A risk-based approach to COVID-19 prevention after exposure in older, immunocompromised, and/or medically vulnerable patients includes risk stratification, preventive/prophylactic measures, and antiviral treatments for when infection develops. Communicating risk, reviewing medication interactions, and ongoing monitoring for infection are also important.

Regarding risk stratification for severe COVID-19, I encourage clinicians to use the Infectious Diseases Society of America (IDSA) 2-tiered system. One category is increased—but not high—risk of progression; the other is high risk of progression. The high-risk group includes people with organ transplants or congenital hypogammaglobulinemia or agammaglobulinemia, as well as those receiving B-cell–depleting agents (eg, rituximab) or CAR T-cell therapy. The increased-risk group is the more common type and includes patients between 65 and 74 years of age, those with a history of smoking, and/or those with cardiovascular disease, diabetes, dementia, or asthma. Risk also rises as multiple comorbidities are layered together.

Overall, risk can reflect 2 different types of concerns. Some patients, such as those with asthma, may lack the respiratory reserve to weather COVID-19 without hospitalization. Patients receiving immunosuppressive therapy, high-dose corticosteroids, or treatment for a rheumatologic condition may be unable to mount a sufficient immune response. Recommendations need to be customized, and it is important to clearly communicate risk using patient-centered language. I also recommend using a systematic practice-based approach (using electronic health records and diagnosis codes when available) to identify patients for proactive respiratory-season outreach.

Vaccination remains the most important population-level measure. The 2025-2026 COVID-19 vaccines reduced hospitalization or severe illness by 55% among immunocompetent adults aged 18 years or older and by 53% among immunocompetent adults aged 65 years or older. Because mutations in the viral spike protein and immune escape continue, staying current with updated vaccines is particularly important for high-risk patients. Exposure can still occur, however, so clinicians need a plan for prophylaxis and rapid treatment.

After an exposure to COVID-19, a person’s test status separates prophylaxis from treatment. If the patient has not tested positive, we consider postexposure prophylaxis. In the SCORPIO-PEP trial, ensitrelvir reduced the relative risk of symptomatic COVID-19 among household contacts by approximately 68% (9% with placebo vs 2.9% with ensitrelvir). It should be noted that patients in SCORPIO-PEP were fairly young (mean age, 42.4 years) and generally healthy; however, many patients who are considered for prophylaxis in clinical practice have substantially greater baseline vulnerability. When prescribing ensitrelvir, clinicians should consult the package insert, review potential drug interactions, and rule out pregnancy in women of reproductive age. For eligible patients, treatment should begin as soon as possible and within 72 hours of contact with an individual who is infected with COVID-19.

Patients receiving prophylaxis require frequent testing to ensure timely treatment. However, when testing, the question is: Will I be able to do something with the result? Testing is useful if the patient’s risk is sufficient to recommend treatment after a positive result. A reasonable protocol is to use 2 antigen tests 48 hours apart for symptomatic individuals and 3 tests at 48-hour intervals for asymptomatic individuals. With repeated household exposure, testing may continue until the index patient has convalesced. Treatment decisions then incorporate progression risk, medication efficacy, adverse effects, and drug interactions. The combination of nirmatrelvir and ritonavir is generally recommended when drug interactions are not a concern; remdesivir and molnupiravir are other options.

Overall, effective COVID-19 prevention and early management for vulnerable patients depend on identifying risk proactively, acting before test conversion when prophylaxis is appropriate, and changing course promptly to treatment if infection develops.