Multi-ancestry GWAS of diarrhea during acute SARS-CoV2 infection identifies multiple novel loci and contrasting etiological roles of irritable bowel syndrome subtypes (preprint)

A substantial proportion of acute SARSCoV2 infection cases exhibit gastrointestinal symptoms, yet the genetic determinants of these extrapulmonary manifestations are poorly understood. Using survey data from 239,866 individuals who tested positively for SARSCoV2, we conducted a multi-ancestry GWAS of 80,289 cases of diarrhea occurring during acute COVID19 infection (33.5%). Six loci (CYP7A1, LZFTl1/CCR9, TEME182, NALCN, LFNG, GCKR) met genomewide significance in a trans-ancestral analysis. The top significant GWAS hit mapped to the CYP7A1 locus, which plays an etiologic role in bile acid metabolism and is in high LD (r2= 0.93) with the SDCBP gene, which was previously implicated in antigen processing and presentation in the COVID-19 context. Another association was observed with variants in the LZTFL1/CCR9 region, which is a known locus for COVID19 susceptibility and severity. PheWAS showed a shared association across three of the six SNPs with irritable bowel syndrome (IBS) and its subtypes. Mendelian randomization showed that genetic liability to IBS-diarrhea increased (OR=1.40,95%,CI[1.33,1.47]), and liability to IBS-constipation decreased (OR=0.86, 95%CI[0.79,0.94]) the relative odds of experiencing COVID19+ diarrhea. Our genetic findings provide etiological insights into the extrapulmonary manifestations of acute SARSCoV2 infection.

Role of the complement system in Long COVID (preprint)

Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears. Furthermore, proteomic analysis of two orthogonal cohorts-one addressing PACS following severe acute phase and another after a mild acute phase-fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.

Exercise Intolerance in Long Covid After 24 Months From Severe Acute Disease: is There Room for Improvement? (preprint)

Introduction: Long COVID is a complex and multisystemic condition, where dyspnea, fatigue, post-exertional malaise, cognitive impairment, decreased functional capacity, and deterioration in quality of life are the most incident clinical features. Few studies have reported cardiopulmonary alterations 24 months after severe COVID-19 infection.  Objective: to evaluate the functional capacity of individuals with persistent symptoms after severe COVID-19 infection compared to control individuals without symptomatic COVID or mild COVID after 24 months.  Methods: This is a case-control study assessing 34 individuals divided into 2 groups (severe COVID-19 with long COVID and a control group consisting of asymptomatic/mild acute COVID-19 with no long COVID) regarding functional capacity by 6-minute walk test (6MWT) associated with gas analysis, spirometry, respiratory muscle strength and quality of life. Results: During the 6MWT, an important lower heart rate (HR) was observed for the COVID group, with greater exertional perception, a significant decrease in the distance covered, and a low value of O2 uptake (V̇O2) and minute ventilation, in addition to very low quality of life scores, especially in aspects of functional capacity and physical limitations.  Conclusion: individuals who have severe COVID-19 and persist with symptoms have low functional capacity, low V̇O2, low HR behavior, and low quality of life. 

Implementing remote monitoring for COVID-19 patients in primary care (preprint)

Background: In Germany, most patients with coronavirus disease 2019 (COVID-19) are treated in an outpatient setting. To improve assessments of the health status of COVID-19 outpatients, various remote monitoring models have been developed. However, little information exists on experiences acquired with remote monitoring in an outpatient setting, particularly from a patient perspective. The aim of our 'COVID-19@home' study was therefore to implement and evaluate an app-based remote monitoring concept for acute and post-acute COVID-19-patients in primary care. In this paper, we focus on the patients' evaluation of our remote monitoring approach. Methods Patients with acute COVID-19 measured heart rate, blood pressure, oxygen saturation, and body temperature daily for 28 days. Patients with post-acute COVID-19 determined the same parameters for 12 weeks, supplemented by lung parameters and daily step count. The data were documented using the 'SaniQ' smartphone app. COVID-19 symptoms were assessed daily using an app-based questionnaire. Patients' GPs could access the data on the 'SaniQ Praxis' telemedicine platform. We used an app-based questionnaire consisting of 11 questions presented with a 4-point Likert scale to evaluate patient satisfaction. Data were analyzed descriptively. Results Of the 51 patients aged 19-77 years that participated in the study, 42 completed the questionnaire. All patients rated home monitoring as 'very good' or 'rather good' and were able to integrate the measuring processes into their daily routines. Overall, 93% would recommend the app and the measuring devices to their family and friends. About 60% felt that their COVID-19 treatment had benefited from home monitoring. Only few patients were unsettled by the app and use of the measuring devices. During the course of the study, the implementation process was optimized. Conclusions The use of remote monitoring in COVID-19 patients is feasible and was evaluated positively by most study patients. However, it is difficult to imagine how general practices could cope with monitoring patients with acute diseases without any further organizational support. Future research should address cost-effectiveness and changes in such clinical outcomes as hospitalization and mortality.

TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL (preprint)

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.

Long-term symptoms after SARS-CoV-2 infection in a cohort of people living with HIV (PLWH): a real-life study (preprint)

Background Our Hospital in Northern Italy assists 3817 people living with HIV (PLWH) and has faced the impact of COVID-19. Little is known about the impact of HIV infection on the risk of post-COVID-19 conditions (PCCs) onset. We aim to assess the incidence of PCC in PLWH and the factors associated with its occurrence.Methods We performed a retrospective, observational study including all PLWH > 18 years registered in the Brescia Health Protection Agency database, assessing SARS-CoV-2 burden, vaccination status, socio-demographic, and viro-immunological parameters from February 2020 until May 2022. Persistence of self-reported symptoms (clustered into gastrointestinal, respiratory, osteo-muscular, and neuro-behavioral symptoms) was evaluated after 3 months by a telephone-administered questionnaire. We estimated the associations between all variables and outcomes through univariate and multivariable logistic models.Results In the study period, 653 PLWH were diagnosed with SARS-CoV-2 infection (17.1%). We observed 19 (2.9%) reinfections, 71 (10.9%) hospitalizations, and 3 (0.5%) deaths. We interviewed 510/653 PLWH (78%), and 178 (PCCs prevalence 34.9%; CI95% 30.7–39.2) reported persistent symptoms. Asthenia/fatigue was the most reported symptom (60/178), followed by muscular pain (54/178). In the multivariate regression model, male sex was protective (adjusted OR = 0.64; CI95% 0.99–3.66), while hospitalization during acute infection was associated with an increased the risk of PCCs (adjusted OR = 1.9; CI95% 0.99–3.66). Notably, no viro-immunological variable modified the PCCs risk onset.Conclusions Our study highlights a substantial prevalence of PCCs among PLWH, three months post-SARS-CoV-2 infection, independent of viro-immunological features or vaccination status.

SARS-COV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice (preprint)

The coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.

IMPACT OF METHYLPREDNISOLONE PULSE ON THE MORTALITY OF PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME SECONDARY TO COVID-19 (preprint)

Corticosteroids are the most important factor to reduce the mortality in patients with moderate-severe COVID-19. The aim of the study was to analyze the impact of methylprednisolone pulse (MPP) on in-hospital mortality of patients with acute respiratory distress syndrome (ARDS) due to COVID-19. We conducted a retrospective, single-center observational study We selected adult patients admitted to the hospital with the diagnosis of COVID-19 between March and June 2020. A total of 306 patients were analyzed. In-hospital crude mortality rate was 17%. Diabetes mellitus (HR 5.5, 95% CI 1.40–4.55), dementia (HR 7.7, 95% CI 4.25-13.87) and ARDS (HR 4.2, 95% CI 2.34-7.46) were associated with in -hospital mortality. In patients diagnosed of ARDS, the only in-hospital mortality risk factor was dementia (HR 5.2, 95% CI 2.44–11.07), whereas MPP was a protective factor (HR 0.2, 95% CI 0.09–0.63)

Respiratory illness virus infections with special emphasis on Covid-19 (preprint)

Viruses that emerge pose challenges for treatment options as their uniqueness would not know completely. In spite of large diversity, viruses share common characteristics for infection. There are at least 12 different respiratory borne viruses that belong to different virus taxonomic families. Many of these viruses multiply and cause damage to the upper and lower respiratory tracts. The description about these viruses in comparison to each other with reference to their epidemiology, molecular characteristics, disease manifestations, diagnosis and treatment is lacking. Such information helps to diagnose, differentiate and for formulating the control measures at faster pace. The leading cause of acute illness worldwide are the acute respiratory infections (ARIs) and are being responsible for nearly 4 million deaths every year which are mostly in young children and infants. Among the above ARIs, influenza, respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV-3), Streptococcus pneumoniae, Haemophilus influenzae and corona viruses are the main infectious agents. WHO recognized respiratory syncytial virus, parainfluenza viruses, coronavirus, rhinovirus, and human metapneumovirus [non-influenza RNA respiratory viruses (NIRVs)], as considerable global health burden. Lower respiratory tract infections are the fourth most common cause of death globally, after the non-infectious chronic conditions. This review aimed at presenting the characteristics of different viruses causing the respiratory infections highlighting the uniqueness of Covid-19. We expect that this review would help in understanding the similarities and differences among the closely related viruses causing respiratory infections and hence to formulate the specific preventive or control measures.

Device-assessed physical activity and sleep quality of post-COVID patients undergoing a rehabilitation program (preprint)

Background: An infection with SARS-CoV-2 can lead to persistent symptoms more than three months after the acute infection and has also an impact on patients’ physical activity behaviour and sleep quality. There is evidence, that inpatient post-COVID rehabilitation can improve physical capacity and mental health impairments, but less is known about the change in physical behaviour and sleep quality. Methods: This longitudinal observational study used accelerometery to assess the level of physical activity and sleep quality before and after an inpatient rehabilitation program. The study sample consists of 100 post-COVID patients who acquired COVID-19 in the workplace. Group differences related to sex, age, COVID-19 severity, and pre-existing diseases were also analysed. Results: Level of physical activity and sleep quality didn’t increase after rehabilitation. Overall, there is a high extent of inactivity time and poor sleep quality at both measurement points. Regarding group differences, male patients showed a significantly higher inactivity time before rehabilitation, and younger patients (<55 years) spend significant more time in vigorous physical activity than older patients. Post-COVID patients with pre-existing cardiovascular, respiratory, and metabolic disease show slightly less physical activity than post-COVID patients without these comorbidities. Female patients and younger patients showed better sleep quality in some sleep parameters at both measurement points. However, no differences could be detected related to COVID-19 severity. Conclusions: Ongoing strategies should be implemented to address the high amount of inactivity time and the poor sleep quality in post-COVID patients.

Systemic SARS-CoV-2-specific antibody responses to infection and to COVID-19 and BCG vaccination (preprint)

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naive Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomized to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/ml, 955.0 IU/ml, and 2290.9 IU/ml for one, two, and three immune events, respectively (p<0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with Long COVID or long-term loss of smell/taste.

A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection (preprint)

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.

Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis (preprint)

Background Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England. Methods With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings We identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record. Interpretation EHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID. Funding This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073))

Quantitative susceptibility mapping at 7 Tesla in COVID-19: mechanistic and outcome associations (preprint)

Post mortem studies have shown that patients dying from severe SARS-CoV-2 infection frequently have pathological changes in their central nervous system, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized COVID-19 patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on magnetic resonance imaging (MRI) is inconclusive. We therefore used ultra-high field (7T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7T QSM data from 30 patients, scanned 93 - 548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-Dimer and platelet levels), functional recovery (modified Rankin scale; mRS), depression (PHQ-9) and anxiety (GAD-7). In COVID-19 survivors the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. Using non-invasive ultra-high field 7T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors. This study contributes to understanding the mechanisms of long-term effects of COVID-19 and recovery.

Recovery of Neurophysiological Measures in Post-COVID Fatigue - a 12-month Longitudinal Follow-up Study (preprint)

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Factors associated with SARS-CoV-2 among persons living with HIV in Zambia: Analysis of three concurrent SARS-CoV-2 prevalence surveys conducted in July 2020 in six districts of Zambia (preprint)

People living with HIV (PLHIV) are a unique population because of their altered immune systems and taking antiretroviral therapy (ART) that may modify risk of SARS-CoV-2. Evidence from sub-Saharan African countries suggests that, despite not having higher SARS-CoV-2 infection prevalence than HIV-negative persons, PLHIV suffer worse COVID-19 outcomes. We assessed the prevalence of SARS-COV-2 infection by HIV status in Zambia in July 2020. We analyzed data from three different concurrent SARS-CoV-2 prevalence surveys (household, outpatient-department, and health-worker) conducted in six districts of Zambia in July 2020. Information on demographics and medical history was collected. Nasopharyngeal swabs were used to screen for SARS-CoV-2 RNA using polymerase-chain-reaction (PCR) and blood specimens were screened for SARS-CoV-2 virus-specific antibodies using an enzyme-linked-immunosorbent-assay (ELISA). Test-specific SARS-CoV-2 prevalence was calculated. Multilevel logistic regression models were used to measure test-specific adjusted odd ratios (aORs) of SARS-CoV-2 positivity by HIV status, controlling for demographic and medical history. We analysed the outcomes of the two different tests separately. Among 7,092 participants, 4,717 (66.5%) consented to blood-draw and 4,642 (65.5%) consented to nasopharyngeal swab. Overall SARS-CoV-2 positivity was 9.4% by PCR and 3.8% by ELISA. SARS-CoV-2 prevalence detected by PCR was higher among PLHIV than HIV-negative respondents (12.4% vs 9.1%, respectively, OR: 1.4, 95% confidence intervals [CI]: 1.0-1.9) and lower by ELISA (1.9% vs 3.9%, respectively, OR: 0.5, 95%CI: 0.2-0.9). Among PLHIV, not being on ART was an independent predictor of SARS-CoV-2 PCR positivity (aOR: 5.24,95% CI: 1.19-22.22) but did not have a significant effect on ELISA results. During the first COVID-19 wave in Zambia, PLHIV were more likely to be acutely infected with SARS-CoV-2 but less likely to be seropositive than participants without HIV. Intervention programs could focus on early access to COVID-19 vaccinations, testing and ART might reduce COVID-19 morbidity among PLHIV.

Association of Cognitive Deficits with Sociodemographic Characteristics among Adults with Post-COVID Conditions: Findings from the United States Household Pulse Survey (preprint)

BackgroundPeople infected with COVID-19 may continue to experience symptoms for several weeks or even months after acute infection, a condition known as long COVID. Cognitive problems such as memory loss are among the most commonly reported symptoms of long COVID. However, a comprehensive evaluation on the risks of cognitive decline following COVID infection among different sociodemographic groups has not been undertaken at the national level in the United States. MethodsWe conducted a secondary analysis on the datasets from U.S. Census Bureau Household Pulse Survey, encompassing the data collected from June 1, 2022 to December 19, 2022. Based on a cohort of 385,370 individuals aged 18 or older, we employed logistic regression analyses to examine the association between self-reported cognitive deficits and different sociodemographic factors among individuals with long COVID conditions. ResultsAmong individuals aged 18 or older, 44.7% percent of survey respondents report having been diagnosed with COVID in the past, and 29.0% of those with previous COVID infection experienced long COVID symptoms lasting for more than 3 months. We have demonstrated that individuals with long COVID had significantly higher risk of experiencing cognitive deficits compared to those with no history of COVID infection. Furthermore, females, young adults, people with multiple races, or low levels of education attainment are at high risk of cognitive deficits if they experience long COVID. At the state level, the prevalence of cognitive deficits among long COVID patients varied across different US states, with the highest prevalence in West Virginia and Kentucky, and the lowest prevalence in Connecticut and Maryland. The variation could be due to differences in racial composition and education level among long COVID patients in the four states. ConclusionsThe risks of cognitive deficits among adults with post-COVID conditions are substantial. Various sociodemographic groups can have different risks of developing cognitive deficits after experiencing long COVID. Findings of this large-scale study can help identify sociodemographic groups at higher risk of cognitive deficits, and facilitate medical interventions and guide resource allocation to target populations at risk and to prioritize areas with a high rate of cognitive decline.

Liver abnormalities following SARS-CoV-2 infection in children under 10 years of age (preprint)

ObjectiveBeginning in October 2021 in the US and elsewhere, cases of severe pediatric hepatitis of unknown etiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading etiologic suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities. DesignWe conducted a study utilizing retrospective cohorts of de-identified, aggregated data from the electronic health records of over 100 million patients contributed by US health care organizations. ResultsCompared to propensity-score-matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (Hazard ratio (HR) (95% Confidence interval (CI)) 2.16 (1.74-2.69)) or total bilirubin (HR (CI) 3.02 (1.91-4.78)), or new diagnoses of liver diseases (HR (CI) 1.67 (1.21-2.30)) from one to six months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years), or illness requiring hospitalization all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections. ConclusionThese results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare ([~]1 in 1,000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver. What is already known on this topicClusters of severe hepatitis in children in 2022 coincident with the increase in COVID-19 infections in children raised the question of the contribution of SARS-CoV-2 to the hepatitis outbreak, though it was soon determined that SARS-CoV-2 was not the primary etiologic agent. What this study addsSARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. How this study might affect research, practice or policyDespite the mild initial disease in children, there may be longer term consequences of COVID-19, such as liver abnormalities, that warrants further investigation.

Temporal profiling of human lymphoid tissues reveals coordinated defence to viral challenge (preprint)

Adaptive immunity is generated in lymphoid organs, but how these structures defend themselves during infection in humans is unknown. The nasal epithelium is a major site of viral entry, with adenoid nasal-associated lymphoid tissue (NALT) generating early adaptive responses. Here, using a nasopharyngeal biopsy, we examined longitudinal immune responses in NALT following viral challenge, using SARS-CoV-2 infection as a natural experimental model. In acute infection, infiltrating monocytes formed a subepithelial and peri-follicular shield, recruiting NET-forming neutrophils, whilst tissue macrophages expressed pro-repair molecules during convalescence to promote the restoration of tissue integrity. Germinal centre B cells expressed anti-viral transcripts that inversely correlated with fate-defining transcription factors. Among T cells, tissue-resident memory CD8 T cells alone showed clonal expansion and maintained cytotoxic transcriptional programmes into convalescence. Together our study provides a unique insight into how human nasal adaptive immune responses are generated and sustained in the face of viral challenge.

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody (preprint)

The COVID-19 pandemic has led to over 760 million cases and 6.9 million deaths worldwide. To mitigate the loss of lives, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with susceptible variants. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response anti-viral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.