Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Dose, Infection, and Disease Outcomes for Coronavirus Disease 2019 (COVID-19): A Review

Abstract

The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dose, infection, and coronavirus disease 2019 (COVID-19) outcomes remains poorly understood. This review summarizes the existing literature regarding this issue, identifies gaps in current knowledge, and suggests opportunities for future research. In humans, host characteristics, including age, sex, comorbidities, smoking, and pregnancy, are associated with severe COVID-19. Similarly, in animals, host factors are strong determinants of disease severity, although most animal infection models manifest clinically with mild to moderate respiratory disease. The influence of variants of concern as it relates to infectious dose, consequence of overall pathogenicity, and disease outcome in dose-response remains unknown. Epidemiologic data suggest a dose-response relationship for infection contrasting with limited and inconsistent surrogate-based evidence between dose and disease severity. Recommendations include the design of future infection studies in animal models to investigate inoculating dose on outcomes and the use of better proxies for dose in human epidemiology studies.

Keywords: COVID-19; SARS-CoV-2; disease severity; infectious dose; inoculum.

Figure 1.

SARS-CoV-2 transmission, exposure, and infection. A, Viral transmission and infection are complex, probabilistic processes. Concentration of infectious respiratory particles, exposure duration, and environmental, viral, and host conditions are critical for an infectious dose leading to SARS-CoV-2 infection. B, Once an individual is infected with SARS-CoV-2, shedding of virus RNA and viable virus ensues. Viral transmission relies heavily on the viral kinetics around symptom onset. The detection of SARS-CoV-2 RNA exceeds the detection of culturable or replication-competent virus. Abbreviations: qRT-PCR, quantitative reverse transcriptase–polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCID₅₀, median tissue culture infectious dose.