BACKGROUND: Risk of severe coronavirus disease 2019 (COVID-19) increases with age, is greater in males, and is associated with decreased numbers of blood lymphoid cells. Though the reasons for these robust associations are unclear, effects of age and sex on innate and adaptive lymphoid subsets, including on homeostatic innate lymphoid cells (ILCs) implicated in disease tolerance, may underlie the effects of age and sex on COVID-19 morbidity and mortality. METHODS: Flow cytometry was used to quantitate subsets of blood lymphoid cells from people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comparing those hospitalized with severe COVID-19 (n=40) and those treated as outpatients for less severe disease (n=51). 86 healthy individuals served as controls. The relationship between abundance of specific blood lymphoid cell types, age, sex, hospitalization, duration of hospitalization, and elevation of blood markers for systemic inflammation, was determined using multiple regression. RESULTS: After accounting for effects of age and sex, hospitalization for COVID-19 was associated with 1.78-fold fewer ILCs (95%CI: 2.34–1.36; p = 4.55 x 10−5) and 2.31-fold fewer CD16+ natural killer (NK) cells (95%CI: 3.1–1.71; p = 1.04 x 10−7), when compared to uninfected controls. Among people infected with SARS-CoV-2, the odds ratio for hospitalization, adjusted for age, sex, and duration of symptoms, was 0.413 (95%CI: 0.197–0.724; p = 0.00691) for every 2-fold increase in ILCs. In addition, higher ILC abundance was associated with less time spent in the hospital and lower levels of blood markers associated with COVID-19 severity: each two-fold increase in ILC abundance was associated with a 9.38 day decrease in duration of hospital stay (95% CI: 15.76–3.01; p= 0.0054), and decrease in blood C-reactive protein (CRP) by 46.29 mg/L (95% CI: 71.34–21.24; p = 6.25 x 10−4), erythrocyte sedimentation rate (ESR) by 11.04 mm/h (95% CI: 21.94–0.13; p = 0.047), and the fibrin degradation product D-dimer by 1098.52 ng/mL (95% CI: 1932.84–264.19; p = 0.011). CONCLUSIONS: Both ILCs and NK cells were depleted in the blood of people hospitalized for severe COVID-19, but, among lymphoid cell subsets, only ILC abundance was independently associated with the need for hospitalization, duration of hospital stay, and severity of inflammation. These results indicate that, by promoting disease tolerance, homeostatic ILCs protect against morbidity and mortality in SARS-CoV-2 infection, and suggest that reduction in the number of ILCs with age and in males accounts for the increased risk of severe COVID-19 in these demographic groups
