospitalised), 224 (7.8%) had not recovered at last contact (28/224 were also hospitalised), 51 (1.8%) died of COVID-19, and 57 (2.0%) were hospitalised without a documented recovery date. Of those followed, 20% recovered by 10 days, 60% at 20, 80% at 30, 91% at 60, 93% at 90 and 96% at 120 days. Compared to those aged 30-49 years, those 0-29 years were more likely to recover while those aged 50-69 and 70+ years were less likely to recover. Men were faster to recover than women and those with pre-existing co-morbidities took longer to recover than those without. In a setting where most cases of COVID-19 were ascertained and followed, 80% of those with COVID-19 recover within a month, but about 5% will continue to experience symptoms 3 months later.

Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people
Juni 2021 (vorläufig)
Among the 508,707 participants, the weighted prevalence of self-reported COVID-19 was 19.2%. 37.7% of 76,155 symptomatic people post COVID-19 experienced at least one symptom, while 14.8% experienced three or more symptoms, lasting 12 weeks or more. This gives a weighted population prevalence of persistent symptoms of 5.75% for one and 2.22% for three or more symptoms. Two stable clusters were identified based on symptoms that persisted for 12 weeks or more: in the largest cluster, tiredness predominated, while in the second there was a high prevalence of respiratory and related symptoms. A substantial proportion of people with symptomatic COVID-19 go on to have persistent symptoms for 12 weeks or more, which is age-dependent. Clinicians need to be aware of the differing manifestations of Long COVID which may require tailored therapeutic approaches. Managing the long-term sequelae of SARS-CoV-2 infection in the population will remain a major challenge for health services in the next stage of the pandemic.

Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation
Juni 2021
Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein–Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher’s exact test). A similar ratio was observed in a secondary group of 18 subjects 21–90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms
Juni 2021
This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.

Long COVID in a prospective cohort of home-isolated patients
Juni 2021
We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. We found that a large proportion of survivors of COVID-19 in our cohort had persistent symptoms 6 months after their initial illness. Although it has previously been reported that patients hospitalized for severe COVID-19 frequently suffer long-term symptoms. We found that more than half of home-isolated, mildly to moderately ill patients with COVID-19 still suffered symptoms 6 months after infection. It is worrying that non-hospitalized, young people (16–30 years old) suffer potentially severe symptoms, such as concentration and memory problems, dyspnea and fatigue, half a year after infection. Particularly for students, such symptoms might interfere with their learning and study progress.

Dysregulation of brain and choroid plexus cell types in severe COVID-19
Juni 2021
We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease. Synaptic signalling of upper-layer excitatory neurons—evolutionarily expanded in humans and linked to cognitive function—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later. To investigate the potential pathologies underlying reported long COVID neurological symptoms, we analyzed the intersection between COVID-19 DEGs across brain cell types with those recently described in chronic CNS diseases, such as Alzheimer’s disease, multiple sclerosis, Huntington’s disease, and autism spectrum disorder. While COVID-19 perturbations in neurons were unique compared to those in chronic CNS diseases, the overlap in glial cells was particularly strong.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?
Juni 2021
As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called “post-COVID syndrome” or “long-COVID”. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with postCOVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

Brain imaging before and after COVID-19 in UK Biobank
Juni 2021 (vorläufig)
There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS-CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID-19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis. Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system.

The Hidden Pandemic: Long COVID
Juni 2021
This paper clearly brings out the nature of Long Covid as a global problem, requiring governments around the world to take the right action to respond to it. The Federal Ministry of Education and Research (BMBF) announced on 31 May that it will award €5 million in funding for research on Long Covid. The funding is primarily aimed at interdisciplinary research associations that already have access to patients, data and samples. Of particular interest to this research are projects on outpatient care, rehabilitation and care, and on the cooperation between specialised Long Covid outpatient clinics and primary care. The new funding was welcomed by scientists and researchers, while at the same time deemed by some to be substantially less than the amount needed to tackle the Long Covid situation in Germany. In terms of existing treatment facilities, it appears that some university hospitals provide special consultation hours for patients with Long Covid, with some having offered multidisciplinary support from as early as July 2020. According to Long Covid Deutschland, as of 4 June 2021 there were 49 Long Covid clinics in Germany, about 17 of which have an interdisciplinary focus, while two are designated clinics for myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS).

A Detailed Study of Patients with Long-Haul COVID
Juni 2021
Using longitudinal data from a database of over 34 billion private healthcare claim records, FAIR Health studied a total of 1,959,982 COVID-19 patients for the prevalence of post-COVID conditions 30 days or more after their initial diagnosis with COVID-19. Of patients who had COVID-19, 23.2 percent had at least one postCOVID condition 30 days or more after their initial diagnosis with COVID-19. Post-COVID conditions were found to a greater extent in patients who had more severe cases of COVID-19, but also in a substantial share (19 percent) of patients whose cases were asymptomatic. The five most common post-COVID conditions across all ages, in order from most to least common, were pain, breathing difficulties, hyperlipidemia, malaise and fatigue, and hypertension. For example, of patients who had post-COVID cardiac inflammation, 52 percent were male and 48 percent female. By age, the largest share (25.4 percent) with this condition was found in individuals aged 19-29.

Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19
Juni 2021
Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without overt neurological manifestations. Higher NFL serum concentrations were associated with worse clinical outcomes. In one hundred hospitalized patients with COVID-19 treated with remdesivir, a trend toward lower NFL serum concentrations was observed. These data suggest that patients with COVID-19 may experience neuroaxonal injury and may be at risk for long-term neurological sequelae. Neuroaxonal injury should be considered as an outcome in acute pharmacotherapeutic trials for COVID-19.

Analysis of cell-mediated immunity in people with long COVID
Juni 2021 (vorläufig)
Patients with LC had negative serology for Covid-19 in 89% of cases but 96% showed specific cellular immunity to SARS-CoV-2 an average of 9.5 months after infection: 89% of this response corresponded to T8 lymphocytes, 58% to NK cells, and 51% to T4 lymphocyte (20% negligibly positive). Most of them had altered immune cell typing and we found that T4 lymphocyte counts were low in 34% of cases and NK cell high in 64%. Macrophage populations were detected in the peripheral blood of 7% of them. Patients displayed a higher percentage of illnesses related to &[Prime]abnormal&[Prime] immune responses, either preceding SARS-CoV-2 infection (43%) or following it in 23% of cases.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment
Juni 2021
We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals.

Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2
Juni 2021
Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.

Prevalence of long-term effects in individuals diagnosed with COVID-19: a living systematic review
Juni 2021 (vorläufig)
Of the 2807 unique citations, 36 observational studies met our inclusion criteria. Over 100 post COVID-19 conditions were reported in laboratory-confirmed individuals. Eighty-three percent (95%CI: 65-93%; low certainty) and 56% (95%CI: 34-75%; very low certainty) reported persistence or presence of one or more symptoms in the short- and long-term, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, sleep disturbances, shortness of breath and anxiety or depression (point estimates ranging from 22-51%; low to very low certainty).


Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19
Juni 2021
Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.

COVID-19: long covid and its societal consequences
Juni 2021
COVID-19 is an acute, highly transmissible respiratory infection that is potentially lethal, but often mild, sometimes asymptomatic, especially in the young. However, it has become clear that, in some patients, there may be sequelae involving tissues other than the lung, resulting in other types of morbidity, and sometimes longer term consequences that are often termed “long covid”. In this Lilliput, we summarize recent findings about COVID-19 sequelae, with a particular focus on long covid. We also discuss some of the long scars that COVID-19 and long covid will collectively leave on society that we term Societal Long Covid.


Pediatric long-COVID: An overlooked phenomenon?
Juni 2021
With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2–18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints. Our study shows that long-COVID is also present in the pediatric population. The main symptoms resemble those previously described in adults. This novel condition demands a multidisciplinary approach with international awareness and consensus to aid early detection and effective management.

Prevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales
Juni 2021 (vorläufig)
Using data from 4678 children participating in VirusWatch, a household cohort study, we estimated the prevalence of persistent symptoms lasting ?4 weeks as 1.7%, and 4.6% in children with a history of SARS-CoV-2 infection. Persistent symptom prevalence was higher in girls, teenagers and children with long-term conditions. Our estimated prevalence of persistent symptoms appears lower than among children seen in secondary care; nationally representative studies following children hospitalised with SARS-CoV-2 infection, including suitable control groups and using standardised definitions of persistent symptoms, are required in order to assess symptom persistence in children with more severe COVID-19 disease. The most common persistent symptom among children in Virus Watch was fatigue, as reported elsewhere.

Association of Obesity with Post-Acute Sequelae of COVID-19 (PASC)
Juni 2021 (vorläufig)
Obesity is a major risk factor for development of severe COVID-19 infection and mortality. However, it is not known whether patients with obesity are at greater risk for development of post-acute sequelae of COVID-19 (PASC). In a median follow-up time of 8 months and counting from 30?days following positive viral test of 2839 patients who did not require ICU admission and survived the acute phase of COVID-19, 1230 (43%) patients required medical diagnostic tests, 1255 (44%) patients had hospital admission, and 29 (1%) patients died. Compared with patients with normal BMI, risk of hospital admission was 28% and 30% higher in patients with moderate and severe obesity, respectively. The need for diagnostic tests to assess different medical problems, compared with patients with normal BMI, was 25% and 39% higher in patients with moderate and severe obesity, respectively. Findings of this study suggest that moderate and severe obesity (BMI ?35 Kg/m2) is associated with a greater risk of PASC.

Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome
Juni 2021
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Postacute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post-coronavirus disease 2019 (COVID-19) syndrome (‚long COVID‘) with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of ‚acute‘ COVID-19, and we speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.


Neurologische Manifestationen bei Patienten mit Post-COVID-19-Syndrom
Juni 2021
Mittels Fluordesoxyglukosepositronenemissionstomographie wurde bei 10 von 15 Long-COVID-Patienten mit neurokognitivem Defizit (weniger als 26/30 Punkte im MoCA[„Montreal cognitive assessment“]-Test) in frontoparietalen Hirnregionen ein Hypometabolismus nachgewiesen. Beim Follow-up von 8 Patienten über 6 Monate zeigte sich eine Symptomverbesserung mit weitgehender Normalisierung des Hirnstoffwechsels in der PET. Erfahrungen mit der SARS-1-Pandemie zeigten bereits, dass einzelne Patienten sehr lang anhaltende klinische Beschwerden zurückbehalten können, insbesondere Schmerzen, Fatigue, Depression und Schlafstörungen. Das Fehlen krankheitsspezifischer Biomarker erschwert die eindeutige ätiologische Zuordnung ebenso wie die Überlappung mit anderen (prämorbiden) Erkrankungen.

Proposed integrative model for post-COVID symptoms
Juni 2021 (vorläufig)
The first consideration is to define which symptoms are of “new-onset” (symptoms never experienced by a patient before COVID-19 and experienced the first time after) and which symptoms are “exacerbated” (symptoms experienced by a patient prior to COVID-19 but aggravated later) after infection. The second consideration includes defining “persistent” (symptoms experienced at the acute phase and continuing after without remission period) and “delayed-onset” (symptoms not experienced at the acute phase of the infection but appearing after a “latency period”). This model integrates predisposing individual factors, biological factors associated to the severity of disease, hospitalization/treatment factors, and outbreak surrounding factors which may promote post-COVID.


Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort
Juni 2021
The aim of this study was to describe the clinical evolution during 6 months of follow-up of adults recovered from COVID-19. We tried to determine how many met the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 130 patients (51.0 ± 14 years, 34.6% female) were enrolled. Symptoms were common, participants reported a median number of 9 (IQR 5-14) symptoms. Fatigue was the most common symptom (61/130; 46.9%). Patients with fatigue were older 53.9 ± 13.5 years compared with 48.5 ± 13.3 years in those without fatigue (p = 0.02) and had a longer length of hospital stay, 17 ± 14 days vs. 13 ± 10 days (p = 0.04). There was no difference in other comorbidities between patients with fatigue and those without it, and no association between COVID-19 severity and fatigue. After multivariate adjustment of all baseline clinical features, only age 40 to 50 years old was positively associated with fatigue, OR 2.5 (95% CI 1.05-6.05) p = 0.03. In our survey, only 17 (13%) patients met the Institute of Medicine’s criteria for „systemic exertion intolerance disease,“ the new name of ME/CFS. In conclusion, in some patients, the features of post-acute COVID-19 syndrome overlap with the clinical features of ME/CFS.


Long COVID in children: Partnerships between families and paediatricians are a priority for better care
Juni 2021
Initially described in a small cohort of five children in Sweden, a larger Italian study and, more recently, an online survey in the UK provided preliminary evidence of Long COVID in children as well. We must understand Long COVID and recognise its impact also in the paediatric age. It is our duty to investigate, to seek the pathophysiological basis of Long COVID, because only in this way will we be able to give answers to these families. Ultimately, children will benefit from this journey of partnership between families and paediatricians.

Physical phenotype of blood cells is altered in COVID-19
Juni 2021
COVID-19 can lead to the impairment of the circulatory system, including effects such as vascular occlusion and hypoxemia. The physical properties of blood cells have crucial roles for proper circulation. Quick and simple examination of these properties would accomplish an unmet clinical need for rapid diagnostics of the cell’s functional status. Here we employed real-time deformability cytometry, a label free, high-throughput imaging technology to assess various physical properties of blood cells. We identified significant and persisting changes of cell size and mechanical properties in acute phase and post COVID-19. These changes might be predictive for cell functionality such as oxygen delivery. Thus, our findings have implications for COVID-19 diagnostics and treatment.

Post-COVID-19 syndrome: epidemiology, diagnostic criteria and pathogenic mechanisms involved
Juni 2021
Post-COVID-19 syndrome is defined by persistent clinical signs and symptoms that appear while or after suffering COVID-19, persist for more than 12 weeks and cannot be explained by an alternative diagnosis. The symptoms can fluctuate or cause relapses. It is a heterogeneous condition that includes post-viral chronic fatigue syndrome, sequelae in multiple organs and the effects of severe hospitalisation/post-intensive care syndrome. It has been reported in patients with mild or severe COVID-19 and irrespective of the severity of the symptoms in the acute phase. Between 10% and 65% of survivors who had mild/moderate COVID-19 present symptoms of post-COVID-19 syndrome for 12 weeks or more. At six months, subjects report an average of 14 persistent symptoms. The most common symptoms are fatigue, dyspnoea, anxiety, depression, and impaired attention, concentration, memory and sleep. The underlying biological mechanisms are unknown, although an abnormal or excessive autoimmune and inflammatory response may play an important role.

Patterns and predictors of sick leave after Covid-19 and long Covid in a national Swedish cohort
Mai 2021
A total of 11,955 people started sick leave for Covid-19 within the inclusion period. The median sick leave was 35?days, 13.3% were on sick leave for long Covid, and 9.0% remained on sick leave for the whole follow-up period. There were 2960 people who received inpatient care due to Covid-19, which was the strongest predictor of longer sick leave. Sick leave the year prior to Covid-19 and older age also predicted longer sick leave. No clear pattern of socioeconomic factors was noted. A substantial number of people are on sick leave due to Covid-19. Sick leave may be protracted, and sick leave for long Covid is quite common. The severity of Covid-19 (needing inpatient care), prior sick leave, and age all seem to predict the likelihood of longer sick leave. However, no socioeconomic factor could clearly predict longer sick leave, indicating the complexity of this condition. The group needing long sick leave after Covid-19 seems to be heterogeneous, indicating a knowledge gap.

Small Airways Disease is a Post-Acute Sequelae of SARS-CoV-2 Infection
Mai 2021 (vorläufig)
In contrast to most published reports of post-acute COVID-19, the majority of PASC patients in our cohort had mild disease during acute infection and did not require hospitalization. Spirometry and lung volumes were normal in these patients and were not different than a cohort of healthy control subjects. We observed a higher DLCO in the ambulatory group compared to healthy controls. Increases in DLCO can be driven by increases in pulmonary capillary blood volume, as occurs in asthma and obesity. Approximately a quarter of patients in the ambulatory group had asthma, and the BMI of the ambulatory group was significantly higher than healthy controls. Alternatively, increases in pulmonary capillary blood volume could be driven by endothelial dysfunction, as has been reported following SARS-CoV-2 infection. Air trapping is present in patients with post-acute sequelae of COVID-19 and is independent of initial infection severity, suggesting obstruction at the level of the small airways. The long-term consequences are not known.

Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19A Systematic Review
Mai 2021
In this systematic review of 45 studies including 9751 participants with COVID-19, the median proportion of individuals who experienced at least 1 persistent symptom was 73%; symptoms occurring most frequently included shortness of breath or dyspnea, fatigue or exhaustion, and sleep disorders or insomnia. However, the studies were highly heterogeneous and needed longer follow-up and more standardized designs. This systematic review found that COVID-19 symptoms commonly persisted beyond the acute phase of infection, with implications for health-associated functioning and quality of life; however, methodological improvements are needed to reliably quantify these risks.

Positive Epstein–Barr virus detection in coronavirus disease 2019 (COVID-19) patients
Mai 2021
In this study, we hypothesized that EBV/SARS-CoV-2 coinfection patients may need more time to recovery than the seronegative patients. We analyzed the recovery time between EBV/SARS-CoV-2 coinfection patients and SARS-CoV-2 infection alone patients. The recovery time is a little more in EBV/SARS-CoV-2 coinfection patients, while the difference was not significant. The reason of this negative result might be that most of our included COVID-19 patients were mild cases (85.1%). In summary, our study showed that high incidence of EBV coinfection was in COVID-19 patients. EBV/SARS-CoV-2 coinfection was associated with fever and increased inflammation in COVID-19 patients. EBV reactivation may associated with the severity of COVID-19. The underlying mechanism of how EBV reactivates and affects the COVID-19 needs to be investigated.

Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection
Mai 2021
Interestingly, one of the major findings of our work is that CGM allowed for detection of alterations in glucose homeostasis not otherwise detectable by self-measurement of fasting blood glucose. In accordance with this observation, we also reported alterations in the hormone profile, both at basal levels and after stimulation testing, with higher insulin, proinsulin and C-peptide levels in patients with COVID-19 (acute COVID-19) and in patients who recovered from COVID-19 (post COVID-19) as compared to healthy controls. Our observations further indicate that COVID-19 disrupts insulin signalling and beta cell function, in addition to the previously reported long-term effects on cardiovascular, neurological and renal function. This study demonstrates that SARS-CoV-2 induces insulin resistance and disrupts proper beta cell function, which can result in clinically evident hyperglycaemia detectable even in the post-acute phase. Our findings suggest the persistence of aberrant glycometabolic control long after recovery from the disease. This persistence should be investigated in larger cohort and its effect on clinical symptoms and sequalae should be carefully addressed.

Hyperpolarized 129Xe MRI Abnormalities in Dyspneic Participants 3 Months after COVID-19 Pneumonia: Preliminary Results
Mai 2021
Although the acute illness secondary to SARS-CoV-2 viral infection has been the main focus of research and clinical management, there are increasing reports of persistent symptoms, now called ‘Long-COVID’, lasting for months after discharge, with no apparent reliable clinical or imaging biomarkers. Our study has investigated the possible etiology of these symptoms. Alveolar capillary thrombosis may be one of the contributing factors to Long COVID, but this hypothesis will require substantiation in a larger population of patients post COVID-19 pneumonia, and also in a non-hospitalized cohort of patients with Long COVID. Xe MRI showed alveolar-capillary diffusion limitation in all 9 post COVID-19 pneumonia patients despite normal or nearly normal CT scans.

Population-based estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) prevalence and characteristics 
Mai 2021
We estimated PASC prevalence, defined as persistent symptoms 30+ (30-day COVID-19) or 60+ days (60-day COVID-19) post COVID-19 onset, overall and by sociodemographic and clinical factors, including self-reported symptom severity and hospitalization status. PASC is highly prevalent among cases reporting severe initial symptoms, and, to a lesser extent, cases reporting mild and moderate symptoms.

Measuring the impact of COVID-19 on the quality of life of the survivors, partners and family members: a cross-sectional international online survey
Mai 2021
One of the key findings of this study is the evidence that in survivors in whom the COVID-19 onset was >12 weeks ago, there was still a major persisting impact on QoL across all domains in both survivors and family members. This provides further evidence of the severe impact of post-acute COVID-19 (‘long COVID-19’) and ‘chronic COVID-19’. Our study has shown that most (87%) survivors had COVID-19 for >4 weeks, and 64% >12 weeks indicating that survivors continued to remain unwell for long periods of time, due to postviral symptoms or ‘long COVID-19’. This is in contrast to a UK COVID-19 symptom study, where only 10% of COVID-19-positive survivors remained unwell at 3 weeks, and a small proportion for >3 months.

Evolving Phenotypes of non-hospitalized Patients that Indicate Long Covid
Mai 2021 (vorläufig)
We identified 28 phenotypes among different age/gender cohorts or time windows that positively associated with a past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records two months or longer after a COVID-19 PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.17, 95% CI [1.42 – 3.25]), alopecia (OR 3.54, 95% CI [2.92 – 4.3]), chest pain (OR 1.35, 95% CI [1.16 – 1.56]), or chronic fatigue syndrome (OR 1.81-2.28, 95% CI [1.38 – 3.68]) are the most significant indicators of a past COVID-19 infection, especially among women younger than 65. Among men, edema (OR 1.83, 95% CI [1.23 – 2.66]) and disease of nail (OR 3.54, 95% CI [1.63 – 7.29]) in patients 65 and older or proteinuria (OR 2.66, 95% CI [1.61 – 4.34]) in patients under 65 are associated with a positive COVID-19 PCR test in the past few months.

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study
Mai 2021
By 6 months, systemic inflammation was resolved in all but one patient. 38 (90%) of 42 patients who had positive SARS-CoV-2 IgG antibodies within 6 weeks of admission remained seropositive at 6 months. Echocardiograms were normal in 44 (96%) of 46 patients by 6 months, and gastrointestinal symptoms that were reported in 45 (98%) of 46 patients at onset were present in six (13%) of 46 patients at 6 months. Renal, haematological, and otolaryngological findings largely resolved by 6 months. Although minor abnormalities were identified on neurological examination in 24 (52%) of 46 patients at 6 weeks and in 18 (39%) of 46 at 6 months, we found minimal functional impairment at 6 months. Ongoing concerns requiring physical re-conditioning and mental health support remained, and physiotherapy assessments revealed persisting poor exercise tolerance. Longer-term follow-up will help define the extended natural history of PIMS-TS.

Post-COVID Syndrome: An Insight on Its Pathogenesis
Mai 2021
The pathogenesis of post-COVID syndrome is multi-factorial and more than one mechanism may be implicated in several clinical manifestations. Prolonged inflammation has a key role in its pathogenesis and may account for some neurological complications, cognitive dysfunction, and several other symptoms. A multisystem inflammatory syndrome in adults (MIS-A) of all ages has been also described recently, similarly to multisystem inflammatory syndrome in children (MIS-C). The post-infectious inflammatory pathogenetic mechanism of MIS-A is supported by the fact that its diagnosis is established through serology in up to one third of cases. Other pathogenetic mechanisms that are implicated in post-COVID syndrome include immune-mediated vascular dysfunction, thromboembolism, and nervous system dysfunction. Although the current data are indicating that the overwhelming majority of patients with post-COVID syndrome have a good prognosis, registries to actively follow them are needed in order to define the full clinical spectrum and its long-term outcome. A consensus-based classification of post-COVID syndrome is essential to guide clinical, diagnostic, and therapeutic management. Further research is also imperative to elucidate the pathogenesis of post-COVID syndrome.

Integrated multidisciplinary post-COVID-19 care in Egypt
Mai 2021
50 patients with PASC currently attend the clinic, which will expand as more resources become available to meet the growing interest. More women than men came to the clinic, which is consistent with previous studies that more women have PASC. The long-term symptoms encompass a wide spectrum, including fatigue, dyspnoea, insomnia, tachycardia, joint pain, prolonged loss of smell, and a variety of psychosocial effects. The most common symptoms seen in the clinic were respiratory, cardiac, and neurological. Follow-up at the centre is high, which we believe is because of the timely and centralised care available.


Dermatan Sulfate Is a Potential Regulator of IgH via Interactions With Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts
Mai 2021
We have proposed that the glycosaminoglycan dermatan sulfate (DS) is a key missing player in autoimmunity in that (i) self-molecules with affinity to DS have a high propensity to be autoAgs and (ii) DS•autoAg complexes work in concert to stimulate autoreactive B cells. In our initial study, we had injected mice with various glycosaminoglycans, including DS, heparan sulfate, chondroitin sulfates A and C, hyaluronic acid, and heparin, and found that DS is the most potent in inducing arthritis in mice. When tested in vitro with mouse splenocytes, DS is found to be the most potent in stimulating CD5+ B (B1) cell proliferation and, moreover, DS exerts unique affinity to autoantigens from apoptotic cells, which prompted our hypothesis that DS and autoAgs form complexes and co-operate to stimulate B1 cells. Based on our DS•autoAg affinity hypothesis, we have thus far identified over 200 potential protein autoAgs from cells lines and murine liver and kidney tissues and autoAgs related to autoimmunity in COVID-19.

Unpacking post-covid symptoms
Mai 2021
It is too early to predict how long clinical sequelae will persist after covid-19, but these symptoms clearly create a major personal burden for many people, with some individuals experiencing difficulty returning to work and some unable to care for dependents. Long covid is also putting a strain on healthcare services, which have been already decimated by the pandemic. Risk factors differ for different new diagnoses, suggesting that a variety of mechanisms could be at play. Applying these risk factors to clinical practice will probably need long covid to be subdivided into more specific phenotypes. Healthcare professionals should be alert to the possibility of long covid in anyone with confirmed or suspected covid-19. How to treat these longer term consequences is now an urgent research priority.

Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments
Mai 2021
Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), although more research is required to substantiate such risk factors. While preliminary evidence suggests that personalized rehabilitation training may help certain long COVID cases, therapeutic drugs repurposed from other similar conditions, such as myalgic encephalomyelitis or chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome, also hold potential. In sum, this review hopes to provide the current understanding of what is known about long COVID.

Diverse Functional Autoantibodies in Patients with COVID-19
Mai 2021
Intriguingly, many tissue autoantibodies we identified were also present across diverse physiological compartments frequently implicated during post-COVID syndrome (PCS). Ultimately, whether the specific autoantibodies identified here play a role in the establishment of PCS, and whether they persist beyond the acute phase of COVID-19, warrants further investigation. Our analyses revealed an expansive autoantibody landscape in COVID-19 patients and identified distinct autoantibodies that exerted striking immunological and clinical outcomes. These results implicate previously underappreciated immunological pathways in the etiology of COVID-19 and suggest novel therapeutic paradigms centered around modulating these pathways, as well as attenuating the autoantibodies themselves.

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study
Mai 2021
We found that 14% (27 ?074 of 193 ?113) of individuals with SARS-CoV-2 infection developed a new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than the 2020 comparator group. An increased and sustained risk for clinical sequelae was seen during the four months after the acute illness, particularly, but not exclusively, in individuals with pre-existing conditions or admitted to hospital for covid-19. More follow-up is needed to determine resolution of risk over time. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study
Mai 2021
We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients. The on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalised patients was observed at four and seven months post-infection and summarised as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19.

Long-term symptoms after SARS-CoV-2 infection in school children: population-based cohort with 6-months follow-up
Mai 2021 (vorläufig)
Overall, 1355 of 2503 children with a serology result in October/November 2020 and follow up questionnaire in March/April 2021 were included. Among seropositive and seronegative 6-to 16-year-old children and adolescents, 9% versus 10% reported at least one symptom beyond 4 weeks, and 4% versus 2% at least one symptom beyond 12 weeks. None of the seropositive children reported hospitalization after October 2020. Seropositive children, all with a history of pauci-symptomatic SARS-CoV-2 infection, did not report long COVID more frequently than seronegative children. This study suggests a very low prevalence of long COVID in a randomly selected population-based cohort of children followed over 6 months after serological testing.

COVID-19 – A Redox Disease: What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About its Treatment
Mai 2021
Host/viral glycan interactions underpin SARS-CoV-2’s extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-driven ’oxidative storm’ alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic and immune dysfunction, and coagulopathy. ‘Redox phenotyping’ of patients to characterise whole-body RSI status as the disease progresses may inform new therapeutic approaches to regain redox balance, reduce mortality in COVID-19 and other redox diseases, and provide opportunities to tackle Long-COVID.

Evolution of COVID-19 symptoms during the first 9 months after illness onset
Mai 2021 (vorläufig)
Fatigue was the most commonly reported symptom both during the acute phase and at 12 weeks from illness onset, including among individuals with mild or moderate disease. Previous analyses have estimated that the societal impact of fatigue can be significant, due to both direct healthcare costs and indirect financial losses resulting from reduced economic productivity. As those with mild COVID-19 represent the majority of COVID-19 cases worldwide in terms of absolute numbers, developing strategies to prevent, diagnose and manage post-COVID fatigue should be an urgent research priority. Among participants with moderate and severe/critical disease, dyspnoea and myalgia additionally persisted beyond 12 weeks in a large proportion of participants.

Long Term Disruption of Cytokine Signalling Networks are Evident Following SARS-CoV-2 Infection
Mai 2021 (vorläufig)
Our data suggests that there are long term immunological consequences following SARS-CoV-2 infection, at least in those that had acute symptoms severe enough to require hospitalisation. While the relatively low number of patients included in our study at this stage does not allow us to perform subgroup analysis, it is possible that these immune mediators may associate with clinically meaningful disease variables and ultimately may be of therapeutic value, if findings are replicated in future studies.

Post COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at the Mayo Clinic and Characteristics of the Initial Patient Cohort
Mai 2021
This study describes the multidisciplinary COVID-19 Activity Rehabilitation Program (CARP), established at Mayo Clinic to evaluate and treat post-COVID-19 syndrome (PCS) patients, and reports the clinical characteristics of the first 100 patients receiving evaluation and management during the timeframe of June 1, 2020 and December 31, 2020. Only 1 in 3 patients had returned to unrestricted work duty at the time of the analysis. For most patients, laboratory and imaging studies were normal or non-diagnostic despite debilitating symptoms. Most patients required physical therapy, occupational therapy, or brain rehabilitation. Face-to-face and virtual care delivery modalities were feasible.

Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19—A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium
Mai 2021
In this cohort study of 3744 patients in 2 large consortia, neurological manifestations were found in approximately 80% of patients hospitalized with COVID-19; the most common self-reported symptoms included headache (37%) and anosmia or ageusia (26%), whereas the most common neurological signs and/or syndromes were acute encephalopathy (49%), coma (17%), and stroke (6%). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death.

Immune profile of children with post-acute sequelae of SARS-CoV-2 infection (Long Covid)
Mai 2021 (vorläufig)
There is increasing reporting by patients organization and researchers of long covid (or post-acute sequelae of SARS-CoV-2 – PASC), characterized by symptoms such as fatigue, dyspnea, chest pain, cognitive and sleeping disturbances, arthralgia and decline in quality of life. In this study, we documented significant immunologic differences between children that completely recovered from acute infection and those with PASC, providing the first objective laboratory sign of the existence of PASC in children.

Persistent COVID-19 symptoms are highly prevalent 6 months after hospitalization: results from a large prospective cohort
Mai 2021
Here we show that 60% of individuals admitted to hospital for COVID-19 still complain of one or more symptom 6 months after admission. A fourth of the participants had three or more persistent symptoms at M6. In addition, our data suggest that symptoms still present at M3 are lingering up to M6, and there is little improvement at M6 when compared with M3. These symptoms had disabling consequences since a third of those who had a professional occupation were not back to work at M6.

A model framework for projecting the prevalence and impact of Long-COVID in the UK
Mai 2021 (vorläufig)
Assuming a 60% final attack rate for SARS-CoV-2 infection in the population, we modelled 299,719 QALYs lost within 1 year of infection (90% due to symptomatic COVID-19 and 10% permanent injury) and 557,754 QALYs lost within 10 years of infection (49% due to symptomatic COVID-19 and 51% due to permanent injury). The UK Government willingness-to-pay to avoid these QALY losses would be £17.9 billion and £32.2 billion, respectively. Additionally, 90,143 people were subject to permanent injury from COVID-19 (0.14% of the population).

Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study
Mai 2021
In conclusion, the absolute risk of delayed acute complications, new onset of chronic disease, and hospital encounters for persisting symptoms 2 weeks to 6 months after SARS-CoV-2 infection not requiring hospital admission is low. However, among those not admitted to hospital, SARS-CoV-2-positive individuals are at a slightly increased risk of venous thromboembolism, receiving a hospital diagnosis of dyspnoea, initiating bronchodilator therapy, and initiating triptans compared with individuals who tested negative for SARS-CoV-2. Moreover, SARS-CoV-2-positive individuals visited their general practitioner and outpatient hospital clinics more often after the primary infection than those who tested negative, which could indicate persistent symptoms that do not lead to specific drug treatment or hospital admission.

Post-acute conditions of patients with COVID-19 not requiring hospital admission
Mai 2021
Most SARS-CoV-2 infections will remain asymptomatic and mild for the foreseeable future, so understanding the long-term consequences of COVID-19 in these populations is crucial to the natural history of the emerging disease. Despite the limitations of this type of cohort study, the results of Lund and colleagues provide evidence of the increased risk of lasting sequelae for a population that should not be ignored—patients with COVID-19 who are not admitted to hospital. In the future, follow-up clinics are needed to establish longer-term outcomes in this population and explore strategies to prevent and mitigate sequelae of COVID-19.

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY
Mai 2021 (vorläufig)
Long COVID is a term to describe new or persistent symptoms at least four weeks after onset of acute COVID-19. Clinical codes to describe this phenomenon were released in November 2020 in the UK, but it is not known how these codes have been used in practice. Working on behalf of NHS England, we used OpenSAFELY data encompassing 96% of the English population. We measured the proportion of people with a recorded code for long COVID, overall and by demographic factors, electronic health record software system, and week. We also measured variation in recording amongst practices. Long COVID coding in primary care is low compared with early reports of long COVID prevalence. This may reflect under-coding, sub-optimal communication of clinical terms, under-diagnosis, a true low prevalence of long COVID diagnosed by clinicians, or a combination of factors. We recommend increased awareness of diagnostic codes, to facilitate research and planning of services; and surveys of clinicians’ experiences, to complement ongoing patient surveys.

COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Mai 2021
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.

Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers
Mai 2021
As the numbers of acute severe acute respiratory syndrome coronavirus 2 infections continue to rise, we are learning that symptoms do not resolve quickly in all patients. Although why some patients experience persistent symptoms is not clear, these individuals suffer. Long-hauler is the term that is associated with these persistent symptoms, and this review of the literature provides information to nurse practitioners working in primary care about symptoms, risk factors, and resources for disease management.

3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study
Mai 2021
In most patients who recovered from severe COVID-19, dyspnoea scores and exercise capacity improved over time; however, in a subgroup of patients at 12 months we found evidence of persistent physiological and radiographic change. A unified pathway for the respiratory follow-up of patients with COVID-19 is required.

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity
Mai 2021
Although acute respiratory manifestations are the most common feature of severe COVID-19, many non-respiratory effects have been reported in the acute phase of the disease, and emerging evidence points to various long-lasting complications after SARS-CoV-2 infection (the post-COVID syndrome or long COVID). Such a complex clinical picture suggests that SARS-CoV-2 generates a dysregulated host response to infection, including wide-ranging immuno-inflammatory derangements. Understanding of the pathophysiology and phenotypes of COVID-19, including the host response to SARS-CoV-2, will be key to developing personalised management strategies for patients. We discuss the potential role of a distinctive endotheliopathy-centred pathophysiology in the respiratory and non-respiratory manifestations of COVID-19, and consider features of the host response to SARS-CoV-2 at the humoral and cellular levels. A complex array of immuno-inflammatory mechanisms underlies the range of phenotypes in COVID-19, but many uncertainties remain.

Post-COVID-19 Syndrome: The Persistent Symptoms at the Post-viral Stage of the Disease. A Systematic Review of the Current Data
Mai 2021
We found that 20.70% of reports on long-term COVID-19 symptoms were on abnormal lung functions, 24.13% on neurologic complaints and olfactory dysfunctions, and 55.17% on specific widespread symptoms, mainly chronic fatigue, and pain. Despite the relatively high heterogeneity of the reviewed studies, our findings highlighted that a noteworthy proportion of patients who have suffered from SARS-CoV-2 infection present a “post-COVID syndrome.” The multifaceted understanding of all aspects of the COVID-19 pandemic, including these long-term symptoms, will allow us to respond to all the global health challenges, thus paving the way to a stronger public health.

Persistent neuropsychiatric symptoms after COVID-19: a systematic review and meta-analysis
Mai 2021 (vorläufig)
The literature on longer-term consequences is still maturing, but indicates a particularly high frequency of insomnia, fatigue, cognitive impairment, and anxiety disorders in the first six months after infection. Persistent neuropsychiatric symptoms are common and appear to be limited neither to the post-acute phase, nor to recovery only from severe COVID-19. Our results imply that health services should plan for high rates of requirement for multidisciplinary services (including neurological, neuropsychiatric and psychological management) as populations recover from the COVID-19 pandemic.

COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters
Mai 2021
We report evidence that the olfactory neuroepithelium may be a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.

Functional Decline in Hospitalized Patients with COVID-19 in the Early Months of the Pandemic
April 2021
Three hundred eleven potential cases were reviewed. The final number of cases included in analysis was N=288, ranging in age from 20-95?years old (mean 66.80±15.31?years). Nearly twenty percent of COVID-19 survivors discharged to a location other than their home. Forty-five percent of survivors experienced functional decline impacting their discharge. Eighty-seven (80.6%) of survivors who showed functional change during hospitalization were referred for additional therapy at discharge. At least 73 (67.6%) of these patients required DME at discharge (in 12 cases this was not clearly documented). Twenty-nine (26.7%) of the survivors who showed functional changes had ongoing dysphagia at the time of hospital discharge. Ninety-seven of the survivors (40.6%) were never assessed by a PM&R physician, physical therapist, occupational therapist, or speech language pathologist during their hospitalization.

Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19
April 2021
ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities.

Single-cell analyses reveal SARS-CoV-2 interference with intrinsic immune response in the human gut
April 2021
In conclusion, in this work we identified a subset of immature enterocytes as the primary site of infection of SARS-CoV-2 in ileum- and colon-derived human intestinal epithelial cells. We could show that upon infection, infected cells mount a strong pro-inflammatory response characterized by a strong activation of the NF?B/TNF pathways while bystander cells mount an IFN-mediated response. This differential response between infected and bystander cells is due to an active block of IFN signaling in infected cells. Although our work was performed in primary non-transformed human intestinal epithelial, it will be important to validate our findings (SARS-CoV-2 tropism, down regulation of ACE2, and inhibition of IFN response) in a tissue from infected patients as the physiological gut environment may modify host/pathogen interactions globally and/or in a cell type-specific manner. Interestingly, recent work performing scRNAseq of SARS-CoV-2 infected HBECs revealed that infected cells were readily responding to secreted interferon and produced large amounts of ISGs. This suggests that there are cell type-specific or tissue-specific regulations of interferon-mediated signaling during SARS-CoV-2 infection. This needs to be considered when studying replication and pathogenesis of SARS-CoV-2 in different organs as well as when developing therapies against COVID-19.

An autoantigen profile of human A549 lung cells reveals viral and host etiologic molecular attributes of autoimmunity in COVID-19
April 2021
Overall, our study demonstrates that SARS-CoV-2 causes extensive alterations of host cellular proteins and produces a large number of potential autoAgs, indicating that there may be an intimate relationship between COVID infection and autoimmunity. Our data provide a deep and comprehensive atlas of autoantigens related to COVID and provide a powerful resource for ongoing studies into the pathophysiology and mechanisms of long-term autoimmune sequelae after acute COVID.

P058 Persistence of neutrophil abnormalities in COVID-19 convalescence
April 2021 
Circulating neutrophils in acute COVID-19 have an altered phenotype and comprise immature and activated cells. This altered phenotype persisted in convalescence and may contribute to the persistence of symptoms and an increased susceptibility to subsequent infections. Future work will aim to investigate the functional implications of these findings.

Systemic and organ-specific immune-related manifestations of COVID-19
April 2021
Immune-related manifestations are increasingly recognized in patients with COVID-19, with a protean clinical presentation affecting a wide range of organ systems in both children and adults. The body of evidence consists predominantly of case series and uncontrolled studies that had reported ~3,000 cases worldwide as of August 2020, including more than 70 different systemic and organ-specific disorders.

Risk factors for long covid in previously hospitalised children using the ISARIC Global follow-up protocol: A prospective cohort study
April 2021 (vorläufig)
A quarter of children experienced persistent symptoms months after hospitalization with acute covid-19 infection, with almost one in ten experiencing multi-system involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up. Our findings highlight the need for replication and further investigation of potential mechanisms as well as clinical support to improve long term outcomes in children.

Long COVID In Adults at 12 Months After Mild-to-Moderate SARS-CoV-2 Infection
April 2021 (vorläufig)
304/354 patients completing the survey at baseline also completed the follow-up interview (85.9%; median [range] age, 47 [18-76] years; 185 [60.9%] women). Persistence of at least one symptom at 12-months follow-up was reported by 161 patients (53.0%). The most commonly reported symptom of long COVID was felt tired (n=83, 27.3%), followed by smell or taste impairment (n=67, 22.0%), shortness of breath (n=39, 12.8%) and muscle pain (n=28, 9.2%). Being females (OR=1.64; 95% CI: 1.00-2.70), aged between 40-54 (OR=1.92; 95% CI: 1.07-3.44), having a BMI ?25 (OR=1.67; 95% CI: 1.00-2.78), and experiencing more symptoms during the acute phase of the disease (OR=8.71 for ?8 symptoms; 95% CI: 2.73-27.76) were associated with long COVID. Persistence of symptoms showed a significant impact on quality of life (p<0.0001) and depression scale scores (p=0.0102). More than half of patients with previous mild-to-moderate symptomatic COVID-19 complained the persistence of at least one symptom 12-months after the onset of the illness.

High-dimensional characterization of post-acute sequalae of COVID-19
April 2021 (vorläufig)
We show that beyond the first 30 days of illness, people with COVID-19 exhibit higher risk of death and health resource utilization. Our high dimensional approach identifies incident sequalae in the respiratory system and several others including nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, and anemia.

COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review
April 2021
Although the symptom patterns seen in post-acute COVID-19 are similar to those seen in ME/CFS, further investigation with longer periods of follow-up and clearly defined diagnostic criteria will be required to establish COVID-19 as an infectious trigger for ME/CFS.

Long Covid-19: Proposed Primary Care Clinical Guidelines for Diagnosis and Disease Management
April 2021
The main long-term manifestations observed in other coronaviruses (Severe Acute Respiratory Syndrome (SARS), Middle East respiratory syndrome (MERS)) are very similar to and have clear clinical parallels with SARS-CoV-2: mainly respiratory, musculoskeletal, and neuropsychiatric. Patients with long COVID-19 should be managed using structured primary care visits based on the time from diagnosis of SARS-CoV-2 infection. Based on the current limited evidence, disease management of long COVID-19 signs and symptoms will require a holistic, longitudinal follow up in primary care, multidisciplinary rehabilitation services, and the empowerment of affected patient groups.

A conceptual framework to accelerate the clinical impact of evolving research into long COVID
April 2021
To facilitate an improved understanding and synthesis of research findings across studies and accelerate progress towards clear case definitions, we propose a conceptual framework that delineates the long-term sequelae of COVID-19 into three distinct categories. The categories are: persistent symptoms with causal pathological correlates; persistent symptoms without pathophysiological correlates and the causative pathology is unknown; and organ pathology without associated symptoms or clinical consequence.

Long COVID: an estrogen-associated autoimmune disease?
April 2021
In general, women appear to be twice as likely to develop Long COVID as men, but only until around age 60, when the risk level becomes similar. In addition to being a woman, older age and a higher body mass index also seem to be risk factors for having Long COVID

Post-COVID-19 syndrome in outpatients: a cohort study
April 2021 (vorläufig)
Four surveyed symptoms were independently associated with COVID-19: fatigue, smell/taste disorder, dyspnea and memory impairment. Among COVID-positive, female gender and overweight/obesity were predictors of persisting symptoms.More than half of COVID-positive outpatients report persisting symptoms up to 10 months after infection and 21% seek medical care for this reason. These data suggest that post-COVID syndrome places a significant burden on society and especially healthcare systems.

Long COVID’s long R&D agenda
April 2021
Long COVID manifests in various ways, affecting the heart, the lungs, the gastrointestinal system, the brain, mental health and more. The most common reported issues are breathlessness, fatigue, smell and taste disturbance, and anxiety, found a living systematic review of studies of the condition in hospitalized and non-hospitalized patients. For some individuals, these issues can be debilitating. But as yet there is still limited insight into the true scope and scale of this post-viral problem. The underlying biology, too, is unclear.

Patient-Led Research Collaborative: embedding patients in the Long COVID narrative
April 2021
A large subset of patients with coronavirus disease 2019 (COVID-19) are experiencing symptoms well beyond the claimed 2-week recovery period for mild cases. These long-term sequelae have come to be known as Long COVID. Originating out of a dedicated online support group, a team of patients formed the Patient-Led Research Collaborative and conducted the first research on Long COVID experience and symptoms. This article discusses the history and value of patient-centric and patient-led research; the formation of Patient-Led Research Collaborative as well as key findings to date; and calls for the following: the acknowledgement of Long COVID as an illness, an accurate estimate of the prevalence of Long COVID, publicly available basic symptom management, care, and research to not be limited to those with positive polymerase chain reaction and antibody tests, and aggressive research and investigation into the pathophysiology of symptoms.

Long COVID: An overview
April 2021
Fatigue, cough, chest tightness, breathlessness, palpitations, myalgia and difficulty to focus are symptoms reported in long COVID. It could be related to organ damage, post viral syndrome, post-critical care syndrome and others. Clinical evaluation should focus on identifying the pathophysiology, followed by appropriate remedial measures. In people with symptoms suggestive of long COVID but without known history of previous SARS-CoV-2 infection, serology may help confirm the diagnosis.

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms
April 2021
Our results indicated that all 29 investigated symptomatic post-COVID-19 patients developed fAABs directed against different GPCRs, known to be able to disturb the balance of neuronal and vascular processes. Most of these patients developed an antibody pattern consisting of ?2fAABs, M2fAABs, AT1-fAABs, and MAS-fAABs. These agonistic fAABs activate their corresponding receptors like classical agonists. The observed specific GPCR-fAAB pattern has been observed before in several neurological and cardiac disorders and might also support the development of neurological and/or cardiovascular symptoms after COVID-19 recovery. These results provide valuable clues that are worth pursuing and investigating further.

6-month neurological and psychiatric outcomes in 236 ?379 survivors of COVID-19: a retrospective cohort study using electronic health records
April 2021
Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities. Complementary study designs, including prospective cohorts, are needed to corroborate and explain these findings.

Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK
April 2021
Self-reported long COVID symptoms were adversely affecting the day-to-day activities of 674,000 people in private households in the UK, with 196,000 of these individuals reporting that their ability to undertake their day-to-day activities had been limited a lot. Of people with self-reported long COVID, 697,000 first had (or suspected they had) COVID-19 at least 12 weeks previously, and 70,000 first had (or suspected they had) COVID-19 at least one year previously. Among a sample of over 20,000 study participants who tested positive for COVID-19 between 26 April 2020 and 6 March 2021, 13.7% continued to experience symptoms for at least 12 weeks.

Refining “long-COVID” by a prospective multimodal evaluation of patients with long-term symptoms related to SARS-CoV-2 infection
April 2021 (vorläufig)
In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation including clinical, psychological, virological, specific immunological assays and were followed longitudinally. Half of patients seeking medical help for long-COVID lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity did not cluster clinically or biologically long haulers, who reported severe fatigue, altered quality of life, and exhibited psychological distress.

Post-COVID-19 syndrome among symptomatic COVID-19 patients: A prospective cohort study in a tertiary care center of Bangladesh
April 2021
Among the 400 recruited patients, 355 patients were analyzed. In total, 46% patients developed post-COVID-19 symptoms, with post-viral fatigue being the most prevalent symptom in 70% cases. Female sex, respiratory distress, lethargy, and long disease duration are critical risk factors for the development of post-COVID-19 syndrome.

Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses
April 2021
Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain—a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain.

An Autoantigen-ome from HS-Sultan B-Lymphoblasts Offers a Molecular Map for Investigating Autoimmune Sequelae of COVID-19
April 2021 (vorläufig)
In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design.

Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers
April 2021
The results of this study showed that a considerable portion of low-risk individuals with mild COVID-19 reported a diversity of long-term symptoms, and that these symptoms disrupted work, social, and home life. Limitations of the study include the possibility of recall bias and the subjective rating of symptoms. Further research is needed to understand the mechanisms underlying COVID-19–related long-term sequelae.

COVID-19 and the human innate immune system
April 2021
More evidence accumulates suggesting that a yet unknown fraction of patients will suffer from what is described as Long COVID-19, a chronic illness with very heterogeneous symptoms. These include chronic fatigue syndrome and a spectrum of psychiatric disorders ranging from cognitive decline, depression, to even neurodegeneration. A better description of the heterogeneity of Long COVID-19 and the underlying molecular mechanisms need to be established to provide therapeutic options for these patients. It will be interesting to see how the immune deviations seen in acute COVID-19 extend or further develop in these patients. It will be important to generate large enough registries of individuals suffering from Long COVID-19 to address the mechanisms involved in this heterogeneous syndrome.

SARS-CoV-2 binding to ACE2 triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction
April (vorläufig)
The reduction of blood flow produced by pericyte-mediated capillary constriction, together with any upregulation of vWF that may occur, will tend to promote clotting in the microvasculature. SARS-CoV-2 infection is associated with thrombus formation in large vessels that can be imaged, but it seems possible that thrombi of microvascular origin may add to this, and could perhaps even seed these larger clots. Together, capillary constriction and thrombus formation will reduce the energy supply to the brain and other organs, initiating deleterious changes that probably contribute to the long duration symptoms of “long Covid”. Indeed, the decrease of cerebral blood flow occurring during SARS-CoV-2 infection outlasts the acute symptoms.Our data suggest an obvious therapeutic approach, i.e. that the reduction of cerebral and renal blood flow that is observed in SARS-CoV-2 infection might be blockable using an AT1 receptor blocker such as losartan. Interestingly, two clinical trials (clinicaltrials.gov/ct2/show/NCT04312009 and clinicaltrials.gov/ct2/show/NCT04311177) of the possible beneficial effects of losartan in SARS-CoV-2 infection are now under way.


SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2
März 2021
Although the use of a noninfectious pseudovirus is a limitation to this study, our data reveals that S protein alone can damage endothelium, manifested by impaired mitochondrial function and eNOS activity but increased glycolysis. It appears that S protein in ECs increases redox stress which may lead to AMPK deactivation, MDM2 upregulation, and ultimately ACE2 destabilization. Although these findings need to be confirmed with the SARS-CoV-2 virus in the future study, it seems paradoxical that ACE2 reduction by S protein would decrease the virus infectivity, thereby protecting endothelium. However, a dysregulated renin-angiotensin system due to ACE2 reduction may exacerbate endothelial dysfunction, leading to endotheliitis. Collectively, our results suggest that the S protein-exerted EC damage overrides the decreased virus infectivity.

Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT
März 2021
The most commonly reported pre-existing conditions were seasonal allergies (42%), asthma (16%) and hypertension (15%). The overall mean self-reported severity rating of their COVID-19 illness was 4.6 out of 10. Individuals with PASC were more likely to have less education, at least one pre-existing chronic condition, seasonal allergies, and greater self-reported severity as compared to participants not experiencing PASC. Females were more likely to experience PASC than males (73 versus 63%), however this did not reach the threshold of statistical significance (p=0.07).

Alterations in T and B cell function persist in convalescent COVID-19 patients
März 2021
Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with one subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalisation with COVID-19 could impact longer term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients.

Early experiences of rehabilitation for patients post-COVID to improve fatigue, breathlessness exercise capacity and cognition
März 2021 (vorläufig)
Patients with lasting symptoms of COVID-19 should be offered a comprehensive recovery programme. Patients that completed a six week, twice supervised adapted pulmonary rehabilitation programme demonstrated statistically significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition. Participants improved by 112m on the Incremental Shuttle Walking Test and 544 seconds on the Endurance Shuttle Walking Test. There were no serious adverse events recorded, and there were no dropouts related to symptom worsening. COVID-19 rehabilitation appears feasible and significantly improves clinical outcomes.

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol
März 2021 (vorläufig)
Long-term symptoms following hospitalisation for COVID-19 are very common and have significant impacts on quality of life. Women under 50 were most likely to have the worst outcomes. Policy makers need to ensure there is long-term support for people experiencing long-Covid and should plan for lasting long-term population morbidity. Funding for research to understand mechanisms underlying long-Covid and identify potential interventions for testing in randomised trials is urgently required.

Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study 
März 2021
In individuals at low risk of COVID-19 mortality with ongoing symptoms, 70% have impairment in one or more organs 4? months after initial COVID-19 symptoms, with implications for healthcare and public health, which have assumed low risk in young people with no comorbidities. Our findings have three research implications. First, as countries face second waves, COVID-19 impact models should include PCS (post-COVID-19 syndrome), whether quality of life, healthcare utilisation or economic effects. Second, there is urgent need for multiorgan assessment, including blood and imaging, as well as primary and secondary care data linkage, to define PCS. Third, longitudinal studies of clustering of symptoms and organ impairment will inform health services research to plan multidisciplinary care pathways.

Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation
März 2021
Immune cell-mediated endothelial injury has been observed in other viral infections, including Ebola, human cytomegalovirus infection, and malaria, where T cells recruited to infected site by inflammation could induce apoptosis of infected endothelial cells, causing vascular leakage. It is also possible that some endothelial cells affected by SARS-CoV-2 infection had elicited pattern recognition receptors such as toll-like receptors, activating interferon pathway and inflammatory cytokine production that persist to convalescent phase. Endothelial instability may be a key mechanism underpinning the development of post-infection vascular complications. Clinical trials in preventive therapy for vascular complications may be needed.

Cardiac performance in patients hospitalized with COVID-19: a 6 month follow-up study
März 2021
Our results provide important insights into the post-COVID-19 cardiovascular consequences. Different studies have reported myocardial injury during the acute COVID-19 phase and our data shown here reveals that patients are likely to display left ventricular diastolic dysfunction 6 months later. Follow-up studies will be needed to understand if this pattern of cardiac diastolic dysfunction reflects a chronic pathological remodelling which ultimately leads to heart failure, or if whether a progressive recovery after the initial damage to the heart likely occurs. We note that recent studies suggest a direct cardiomyocyte tropism for SARS-CoV-2 with consequent myocarditis and the development of myocardial fibrosis. SARS-CoV-2 can also infect endothelial cell and induce endothelial dysfunction.

Long-COVID postural tachycardia syndrome: an American Autonomic Society statement
März 2021
Commonly described symptoms of Long-COVID include some combination of breathlessness, palpitation, chest discomfort, fatigue, pain, cognitive impairment (“brain fog”), sleep disturbance, orthostatic intolerance, peripheral neuropathy symptoms (pins and needles, and numbness), abdominal discomfort, nausea, diarrhea, joint and muscle pains, symptoms of anxiety or depression, skin rashes, sore throat, headache, earache and tinnitus. These symptoms, when combined with excessive orthostatic tachycardia, can lead to a diagnosis of postural tachycardia syndrome (POTS) post-COVID-19. Addressing the patient needs of Long-COVID, and especially Long-COVID POTS, will take a significant investment of resources and funding, both for clinical care and research. It is imperative to act during this window of opportunity in hopes of reducing or shortening the burden of symptoms for these patients.

‘Long COVID’: persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria
März 2021
A total of 274 patients were enrolled in the study. A majority were within the age group >?35 to ?49?years (38.3%), and male (66.1%). More than one-third (40.9%) had persistent COVID-19 symptoms after discharge, and 19.7% had more than three persistent COVID-like symptoms. The most persistent COVID-like symptoms experienced were easy fatigability (12.8%), headaches (12.8%), and chest pain (9.8%). Symptomatic COVID-19 disease with moderate severity compared to mild severity was a predictor of persistent COVID-like symptoms after discharge.

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information
März 2021(vorläufig)
In the present study, we investigate the definitions used in the literature published to date and compare them against data available from electronic health records and patient-reported information collected via surveys. Long COVID holds the potential to produce a second public health crisis on the heels of the pandemic itself. Proactive efforts to identify the characteristics of this heterogeneous condition are imperative for a rigorous scientific effort to investigate and mitigate this threat.

Research priorities for Long Covid: refined through an international multi-stakeholder forum
März 2021
Research on Long Covid will require a multi-disciplinary and globally coordinated approach that supports harmonised and large-scale case-control and interventional studies that have the power to provide quality evidence to inform policy and patient care across the full range of populations and countries affected. Governments of the world need to ensure the strengthening of health systems to be able to provide treatment, support and rehabilitation to improve long-term COVID-19 outcomes. To prevent Long Covid becoming the pandemic of 2021, controlling the high rates of infection has to remain a global priority.

Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study
März 2021
Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14?060 of 47?780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.

Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience
März 2021
POTS affects primarily women (?80%) and is manifested by orthostatic tachycardia, in association with various symptoms including palpitations, dizziness, headache, fatigue, and blurred vision. The syndrome can be precipitated by viral illness or severe infection in 30% to 50% of all patients. The mechanism of POTS is generally undetermined. Similarly, the mechanism of post–COVID-19 POTS remains unknown, although a chronic inflammatory or autoimmune response may be at play. Whereas few reports have been published, the number of patients affected by long-haul post–COVID-19 will likely grow. Much remains unknown about the specific mechanisms responsible for the POTS-like symptoms in post–COVID-19 patients or how long these symptoms will last but chronic symptoms are expected in a subset of patients based on this initial clinical experience.

Post-acute COVID-19 syndrome
März 2021
Given the global scale of this pandemic, it is apparent that the healthcare needs for patients with sequelae of COVID-19 will continue to increase for the foreseeable future. Rising to this challenge will require harnessing of existing outpatient infrastructure, the development of scalable healthcare models and integration across disciplines for improved mental and physical health of survivors of COVID-19 in the long term.

Characteristics of Long Covid: findings from a social media survey
März 2021 (vorläufig)
We analysed data from 2550 participants with a median duration of illness of 7.7 months. 89.5% described their health as good, very good or excellent before COVID-19. The most common initial symptoms that persisted were exhaustion, chest pressure/tightness, shortness of breath and headache. Cough, fever, and chills were common initial symptoms that became less prevalent later in the illness, whereas cognitive dysfunction and palpitations became more prevalent later in the illness.

Living with Covid19 – Second review
März 2021
Long Covid is a broad term and can be a multi-system condition. People need investigation and, where indicated, specific clinical interventions. Some will require full rehabilitation programmes, and others may benefit from psychological services. Others will need long-term support in the community, including help with self-management strategies. The impact of Long Covid on vulnerable communities and pre-existing conditions has not been researched, and the long-term needs of these groups is unclear.

Physical, cognitive and mental health impacts of COVID-19 following hospitalisation: a multi-centre prospective cohort study
März 2021 (vorläufig)
We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.

Health-related quality of life, functional decline, and long-term mortality in older patients following hospitalisation due to COVID-19
März 2021
More than half of the patients reported a negative change in HR-QoL 6 months following hospitalisation due to COVID-19, and one out of three experienced a persistently impaired mobility and ability to carry out activities of daily living. The results suggest awareness of long-term functional decline in older COVID-19 patients.

Persistent neurologic symptoms and cognitive dysfunction in non?hospitalized Covid?19 “long haulers”
März 2021
Non?hospitalized Covid?19 “long haulers” experience prominent and persistent “brain fog” and fatigue that affect their cognition and quality of life. The constellation of “long hauler” symptoms, particularly fatigue and a sense of cognitive dysfunction, present in our “long hauler” patients resemble the prominent fatigue and cognitive complaints seen in those after mild traumatic brain injury, and in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Attributes and predictors of long COVID
März 2021
We found that early disease features were predictive of duration. With only three features—the number of symptoms in the first week, age and sex—we built a model designed to separate short (<10?d) and long (?28?d) duration of COVID-19.

COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic
März 2021 (vorläufig)
Data are emerging to suggest that infection with SARS-CoV-2 may lead to prolonged and persistent symptoms. These long-term consequences of becoming a long-hauler are unclear, and further research is urgently needed to corroborate our findings. 

A pilot study of burnout and long covid in senior specialist doctors
März 2021
A total of 114 responses were received. Nearly two-thirds reported that Covid-19 has had an adverse effect on their mental health. One-quarter reported that they or colleagues had experience of ‘long-covid’ secondary to the virus. More comprehensive evaluation of the effect of the pandemic on front-line staff is needed to identify the extent of the problem and the factors which contribute to it. 

Are vaccines safe in patients with Long COVID? A prospective observational study
März 2021 (vorläufig)
Receipt of vaccination with either an mRNA or adenoviral vector vaccine was not associated with a worsening of Long Covid symptoms, quality of life, or mental wellbeing. Individuals with prolonged COVID-19 symptoms should receive vaccinations as suggested by national guidance.

Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID
März 2021 (vorläufig)
Of 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2-months and 6-months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct=38) and 3% (median Ct=36) patients at 2-months and 6-months, respectively, but no reinfections were demonstrated. Late clinical events and persistent symptoms in the medium and long term occurred in a significant proportion of patients hospitalized for COVID-19. Gender, severity of illness and weaker antibody responses, but not viral shedding, were associated with long-COVID.

Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19
März 2021 (vorläufig)
We have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.

Clinical Characteristics, Activity Levels and Mental Health Problems in Children with Long COVID: A Survey of 510 Children
März 2021 (vorläufig)
Our study provides further evidence on Long COVID in children. Symptoms like fatigue, headache, muscle and joint pain, rashes and heart palpitations, and mental health issues like lack of concentration and short memory problems, were particularly frequent and confirm previous observations, suggesting that they may characterize this condition. A better comprehension of Long COVID is urgently needed.

Häufigkeit von Long COVID im Kanton Zürich: Implikationen für die Versorgungsplanung
März 2021
Unsere Ergebnisse zeigen, dass ein relevanter Anteil von Personen nach einer SARS-CoV-2-Infektion an längerfristigen Folgen leidet. Unsere Ergebnisse deuten darauf hin, dass eine breite Palette von Versorgungsangeboten und integrative Ansätze erforderlich sein wird, um die Genesung dieser Personen zu unterstützen. Neben Maßnahmen zur Eindämmung der Ausbreitung von SARS-CoV-2 wird die frühzeitige Planung von Ressourcen und bedarfsgerechten Angebote für die an Long COVID Erkrankten entscheidend sein für eine Reduktion der Krankheitslast durch Long COVID.

An Autoantigen Profile of Human A549 Lung Cells Reveals Viral and Host Etiologic Molecular Attributes of Autoimmunity in COVID-19
Februar 2021 (vorläufig)
Comparison with current COVID data identified 291 proteins that are altered at protein or transcript level in SARS-CoV-2 infection, with 191 being known autoantigens. These known and putative autoantigens are significantly associated with viral replication and trafficking processes, including gene expression, ribonucleoprotein biogenesis, mRNA metabolism, translation, vesicle and vesicle-mediated transport, and apoptosis. They are also associated with cytoskeleton, platelet degranulation, IL-12 signaling, and smooth muscle contraction. This study provides a large list of autoantigens as well as new targets for future investigation, e.g., UBA1, UCHL1, USP7, CDK11A, PRKDC, PLD3, PSAT1, RAB1A, SLC2A1, platelet activating factor acetylhydrolase, and mitochondrial ribosomal proteins. This study illustrates how viral infection can modify host cellular proteins extensively, yield diverse autoantigens, and trigger a myriad of autoimmune sequelae.

Long COVID neuropsychological deficits after severe, moderate or mild infection
Februar 2021 (vorläufig)
Standardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 ± 22.54 days post-discharge following SARS-CoV-2 infection. Deficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed.

Sequelae in Adults at 6 Months After COVID-19 Infection
Februar 2021
In this cohort of individuals with COVID-19 who were followed up for as long as 9 months after illness, approximately 30% reported persistent symptoms. A unique aspect of our cohort is the high proportion of outpatients with mild disease. Persistent symptoms were reported by one-third of outpatients in our study, consistent with a previously reported study, in which 36% of outpatients had not returned to baseline health by 14 to 21 days following infection. However, this has not been previously described 9 months after infection.

Children with long covid
Februar 2021
Children seem to be fairly well-protected from the most severe symptoms of covid-19. According to the European Centre for Disease Prevention and Control, the majority of children don’t develop symptoms when infected with the coronavirus, or their symptoms are very mild. However, it is becoming increasingly apparent that a large number of children with symptomatic and asymptomatic covid-19 are experiencing long-term effects, many months after the initial infection.

COVID-19-related symptoms 6 months after the infection – Update on a prospective cohort study in Germany
Februar 2021 (vorläufig)
Based on this study, the prevalence of COVID-19-related symptoms 6 months after the infection is high. Some bias for overestimation may have affected this result. Nevertheless, ‘long COVID’ requires attention in medical care and a better scientific understanding.

Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany – a first analysis of a prospective observational study
Februar 2021 (vorläufig)
Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.

Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19
Februar 2021
Our results provide an early benchmark for studying the evolution of cognitive difficulties in recovering COVID-19 patients. They also highlight the importance of studying interventions that target attention and executive functioning after COVID-19. Given the prevalence of COVID-19, targeting these deficits through scalable cognitive interventions that have been demonstrated to improve similar deficits and can be widely disseminated in patients’ homes through reliance on technology may support optimal cognitive and functional outcomes.

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis
Febrar 2021
As neurological manifestations appear even in mild cases of COVID-19, the brainstem could be affected in the early disease phase. Since neurons rarely regenerate, the brainstem damage from COVID-19 may be long-lasting. Following this, the respiratory, cardiovascular, gastrointestinal, and neurological functions of the brainstem may get compromised indefinitely. Interestingly, these systems are also suspected to have malfunctioned in long-COVID. Indeed, brainstem dysfunction has also been implicated in other chronic disorders, such as chronic pain and migraine and ME/CFS. Therefore, it can be hypothesized that long-COVID may stem from persistent brainstem dysfunction.

Risk factors for long-term consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study
Februar 2021
6 to 8 months after acute infection episode almost a half of patients experience symptoms lasting since hospital discharge. One in ten individuals experiences MSI. Female sex is the main risk factor for majority of the LS categories. chronic pulmonary disease is associated with a higher risk of chronic fatigue development, and asthma with neurological and mood and behaviour changes. Individuals with LS and MSI should be the main target for future research and intervention strategies.

Assessment and management of post?COVID fatigue
Februar 2021
For most patients post?viral fatigue is a self?limiting condition. The rehabilitation programme’s main aim is to prevent chronicity. In the UK an infrastructure of local and regional ME/CFS rehabilitation teams was established in the early 21st century. These teams should be in the vanguard of the rehabilitation process with support from respiratory, mental health and occupational health clinicians.

Patients With Uncomplicated Coronavirus Disease 2019 (COVID-19) Have Long-Term Persistent Symptoms and Functional Impairment Similar to Patients with Severe COVID-19: A Cautionary Tale During a Global Pandemic 
Februar 2021
At 3–4 month follow-up, the most common persistent symptoms were fatigue, dyspnea and anosmia, consistent with other reports. We also noted significant memory problems (17%) and hair loss (12%) at follow-up. Persistent symptoms 3–4 months after COVID-19 diagnosis was common with similar levels in hospitalized vs. non-hospitalized patients. Functional impairment at long-term follow-up was higher in hospitalized patients but also prevalent in non-hospitalized patients. With burgeoning cases throughout the country, there is concern for significant morbidity due to persistent symptoms and functional impairment even in patients with uncomplicated COVID-19 and efforts to dissect the cause and mitigate the impact are needed.

Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19
Februar 2021
COVID-19 has affected many people throughout the world. In light of public health concerns about the COVID-19 infection’s adverse effects, and according to the available evidence for SARS-COV-1 and H1N1 fatigue-related symptoms, we assessed the prevalence of CFS/ME following COVID-19 infection. This study found that 17.5% of patients experienced various fatigue levels; only 14.2% qualified for CFS criteria. According to the literature, CFS/ME prevalence rates following viral infections were varied by population group, case definitions, and diagnostic techniques.

An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19
Januar 2021
Comparing with available COVID data, 352 proteins of the autoantigenome have thus far been found to be altered at protein or RNA levels in SARS-Cov-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a strong connection between viral infection and autoimmunity. The vast number of COVID-altered proteins with propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients.

18F-FDG brain PET hypometabolism in patients with long COVID
Januar 2021
In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel <?0.001 uncorrected, p-cluster <?0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p?<?0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p?=?0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p?<?0.001).


6-month consequences of COVID-19 in patients discharged from hospital: a cohort study
Januar 2021
At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery.

Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study
Januar 2021
A Post-acute COVID-19 syndrome was detected in a half of COVID19 survivors. Radiological and spirometric changes were mild and observed in less than 25% of patients. No baseline clinical features behaved as independent predictors of Post-acute COVID-19 syndrome development.

Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies
Januar 2021
We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management.

Preliminary Evidence on Long COVID in children
Januar 2021 (vorläufig)
The evidence that COVID-19 can have long-term impacts on children as well, including those with asymptomatic/ paucisymptomatic COVID-19, highlights the need for pediatricians, mental health experts and policy makers of implementing measures to reduce impact of the pandemic on child’s health.

Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?
Januar 2021
We should not forget the importance of studying all people who become infected with SARS-CoV-2, even those with only mild initial illnesses, and to study the recovery period and the long-term health consequences of COVID-19. We need to know how to prevent and treat “long COVID.” What we learn may apply to the prevention and treatment of ME/CFS, as well.

The prevalence of long COVID symptoms and COVID-19 complications
Dezember 2020
Using these estimates (along with the equivalent proportions for durations of 6 to 11 weeks) and the published weekly incidence rates from the COVID-19 Infection Survey, we estimate that during the week commencing 22 November 2020, around 186,000 people in private households in England were living with symptoms that had persisted for between 5 and 12 weeks, with a 95% confidence interval of 153,000 to 221,000.

Long COVID guidelines need to reflect lived experience
Dezember 2020
Guidelines must represent the complexity of long COVID, including the areas where evidence is still emerging. Hasty attempts to rename the condition or compare it to other conditions is a disservice to thousands of people, and could result in missed pathology to the detriment of the patient. Comprehensive long COVID guidelines are essential to prevent an epidemic of long-term, chronic disease as a result of early mismanagement of pathology, and the potential implications of such an epidemic for health systems and economies.

Facing up to long COVID
Dezember 2021
Although vaccination has become the immediate focus of the pandemic response for many countries, patients with long COVID must not be forgotten or sidelined as countries begin to consider the end of the pandemic. Acknowledging the potential scale of the problem now and the complexities and variabilities of the disease course, and pressing for better research and care, could avoid years of struggle and mismanagement for patients with long COVID.

Persistent symptoms after Covid-19: qualitative study of 114 “long Covid” patients and draft quality principles for services
Dezember 2020
Suggested quality principles for a long Covid service include ensuring access to care, reducing burden of illness, taking clinical responsibility and providing continuity of care, multi-disciplinary rehabilitation, evidence-based investigation and management, and further development of the knowledge base and clinical services.

Long COVID: where do we start with the case definitions?
Dezember 2020 (vorläufig)
Long COVID is the condition whereby individuals do not recover for several weeks or months following the onset of COVID19 symptoms. The range of reported symptoms is very wide. There are no agreed case definitions for Long COVID leading to variation in clinical diagnosis, especially if individuals were not tested when initially infected. We propose criteria to establish a retrospective diagnosis of ‘Past Acute COVID’.

Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection
November 2020
In a similar fashion to previous coronavirus pandemics, COVID-19 appears to result in symptoms of severe fatigue that outlast the initial acute illness. Over half of individuals in the current study demonstrated symptoms consistent with severe fatigue a median of 10 weeks after their initial illness, while almost one-third of those previously employed had not returned to work. Most interestingly, fatigue was not associated with initial disease severity, and there were no detectable differences in pro-inflammatory cytokines or immune cell populations.

Case report and systematic review suggest that children may experience similar long?term effects to adults after clinical COVID?19
November 2020
The five children with potential long COVID had a median age of 12 years (range 9–15) and four were girls. They had symptoms for 6–8 months after their clinical diagnoses of COVID?19. None were hospitalised at diagnosis, but one was later admitted for peri?myocarditis. All five children had fatigue, dyspnoea, heart palpitations or chest pain, and four had headaches, difficulties concentrating, muscle weakness, dizziness and sore throats. Some had improved after 6–8 months, but they all suffered from fatigue and none had fully returned to school.

Long COVID in the Faroe Islands: A Longitudinal Study Among Nonhospitalized Patients
November 2020
Of the 180 participants (96.3% of the 187 eligible COVID-19 patients), 53.1% reported persistence of at least 1 symptom after a mean of 125 days after symptoms onset, 33.0% reported 1 or 2 symptoms, and 20.1% reported 3 or more symptoms. At the last follow-up, 46.9% were asymptomatic compared with 4.4% during the acute phase. The most prevalent persistent symptoms were fatigue, loss of smell and taste, and arthralgias.

Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome
November 2020
Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.

Post-acute COVID-19 syndrome negatively impacts health and wellbeing despite less severe acute infection
November 2020 (vorläufig)
Persistent symptoms following COVID-19 infection are prevalent, debilitating and appear to affect individuals regardless of acute infection severity or prior health status. More detailed research is required in order to identify specific symptom clusters associated with PACS, and to devise effective interventional strategies.

Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations
Oktober 2020
Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App
Oktober 2020 (vorläufig)
A simple model to distinguish between short and long-COVID at 7 days, which gained a ROC-AUC of 76%, was replicated in an independent sample of 2472 antibody positive individuals. This model could be used to identify individuals for clinical trials to reduce long-term symptoms and target education and rehabilitation services.

Living with Covid19
Oktober 2020
People experience a wide range of fluctuating and multisystem symptoms that need to be acknowledged. A common theme is that symptoms arise in one physiological system then abate only for symptoms to arise in a different system. The varying degrees of dependency mean support in the community should be considered alongside hospital one stop clinics. There are significant psychological and social impacts that will have long-term consequences for individuals and for society if not well managed. Health and social care services are not equipped to support people living with Covid19. Staff need better information and education on the ongoing effects.

How and why patients made Long Covid
Oktober 2020
Long Covid challenges common assumptions that were in place in the early pandemic and which often persisted despite patient testimony. In the making of Long Covid, conventional hierarchies of evidence, and normative routes for scientific dissemination were frequently disrupted. A patient-led survey released on a collective’s website; the self-appellation of a community after a trucker hat; a single case study authored by a patient, and taken by others to clinical appointments; the circulation of a hashtag first used by a patient to refine the model of COVID-19 in published articles.

Surveillance is underestimating the burden of the COVID-19 pandemic
September 2020
A universal surveillance case definition of recovery from COVID-19 is still absent. Many people have prolonged symptoms, ill health, and reduced functionality for months, even if they were not hospitalised for SARS-CoV-2 infection. We must move long-haul COVID from anecdote to something that is routinely quantified and monitored, as is currently being done with deaths and positive tests. To make this move, we must count COVID-19 cases beyond positive test statistics. We also need to define recovery, taking into account symptom duration, fluctuation, severity, quality of life, and functionality, and not base this definition solely on testing negative for active SARS-CoV-2 infection or discharge from hospital.

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings
Juli 2020
SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Post-viral fatigue and COVID-19: lessons from past epidemics
Juni 2020
The current article reviews the literature on short- and long-term health consequences of prior epidemics and infections to assess potential health complications that may be associated with post-COVID-19 recovery. Past research on post-epidemic and post-infection recovery has suggested that such complications include the development of severe fatigue. Certain factors, such as the severity of infection, in addition to the ‘cytokine storm’ experienced by many COVID-19 patients, may contribute to the development of later health problems. We suggest that the patterns observed in past epidemics and infections may re-occur in the current COVID-19 pandemic.

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