Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality.

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology.

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.

Activated sputum eosinophils associated with exacerbations in children on mepolizumab.

BACKGROUND: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. OBJECTIVE: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. METHODS: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. RESULTS: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). CONCLUSIONS: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.

Host-Microbe Multiomic Profiling Reveals Age-Dependent COVID-19 Immunopathology.

Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 years of age. We performed blood transcriptomics and nasal metatranscriptomics, and measured peripheral blood immune cell populations, inflammatory protein expression, anti-SARS-CoV-2 antibodies, and anti-interferon (IFN) autoantibodies. We found that older age correlated with an increased SARS-CoV-2 viral load at the time of admission, and with delayed viral clearance over 28 days. This contributed to an age-dependent increase in type I IFN gene expression in both the respiratory tract and blood. We also observed age-dependent transcriptional increases in peripheral blood IFN-γ, neutrophil degranulation, and Toll like receptor (TLR) signaling pathways, and decreases in T cell receptor (TCR) and B cell receptor signaling pathways. Over time, older adults exhibited a remarkably sustained induction of proinflammatory genes (e.g., CXCL6) and serum chemokines (e.g., CXCL9) compared to younger individuals, highlighting a striking age-dependent impairment in inflammation resolution. Augmented inflammatory signaling also involved the upper airway, where aging was associated with upregulation of TLR, IL17, type I IFN and IL1 pathways, and downregulation TCR and PD-1 signaling pathways. Metatranscriptomics revealed that the oldest adults exhibited disproportionate reactivation of herpes simplex virus and cytomegalovirus in the upper airway following hospitalization. Mass cytometry demonstrated that aging correlated with reduced naïve T and B cell populations, and increased monocytes and exhausted natural killer cells. Transcriptional and protein biomarkers of disease severity markedly differed with age, with the oldest adults exhibiting greater expression of TLR and inflammasome signaling genes, as well as proinflammatory proteins (e.g., IL6, CXCL8), in severe COVID-19 compared to mild/moderate disease. Anti-IFN autoantibody prevalence correlated with both age and disease severity. Taken together, this work profiles both host and microbe in the blood and airway to provide fresh insights into aging-related immune changes in a large cohort of vaccine-naïve COVID-19 patients. We observed age-dependent immune dysregulation at the transcriptional, protein and cellular levels, manifesting in an imbalance of inflammatory responses over the course of hospitalization, and suggesting potential new therapeutic targets.

Analytical challenges in omics research on asthma and allergy: A National Institute of Allergy and Infectious Diseases workshop.

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants.

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

Updates in SJS/TEN: collaboration, innovation, and community.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

Relationship of Heterologous Virus Responses and Outcomes in Hospitalized COVID-19 Patients.

The clinical trajectory of COVID-19 may be influenced by previous responses to heterologous viruses. We examined the relationship of Abs against different viruses to clinical trajectory groups from the National Institutes of Health IMPACC (Immunophenotyping Assessment in a COVID-19 Cohort) study of hospitalized COVID-19 patients. Whereas initial Ab titers to SARS-CoV-2 tended to be higher with increasing severity (excluding fatal disease), those to seasonal coronaviruses trended in the opposite direction. Initial Ab titers to influenza and parainfluenza viruses also tended to be lower with increasing severity. However, no significant relationship was observed for Abs to other viruses, including measles, CMV, EBV, and respiratory syncytial virus. We hypothesize that some individuals may produce lower or less durable Ab responses to respiratory viruses generally (reflected in lower baseline titers in our study), and that this may carry over into poorer outcomes for COVID-19 (despite high initial SARS-CoV-2 titers). We further looked at longitudinal changes in Ab responses to heterologous viruses, but found little change during the course of acute COVID-19 infection. We saw significant trends with age for Ab levels to many of these viruses, but no difference in longitudinal SARS-CoV-2 titers for those with high versus low seasonal coronavirus titers. We detected no difference in longitudinal SARS-CoV-2 titers for CMV seropositive versus seronegative patients, although there was an overrepresentation of CMV seropositives among the IMPACC cohort, compared with expected frequencies in the United States population. Our results both reinforce findings from other studies and suggest (to our knowledge) new relationships between the response to SARS-CoV-2 and Abs to heterologous viruses.

Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. METHODS: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0-5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment. FINDINGS: 40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5-11) in the IC14 group vs. 5 days (95% CI, 4-10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1ß and TNF-α. INTERPRETATION: IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation. FUNDING: National Institute of Allergy and Infectious Diseases.

Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients.

The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention.

Type 2 inflammation reduces SARS-CoV-2 replication in the airway epithelium in allergic asthma through functional alteration of ciliated epithelial cells.

BACKGROUND: Despite well-known susceptibilities to other respiratory viral infections, individuals with allergic asthma have shown reduced susceptibility to severe coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to identify mechanisms whereby type 2 inflammation in the airway protects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by using bronchial airway epithelial cells (AECs) from aeroallergen-sensitized children with asthma and healthy nonsensitized children. METHODS: We measured SARS-CoV-2 replication and ACE2 protein and performed bulk and single-cell RNA sequencing of ex vivo infected AEC samples with SARS-CoV-2 infection and with or without IL-13 treatment. RESULTS: We observed that viral replication was lower in AECs from children with allergic asthma than those from in healthy nonsensitized children and that IL-13 treatment reduced viral replication only in children with allergic asthma and not in healthy children. Lower viral transcript levels were associated with a downregulation of functional pathways of the ciliated epithelium related to differentiation as well as cilia and axoneme production and function, rather than lower ACE2 expression or increases in goblet cells or mucus secretion pathways. Moreover, single-cell RNA sequencing identified specific subsets of relatively undifferentiated ciliated epithelium (which are common in allergic asthma and highly responsive to IL-13) that directly accounted for impaired viral replication. CONCLUSION: Our results identify a novel mechanism of innate protection against SARS-CoV-2 in allergic asthma that provides important molecular and clinical insights during the ongoing COVID-19 pandemic.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Host-Microbe Multi-omic Profiling Identifies a Unique Program of COVID-19 Inflammatory Dysregulation in Solid Organ Transplant Recipients.

Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant (SOT) recipients, who have atypical but poorly characterized immune responses to SARS-CoV-2 infection. We sought to understand and the host immunologic and microbial features of COVID-19 in SOT recipients by leveraging a prospective multicenter cohort of 1164 hospitalized patients. Using multi-omic immuoprofiling, we studied 86 SOT recipients in this cohort, who were age- and sex-matched 2:1 with 172 non-SOT controls. PBMC and nasal transcriptional profiling unexpectedly demonstrated upregulation of innate immune pathways related to interferon (IFN) and Toll-like receptor signaling, and complement activation, in SOT recipients. Longitudinal analyses across the first 30-days post-hospitalization demonstrated persistent upregulation of these innate immunity pathways in SOT recipients. The levels of several proinflammatory serum chemokines, such as CX3CL1 and KITLG, were also higher in SOT recipients at the time of hospitalization, although IFN-gamma levels were lower. We observed differential dynamics of CXCL11, which remained persistently elevated in SOT recipients over the course of hospitalization. Nasal microbiome alpha diversity was higher in SOT recipients versus controls, but no differences in taxonomic abundance beyond SARS-CoV-2 were observed. SOT recipients had higher nasal SARS-CoV-2 viral loads and impaired viral clearance compared to controls. Antibody analysis demonstrated lower anti-SARS-CoV-2 spike IgG levels in SOT recipients upon hospitalization, but no distinctions over time compared to controls. Mass cytometry demonstrated marked differences in blood immune cell populations, with SOT recipients exhibiting decreased plasmablasts and transitional B cells, and increased senescent T cells. Severe disease in SOT recipients was characterized by a less robust induction of inflammatory chemokines, such as IL-6 and CCL7, and a more subtle proinflammatory transcriptional response in the blood and airway. Together, our study reveals distinct immune features and altered viral dynamics in SOT recipients compared to non-SOT controls. We unexpectedly find that SOT recipients exhibit an augmented, predominantly innate immune response in both the blood and upper respiratory tract that remains relatively stable across disease severity, in contrast to non-SOT controls. These findings may relate to the paradoxical observation that SOT recipients have similar COVID-19 mortality rates versus the general population, despite being more susceptible to SARS-CoV-2 infection, remaining infectious longer, and having higher rates of hospitalization. In summary, we find that COVID-19 in SOT recipients is characterized by a biologically distinct immune state, suggesting the potential for unique prognostic biomarkers and therapeutic approaches in this vulnerable population.

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. METHODS: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per µL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. FINDINGS: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. INTERPRETATION: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. FUNDING: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study.

BACKGROUND: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. METHODS: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. FINDINGS: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63- 4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. INTERPRETATION: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. FUNDING: NIH.

Repository corticotropin injection attenuates collagen-induced arthritic joint structural damage and has enhanced effects in combination with etanercept.

BACKGROUND: Melanocortin receptor (MCR) agonists have anti-inflammatory and immunomodulatory properties mediated by receptors expressed on cells relevant to arthritis. Repository corticotropin injection (RCI; Acthar® Gel), an MCR agonist preparation, is approved as adjunctive therapy for rheumatoid arthritis (RA), but its mechanism of action in RA is unclear. This study explored the efficacy of RCI as monotherapy or adjunctive therapy with etanercept (ETN) in an established animal model of collagen-induced arthritis (CIA). METHODS: After induction of CIA, rats (n = 10 per group) were randomized to receive subcutaneous RCI (40, 160, or 400 U/kg twice daily) alone or in combination with ETN (10 mg/kg 3 times daily), ETN alone, or vehicle (on days 13 through 19). Inflammation was assessed via changes in paw edema. Bone damage was determined by microfocal computed tomography histopathology, and immunohistochemistry. Statistical analyses were performed using a 2-way analysis of variance (ANOVA) followed by the Newman-Keuls, Dunn's, or Dunnett's multiple comparisons test or a 1-way ANOVA followed by the Dunnett's or Holm-Sidak multiple comparisons test. RESULTS: RCI administration resulted in dose-dependent decreases in ankle edema and histopathologic measures of inflammation, pannus formation, cartilage damage, bone resorption, and periosteal bone formation. RCI and ETN showed combined benefits on all parameters measured. Radiographic evidence of bone damage was significantly reduced in rats that received RCI alone or in combination with ETN. This reduction in bone density loss correlated with decreases in the number of CD68-positive macrophages and cathepsin K-positive osteoclasts within the lesions. CONCLUSIONS: As monotherapy or adjunctive therapy with ETN, RCI attenuated CIA-induced joint structural damage in rats. These data support the clinical efficacy of RCI as adjunctive therapy for patients with RA.

Polyester vs polypropylene, do mesh materials matter? A meta-analysis and systematic review.

PURPOSE: Controversy exists regarding the outcomes following ventral hernia repair with polypropylene (PP) or polyester (PET) mesh. Monofilament PP less frequently requires extraction in the setting of contamination compared to multifilament PET mesh. The purpose of this systematic review and meta-analysis was to analyze the clinical outcomes of ventral hernia repair with PP and PET mesh. PATIENTS AND METHODS: A comprehensive literature search was performed using the Ovid search platform. Criteria included ventral hernia repair publications using either PP or PET mesh with a minimum follow-up duration of one year. Included studies were subject to data extraction including mesh position, weight, recurrence rates, infection, and complications. Random effect meta-analysis was run to provide pooled event rate and 95% CI. RESULTS: Ninety-seven studies including a total of 10,022 patients were included in the final analysis. Hernia recurrence rates are similar (4.8%, 95% CI [3.5-6.5] vs 4.7%, 95% CI [3.7-6.0]) as well as mesh infection rates (3.5%, 95% CI [2.5-4.9] vs 5.0%, 95% CI [3.9-6.3]) between PET and PP, respectively. Mesh infections occurred less frequently in laparoscopic repair compared to open (1.6%, 95% CI [0.9-2.6] vs 5.2%, 95% CI [4.3-6.3]). CONCLUSION: This study suggests that mesh material does not affect recurrence or infection in ventral hernia repair and that surgery can be safely performed with both PP and PET mesh. A laparoscopic approach is associated with a decreased infection rate compared to open repair independent of mesh type.