A phase II study of N-acetylcysteine in cancer patients with severe COVID-19: clinical outcomes and biological correlates (preprint)

Acute SARS-CoV-2 infection results in high mortality rates in patients with cancer with patients dying from a combination of virus and inflammation-driven respiratory failure. We conducted a two-arm, single-institution phase II study of N-acetylcysteine in patients admitted to Memorial Sloan Kettering Cancer Center with severe COVID-19 from May 2020 to April 2021. A total of 42 patients were treated: 13 patients in arm A (ICU) and 29 patients in arm B (non-ICU). In total, 23% of patients in arm A and 69% of patients in arm B met the predetermined clinical definition of treatment success. Patients meeting a successful primary endpoint were more likely to exhibit decreases in systemic levels of interleukin-6 and C-reactive protein and had both higher proportions of PD-1-expressing effector memory and fewer terminally differentiated CD8+ T-cells. These results suggest that many patients with cancer and severe COVID-19 experience clinical and immunologic improvement with N-acetylcysteine therapy.

Making the Most of Adversity: A Fully Remote Ecological Momentary Assessment and Actigraphy Study of Hospital Nurses

The COVID-19 pandemic has created challenges and opportunities for research. This is especially true for research on essential workers, such as hospital nurses. In adaptation to the pandemic, the current study aimed to assess the feasibility and acceptability of a fully remote study to collect data on psychological and behavioral measures such as daily stress and sleep, utilizing ecological momentary assessments (EMA) and sleep actigraphy. Our remote study protocol was conducted through a web platform that provided detailed video and written instructions regarding the study and facilitated virtual onboarding meetings with participants. Outpatient day shift nurses (n=86) responded to a background survey, 84 of whom completed 14 days of EMA and sleep actigraphy. Feasibility was assessed by compliance rates to the 14-day study protocol. Acceptability was assessed by analyzing qualitative feedback provided during onboarding meetings (n=82). The compliance rates of EMA (91.8%) and actigraphy (97.9%) were high. The EMA compliance was higher than that from a pre-COVID, non-remote study of inpatient day shift nurses from the same hospital (86.6%, p=.030). Themes from content analysis were mostly positive with 51.2% reporting “easy, clear, simple onboarding process” and 16.3% reporting “helpful website”. Only six participants provided solely negative feedback (e.g., “communication problems” or “technical difficulties/preferences”). Our remote study protocol was feasible and well-accepted by nurses. A similar methodology could be used in studies on broader healthcare workers and those caring for aging populations to better understand their unique challenges and develop effective strategies to help them, both during and after the pandemic.

Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity (preprint)

Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.

Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity (preprint)

Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.

Immune responses to SARS-CoV-2 in children of parents with symptomatic COVID-19 (preprint)

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have mild or asymptomatic infection, but the underlying immunological differences remain unclear. We describe clinical features, virology, longitudinal cellular and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who were repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children were similar to their parents at all timepoints. All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincided with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child had IgG antibody detected against the S1 protein and virus neutralising activity ranging from just detectable to robust titers. Using a systems serology approach, we show that all family members demonstrated higher levels of SARS-CoV-2-specific antibody features than healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological evidence of infection. This raises the possibility that despite chronic exposure, immunity in children prevents establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may therefore not identify exposed children, with implications for epidemiological and clinical studies across the life-span.

Population-scale Longitudinal Mapping of COVID-19 Symptoms, Behavior, and Testing Identifies Contributors to Continued Disease Spread in the United States (preprint)

Despite social distancing and shelter-in-place policies, COVID-19 continues to spread in the United States. A lack of timely information about factors influencing COVID-19 spread and testing has hampered agile responses to the pandemic. We developed How We Feel, an extensible web and mobile application that aggregates self-reported survey responses, to fill gaps in the collection of COVID-19-related data. How We Feel collects longitudinal and geographically localized information on users' health, behavior, and demographics. Here we report results from over 500,000 users in the United States from April 2, 2020 to May 12, 2020. We show that self- reported surveys can be used to build predictive models of COVID-19 test results, which may aid in identification of likely COVID-19 positive individuals. We find evidence among our users for asymptomatic or presymptomatic presentation, as well as for household and community exposure, occupation, and demographics being strong risk factors for COVID-19. We further reveal factors for which users have been SARS-CoV-2 PCR tested, as well as the temporal dynamics of self- reported symptoms and self-isolation behavior in positive and negative users. These results highlight the utility of collecting a diverse set of symptomatic, demographic, and behavioral self- reported data to fight the COVID-19 pandemic.