Influenza A virus (IAV) infection is a significant risk factor for invasive pulmonary aspergillosis, particularly in severe influenza patients, where the incidence and mortality of influenza-associated pulmonary aspergillosis (IAPA) are markedly elevated. IAPA creates a state of acute acquired immunodeficiency in patients who were previously healthy, challenging the traditional view of fungal disease as a condition restricted to the classically immunocompromised. Drawing on emerging evidence, this review maps out the pathogenesis of IAPA as a specific, sequential cascade of host failure. The process begins with barrier disruption, where the virus induces Type III interferons and interleukin-1β (IL-1β) signalling to arrest epithelial repair and compromise tissue integrity. This is followed by recognition failure, characterized by the specific depletion of innate B1a lymphocytes and natural IgG antibodies, rendering fungal spores undetectable to phagocytes. The final stage is effector paralysis, where a cytokine storm drives neutrophil oxidative shutdown and transcriptional suppression. Ultimately, IAPA is a disorder of functional dissociation: The body is hyper-inflamed, yet its antimicrobial metabolism is paralysed. Understanding this framework reveals precise therapeutic windows for host-directed interventions, such as timed IL-1 receptor blockade or nebulized immunostimulants, which can restore immune competence and improve clinical outcomes.
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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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