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Although most individuals recover from acute SARS-CoV-2 infection, a significant number continue to suffer from Post-Acute Sequelae of SARS-CoV-2 (PASC), including the unexplained symptoms that are frequently referred to as long COVID, which could last for weeks, months, or even years after the acute phase of illness. The National Institutes of Health is currently funding large multi-center research programs as part of its Researching COVID to Enhance Recover (RECOVER) initiative to understand why some individuals do not recover fully from COVID-19. Several ongoing pathobiology studies have provided clues to potential mechanisms contributing to this condition. These include persistence of SARS-CoV-2 antigen and/or genetic material, immune dysregulation, reactivation of other latent viral infections, microvascular dysfunction, and gut dysbiosis, among others. Although our understanding of the causes of long COVID remains incomplete, these early pathophysiologic studies suggest biological pathways that could be targeted in therapeutic trials that aim to ameliorate symptoms. Repurposed medicines and novel therapeutics deserve formal testing in clinical trial settings prior to adoption. While we endorse clinical trials, especially those that prioritize inclusion of the diverse populations most affected by COVID-19 and long COVID, we discourage off-label experimentation in uncontrolled and/or unsupervised settings. Here, we review ongoing, planned, and potential future therapeutic interventions for long COVID based on the current understanding of the pathobiological processes underlying this condition. We focus on clinical, pharmacological, and feasibility data, with the goal of informing future interventional research studies.

Nirmatrelvir–ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease. There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir–ritonavir with 10-day and 15-day regimens. This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigned and dosed participants with sustained nasopharyngeal SARS-CoV-2 RNA concentrations below the lower limit of quantification (2·0 log10 copies per mL) from days 15 to 44. Secondary endpoints included the incidence of viral rebound after the end of treatment up to day 44. Safety, a secondary endpoint, was assessed in all randomly assigned participants who received at least one dose of nirmatrelvir–ritonavir. This trial was registered with ClinicalTrials.gov (NCT05438602) and is completed. Among 156 participants (84 female, 72 male) randomly assigned from Aug 3, 2022 to July 17, 2023, 150 comprised the analysis population. The primary endpoint was reached in 32 (61·5%, 95% CI 48·3–74·8) of 52 participants in the 5-day treatment group, 34 (70·8%, 58·0–83·7) of 48 participants in the 10-day treatment group, and 33 (66·0%, 52·9–79·1) of 50 participants in the 15-day treatment group. Viral rebound occurred in 17·3% (95% CI 8·2–30·3) of participants in the 5-day group, 2·1% (0·1–11·1) in the 10-day group, and 2·0% (0·1–10·6) in the 15-day group. Adverse events occurred in 28 (52·8%) of 53, 34 (66·7%) of 51, and 31 (60·8%) of 51 participants across the 5-day, 10-day, and 15-day groups, respectively. Two COVID-19-related hospitalisations were reported, both in the 5-day treatment group. No difference was observed between the three treatment durations in the primary endpoint. Extending nirmatrelvir–ritonavir treatment beyond 5 days resulted in a nominal improvement in the frequency of viral rebound and was generally well tolerated. Pfizer.

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from “higher-risk” units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. “Higher-risk” CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with “lower-risk” units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex–activated coagulopathy.

Background Low blood absolute lymphocyte count (ALC) may predict severe COVID-19 outcomes. Knowledge gaps remain regarding the relationship of ALC trajectory with clinical outcomes and factors associated with lymphopenia. Methods Our post hoc analysis of the Therapeutics for Inpatients with COVID-19 platform trial utilized proportional hazards models to assess relationships between Day (D) 0 lymphopenia (ALC < 0.9 cells/uL), D0 severe lymphopenia (ALC < 0.5 cells/uL) or lymphopenia trajectory between D0 and D5 with mortality and secondary infections, and with sustained recovery using Fine-Gray models. Logistic regression was used to assess relationships between clinical variables and D0 lymphopenia or lymphopenia trajectory. Results D0 lymphopenia (1426/2579) and severe lymphopenia (636/2579) were associated with increased mortality (aHR 1.48; 1.08, 2.05, p  = 0.016 and aHR 1.60; 1.20, 2.14, p  = 0.001) and decreased recovery (aRRR 0.90; 0.82, 0.99, p  = 0.033 and aRRR 0.78; 0.70, 0.87, p  < 0.001 respectively). Trial participants with persistent D5 lymphopenia had increased mortality, and increased secondary infections, and participants with persistent or new lymphopenia had impaired recovery, as compared to participants with no lymphopenia. Persistent and new lymphopenia were associated with older age, male sex; prior immunosuppression, heart failure, aspirin use, and normal body mass index; biomarkers of organ damage (renal and lung), and ineffective immune response (elevated IL-6 and viral nucleocapsid antigen levels). Similar results were observed with severe lymphopenia. Conclusions Lymphopenia was predictive of severe COVID-19 outcomes, particularly when persistent or new during hospitalization. A better understanding of the underlying risk factors for lymphopenia will help illuminate disease pathogenesis and guide management strategies.

(1) Background: Several retrospective observational analyzed treatment outcomes for COVID-19; (2) Methods: Inverse probability of censoring weighting (IPCW) was applied to correct for bias due to informative censoring in database of hospitalized patients who did and did not receive convalescent plasma; (3) Results: When compared with an IPCW analysis, overall mortality was overestimated using an unadjusted Kaplan–Meier curve, and hazard ratios for the older age group compared to the youngest were underestimated using the Cox proportional hazard models and 30-day mortality; (4) Conclusions: An IPCW analysis provided stabilizing weights by hospital admission.

Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm , exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm at any time during 48-week analysis periods through week 192. Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm , 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm at any time vs those sustaining <200 cells/mm . No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm . Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Background Patients with malignancy are particularly vulnerable to infection with Severe Acute Respiratory Disease‐Coronavirus‐2 (SARS‐CoV‐2) given their immunodeficiency secondary to their underlying disease and cancer‐directed therapy. We report a case series of patients with cancer who received convalescent plasma, an investigational therapy for severe Coronavirus Disease 2019 (COVID‐19). Methods Patients with cancer were identified who received convalescent plasma. Enrolled patients had confirmed COVID‐19 with severe or life‐threatening disease and were transfused with convalescent plasma from donors with a SARS‐CoV‐2 anti‐spike antibody titer of ≥ 1:320 dilution. Oxygen requirements and clinical outcomes of interests were captured as well as laboratory parameters at baseline and 3 days after treatment. Results We identified 24 patients with cancer, 14 of whom had a hematological malignancy, who were treated with convalescent plasma. Fifteen patients (62.5%) were on cancer‐directed treatment at the time of COVID‐19 infection. After a median of hospital duration of 9 days, 13 patients (54.2%) had been discharged home, 1 patient (4.2%) was still hospitalized, and 10 patients had died (41.7%). Non‐intubated patients, particularly those on nasal cannula alone, had favorable outcomes. Three mild febrile non‐hemolytic transfusion reactions were observed. C‐reactive protein significantly decreased after 3 days of treatment, while other laboratory parameters including ferritin and D‐dimer remained unchanged. Conclusions Convalescent plasma may be a promising therapy in cancer patients with COVID‐19. Patients with cancer are particularly vulnerable to infection with COVID‐19 given immunodeficiency secondary to their underlying disease and cancer‐directed therapy. Here, we report a case series of 24 cancer patients with COVID‐19 treated with convalescent plasma. Non‐intubated patients, particularly those on nasal cannula alone, had favorable outcomes, suggesting convalescent plasma may be a viable treatment options for cancer patients with COVID‐19, particularly if utilized early in the disease course.

Diversity drives excellence. Diversity enhances innovation in biomedical sciences and, as it relates to novel findings and treatment of diverse populations, in the field of infectious diseases. There are many obstacles to achieving diversity in the biomedical workforce, which create challenges at the levels of recruitment, retention, education, and promotion of individuals. Here we present the challenges, opportunities, and suggestions for the field, institutions, and individuals to adopt in mitigating bias and achieving greater levels of equity, representation, and excellence in clinical practice and research. Our findings provide optimism for a bright future of fair and collaborative approaches that will enhance the power of our biomedical workforce.

Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients ( n  = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival ( P  < 0.0001, P  = 0.0205 and P  = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients ( n  = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. Elevated levels of serum IL-6 and TNF-α at the time of hospitalization are independent and significant predictors of clinical outcome in two cohorts of patients with COVID-19.