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.

Clusters of post-acute COVID-19 symptoms: a latent class analysis across 9 databases and 7 countries (preprint)

Prior evidence has suggested the multisystem symptomatic manifestations of post-acute COVID-19 condition (PCC). Here we conducted a network cluster analysis of 24 WHO proposed symptoms to identify potential latent subclasses of PCC. Individuals with a positive test of or diagnosed with SARS-CoV-2 after 09/2020 and with at least one symptom within ≥ 90 to 365 days following infection were included. Sub-analyses were conducted among people with ≥ 3 different symptoms. Summary characteristics were provided for each cluster. All analyses were conducted separately in 9 databases from 7 countries, including data from primary care, hospitals, national health claims and national health registries, allowing to validate clusters across the different healthcare settings. 787,078 persons with PCC were included. Single-symptom clusters were common across all databases, particularly for joint pain, anxiety, depression and allergy. Complex clusters included anxiety-depression and abdominal-gastrointestinal symptoms. Substantial heterogeneity within and between PCC clusters was seen across healthcare settings. Current definitions of PCC should be critically reviewed to reflect this variety in clinical presentation.

SERVAL: Synergy Learning between Vertical Models and LLMs towards Oracle-Level Zero-shot Medical Prediction (preprint)

Recent development of large language models (LLMs) has exhibited impressive zero-shot proficiency on generic and common sense questions. However, LLMs' application on domain-specific vertical questions still lags behind, primarily due to the humiliation problems and deficiencies in vertical knowledge. Furthermore, the vertical data annotation process often requires labor-intensive expert involvement, thereby presenting an additional challenge in enhancing the model's vertical capabilities. In this paper, we propose SERVAL, a synergy learning pipeline designed for unsupervised development of vertical capabilities in both LLMs and small models by mutual enhancement. Specifically, SERVAL utilizes the LLM's zero-shot outputs as annotations, leveraging its confidence to teach a robust vertical model from scratch. Reversely, the trained vertical model guides the LLM fine-tuning to enhance its zero-shot capability, progressively improving both models through an iterative process. In medical domain, known for complex vertical knowledge and costly annotations, comprehensive experiments show that, without access to any gold labels, SERVAL with the synergy learning of OpenAI GPT-3.5 and a simple model attains fully-supervised competitive performance across ten widely used medical datasets. These datasets represent vertically specialized medical diagnostic scenarios (e.g., diabetes, heart diseases, COVID-19), highlighting the potential of SERVAL in refining the vertical capabilities of LLMs and training vertical models from scratch, all achieved without the need for annotations.

Attenuated replication and damaging effects of SARS-CoV-2 Omicron in an intestinal epithelial barrier model (preprint)

Many COVID-19 patients suffer from gastrointestinal symptoms and impaired intestinal barrier function may play a key role in Long COVID. Despite its importance, the impact of SARS-CoV-2 on intestinal epithelia is poorly understood. To address this, we established an intestinal barrier model integrating epithelial Caco-2 cells, mucus-secreting HT29 cells and human Raji cells. This gut epithelial model allows efficient differentiation of Caco-2 cells into microfold-like cells, faithfully mimics intestinal barrier function, and is highly permissive to SARS-CoV-2 infection. Early strains of SARS-CoV-2 and the Delta variant replicated with high efficiency, severely disrupted barrier function, and depleted tight junction proteins, such as claudin-1, occludin and ZO-1. In comparison, Omicron subvariants also depleted ZO-1 from tight junctions but had fewer damaging effects on mucosal integrity and barrier function. Remdesivir and the TMPRSS2 inhibitor Camostat prevented SARS-CoV-2 replication and thus epithelial barrier damage, while the Cathepsin inhibitor E64d was ineffective. Our results support that SARS-CoV-2 disrupts intestinal barrier function but further suggest that circulating Omicron variants are less damaging than earlier viral strains.

Menstrual Symptom Disorders After COVID-19 in Relation To Anxiety and Long COVID Symptoms (preprint)

Aim: and objectives: Coronavirus disease (COVID-19) can affect the menstrual cycle and menstrual volume. We aimed to examine the changes in menstrual symptoms of women who had recovered from COVID-19 and determine the factors affecting these changes. Methods: A questionnaire, prepared using Google Forms, was completed online in May 18-31, 2021 by 180 women (26.08±6.62 years) who had recovered from COVID-19. Menstrual symptoms, menstrual pain severity, fatigue severity and anxiety levels of the participants were assessed with Menstrual Symptom Questionnaire (MSQ), Visual Analogue Scale (VAS) and Fatigue Severity Scale (FSS), Coronavirus Anxiety Scale (CAS), respectively. Results: Post-COVID-19 individuals’ MSQ total scores and subgroup scores, FSS scores and menstrual pain showed a statistically significant increase compared to pre-COVID-19 (p < 0.001 for all). Multiple linear regression analysis identified age at menarche and change in FSS and VAS scores as significant contributors to 38.4% of the variance explained in the significant regression for change in MSQ score (F (3.176) = 38.23, p < 0.001). Individuals with prolonged fatigue, muscle–joint pain and dyspnea symptoms showed increased MSQ total scores (p = 0.006, p = 0.009, p = 0.046 respectively) and negative effects/somatic complaints subgroup scores (p = 0.004, p = 0.002, p = 0.017 respectively). Also, individuals with prolonged gastrointestinal symptoms showed increased pain symptoms (p = 0.029) and coping methods subgroup scores (p = 0.002), while those with prolonged muscle and joint pain showed increased coping methods (p = 0.022) subgroup scores. Conclusion: In this study, we observed worsened menstrual symptoms, fatigue, and menstrual pain severity in women recovered from COVID-19. In addition, age at menarche and fatigue and menstrual pain scores differences after COVID-19 were determiners of the changes in menstrual symptoms. Menstrual symptoms were more severe in women who have prolonged fatigue, dyspnea, muscle–joint pain, and gastrointestinal symptoms.

Symptoms of children and adolescents infected with SARS-CoV-2 variants alpha, delta or omicron (preprint)

Symptoms experienced by children and adolescents with SARS-CoV-2 infections in the alpha, delta and omicron variant dominated phases were investigated using an online survey, and the frequencies of reported symptoms and changes over time were analyzed. The most prevalent symptoms were fever above 38 {degrees}C, tiredness, headache, runny or blocked nose, sneezing and dry cough. Lethargy and nausea were reported significantly more frequently in the omicron variant dominated phase than in the earlier phases of the pandemic. Compared to symptoms reported by adults, fever and gastrointestinal symptoms were reported more frequently for children, especially in the omicron variant dominated phase, whereas the frequency of loss of smell and loss of taste was significantly lower in children than in adults.

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

A systematic review of the prevalence of persistent gastrointestinal symptoms and incidence of new gastrointestinal illness after acute SARS-CoV-2 infection (preprint)

It is known that SARS-CoV-2 infection can result in gastrointestinal symptoms. For some, these symptoms may persist beyond acute infection, in what is known as post-COVID syndrome. We conducted a systematic review to examine the prevalence of persistent gastrointestinal symptoms and the incidence of new gastrointestinal illness following acute SARS-CoV-2 infection. We searched scientific literature using MedLine, SCOPUS, Embase, Europe PubMed Central, medRxiv and Google Scholar from December 2019 to October 2022. Two reviewers independently identified 28 eligible articles which followed participants for various gastrointestinal outcomes after acute SARS-CoV-2 infection. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools. The weighted pooled prevalence for persistent gastrointestinal symptom of any nature and duration was 10.7%, compared to 4.9% in healthy controls. For six studies at a low risk of methodological bias, the symptom prevalence ranged from 0.2% to 24.1% with a median follow-up time of 13 weeks. We also identified the presence of functional gastrointestinal disorders in historically SARS-CoV-2 exposed individuals. Our review has shown that, from a limited pool of mostly low-quality studies, previous SARS-CoV-2 exposure may be associated with ongoing gastrointestinal symptoms and the development of functional gastrointestinal illness. Furthermore, we show the need for high-quality research to better understand the SARS-CoV-2 association with gastrointestinal symptoms, particularly as population exposure to enteric infections returns to pre-COVID-19-restriction levels.

Increase in Clostridioides difficile infection resulting from over usage of antibiotics during COVID 19 pandemic (preprint)

Healthcare-associated infections (HAIs) due to Clostridioides difficile infections (CDIs) are a significant public health problem globally. The emergence of the novel coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in 2019 has exacerbated the situation. Elderly and chronically ill individuals are particularly vulnerable to COVID-19, and gastrointestinal (GI) symptoms are increasingly recognized as essential symptoms of COVID-19. Bacterial infections in COVID-19 patients are prevalent, and the rates of Clostridioides difficile infection (CDI) are high and associated with antibiotic use. The study aims to investigate the correlation between CDI and community antibiotic usage patterns during COVID-19 in 2021 compared to the previous year to identify the impact on overall CDI infection rates. The study design is a non-interventional retrospective study evaluating antibiotic usage patterns in CDI patients during the pandemic, and the data will be analysed based on the number of patients and test positivity rates. The preliminary findings of the study reveal a 27% increase in the number of symptomatic CDI infections in 2021 as compared to pre-COVID years.

Parameter Identification Problem in the Discrete-time Sir Model (preprint)

We investigate the problem of determining time dependent parameters for discrete-time epidemiological compartmental models such as the Susceptible-Infected-Recovered (SIR). We show how to determine parameters based on minimal error type iterative schemes. Such methods involve the computation of the adjoint of the derivative operator of a nonlinear function. This is a nontrivial task that we accomplish by carefully crafting auxiliary problems. To show the efficiency of the method, we consider examples involving real COVID-19 data.

Effect of gastrointestinal symptoms and skipping breakfast on anxiety and depression in quarantined Chinese college students during the COVID-19 pandemic: A cross sectional survey (preprint)

Background: Strict quarantine is an effective measure to prevent the spread of the Coronavirus disease (COVID-19) pandemic, but it probably increases the risk of anxiety and depression. We aimed to evaluate the anxiety and depression among quarantined college students at school during the COVID-19 pandemic and investigate whether gastrointestinal discomfort related-factors and skipping breakfast lead to increased risk of anxiety and depression. Methods: 384 quarantined college students in Shanghai China were recruited in this cross-sectional study from April 5th to May 29th, 2022. Generalized Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9) were used to assess anxiety and depression, respectively.Results: The prevalence of anxiety and depression were 56.8% and 62.8%, respectively. Longer quarantine duration, higher education level, skipping breakfast, stomachache or abdominal pain, and nausea or dyspepsia were the risk factors for anxiety. Moreover, longer quarantine duration, being woman, skipping breakfast, stomachache or abdominal pain, and nausea or dyspepsia increased the risk of depression. Notably, regularly physical exercising and taking positive attitude towards COVID-19 can reduce the risk of anxiety and depression. Conclusions: More attention should be paid to anxiety and depression of quarantined college students and universities should provide timely psychological monitoring and intervention services to mitigate the impact of negative emotions on students. And effectively relieving gastrointestinal symptoms, insisting on eat breakfast, regularly exercising, and taking a positive attitude towards to COVID-19 might contribute to preventing the anxiety and depression for those college students experiencing a long-term quarantine.

Spectrum of Neurological Manifestations in Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) Linked to COVID-19 (preprint)

Background Since December 2019, Covid-19 has resulted in high morbidity and mortality worldwide. MIS-C associated with SARS-CoV-2 infection led to serious and life-threatening illness in children causing severe multisystem inflammation. It presented with new neurological symptoms involving both the central and peripheral nervous systems. The aim is to evaluate the neurological manifestations in pediatric patients with MIS-C associated to COVID-19.Aim To evaluate the neurological manifestations in Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS-C) associated to COVID-19.Methods This cross section study included patients who were admitted to Pediatric Intensive Care Unit (PICU) isolation unit at Minia University Hospital during the period from December 2020 to April 2022. The study included a total of 303 patients who were classified in to 3 groups; Group (I) (MIS-C, PCR positive), Group (II) (MIS-C, PCR negative), and Group (III) (Non-MIS-C, PCR positive).Results The respiratory, cardiovascular, hematologic and gastrointestinal symptoms were significantly greater among Group (II). Convulsions, DCL, Headache, and Weakness were significantly more demonstrated in Group (I) (19 (31.7%), 17 (28.3%), 17 (28.3%), and 15 (25.0%), respectively). While, drowsiness was significantly more demonstrated in Group (II) (41 (21.9%)). Lymphocytes (%) showed significant lower values in Group (I) and Group (II) (Mean ± SD is 18.9 ± 1.8(, compared to Group (III) (Mean ± SD is 21.4 ± 1.8), p-value < 0.01. D-dimer, CRP and S. Ferritin levels were significantly increased among Group (I) while albumin levels were significantly decreased in Group (I). Troponin levels were significantly increased in patients of Group (II). The majority of patients in the three studied groups showed abnormal Chest CT findings in the form of ground glass opacities (CO-RADS III). The percentage of non-survived patients was significantly increased in Group (I).Conclusion Pediatric patients with MIS-C and associated to COVID-19 presenting with neurological, respiratory, cardiovascular, gastrointestinal, and hematologic symptoms. The neurological manifestations could include convulsions, DCL, headache, and weakness.

coronabambini.ch: Development and usage of an online decision support tool for pediatric COVID-testing in Switzerland: a cross-sectional analysis (preprint)

Objectives: To describe the development and usage of coronabambini.ch as an example of a pediatric electronic public health application and to explore its potential and limitations in providing information on disease epidemiology and public health policy implementation. Design: We developed and maintained a non-commercial online decision support tool, coronabambini.ch, to translate the Swiss FOPH pediatric (age 0-18 years) COVID-19 guidelines around testing and school/daycare attendance for caregivers, teachers, and healthcare personnel. We analyzed the online decision tool as well as a voluntary follow-up survey from October 2020 to September 2021 to explore its potential as a surveillance tool for public health policy and epidemiology. Participants 68′269 users accessed and 52′726 filled out the complete online decision tool. 3% (1′399/52′726) filled out a voluntary follow-up. 92% (18′797/20′330) of users were parents. Results: Certain dynamics of the pandemic and changes in testing strategies were reflected in the data captured by coronabambini.ch: e.g. in terms of disease epidemiology, gastrointestinal symptoms were reported more frequently in younger age-groups (13% (3′308/26′180) in children 0-5 years versus 9% (3′934/42′089) in children ≥6 years, X 2 =184, P =<.001). As a reflection of public health policy, the proportion of users consulting the tool for a positive contact without symptoms in children 6-12 years increased from 4% (1′415/32′215) to 6% (636/9′872) after the FOPH loosened testing criteria in this age-group, X 2 =69, P =<.001. Adherence to the recommendation was generally high (84% (1′131/1′352)) but differed by the type of recommendation: 89% (344/385) for ″stay at home and observe″, 75% (232/310) for ″school attendance″. Conclusions: Usage of coronabambini.ch was generally high in areas where it was developed and promoted. Certain patterns in epidemiology and adherence to public health policy could be depicted but selection bias was difficult to measure showing the potential and challenges of digital decision support as public health tools.

Impact of the COVID-19 restrictions on the epidemiology of Cryptosporidium spp. in England and Wales, 2015-2021A time-series analysis (preprint)

BackgroundIn England and Wales, cryptosporidiosis cases peak in spring and autumn, usually associated with zoonotic and environmental exposures (Cryptosporidium parvum, spring/autumn) and with overseas travel and water-based activities (Cryptosporidium hominis, autumn). Restrictions to control the COVID-19 pandemic prevented social mixing and access to swimming pools and restaurants for many months. Foreign travel from the UK also reduced by 74% in 2020. However, these restrictions potentially increased environmental exposures as people sought alternative countryside activities locally. To inform and strengthen surveillance programmes, we investigated the impact of COVID-19 restrictions on the epidemiology of C. hominis and C. parvum cases. MethodsCryptosporidium-positive stools, with case demographic data, are referred routinely for genotyping to the national Cryptosporidium Reference Unit (CRU). Cases were extracted from the CRU database (01 January 2015 to 31 December 2021). We defined two periods for pre- and post-COVID-19 restrictions implementation corresponding to the first UK-wide lockdown on 23 March 2020: "pre-restrictions" between week 1, 2015 and week 12, 2020, and "post restrictions-implementation" between week 13, 2020 and week 52, 2021. We conducted an interrupted time-series analysis, assessing differences in C. parvum and C. hominis incidence, trends and periodicity between these periods using negative binomial regression with linear-splines and interactions. ResultsThere were 21,304 cases between 01 January 2015 and 31 December 2021 (C. parvum = 12,246; C. hominis = 9,058). Post restrictions-implementation incidence of C. hominis dropped by 97.5% (95%CI: 95.4%-98.6%; p<0.001). The decreasing incidence-trend observed pre-restrictions (IRR=0.9976; 95%CI: 0.9969-0.9982; p<0.001) was not observed post restrictions-implementation (IRR=1.0081; 95%CI: 0.9978-1.0186; p=0.128) due to lack of cases. No periodicity change was observed post restrictions-implementation. Where recorded, 22% of C. hominis cases had travelled abroad. There was also a strong social gradient, with those who lived in deprived areas experiencing a higher proportion of cases. This gradient did not exist post restrictions-implementation, but the effect was exacerbated for the most deprived: 27.2% of cases from the most deprived decile compared to 12.7% in the pre-restrictions period. For C. parvum, post restrictions-implementation incidence fell by 49.0% (95%CI: 38.4%-58.3%; p<0.001). There was no pre-restrictions incidence-trend (IRR=1.0003; 95%CI: 0.9997-1.0009; p=0.322) but a slight increasing incidence-trend existed post restrictions-implementation (IRR=1.0071; 95%CI: 1.0038-1.0104; p<0.001). A periodicity change was observed for C. parvum post restrictions-implementation, peaking one week earlier in spring and two weeks later in autumn. Where recorded, 8% of C. parvum cases had travelled abroad. The social gradient observed for C. parvum was inverse to that for C. hominis, and was stable pre-restrictions and post restrictions-implementation. ConclusionC. hominis cases were almost entirely arrested post restrictions-implementation, reinforcing that foreign travel is a major driver of seeding infections. Increased hand-hygiene, reduced social mixing, limited access to swimming pools and limited foreign travel affected incidence of most gastrointestinal (GI) pathogens, including Cryptosporidium, in the same period. C. parvum incidence fell sharply but recovered throughout the post restrictions-implementation period, back to pre-restrictions levels by the end of 2021; this is consistent with relaxation of restrictions, reduced compliance and increased countryside use. The effect on our results of changes in health-seeking behaviours, healthcare access and diagnostic laboratory practices post restrictions-implementation is uncertain, but it is likely that access to GPs and specimen referral rate to CRU decreased. Future exceedance reporting for C. hominis should exclude the post restrictions-implementation period but retain it for C. parvum (except the first six weeks post restrictions-implementation where the incidence fell sharply). Advice on infection prevention and control should be improved for people with GI symptoms, including returning travellers, to ensure hand hygiene and appropriate swimming pool avoidance. Data summaryCryptosporidium is a notifiable agent in the UK which diagnostic laboratories must report to local health protection teams. Submission of Cryptosporidium-positive stools to the CRU is voluntary, but allows characterisation of the species. We used these data, where the specimen originated from English and Welsh diagnostic laboratories, to describe the epidemiology of Cryptosporidium spp. between 2015 and 2021. Impact statementCryptosporidium infections in industrialised countries can cause serious disease and lead to complicated and lasting sequelae, especially in the immunocompromised. Even in the general population, as well as long term gastrointestinal upset, joint pain, headache and eye pain have also been identified more frequently following cryptosporidiosis (1). There is an established association between cryptosporidiosis and colorectal cancer, although no conclusive evidence regarding causality in either direction (2-5). There has never been such a dramatic reduction in international travel in the modern era than during the COVID-19 pandemic, which is a key driver of C. hominis infections. Conversely, pressure on outdoor amenities has rarely been higher, which posed an increase in the likelihood of infection and cross-contamination for C. parvum infections. There have been few time-series analyses of cryptosporidiosis; in order to inform and strengthen surveillance programmes, we aimed to assess if there was a significant change to the epidemiology of C. parvum and C. hominis during the COVID-19 pandemic.

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial (preprint)

Background: Dimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19. Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified. Interpretation: In adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.

Long COVID in Cancer patients: Preponderance of Symptoms in Majority of Patients over Long Time Period (preprint)

Background:An increasing number of observational studies have reported the persistence of symptoms following recovery from acute COVID-19 disease in non-cancer patients. The long-term consequences of COVID-19 are not fully understood particularly in the cancer patient population. The purpose of this study is to assess post-acute sequelae of SARS-CoV-2 infection (PASC) in cancer patients following acute COVID-19 recovery.Methods:We identified cancer patients at MD Anderson Cancer Center who were diagnosed with COVID-19 disease between March 1, 2020 and Sept 1, 2020 and followed them till May 2021. To assess PASC, we collected patients reported outcomes through questionnaires that were sent to patients daily for 14 days after COVID-19 diagnosis then weekly for 3 months, and then monthly thereafter. We also reviewed patients electronic medical records to capture the the persistence or emergence of new COVID19-related symptoms reported during any clinic or hospital encounter beyond 30 days of the acute illness and up to 14 months.Results:We included 312 cancer patients with a median age of 57 years (18-86). The majority of patients had solid tumors (75%). Of the 312 patients, 188 (60%) reported long COVID-19 symptoms with a median duration of 7 months and up to 14 months after COVID-19 diagnosis. The most common symptoms reported included fatigue (82%), sleep disturbances (78%), myalgias (67%) and gastrointestinal symptoms (61%), followed by headache, altered smell or taste, dyspnea (47%) and cough (46%). A higher number of females reported a persistence of symptoms compared to males (63% vs 37%; p=0.036). Cancer type, neutropenia, lymphocytopenia, and hospital admission during acute COVID-19 disease were comparable in both groups. Among the 188 patients with PASC, only 16 (8.5%) were readmitted for COVID-related reasons.Conclusions:More than one out of two cancer patients, and more likely females, report PASC that may persist beyond 6 months and even one year. The most common symptoms are non-respiratory and consist of fatigue, sleep disturbance, myalgia and gastro-intestinal symptoms. Most of the cancer patients with PASC were managed on outpatient basis with only 8,5% requiring a COVID-19 related re-admission.

Demographic and Clinical Characteristics of Pediatric COVID-19 in Arkansas: March-December 2020 (preprint)

The COVID-19 pandemic reached the United States in early 2020 and spread rapidly across the country. This retrospective study describes the demographic and clinical characteristics of 308 children presenting to an Arkansas Childrens emergency department or admitted to an Arkansas Childrens hospital with COVID-19 in the first ten months of the COVID-19 pandemic, prior to the emergence of clinically significant variants and available vaccinations. Adolescents aged 13 and older represented the largest proportion of this population. The most common presenting symptoms were fever, gastrointestinal symptoms, and upper respiratory symptoms. Patients with multisystem inflammatory syndrome in children (MIS-C) had a longer length of stay than patients with acute COVID-19. Children from urban zip codes had lower odds of admission but were more likely to be readmitted after discharge. Nearly twenty percent of the study population incidentally tested positive for COVID-19. Despite lower mortality in children with COVID than in adults, morbidity and resource utilization are significant. With many Arkansas children living in rural areas and therefore far from pediatric hospitals, community hospitals should be prepared to evaluate children presenting with COVID-19 and to determine which children warrant transport to pediatric-specific facilities.

Epidemiology and role of SARS-CoV-2 Linkage in Paediatric Inflammatory Multisystem Syndrome (PIMS): A Canadian Paediatric Surveillance Program National Prospective Study (preprint)

Background: Paediatric inflammatory multisystem syndrome (PIMS) is a rare but serious condition temporally associated with SARS CoV2 infection. Using the Canadian Paediatric Surveillance Program (CPSP), a national surveillance system, we aimed to 1) study the impact of SARS CoV2 linkage on clinical and laboratory characteristics, and outcomes in hospitalized children with PIMS across Canada 2) identify risk factors for ICU admission, and 3) establish the minimum national incidence of hospitalizations due to PIMS and compare it to acute COVID 19. Methods: Weekly online case reporting was distributed to the CPSP network of more than 2800 pediatricians, from March 2020 to May 2021. Comparisons were made between cases with respect to SARS CoV2 linkage. Multivariable modified Poisson regression was used to identify risk factors for ICU admission and Minimum incidence proportions were calculated. Findings: In total, 406 PIMS cases were analyzed, of whom 202 (49.8%) had a positive SARS CoV2 linkage, 106 (26.1%) had a negative linkage, and 98 (24.1%) had an unknown linkage. The median age was 5.4 years (IQR 2.5 to 9.8), 60% were male, and 83% had no identified comorbidities. Compared to cases with a negative SARS CoV2 linkage, children with a positive SARS CoV2 linkage were older (8.1 years [IQR 4.2 to 11.9] vs 4.1 years [IQR 1.7 to 7.7]; p<0.001), had more cardiac involvement (58.8% vs 37.4%; p<0.001), gastrointestinal symptoms (88.6% vs 63.2%; p<0.001), and shock (60.9% vs 16.0%; p<0.001). At risk groups for ICU admission include children >=6 years and those with a positive SARS CoV2 linkage. No deaths were reported. The minimum incidence of PIMS hospitalizations during the study period was 5.6 hospitalizations per 100,000 population <18 years. Interpretation: While PIMS is rare, almost 1 in 3 hospitalized children required ICU admission and respiratory/hemodynamic support, particularly those >=6 years and with a positive SARS CoV2 linkage. Funding: Financial support for the CPSP was received from the Public Health Agency of Canada.

SARS-CoV-2 Omicron BA.1 variant infection of human colon epithelial cells (preprint)

Omicron B.1.1.529 became the predominant SARS-CoV-2 variant in early 2022, causing a new wave of public anxiety. Compared to the ancestral strain, Omicron has 50 mutations, with over 30 mutations in the spike protein. These differences likely underlie the changes in Omicron biology noted in other studies, including an attenuation in the lung parenchyma, compared to the ancestral SARS-CoV-2 strain and other variants, as well as a preference for endosomal entry, in place of the TMPRSS2-mediated membrane fusion pathway. This raises questions on Omicron tropism and infectivity in various target organ systems, including the gastrointestinal (GI) tract. Up to 70% of COVID-19 patients report GI symptoms, including nausea, vomiting, and diarrhea. Here, we show that in the context of donor intrinsic genetic heterogeneity, the SARS-CoV-2 Omicron variant infects human colonoids similarly, if not less effectively, than the ancestral WT (WA1) strain or the Delta variant. Additionally, we note a higher ratio of viral RNA to infectious virus titer, which may suggest that Omicron is potentially less infectious in the intestine. This study lays the foundation for further work defining mechanisms mediating intestinal infection and pathogenesis by Omicron.

Dissecting the Role of the Human Microbiome in COVID-19 via Metagenome-assembled Genomes (preprint)

Coronavirus disease 2019 (COVID-19), primarily a respiratory disease caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is often accompanied by gastrointestinal symptoms. However, little is known about the relation between the human microbiome and COVID-19, largely due to the fact that previous studies fail to provide high taxonomic resolution to identify microbes that likely interact with SARS-CoV-2 infection. Here we used whole-metagenome shotgun sequencing data together with assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from a total of 514 nasopharyngeal and fecal samples of patients with COVID-19 and controls. We reconstructed a total of 11,584 medium-and high-quality microbial MAGs and obtained 5,403 non-redundant MAGs (nrMAGs) with strain-level resolution. We found that, thanks to the high taxonomic resolution of nrMAGs, the gut microbiome signatures can accurately distinguish COVID-19 cases from healthy controls and predict the progression of COVID-19. Moreover, we identified a set of nrMAGs with a putative causal role in the clinical manifestations of COVID-19 and revealed their functional pathways that potentially interact with SARS-CoV-2 infection. The presented results highlight the importance of incorporating the human gut microbiome in our understanding of SARS-CoV-2 infection and disease progression. The genomic content of nrMAGs presented here has the potential to inform microbiome-based therapeutic developments for COVID-19 progression and post-COVID conditions.