The influence of comorbidities on COVID-19 outcomes has been recognized since the earliest days of the pandemic. But establishing causality and determining underlying mechanisms and clinical implications has been challenging-owing to the multitude of confounding factors and patient variability. Several distinct pathological mechanisms, not active in every patient, determine health outcomes in the three different phases of COVID-19-from the initial viral replication phase to inflammatory lung injury and post-acute sequelae. Specific comorbidities (and overall multimorbidity) can either exacerbate these pathological mechanisms or reduce the patient's tolerance to organ injury. In this Review, we consider the impact of specific comorbidities, and overall multimorbidity, on the three mechanistically distinct phases of COVID-19, and we discuss the utility of host genetics as a route to causal inference by eliminating many sources of confounding. Continued research into the mechanisms of disease-state interactions will be crucial to inform stratification of therapeutic approaches and improve outcomes for patients.
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