Viral reactivations and fungal infections in nonresolving acute respiratory distress syndrome

Abstract

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.

FIGURE 1

Vicious circle of tissue damage, immune dysregulation and viral or fungal infection. Tissue damage, as seen in (nonresolving) lung injury, provokes immune dysregulation, which on its own may lead to more tissue damage. Immune dysregulation and tissue damage can both enable reactivation of latent viruses (cytomegalovirus (CMV) and herpes simplex virus (HSV)) and growth and germination of fungal spores (especially Aspergillus). These pathogens can directly lead to tissue damage or can cause tissue damage by further dysregulating the immune response. Figure created with BioRender.com.

FIGURE 2

The interplay between lung injury, the immune response, herpes simplex virus (HSV) or cytomegalovirus (CMV) reactivation and Aspergillus infection. Lung injury can enable reactivation of latent HSV and CMV and Aspergillus growth and germination via several mechanisms (depicted in the upper and lower panels in red). These pathogens can further maintain or aggravate lung injury directly or by eliciting an inflammatory response with collateral damage (depicted in the central panel). Viruses may reactivate in extrapulmonary tissue (notably the spinal cord for HSV and the bone marrow or endothelial cells for CMV) and then spread to the lungs. Anti-inflammatory drugs (notably corticosteroids) can prevent lung injury, but may at the same time impair immunity against these pathogens. ^#: CMV reactivation can affect a number of tissues beyond the bone marrow and endothelial cells, including, but not limited to, the lungs, gastrointestinal tract and liver. Af: Aspergillus fumigatus; DC: dendritic cell; IL: interleukin; NETosis: neutrophil extracellular trap formation; ROS: reactive oxygen species; TNF-α: tumour necrosis factor-α. Figure created with BioRender.com.