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P168 Table 1Overall safety showing proportion of participants with AEsParticipants, n (%) Cohort 1n=12 Cohort 2n=12 Cohort 3n=12 Cohort 4n=12 Cohort 8n=5 TotalN=53 Any AE 11 (92) 7 (58) 9 (75) 7 (58) 4 (80) 38 (72) Grade ≥3 AE 6 (50) 2 (17) 1 (8) 4 (33) 2 (40) 15 (28) SAE 5 (42) 2 (17) 0 3 (25) 1 (20) 11 (21) Treatment discontinuation due to AE 2 (17) 0 0 0 0 2 (4) Treatment-emergent death 1 (8) 1 (8) 0 0 1 (20) 3 (6) Grade 3–4 laboratory abnormalities 9 (75) 2 (17) 4 (33) 4 (36) 3 (60) 22 (42) ConclusionsRDV was generally well tolerated in children hospitalised for COVID-19 who were 28 days and older, weighing at least 3 kg. No new safety trends for RDV were identified and a high proportion of participants had clinical improvement. CARAVAN is ongoing for enrolment of full term and preterm neonates.
ABSTRACT
Background: The continuing spread of SARS-CoV-2 provides opportunities for the virus to evolve. Compared to ancestral strains, the 4 major variants of concern (VOC) exhibit Spike mutations that improve entry and/or diminish antibody neutralization. However, mutations have arisen in other viral genes. Several of these genes may counteract innate immunity mediated by antiviral interferons (IFNs). IFNs show extensive diversity, but only IFNα2 and IFNβ are approved for clinical use. We showed previously that diverse IFNs exhibit variable activities against HIV-1 and trigger distinct transcriptomes. Methods: To assess whether SARS-CoV-2 acquired human IFN resistance over time, isolates representing early lineages A, B, B.1, and VOC lineages B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.2 (delta) were tested for sensitivity to multiple IFNs in an alveolar type II epithelial cell (AT2) line, A549, overexpressing ACE2. Cells were pre-treated with IFNs for 18 h in triplicate, then infected to yield ∼105 copies/reaction. Virus copy numbers were evaluated at 24 h by qPCR. We compared the sensitivity of 5 SARS-CoV-2 isolates to 12 IFNα subtypes, IFNβ, IFNω and 3 IFNa;subtypes at 2 pM, within the dynamic range of preliminary IFN inhibition curves. IC50s for IFNβ and IFNa;1 were compared between lineage B and VOC isolates. Results: Among the 17 IFNs tested, IFNβ, IFNα8, IFNω and IFNα5 most potently inhibited SARS-CoV-2 in A549-ACE2 cells. Inhibition curves with a delta variant isolate showed that IFNα2 and IFNa;1 had >10-fold and >1000-fold higher IC50 than IFNβ, respectively. Interestingly, the antiviral activity patterns of diverse IFNα subtypes against SARS-CoV-2 and HIV-1 were different and did not significantly correlate. Compared to the ancestral lineage B, the alpha, beta, gamma and delta variants exhibited on average 5.2-fold (range: 1.9-8.2) and 6.7-fold (range: 1.3-21) fold higher IC50s for IFNβ and IFNa;1, respectively. The alpha and delta isolates were also more resistant to IFNβ and IFNa;1 than a lineage B.1 isolate in another AT2 cell line, Calu-3. Conclusion: Our findings suggest that diverse IFNs may have evolved to restrict distinct virus families. Emerging SARS-CoV-2 variants are more effective than earlier pandemic viruses at antagonizing antiviral IFN responses. These data have implications for deploying IFNs for early COVID-19 therapy and suggest that innate immunity may be a driving force for SARS-CoV-2 evolution.
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Study Objectives: For several weeks in March and April 2020, New York City was the global epicenter of the COVID-19 outbreak. Minority populations in the Bronx were disproportionately affected. Since the beginning of the outbreak, there has been speculation that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) may worsen outcomes among patients with COVID-19. Methods: This was a retrospective case series. We included patients >= 16 years with COVID-19 who presented to one of five EDs between March 9, 2020 and April 4, 2020 in the New York City borough of the Bronx. The population was largely Black and Hispanic. Included were 1,122 laboratory-confirmed cases of COVID-19, and 22 COVID-negative cases in which the clinical suspicion for disease remained high despite negative testing. Laboratory confirmation of COVID-19 was performed with reverse-transcriptase polymerase chain reaction (RT-PCR) assays on nasopharyngeal swab specimens. We abstracted data from the medical record on whether the patient had a current prescription for an ACE-I or ARB, as well as data on hypertension (HTN), diabetes (DM), chronic kidney disease (CKD), and congestive heart failure (CHF). Clinical outcomes included death, ICU admission, and need for renal replacement therapy (RRT). We determined inter-rater reliability for 10% of the data. We report Spearman’s rho and p values for each variable and clinical outcomes. We performed a logistic regression model in which death was the primary outcome and each of the predictor variables listed above were entered and retained in the model. P <0.05 was considered statistically significant. Results: The mean age of our patient population was 62.0 (SD 16.1). Thirty-two percent of patients self-reported Spanish/Hispanic/Latino ethnicity, 42% reported their race as Black or African-American, 9% reported their race as non-Hispanic white, 2% reported their race as Asian, and 13% reported their race as mixed or other. There were no statistically significant associations between ACE-I or ARB prescription with admission to the ICU or the need for RRT. There was an association between ACE-I and ARB prescription and mortality (rho = 0.11, p<0.001), though not between ACEI/ARB prescription and ICU admission or need for RRT. In a multivariable logistic regression model in which we controlled for medical co-morbidities, ACEI/ARB prescription was associated with mortality (OR 1.39, 95% CI 1.03-1.87) after controlling for HTN (OR 1.72, 95% CI 1.20-2.47), CKD (OR = 1.45, 95% CI = 1.05-1.90), DM (OR 1.00, 95% CI 0.96-1.05), and HF (OR 1.14, 95% CI 0.77-1.70). Inter-rater reliability was 96%. Conclusion: Prescriptions for ACE-I or ARB were associated with increased mortality among patients >= 16 years old admitted to the hospital with COVID-19 after controlling for medical comorbidities.
ABSTRACT
Study Objectives: For several weeks in March and April 2020, New York City was the global epicenter of the COVID-19 outbreak. Minority populations in the Bronx were disproportionately affected. Clinical practice changed significantly, with clinicians ordering many non-routine labs and inflammatory markers from the emergency department (ED) on patients with suspected COVID-19 in a frantic attempt to gain more information about the disease and the patient. The objective of this study is to assess the utility of these laboratory tests in predicting poor clinical outcomes. Methods: This was a retrospective case series including all admissions of adult and pediatric patients >= 16 years with COVID-19 who presented to one of five EDs between March 9, 2020 and April 4, 2020 in the New York City borough of the Bronx. The population was largely Black and Hispanic. Included were 1,122 laboratory-confirmed cases of COVID-19, and 22 COVID-19-negative cases in which the clinical suspicion for false remained high. Laboratory confirmation of COVID-19 was performed with reverse-transcriptase polymerase chain reaction (RT-PCR) assays on nasopharyngeal swab specimens. The lab values analyzed were lactate dehydrogenase (LDH), white blood cell count (WBC), absolute lymphocyte count (ALC), D-dimer, ferritin, procalcitonin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Clinical outcomes included death, ICU admission, and need for renal replacement therapy (RRT). Each variable was manually extracted from electronic health records. The first lab value within 48 hours of arrival to the ED was recorded. We determined inter-rater reliability for 10% of the data. We report Spearman’s rho and p values for each variable and clinical outcomes. P <0.05 was considered statistically significant. Results: The mean age of our patient population was 62.0 (SD 16.1). Thirty-two percent of patients self-reported Spanish/Hispanic/Latino ethnicity, 42% reported their race as Black or African-American, 9% reported their race as non-Hispanic white, 2% reported their race as Asian, and 13% reported their race as mixed or other. We observed the following statistically significant associations between the laboratory values and patient death, ICU admission, or need for RRT: procalcitonin (0.44 for death, 0.38 for ICU admission, 0.38 for RRT), CRP (0.29 for death, 0.29 for ICU admission, 0.15 for RRT), and D-dimer (0.28 for death, 0.15 for ICU admission, 0.12 for RRT). ALC and creatinine were also significantly correlated with outcomes. WBC was not consistently or meaningfully associated with outcomes. ESR and ferritin did not show significant correlation with outcomes. Inter-rater reliability was 96%. Conclusion: Procalcitonin, CRP, and D-dimer are correlated with clinical outcomes like death, admission to the ICU, and the need for RRT. WBC, ESR and ferritin were not meaningfully associated with outcomes. If these tests are being ordered for their prognostic value, we suggest ED providers not order these latter tests routinely in patients with suspected COVID-19.