Immunocompromised individuals—including recipients of solid organ transplants (SOT) or hematopoietic cell transplants (HCT), people receiving chimeric antigen receptor (CAR) T-cell therapy, and those with untreated or advanced human immunodeficiency virus (HIV) infection—face markedly elevated risks of severe influenza, prolonged viral shedding, and antiviral resistance. The growing global prevalence of immunocompromised conditions underscores an urgent need for optimized influenza prevention and treatment strategies.

Influenza in immunocompromised individuals often manifests atypically, with fever and myalgia less common than in immunocompetent individuals, leading to diagnostic delays. These patients are prone to secondary bacterial or fungal pneumonias and develop lower respiratory tract infection (LRTI) in up to 30% of cases, with mortality ranging from 2% to 25%. Risk factors for severe outcomes include lymphopenia, graft-versus-host disease, high-dose corticosteroids, and older age. Among lung transplant recipients, influenza can trigger chronic lung allograft dysfunction (CLAD). CAR T-cell and other cellular therapy recipients may also experience severe, protracted infections.

Although vaccination remains the cornerstone of influenza prevention, its effectiveness is limited in immunocompromised individuals due to impaired serologic and cellular responses, particularly in those on B-cell–depleting agents such as rituximab or belatacept. Even enhanced vaccines (high-dose, adjuvanted, or two-dose regimens) elicit weaker responses than in healthy individuals. Consequently, antivirals serve as a critical line of defense for both prophylaxis and treatment.

Neuraminidase inhibitors (NAIs)—oseltamivir, peramivir, zanamivir, and laninamivir—constitute the mainstay of antiviral therapy. Early initiation within 48 hours of symptom onset is ideal but even delayed treatment benefits immunocompromised individuals because of prolonged viral replication. Standard oseltamivir dosing (75 mg twice daily for 5 days) may be insufficient in these patients; higher doses (150 mg twice daily) or extended courses (up to 10 days) are often recommended. Such approaches, however, increase the risk of resistance mutations, notably the NA-H275Y substitution. Zanamivir and laninamivir retain activity against some resistant strains but are limited by inhalation route or availability.

Baloxavir marboxil, a cap-dependent endonuclease inhibitor, offers rapid viral load reduction and potential benefits in reducing transmission, particularly for influenza B. Combination therapy with NAIs may help prevent resistance emergence, though robust data in immunocompromised individuals are lacking. Other antivirals—including peramivir, favipiravir, and experimental polymerase inhibitors—have niche or investigational roles. Adamantanes are no longer recommended due to widespread resistance.

Immunotherapeutic strategies such as hyperimmune intravenous immunoglobulin (hIVIG), monoclonal antibodies targeting conserved hemagglutinin stalk epitopes, and virus-specific T-cell (VST) therapy hold promise for high-risk patients with deficient humoral immunity. However, clinical data remain limited, and cost, logistics, and donor matching challenges restrict their use.

Prophylactic antivirals can provide added protection during high-incidence seasons or outbreaks. Oseltamivir is the best-studied agent for both pre- and postexposure prophylaxis, reducing laboratory-confirmed influenza without major side effects. Household contacts of immunocompromised individuals should also receive antiviral prophylaxis or treatment to reduce transmission risk.

The authors highlight a critical evidence gap: immunocompromised individuals are systematically excluded from most vaccine and antiviral clinical trials. This exclusion limits understanding of drug efficacy, optimal dosing, and resistance dynamics in this vulnerable population. Future studies should prioritize inclusion of immunocompromised individuals, evaluation of combination antiviral regimens, and integration of immunotherapies.

Ultimately, optimizing influenza management in immunocompromised individuals requires a multifaceted approach—integrating timely diagnosis, vaccination, antiviral therapy, and prophylaxis—to mitigate individual morbidity and prevent the emergence and spread of resistant influenza strains.

Reference

Heldman, M.R., Boeckh, M.J., Ison, M.G. Influenza antivirals for prevention and treatment in immunocompromised people. J Infect Dis (2025); 232 (3): S243–S253. https://doi.org/10.1093/infdis/jiaf217