Association of GLP-1 receptor agonists and hepatocellular carcinoma incidence and hepatic decompensation in patients with type 2 diabetes.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer death. HCC is preventable with about 70 percent of HCC attributable to modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), FDA-approved medications for treating type 2 diabetes mellitus (T2DM), have pleiotropic effects on counteracting risk factors for HCC. Here we evaluate the association of GLP-1RAs with incident HCC risk in a real-world population. METHODS: This retrospective cohort included 1,890,020 patients with a diagnosis of T2DM who were prescribed GLP-1RAs or other non-GLP-1RA anti-diabetes medications and had no prior diagnosis of HCC. Incident (first-time) diagnosis of HCC and hepatic decompensating events during a 5-year follow-up was compared between cohorts of patients prescribed GLP-1 RAs vs other anti-diabetes medications. Time-to-first-event analysis was performed using Kaplan-Meier survival analysis with hazard ratio (HR) and 95% confidence interval (CI) calculated. RESULTS: GLP-1RAs were associated with a lower risk of incident HCC with HR of 0.20 [0.14-0.31], 0.39 [0.21-0.69], 0.63 [0.26-1.50] compared with insulin, sulfonylureas, and metformin respectively. GLP-1RAs were associated with a significantly lower risk of hepatic decompensation compared with six other anti-diabetes medications. Reduced risks were observed in patients without and with different stages of fatty liver diseases, with more profound effects in patients without liver diseases. Similar findings were observed in patients with and without obesity and alcohol or tobacco use disorders. GLP-1RA combination therapies were associated with decreased risk for HCC and hepatic decompensations compared with monotherapies. CONCLUSIONS: GLP-1RAs were associated with a reduced risk of incident HCC and hepatic decompensation compared to other anti-diabetes medications in patients with T2DM. These findings provide supporting evidence for future studies to investigate the underlying mechanisms and their clinical use.

GLP-1 Receptor Agonists and Colorectal Cancer Risk in Drug-Naive Patients With Type 2 Diabetes, With and Without Overweight/Obesity.

This cohort study compares glucagon-like peptide 1 receptor agonists (GLP-1RAs) with 7 non­GLP-1RA antidiabetics among drug-naive patients with type 2 diabetes.

Time trend and seasonality in medically attended respiratory syncytial virus (RSV) infections in US children aged 0-5 years, January 2010-January 2023.

OBJECTIVE: The long-term time trend and seasonality variations of first-time medically attended respiratory syncytial virus (RSV) infections among young children are unknown. We aim to examine the time trend of medically attended first-time RSV infections among young children in the USA from January 2010 through January 2023. DESIGN: This is a population-based cohort study using electronic health records (EHRs). Monthly incidence rate of medically attended first-time RSV infection (cases per 10 000 000 person-days). A time-series regression model was used to model and predict time trends and seasonality. SETTING: Multicenter and nationwide TriNetX Network in the USA. PARTICIPANTS: The study population comprised children aged 0-5 years who had medical visits during the period of January 2010 to January 2023. RESULTS: The data included 29 013 937 medical visits for children aged 0-5 years (46.5% girls and 53.5% boys) from January 2010 through January 2023. From 2010 through 2019, the monthly incidence rate of first-time medically attended RSV infection in children aged 0-5 years followed a consistent seasonal pattern. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. In 2020, the seasonal variation disappeared with a peak incidence rate of 20 cases per 1 000 000 person-days, a decrease of 97.4% from the expected peak rate (rate ratio or RR: 0.026, 95% CI 0.017 to 0.040). In 2021, the seasonality returned but started 4 months earlier, lasted for 9 months, and peaked in August at a rate of 753 cases per 1 000 000 person-days, a decrease of 9.6% from the expected peak rate (RR: 0.90, 95% CI 0.82 to 0.99). In 2022, the seasonal pattern is similar to prepandemic years but reached a historically high rate of 2182 cases per 10 000 000 person-days in November, an increase of 143% from the expected peak rate (RR: 2.43, 95% CI 2.25 to 2.63). The time trend and seasonality of the EHR-based medically attended RSV infections are consistent with those of RSV-associated hospitalisations from the Centers for Disease Control and Prevention (CDC) survey-based surveillance system. CONCLUSION: The findings show the disrupted seasonality during the COVID-19 pandemic and a historically high surge of paediatric RSV cases that required medical attention in 2022. Our study demonstrates the potential of EHRs as a cost-effective alternative for real-time pathogen and syndromic surveillance of unexpected disease patterns including RSV infection.

Association of COVID-19 with respiratory syncytial virus (RSV) infections in children aged 0-5 years in the USA in 2022: a multicentre retrospective cohort study.

OBJECTIVE: To investigate whether COVID-19 infection was associated with increased risk for incident respiratory syncytial virus (RSV) infections and associated diseases among young children that might have contributed to the 2022 surge of severe paediatric RSV cases in the USA. DESIGN: This is a retrospective population-based cohort study. Five outcomes were examined, including overall RSV infection, positive lab test-confirmed RSV infection, clinically diagnosed RSV diseases, RSV-associated bronchiolitis and unspecified bronchiolitis. Risk ratio (RR) and 95% CI of the outcomes that occurred during the 2022 and 2021 RSV seasons were calculated by comparing propensity-score matched cohorts. SETTING: Nationwide multicentre database of electronic health records (EHRs) of 61.4 million patients in the USA including 1.7 million children 0-5 years of age, which was accessed through TriNetX Analytics that provides web-based and secure access to patient EHR data from hospitals, primary care and specialty treatment providers. PARTICIPANTS: The study population consisted of 228 940 children of 0-5 years with no prior RSV infection who had medical encounters in October 2022. Findings were replicated in a separate study population of 370 919 children of 0-5 years with no prior RSV infection who had medical encounters in July 2021-August 2021 during a non-overlapping time period. RESULTS: For the 2022 study population (average age 2.4 years, 46.8% girls, 61% white, 16% black), the risk for incident RSV infection during October 2022-December 2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (RR 1.40, 95% CI 1.27 to 1.55); and among 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 to 1.62). For the 2021 study population (average age 2.2 years, 46% girls, 57% white, 20% black), the risk for incident RSV infection during July 2021-December 2021 was 4.85% for children with prior COVID-19 infection, higher than 3.68% for the matched children without COVID-19 (RR 1.32, 95% CI 1.12 to 1.56); and 7.30% for children aged 0-1 year with prior COVID-19 infection, higher than 4.98% for matched children without (RR 1.47, 95% CI 1.18 to 1.82). CONCLUSION: COVID-19 was associated with a significantly increased risk for RSV infections among children aged 0-5 years in 2022. Similar findings were replicated for a study population of children aged 0-5 years in 2021. Our findings suggest that COVID-19 contributed to the 2022 surge of RSV cases in young children through the large buildup of COVID-19-infected children and the potential long-term adverse effects of COVID-19 on the immune and respiratory system.

Cardiac and mortality outcome differences between methadone, buprenorphine and naltrexone prescriptions in patients with an opioid use disorder.

IMPORTANCE: More than 109,000 Americans died of drug overdose in 2022, with 81,231 overdose deaths involving opioids. Methadone, buprenorphine and naltrexone are the most widely used medications for opioid use disorders (MOUD) and the most effective intervention for preventing overdose deaths. However, there is a concern that methadone results in long QT syndrome, which increases the risk for fatal cardiac arrythmias. Currently few studies have systematically evaluated both the short-term and long-term differences in cardiac and mortality outcomes between MOUD. OBJECTIVES: To compare the risks of cardiac arrythmias, long QT syndrome and overall mortality between patients with opioid use disorders (OUD) who were prescribed methadone, buprenorphine or naltrexone. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study based on a multicenter and nationwide database of electronic health records (EHRs) in the United States. The study population was comprised of 144,141 patients who had medical encounters for OUD in 2016-2022, were prescribed MOUD within 1 month following a medical encounter for OUD diagnosis and had no diagnosis of cardiac arrythmias or long QT syndrome before any MOUD prescription. The study population was divided into three cohorts: (1) Methadone cohort (n = 40,938)-who were only prescribed methadone. (2) Buprenorphine cohort (n = 80,055)-who were only prescribed buprenorphine. (3) Naltrexone cohort (n = 5,738)-who were only prescribed naltrexone. EXPOSURES: methadone, buprenorphine, or naltrexone. MAIN OUTCOMES AND MEASURES: Cardiac arrythmias, long QT syndrome, and death. Hazard ratio (HR) and 95% confidence interval (CI) of outcomes at six different follow-up time frames (1-month, 3-month, 6-month, 1-year, 3-year, and 5-year) by comparing propensity-score matched cohorts using Kaplan-Meier survival analysis. RESULTS: Patients with OUD who were prescribed methadone had significantly higher risks of cardiac arrhythmias, long QT syndrome and death compared with propensity-score matched patients with OUD who were prescribed buprenorphine or naltrexone. For the 1-month follow-up, the overall risk for cardiac arrythmias was 1.03% in the Methadone cohort, higher than the 0.87% in the matched Buprenorphine cohort (HR: 1.20, 95% CI: 1.04-1.39); The overall risk for long QT syndrome was 0.35% in the Methadone cohort, higher than the 0.15% in the matched Buprenorphine cohort (HR: 2.40, 95% CI: 1.75-3.28); The overall mortality was 0.59% in the Methadone cohort, higher than the 0.41% in the matched Buprenorphine cohort (HR: 1.48, 95% CI: 1.21-1.81). The increased risk persisted for 5 years: cardiac arrhythmias (HR: 1.31, 95% CI: 1.23-1.38), long QT syndrome (HR: 3.14, 95% CI: 2.76-3.58), death (HR: 1.50, 95% CI: 1.41-1.59). CONCLUSIONS AND RELEVANCE: Methadone was associated with a significantly higher risk for cardiac and mortality outcomes than buprenorphine and naltrexone. These findings are relevant to the development of guidelines for medication selection when initiating MOUD treatment and inform future medication development for OUD that minimizes risks while maximizing benefits.

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

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.

Efficacy of oseltamivir treatment in influenza virus-infected obese mice.

Obesity has been epidemiologically and empirically linked with more severe diseases upon influenza infection. To ameliorate severe disease, treatment with antivirals, such as the neuraminidase inhibitor oseltamivir, is suggested to begin within days of infection especially in high-risk hosts. However, this treatment can be poorly effective and may generate resistance variants within the treated host. Here, we hypothesized that obesity would reduce oseltamivir treatment effectiveness in the genetically obese mouse model. We demonstrated that oseltamivir treatment does not improve viral clearance in obese mice. While no traditional variants associated with oseltamivir resistance emerged, we did note that drug treatment failed to quench the viral population and did lead to phenotypic drug resistance in vitro. Together, these studies suggest that the unique pathogenesis and immune responses in obese mice could have implications for pharmaceutical interventions and the within-host dynamics of the influenza virus population. IMPORTANCE Influenza virus infections, while typically resolving within days to weeks, can turn critical, especially in high-risk populations. Prompt antiviral administration is crucial to mitigating these severe sequalae, yet concerns remain if antiviral treatment is effective in hosts with obesity. Here, we show that oseltamivir does not improve viral clearance in genetically obese or type I interferon receptor-deficient mice. This suggests a blunted immune response may impair oseltamivir efficacy and render a host more susceptible to severe disease. This study furthers our understanding of oseltamivir treatment dynamics both systemically and in the lungs of obese mice, as well as the consequences of oseltamivir treatment for the within-host emergence of drug-resistant variants.

Association of COVID-19 with endocarditis in patients with cocaine or opioid use disorders in the US.

The incidence of endocarditis in the US is increasing, driven in part by the rise in intravenous drug use, mostly opioids and stimulant drugs (cocaine and methamphetamine). Recent reports have documented that individuals with COVID-19 are at increased risk for cardiovascular diseases. However, it is unknown whether COVID-19 is associated with increased risk for endocarditis in patients with opioid or stimulant use disorders. This is a retrospective cohort study based on a nationwide database of electronic health records (EHRs) of 109 million patients in the US, including 736,502 patients with a diagnosis of opioid use disorder (OUD) and 379,623 patients with a diagnosis of cocaine use disorder (CocaineUD). Since Metamphetamine use disorder is not coded we could not analyze it. We show that the incidence rate of endocarditis among patients with OUD or CocaineUD significantly increased from 2011 to 2022 with acceleration during 2021-2022. COVID-19 was associated with increased risk of new diagnosis of endocarditis among patients with OUD (HR: 2.23, 95% CI: 1.92-2.60) and with CocaineUD (HR: 2.24, 95% CI: 1.79-2.80). Clinically diagnosed COVID-19 was associated with higher risk of endocarditis than lab-test confirmed COVID-19 without clinical diagnosis. Hospitalization within 2 weeks following COVID-19 infection was associated with increased risk of new diagnosis of endocarditis. The risk for endocarditis did not differ between patients with and without EHR-recorded vaccination. There were significant racial and ethnic differences in the risk for COVID-19 associated endocarditis, lower in blacks than in whites and lower in Hispanics than in non-Hispanics. Among patients with OUD or CocaineUD, the 180-day hospitalization risk following endocarditis was 67.5% in patients with COVID-19, compared to 58.7% in matched patients without COVID-19 (HR: 1.21, 95% CI: 1.07-1.35). The 180-day mortality risk following the new diagnosis of endocarditis was 9.2% in patients with COVID-19, compared to 8.0% in matched patients without COVID-19 (HR: 1.16, 95% CI: 0.83-1.61). This study shows that COVID-19 is associated with significantly increased risk for endocarditis in patients with opioid or cocaine use disorders. These results highlight the need for endocarditis screening and for linkage to infectious disease and addiction treatment in patients with opioid or cocaine use disorders who contracted COVID-19. Future studies are needed to understand how COVID-19 damages the heart and the vascular endothelium among people who misuse opioids or cocaine (presumably also methamphetamines).

COVID-19 breakthrough infections and hospitalizations among vaccinated patients with dementia in the United States between December 2020 and August 2021.

INTRODUCTION: There is lack of data on COVID-19 breakthrough infections in vaccinated patients with dementia in the United States. METHODS: This is a retrospective cohort study of 262,847 vaccinated older adults (age 73.8 ± 6.81 years old) between December 2020 and August 2021. RESULTS: Among the fully vaccinated patients with dementia, the overall risk of COVID-19 breakthrough infections ranged from 8.6% to 12.4%. Patients with dementia were at increased risk for breakthrough infections compared with patients without dementia, with the highest odds for patients with Lewy body dementia (LBD) (adjusted odds ratio or AOR: 3.06, 95% confidence interval or CI [1.45 to 6.66]), followed by vascular dementia (VD) (AOR: 1.99, 95% CI [1.42 to 2.80]), Alzheimer's disease (AD) (1.53, 95% CI [1.22 to 1.92]), and mild cognitive impairment (MCI) (AOR: 1.78, 95% CI [1.51 to 2.11]). The incidence rate of breakthrough infections among fully vaccinated patients with dementia increased since December 2020 and accelerated after May 2021. The overall risk for hospitalization after breakthrough infections in patients with dementia was 39.5% for AD, 46.2% for VD, and 30.4% for MCI. DISCUSSION: These results highlight the need to continuously monitor breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and outcomes in vaccinated patients with dementia.

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.

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 (<5 years of age) and very young children (<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.

SARS-CoV-2 primary and breakthrough infections in patients with cancer: Implications for patient care.

Initial reports of SARS-CoV-2 caused COVID-19 suggested that patients with malignant diseases were at increased risk for infection and its severe consequences. In order to provide early United States population-based assessments of SARS-CoV-2 primary infections in unvaccinated patients with hematologic malignancies or cancer, and SARS-CoV-2 breakthrough infections in vaccinated patients with hematologic malignancies or cancer, we conducted retrospective studies using two, unique nationwide electronic health records (EHR) databases. Using these massive databases to provide highly statistically significant data, our studies demonstrated that, compared to patients without malignancies, risk for COVID-19 was increased in patients with all cancers and with all hematologic malignancies. Risks varied with specific types of malignancy. Patients with hematologic malignancies or cancer were at greatest risk for COVID-19 during the first year after diagnosis. Risk for infection was increased for patients 65 years and older, compared to younger patients and among Black patients compared to white patients. When patients with hematologic malignancies or cancer were vaccinated against SARS-CoV-2, their risk for breakthrough infections was decreased relative to primary infections but remained elevated relative to vaccinated patients without malignancies. Compared to vaccinated patients without malignancies, vaccinated patients with hematologic malignancy or cancer showed increased risk for infection at earlier post vaccination time points. As with primary infections, risk for breakthrough infections was greatest in patients during their first year of hematologic malignancy or cancer. There were no signs of racial disparities among vaccinated patients with hematologic malignancies or cancer. These results provide the population basis to understand the significance of subsequent immunologic studies showing relative defective and delayed immunoresponsiveness to SARS-CoV-2 vaccines among patients with hematologic malignancies and cancers. These studies further provide the basis for recommendations regarding COVID-19 vaccination, vigilance and maintaining mitigation strategies in patients with hematologic malignancies and cancers.

Time Trend and Association of Early-Onset Colorectal Cancer with Diverticular Disease in the United States: 2010-2021.

Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 young adults aged 20−49, including 298,117 with diverticular disease. We examined yearly incidence rate of first diagnosis of EOCRC from 2010 through 2021 among patients with and without diverticular disease. The 5-year risk of EOCRC among patients with pre-existing diverticular disease was compared to propensity-matched patients without diverticular disease and EOCRC and odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: The yearly incidence rate of new diagnosis of EOCRC (measured as new cases per 100,000 people per year) in young adults with pre-existing diverticular disease increased from 100 in 2010 to 402 in 2021, 4−6 times higher than in those without diverticular disease (24 in 2010 to 77 in 2021) (p < 0.001). Patients with diverticular disease were at higher risk for EOCRC than those without (OR: 1.76, 95% CI: 1.40−2.32). Conclusion: The incidence of EOCRC continuously increased from 2010 through 2021 in patients with and without diverticular disease and was 4−6 times higher among patients with diverticular disease. Patients with pre-existing diverticular disease were at a significantly increased risk for EOCRC.

Association of COVID-19 with New-Onset Alzheimer's Disease.

An infectious etiology of Alzheimer's disease has been postulated for decades. It remains unknown whether SARS-CoV-2 viral infection is associated with increased risk for Alzheimer's disease. In this retrospective cohort study of 6,245,282 older adults (age ≥65 years) who had medical encounters between 2/2020-5/2021, we show that people with COVID-19 were at significantly increased risk for new diagnosis of Alzheimer's disease within 360 days after the initial COVID-19 diagnosis (hazard ratio or HR:1.69, 95% CI: 1.53-1.72), especially in people age ≥85 years and in women. Our findings call for research to understand the underlying mechanisms and for continuous surveillance of long-term impacts of COVID-19 on Alzheimer's disease.

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

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) - 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) - 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.

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 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.

Background: SARS-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. Method: We 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. Findings: Among 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. Interpretation: The 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-19 breakthrough infections, hospitalizations and mortality in fully vaccinated patients with hematologic malignancies: A clarion call for maintaining mitigation and ramping-up research.

There has been limited data presented to characterize and quantify breakthrough SARS-CoV-2 infections, hospitalizations, and mortality in vaccinated patients with hematologic malignancies (HM). We performed a retrospective cohort study of patient electronic health records of 514,413 fully vaccinated patients from 63 healthcare organizations in the US, including 5956 with HM and 508,457 without malignancies during the period from December 2020 to October 2021. The breakthrough SARS-CoV-2 infections in patients with HM steadily increased and reached 67.7 cases per 1000 persons in October 2021. The cumulative risk of breakthrough infections during the period in patients with HM was 13.4%, ranging from 11.0% for acute lymphocytic leukemia to 17.2% and 17.4% for multiple myeloma and chronic myeloid leukemia respectively, all higher than the risk of 4.5% in patients without malignancies (p < 0.001). No significant racial disparities in breakthrough infections were observed. The overall hospitalization risk was 37.8% for patients with HM who had breakthrough infections, significantly higher than 2.2% for those who had no breakthrough infections (hazard ratio or HR: 34.49, 95% CI: 25.93-45.87). The overall mortality risk was 5.7% for patients with HM who had breakthrough infections, significantly higher than the 0.8% for those who had no breakthrough infections (HR: 10.25, 95% CI: 5.94-17.69). In summary, this study shows that among the fully vaccinated population, patients with HM had significantly higher risk for breakthrough infections compared to patients without cancer and that breakthrough infections in patients with HM were associated with significant clinical outcomes including hospitalizations and mortality.

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

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 ± 24.3 years), 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.