A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021

ImportanceWhile much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID. ObjectiveTo estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery DesignWe jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study. ResultsAnalyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms. Conclusions and relevanceThe occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021? FindingsGlobally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered. MeaningThe substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. Author SummaryCOVID-19 clinical outcomes vary immensely, but a patients genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isnt clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

COVID-19 shows an unexplained, strong male bias for severity and mortality. Loss of Y (LOY) in myeloid cells is a risk factor candidate in COVID-19 because of associations with many age-related diseases and its effect on transcription of immune genes. We report the highest levels of LOY in cells that are crucial for the development of severe COVID-19 phenotype, such as low-density neutrophils, granulocytes, and monocytes reaching 46%, 32%, and 29%, respectively, from men with critical COVID-19 (n=139). LOY in sorted subpopulations of leukocytes correlated with increased thrombocyte count, thromboembolic events, invasive mechanical ventilation and a history of vessel disease. In recovered patients, LOY decreased in whole blood and peripheral blood mononuclear cells. Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, notably affecting HLA class I and II genes important for antigen presentation. The data support a link between LOY and emergency myelopoiesis as well as the role of LOY in modulation of COVID-19 severity. Our results might also be relevant for other viral infections showing similar male bias.

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive individuals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

Clinical echocardiography does not indicate cardiac dysfunction in critically ill Covid-19 patients

ObjectiveWe aimed to investigate the acute cardiac effects of severe SARS-CoV-2. MethodsThis is an observational study generated from the first 79 patients admitted to Uppsala intensive care due to respiratory failure with SARS-CoV-2 infection. 34 underwent echocardiography of which 25 were included in the study and compared to 44 non-echo patients. Exclusion was based on absence of normofrequent sinus rhythm and mechanical respiratory support. Biomarker analysis was carried out on all patients. ResultsMortality was increased in the echo compared to non-echo group (44 % vs. 16%, p<0.05). Right sided dimensions and functional parameters were not affected. Tricuspid regurgitation velocity indicated how increased pulmonary artery pressure was associated with mortality (survivors (n=5): 2.51 {+/-} 0.01 m/s vs. non-survivors (n=5): 3.06 {+/-} 0.11 m/s, p<0.05). Cardiac markers and D-dimer correlated to initiation of echocardiography (hs-TnI (ng/L): echo (n=23): 133 {+/-} 45 vs. non-echo (n=41): 81.3 {+/-} 45, p<0.01; NTproBNP (ng/L): echo (n=25): 2959 {+/-} 573 vs. non-echo (n=42): 1641 {+/-} 420, p<0.001; D-dimer (mg/L): echo (n=25): 16.1 {+/-} 3.7 vs. non-echo (n=43: 6.1 {+/-} 1.5, p<0.01) and mortality (hs-TnI (ng/L): survivors (n=48): 59.1 {+/-} 21 vs. non-survivors (n=17): 211 {+/-} 105, p<0.0001; NT-proBNP (ng/L): survivors (n=47): 1310 {+/-} 314 vs. non-survivors (n=20): 4065 {+/-} 740, p<0.0001; D-dimer (mg/L): survivors (n=50): 7.2 {+/-} 1.5 vs. non-survivors (n=18): 17.1 {+/-} 4.8, p<0.01). All intervals refer to standard error of the mean. Tricuspid regurgitation velocity was correlated with troponin I (r=0.93, r2=0.74, p<0.001, n=10). ConclusionsThese results suggest that there is no clear negative effect on cardiac function in critical SARS-CoV-2. There are indications that pulmonary pressure elevation carries a negative predictive outcome suggesting pulmonary disease as the driver of mortality. Cardiac biomarkers as well as D-dimer carry predictive value. Trial registration numberPatients were included in "Clinical trials NCT04316884" Article summaryO_ST_ABSStrength and limitations of this studyC_ST_ABS- The patient body is recruited from all patients admitted to ICU in need of mechanical respiratory support independent of background which makes it relevant to clinical practice. - The echocardiographic image acquisition was carried out by hospital assigned agents on clinical indication, which makes the results applicable in a clinical setting. - Since the image acquisition was carried out on a clinical indication, the results may be skewed towards the false positive if applied to all Covid19 patients.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

BackgroundThere is considerable variability in COVID-19 outcomes amongst younger adults--and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. MethodThe major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FindingsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1{middle dot}4, 95% confidence interval [CI] 1{middle dot}2-1{middle dot}6) and COVID-19 related mortality (HR 1{middle dot}5, 95%CI 1{middle dot}3-1{middle dot}8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2{middle dot}0, 95%CI 1{middle dot}6-2{middle dot}6), venous thromboembolism (OR 1{middle dot}7, 95%CI 1{middle dot}2-2{middle dot}4), and hepatic injury (OR 1{middle dot}6, 95%CI 1{middle dot}2-2{middle dot}0). Risk allele carriers [≤] 60 years had higher odds of death or severe respiratory failure (OR 2{middle dot}6, 95%CI 1{middle dot}8-3{middle dot}9) compared to those > 60 years OR 1{middle dot}5 (95%CI 1{middle dot}3-1{middle dot}9, interaction p-value=0{middle dot}04). Amongst individuals [≤] 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31{middle dot}8% (95%CI 27{middle dot}6-36{middle dot}2) were risk variant carriers, compared to 13{middle dot}9% (95%CI 12{middle dot}6-15{middle dot}2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those [≤] 60 years improved when including the risk allele (AUC 0{middle dot}82 vs 0{middle dot}84, p=0{middle dot}016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. InterpretationThe major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality--and these are more pronounced amongst individuals [≤] 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FundingFunding was obtained by each of the participating cohorts individually.

Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill COVID-19 patients

Several studies suggest that hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections. We hypothesized that the high levels of the inflammatory cytokine Angiopoietin-2 (ANGPT2) reported in hospitalized COVID-19 patients might promote hypercoagulation through ANGPT2 binding to thrombomodulin with resulting inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Plasma was collected from critically ill COVID-19 patients treated in the intensive care unit (ICU) at Uppsala University Hospital and ANGPT2 was measured at admission (61 patients) and after ten days (40 patients). ANGPT2 levels were compared with biochemical parameters, clinical outcome, and survival. We found that ANGPT2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. To test causality, we administered ANGPT2 to wildtype mice and found that it shortened bleeding time in a tail injury model. In further support of a role for ANGPT2 in physiological coagulation, bleeding time was increased in endothelial-specific Angpt2 knockout mice. Using in vitro assays, we found that ANGPT2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data reveal a novel mechanism for ANGPT2 in hypercoagulation and suggest that Angiopoietin-2 inhibition may be tested in the treatment of hypercoagulation in severe COVID-19 infection.

Circulating Proteins Influencing COVID-19 Susceptibility and Severity: a Mendelian Randomization Study

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7x10-8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8x10-8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8x10-6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.

Autoimmune Encephalitis Presenting with Acute Excited Catatonia in a 40-Year-Old Male Patient with Covid-19

Acute malignant catatonia with autonomic instability developed in a previously healthy man with PCR-verified SARS-CoV-2. CT and MRI were normal, EEG showed slowing and cerebrospinal fluid showed a subtle indication of inflammation. There were no signs of pathology in other organs. 18F-FDG-PET conveyed high bilateral uptake in the striatum. While commercial tests were negative, immunohistochemical staining of mouse brain revealed anti-neuronal IgG antibodies against neuronal targets in the hippocampus, thalamus, striatum and cortex. Early treatment with plasmapheresis and corticosteroid reversed disease progression and may have prevented large-scale neurological damage. We are not aware of other types of encephalitis with such distinct pyramidal tract symptoms and raise the possibility that this may be a novel form of autoimmune encephalitis induced by infection with SARS-CoV-2.