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Division of Primary Care
Department of Internal Medicine
University of Chicago
Rasika Karnik, MD, has no conflicts of interest to disclose.
Director, International HIV Training Center
Professor of Medicine
Section of Infectious Diseases and Global Health
Department of Medicine
University of Chicago
Renslow Sherer, MD, has disclosed that he has received an unrestricted research grant from Gilead Sciences.
How Long Is Long Enough?
Are current definitions of COVID-19 outcomes appropriate? At IDWeek 2021, Moestrup and colleagues presented data from a Danish study that added a longitudinal dimension to severe COVID-19 illness. Their analysis showed that readmissions or death at 90 days post discharge occurred in more than 20% of 3386 patients hospitalized with COVID-19 from March 2020 to January 2021. Older age, comorbidities, and ICU care predicted poorer long-term outcomes and a lower rate of sustained recovery, which was defined as discharge to home without readmission for ≥2 weeks. Although lower overall mortality and higher sustained recovery were seen in the second wave of COVID-19, likely due to improving standards of care, the rate of hospital readmissions and postdischarge mortality remained high. The investigators concluded that 28 days was too short a time period in which to determine COVID-19 clinical outcomes among hospitalized patients.
Similarly, we have previously argued that current definitions of severe COVID-19 illness based on oxygenation alone are incomplete at best. In our Chicago cohort, deaths and hospital readmissions still occurred among patients who met a definition of mild to moderate COVID-19. We believe that incident renal failure, myocardial infarction, myocarditis, thromboembolic disease, stroke, dementia, and other disabling sequelae should be factors in the definition of severe COVID-19 illness.
Postacute sequelae of SARS-CoV-2 (PASC) further challenge current definitions of severe COVID-19 illness. The estimated prevalence of PASC among previously hospitalized patients ranges from 10% to 33% after 2-6 months and is even higher in older patients and patients with comorbidities. In addition, a separate study found that 52% of nonhospitalized patients aged 16-30 years with COVID-19 had persistent symptoms after 6 months of illness, underscoring the high prevalence of PASC both in hospitalized patients at higher risk for severe illness and in younger, nonhospitalized patients. Taken together, these published studies and new data from IDWeek demonstrate the need to reconsider definitions of disease severity and length of follow-up when assessing COVID-19 outcomes.
Potential Treatments on the Horizon
Although the pandemic loomed over IDWeek 2021, promising data were presented on prevention and potential COVID-19 treatments for both inpatients and outpatients. The novel GM-CSF inhibitor lenzilumab significantly increased survival without ventilation for hospitalized patients receiving supplemental oxygen but not mechanical ventilation. The JAK1/2 inhibitor baricitinib—already known to reduce the risk of severe illness or death in high-risk individuals with COVID-19—was shown to reduce mortality by 19% in patients with COVID-19 receiving mechanical ventilation. In addition, the monoclonal antibody combination of casirivimab plus imdevimab reduced the risk of death or mechanical ventilation by 47% in antibody-seronegative patients with mild to moderate illness.
Among studies of antivirals, 3 doses of IV remdesivir over 3 days significantly reduced the risk of hospitalization or death in ambulatory patients with mild to moderate illness (risk reduction: 87%; P = .008) when given within 1 week of COVID-19 symptom onset. Also, the oral antiviral molnupiravir—which promotes SARS-CoV-2 mutagenesis—was shown to be active in vitro against variants of concern, including Delta, without generating treatment-emergent resistance mutations. Concomitant with the conference, a press release reported a reduction in mortality of almost 50% for outpatients with mild to moderate COVID-19 receiving molnupiravir orally for 5 days. An application for Emergency Use Authorization for molnupiravir has been submitted to the FDA.
Prevention of COVID-19 in Unvaccinated Individuals
A previous study demonstrated the efficacy of bamlanivimab as COVID-19 prophylaxis in skilled nursing facilities following exposure to a new infection. At IDWeek, Levin and colleagues broadened the scope of pre-exposure prophylaxis with monoclonal antibodies in the PROVENT study of a single IM injection of tixagevimab plus cilgavimab in unvaccinated adults at higher risk for COVID-19. They studied more than 5000 individuals with a mean age of 54 years at increased risk for severe COVID-19 illness (due to older age, obesity, or other comorbidities) for an average follow-up period of 83 days. There were 8 infections and no deaths in the tixagevimab plus cilgavimab group compared with 17 infections and 2 deaths in the placebo group, for a relative risk reduction of 77%. The pharmacology of this combination supports activity for up to 12 months, but data regarding long-term efficacy were not presented. This monoclonal antibody combination may offer a new option for COVID-19 prevention in immunocompromised patients with suboptimal vaccine responses or for unvaccinated individuals.
Should clinical trials measure COVID-19 outcomes beyond 28 days? Have you observed hospital readmissions or postdischarge deaths in patients previously hospitalized with COVID-19? Should prophylaxis with monoclonal antibodies be offered to unvaccinated individuals? Answer the polling question and join the conversation by posting in the discussion section.