Clinical and genomic signatures of rising SARS-CoV-2 Delta breakthrough infections in New York (preprint)

In 2021, Delta has become the predominant SARS-CoV-2 variant worldwide. While vaccines effectively prevent COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occur. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contribute to increased rates of breakthrough infections compared to unvaccinated controls. Here, we show a steep and near complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25, its spike mutation S112L, and nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthroughs increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. Our data indicate a limited impact of vaccine escape in favor of Delta’s increased epidemic growth in times of waning vaccine protection.

Trends in Covid-19 risk-adjusted mortality rates in a single health system (preprint)

Early reports showed high mortality from Covid-19; by contrast, the current outbreaks in the southern and western United States are associated with fewer deaths, raising hope that treatments have improved. However, in Texas for instance, 63% of diagnosed cases are currently under 50, compared to only 52% nationally in March-April. Current demographics in Arizona and Florida are similar. Therefore, whether decreasing Covid-19 mortality rates are a reflection of changing demographics or represent improvements in clinical care is unknown. We assessed outcomes over time in a single health system, accounting for changes in demographics and clinical factors. Methods We analyzed biweekly mortality rates for admissions between March 1 and June 20, 2020 in a single health system in New York City. Outcomes were obtained as of July 14, 2020. We included all hospitalizations with laboratory-confirmed Covid-19 disease. Patients with multiple hospitalizations (N=157, 3.3%) were included repeatedly if they continued to have laboratory-confirmed disease. Mortality was defined as in-hospital death or discharge to hospice care. Based on prior literature, we constructed a multivariable logistic regression model to generate expected risk of death, adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, C reactive protein, ferritin, and cycle threshold for RNA detection. All data were obtained from the electronic health record. We then calculated the sum of observed and expected deaths in each two-week period and multiplied each period's observed/expected (O/E) risk by the overall average crude mortality to generate biweekly adjusted rates. We calculated Poisson control limits and indicated points outside the control limits as significantly different, following statistical process control standards. The NYU institutional review board approved the study and granted a waiver of consent. Results We included 4,689 hospitalizations, of which 4,661 (99.4%) had died or been discharged. The median age, and the proportion male or with any comorbidity decreased over time; median real-time PCR cycle threshold increased (indicating relatively less concentration of virus) (Table). For instance, median age decreased from 67 years in the first two weeks to 49 in the last two. Peak hospitalizations were during the fifth and sixth study weeks, which accounted for 40% of the hospitalizations. Median length of stay for patients who died or were discharged to hospice was 8 days (interquartile range, 4-16). Unadjusted mortality dropped each period, from 30.2% in the first two weeks to 3% in the last two weeks, with the last eight weeks being lower than the 95% control limits. Risk adjustment partially attenuated the mortality decline, but adjusted mortality rates in the second-to-last two weeks remained outside the control limits (Figure, Table). The O/E risk of mortality decreased from 1.07 (0.64-1.67) in the first two weeks to 0.39 (0.08-1.12) in the last two weeks. Discussion In this 16-week study of Covid-19 mortality at a single health system, we found that changes in demographics and severity of illness at presentation account for some, but not all, of the decrease in unadjusted mortality. Even after risk adjustment for a variety of clinical and demographic factors, mortality was significantly lower towards the end of the study period. Incremental improvements in outcomes are likely a combination of increasing clinical experience, decreasing hospital volume, growing use of new pharmacologic treatments (such as corticosteroids, remdesivir and anti-cytokine treatments), non-pharmacologic treatments (such as proning), earlier intervention, community awareness, and lower viral load exposure from increasing mask wearing and social distancing. It is also possible that earlier periods had a more virulent circulating strain. In summary, data from one health system suggest that Covid-19 remains a serious disease for high risk patients, but that outcomes may be improving.

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City (preprint)

Background: Little is known about factors associated with hospitalization and critical illness in Covid-19 positive patients. Methods: We conducted a cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020. Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death). We conducted multivariable logistic regression to identify risk factors for adverse outcomes, and maximum information gain decision tree classifications to identify key splitters. Results: Among 4,103 Covid-19 patients, 1,999 (48.7%) were hospitalized, of whom 981/1,999 (49.1%) have been discharged home, and 292/1,999 (14.6%) have died or were discharged to hospice. Of 445 patients requiring mechanical ventilation, 162/445 (36.4%) have died. Strongest hospitalization risks were age [≥]75 years (OR 66.8, 95% CI, 44.7-102.6), age 65-74 (OR 10.9, 95% CI, 8.35-14.34), BMI>40 (OR 6.2, 95% CI, 4.2-9.3), and heart failure (OR 4.3 95% CI, 1.9-11.2). Strongest critical illness risks were admission oxygen saturation <88% (OR 6.99, 95% CI 4.5-11.0), d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95% CI, 2.6-13.8). In the decision tree for admission, the most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200. Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.