Viral reactivations and fungal infections in nonresolving acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a condition affecting 10% of patients requiring admission to the intensive care unit and results from endothelial dysfunction, alveolar epithelial injury and unbalanced inflammation, leading to exudative pulmonary oedema. A significant portion of these patients experience a lung injury that fails to resolve. Persistent or worsening respiratory failure beyond 5 days after the initiation of mechanical ventilation is referred to as nonresolving ARDS. Viral and fungal pathogens can exploit the hyperinflammatory environment and altered immune landscape in ARDS, perpetuating a cycle of ongoing inflammation and lung injury, thereby contributing to the progression towards and persistence of nonresolving ARDS, even in previously immunocompetent patients. This review discusses the significance, pathophysiology, diagnostic challenges and key knowledge gaps concerning various viral and fungal pathogens in nonresolving ARDS, with a particular focus on influenza-associated and COVID-19-associated pulmonary aspergillosis and pulmonary reactivation of Herpesviridae, such as cytomegalovirus and herpes simplex virus. Diagnosing these infections is challenging due to their nonspecific clinical presentation and the inability of current tests to distinguish between fungal colonisation or asymptomatic viral shedding and clinically significant infections or reactivations. A deeper understanding of the complex interplay between these pathogens and the host immune system in the context of ARDS, combined with advances in diagnostic and therapeutic strategies, has the potential to enhance the management and prognosis of patients with nonresolving ARDS.