Disrupted seasonality and association of COVID-19 with medically attended respiratory syncytial virus infections among young children in the US: January 2010-January 2023 (preprint)

Respiratory syncytial virus (RSV) infections and hospitalizations surged sharply in 2022 among young children. To assess whether COVID-19 contributed to this surge, we leveraged a real-time nation-wide US database of electronic health records (EHRs) using time series analysis from January 1, 2010 through January 31, 2023, and propensity-score matched cohort comparisons for children aged 0-5 years with or without prior COVID-19 infection. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. The monthly incidence rate for first-time medically attended cases, most of which were severe RSV-associated diseases, reached a historical high rate of 2,182 cases per 1,0000,000 person-days in November 2022, corresponding to a related increase of 143% compared to expected peak rate (rate ratio: 2.43, 95% CI: 2.25-2.63). Among 228,940 children aged 0-5 years, the risk for first-time medically attended RSV during 10/2022-12/2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (risk ratio or RR: 1.40, 95% CI: 1.27-1.55); and among 99,105 children aged 0-1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR: 1.40, 95% CI: 1.21-1.62). These data provide evidence that COVID-19 contributed to the 2022 surge of severe pediatric RSV cases.

Disruption in seasonality, patient characteristics and disparities of respiratory syncytial virus infection among young children in the US during and before the COVID-19 pandemic: 2010-2022 (preprint)

Respiratory syncytial virus (RSV) infections and hospitalization have surged sharply among young children. Here we test how the seasonal patterns of RSV infections in 2022 compared with those from other COVID-19 pandemic and pre-pandemic years. For this purpose, we analyzed a nation-wide and real-time database of electronic health records of 56 million patients across 50 states in the US. The monthly incidence rate of first-time RSV infection in young children (0-5 years of age) and very young children (0-1 year of age) followed a seasonal pattern from 2010 to 2019 with increases during the autumn, peaking in winter, subsiding in spring and summer. This seasonal pattern was significantly disrupted during the COVID-19 pandemic. In 2020, the incidence rate of RSV infections was remarkably low throughout the year. In 2021, the RSV season expanded to 9 months starting in the early summer and peaking in October. In 2022, RSV infections started to rise in May and were significantly higher than in previous years reaching a historically highest incidence rate in November 2022. There were significant racial and ethnic disparities in the peak RSV infection rate during 2010-2021 and the disparities further exacerbated in 2022 with peak incidence rate in black and Hispanic children 2-3 times that in white children. Among RSV-infected children in 2022, 19.2% had prior documented COVID-19 infection, significantly higher than the 9.7% among uninfected children, suggesting that prior COVID-19 could be a risk factor for RSV infection or that there are common risk factors for both viral infections. Our study calls for continuous monitoring of RSV infection in young children alongside its clinical outcomes and for future work to assess potential COVID-19 related risk factors.

COVID-19 rebound after Paxlovid treatment during Omicron BA.5 vs BA.2.12.1 subvariant predominance period (preprint)

Paxlovid was authorized by FDA to treat mild-to-moderate COVID-19. In May 2022, the Centers for Disease Control and Prevention (CDC) issued a Health Alert Network Health Advisory on potential COVID-19 rebound after Paxlovid treatment. Since June 2022, Omicron BA.5 has become the dominant subvariant in the US, which is more resistant to neutralizing antibodies than the previous subvariant BA.2.12.1. Questions remain as to how COVID-19 rebound after Paxlovid treatment differs between the BA.5 and BA.2.12.1 subvariants. This is a retrospective cohort study of 15,913 patients who contracted COVID-19 between 5/8/2022-7/18/2022 and were prescribed Paxlovid within 5 days of their COVID-19 infection. The study population was divided into 2 cohorts: (1) BA.5 cohort (n=5,161) that comprised patients who contracted COVID-19 during 6/19/22-7/18/22 when BA.5 was the predominant subvariant2. (2) BA.2.12.1 cohort (n=10,752) that comprised patients who contracted COVID-19 during 5/8/22-6/18/22 when the BA.2.12.1 was the predominant subvariant. The risks of both COVID-19 rebound infections and symptoms 2-8 days after Paxlovid treatment were higher in the BA.5 cohort than in the propensity-score matched BA.2.12.1 cohort: rebound infections (Hazard Ratio or HR: 1.32, 95% CI: 1.06-1.66), rebound symptoms (HR: 1.32, 95% CI: 1.04-1.68). As SARS-CoV-2 evolves with successive subvariants more evasive to antibodies, continuous vigilant monitoring is necessary for COVID-19 rebounds after Paxlovid treatment and longer time duration of Paxlovid treatment warrants evaluation.

COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022 (preprint)

Abstract Importance Recent case reports document that some patients who were treated with Paxlovid experienced rebound COVID-19 infections and symptoms 2 to 8 days after completing a 5-day course of Paxlovid. The Centers for Disease Control and Prevention (CDC) has recently issued a Health Alert Network Health Advisory to update the public on the potential for COVID-19 rebound after Paxlovid treatments. However, the rates of COVID-19 rebound in a real-world population or whether rebound is unique to Paxlovid remains unknown. Objectives To examine the rates and relative risks of COVID-19 rebound in patients treated with Paxlovid or with Molnupiravir and to compare characteristics of patients who experienced COVID-19 rebound to those who did not. Design, Setting, and Participants Retrospective cohort study of electronic health records (EHRs) of 92 million patients from a multicenter and nationwide database in the US. The study population comprised 13,644 patients age 18 years or older who contracted COVID-19 between 1/1/2022-6/8/2022 and were treated with Paxlovid (n =11,270) or with Molnupiravir (n =2,374) within 5 days of their COVID-19 infection. Exposures Paxlovid or Molnupiravir. Main Outcomes and Measures Three types of COVID-19 rebound outcomes (COVID-19 infections, COVID-19 related symptoms, and hospitalizations) were examined. Hazard ratios and 95% confidence interval (CI) of 7-day and 30-day risk for COVID-19 rebound between patients treated with Paxlovid and patients treated with Molnupiravir were calculated before and after propensity-score matching. Results The 7-day and 30-day COVID-19 rebound rates after Paxlovid treatment were 3.53% and 5.40% for COVID-19 infection, 2.31% and 5.87% for COVID-19 symptoms, and 0.44% and 0.77% for hospitalizations. The 7-day and 30-day COVID-19 rebound rates after Molnupiravir treatment were 5.86% and 8.59% for COVID-19 infection, 3.75% and 8.21% for COVID-19 symptoms, and 0.84% and 1.39% for hospitalizations. After propensity-score matching, there were no significant differences in COVID-19 rebound risks between Paxlovid and Molnupiravir: infection (HR 0.90, 95% CI: 0.73-1.11), COVID-19 symptoms (HR: 1.03, 95% CI: 0.83-1.27), or hospitalizations (HR: 0.92, 95% CI: 0.56-1.55). Patients with COVID-19 rebound had significantly higher prevalence of underlying medical conditions than those without. Conclusions and Relevance COVID-19 rebound occurred both after Paxlovid and Molnupiravir, especially in patients with underlying medical conditions. This indicates that COVID-19 rebound is not unique to Paxlovid and the risks were similar for Paxlovid and Molnupiravir. For both drugs the rates of COVID-19 rebound increased with time after treatments. Our results call for continuous surveillance of COVID-19 rebound after Paxlovid and Molnupiravir treatments. Studies are necessary to determine the mechanisms underlying COVID-19 rebounds and to test dosing and duration regimes that might prevent such rebounds in vulnerable patients.

COVID infection rates, clinical outcomes, and racial/ethnic and gender disparities before and after Omicron emerged in the US (preprint)

BackgroundSARS-CoV-2 infections and hospitalizations are rising in the US and other countries after the emergence of the Omicron variant. Currently, data on infection rates, severity and racial/ethnic and gender disparities from Omicron in the US is limited. MethodWe performed a retrospective cohort study of a large, geographically diverse database of patient electronic health records (EHRs) in the US. The study population comprised 881,473 patients who contracted SARS-CoV-2 infection for the first time between 9/1/2021-1/16/2022, including 147,964 patients infected when Omicron predominated (Omicron cohort), 633,581 when Delta predominated (Delta cohort) and another 99,928 infected when the Delta predominated but just before the Omicron variant was detected in the US (Delta-2 cohort). We examined monthly incidence rates of COVID-19 infections stratified by age groups, gender, race and ethnicity, compared severe clinical outcomes including emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and mechanical ventilation use between propensity-score matched Omicron and Delta cohorts stratified by age groups (0-4, 5-17, 18-64 and [≥] 65 years), and examined racial/ethnic and gender differences in severe clinical outcomes. FindingsAmong 147,964 infected patients in the Omicron cohort (average age: 39.1 years), 56.7% were female, 2.4% Asian, 21.1% Black, 6.2% Hispanic, and 51.8% White. The monthly incidence rate of COVID infections (new cases per 1000 persons per day) was 0.5-0.7 when Delta predominated, and rapidly increased to 3.8-5.2 when Omicron predominated. In January 2022, the infection rate was highest in children under 5 years (11.0) among all age groups, higher in Black than in White patients (14.0 vs. 3.8), and higher in Hispanic than in non-Hispanic patients (8.9 vs. 3.1). After propensity-score matching for demographics, socio-economic determinants of health, comorbidities and medications, risks for severe clinical outcomes in the Omicron cohort were significantly lower than in the Delta cohort: ED visits: 10.2% vs. 14.6% (risk ratio or RR: 0.70 [0.68-0.71]); hospitalizations: 2.6% vs. 4.4% (RR: 0.58 [0.55-0.60]); ICU admissions: 0.47% vs. 1.00% (RR: 0.47 [0.43-0.51]); mechanical ventilation: 0.08% vs. 0.3% (RR: 0.25 [0.20-0.31]). Similar reduction in disease severity was observed for all age groups. There were significant racial/ethnic and gender disparities in severe clinical outcomes in the Omicron cohort, with Black, Hispanic patients having more ED visits and ICU admissions than White and non-Hispanic patients, respectively and women had fewer hospitalization and ICU admission than men. InterpretationThe incidence rate of COVID infection during the omicron predominant period (prevalence >92%) was 6-8 times higher than during the Delta predominant period that preceded it consistent with greater infectivity. The incidence rate was highest among those less than 5 years of age, and in Black and Hispanic patients. COVID infections occurring when the Omicron predominated were associated with significantly less frequent severe outcomes than in matched patients when the Delta variant predominated. There were significant racial, ethnic and gender disparities in severe clinical outcomes, with Black and Hispanic patients and men disproportionally impacted.

COVID infection severity in children under 5 years old before and after Omicron emergence in the US (preprint)

Abstract Importance Pediatric SARS-CoV-2 infections and hospitalizations are rising in the US and other countries after the emergence of Omicron variant. However data on disease severity from Omicron compared with Delta in children under 5 in the US is lacking. Objectives To compare severity of clinic outcomes in children under 5 who contracted COVID infection for the first time before and after the emergence of Omicron in the US. Design, Setting, and Participants This is a retrospective cohort study of electronic health record (EHR) data of 79,592 children under 5 who contracted SARS-CoV-2 infection for the first time, including 7,201 infected when the Omicron predominated (Omicron cohort), 63,203 infected when the Omicron predominated (Delta cohort), and another 9,188 infected when the Omicron predominated but immediately before the Omicron variant was detected in the US (Delta-2 cohort). Exposures First time infection of SARS-CoV-2. Main Outcomes and Measures After propensity-score matching, severity of COVID infections including emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and mechanical ventilation use in the 3-day time-window following SARS-CoV-2 infection were compared between Omicron and Delta cohorts, and between Delta-2 and Delta cohorts. Risk ratios, and 95% confidence intervals (CI) were calculated. Results Among 7,201 infected children in the Omicron cohort (average age of 1.49 years), 47.4% were female, 2.4% Asian, 26.1% Black, 13.7% Hispanic, and 44.0% White. Before propensity score matching, the Omicron cohort were younger than the Delta cohort (average age 1.49 vs 1.73 years), comprised of more Black children, and had fewer comorbidities. After propensity-score matching for demographics, socio-economic determinants of health, comorbidities and medications, risks for severe clinical outcomes in the Omicron cohort were significantly lower than those in the Delta cohort: ED visits: 18.83% vs. 26.67% (risk ratio or RR: 0.71 [0.66-0.75]); hospitalizations: 1.04% vs. 3.14% (RR: 0.33 [0.26-0.43]); ICU admissions: 0.14% vs. 0.43% (RR: 0.32 [0.16-0.66]); mechanical ventilation: 0.33% vs. 1.15% (RR: 0.29 [0.18-0.46]). Control studies comparing Delta-2 to Delta cohorts show no difference. Conclusions and Relevance For children under age 5, first time SARS-CoV-2 infections occurring when the Omicron predominated (prevalence >92%) was associated with significantly less severe outcomes than first-time infections in similar children when the Delta variant predominated.

Comparison of outcomes from COVID infection in pediatric and adult patients before and after the emergence of Omicron (preprint)

Abstract Background The Omicron SARS-CoV-2 variant is rapidly spreading in the US since December 2021 and is more contagious than earlier variants. Currently, data on the severity of the disease caused by the Omicron variant compared with the Delta variant is limited. Here we compared 3-day risks of emergency department (ED) visit, hospitalization, intensive care unit (ICU) admission, and mechanical ventilation in patients who were first infected during a time period when the Omicron variant was emerging to those in patients who were first infected when the Delta variant was predominant. Method This is a retrospective cohort study of electronic health record (EHR) data of 577,938 first-time SARS-CoV-2 infected patients from a multicenter, nationwide database in the US during 9/1/2021-12/24/2021, including 14,054 who had their first infection during the 12/15/2021-12/24/2021 period when the Omicron variant emerged (Emergent Omicron cohort) and 563,884 who had their first infection during the 9/1/2021-12/15/2021 period when the Delta variant was predominant (Delta cohort). After propensity-score matching the cohorts, the 3-day risks of four outcomes (ED visit, hospitalization, ICU admission, and mechanical ventilation) were compared. Risk ratios, and 95% confidence intervals (CI) were calculated. Results Of 14,054 patients in the Emergent Omicron cohort (average age, 36.4), 27.7% were pediatric patients (<18 years old), 55.4% female, 1.8% Asian, 17.1% Black, 4.8% Hispanic, and 57.3% White. The Emergent Omicron cohort differed significantly from the Delta cohort in demographics, comorbidities, and socio-economic determinants of health. After propensity-score matching for demographics, socio-economic determinants of health, comorbidities, medications and vaccination status, the 3-day risks in the Emergent Omicron cohort outcomes were consistently less than half those in the Delta cohort: ED visit: 4.55% vs. 15.22% (risk ratio or RR: 0.30, 95% CI: 0.28-0.33); hospitalization: 1.75% vs. 3.95% (RR: 0.44, 95% CI: 0.38-0.52]); ICU admission: 0.26% vs. 0.78% (RR: 0.33, 95% CI:0.23-0.48); mechanical ventilation: 0.07% vs. 0.43% (RR: 0.16, 95% CI: 0.08-0.32). In children under 5 years old, the overall risks of ED visits and hospitalization in the Emergent Omicron cohort were 3.89% and 0.96% respectively, significantly lower than 21.01% and 2.65% in the matched Delta cohort (RR for ED visit: 0.19, 95% CI: 0.14-0.25; RR for hospitalization: 0.36, 95% CI: 0.19-0.68). Similar trends were observed for other pediatric age groups (5-11, 12-17 years), adults (18-64 years) and older adults (>= 65 years). Conclusions First time SARS-CoV-2 infections occurring at a time when the Omicron variant was rapidly spreading were associated with significantly less severe outcomes than first-time infections when the Delta variant predominated.