Viral, Fungal Infections May Contribute to Nonresolving ARDS

Review links viral and fungal infections to persistent lung injury in nonresolving ARDS

By
Kerri Miller
April 16, 2026
6 min

Conexiant

Overview

Nonresolving acute respiratory distress syndrome (ARDS) is frequently complicated by viral reactivations and fungal superinfections, notably cytomegalovirus (CMV), herpes simplex virus (HSV), and Aspergillus species. These infections contribute to a self-reinforcing cycle of lung injury and immune dysregulation, significantly increasing morbidity and mortality in affected patients.

Background

Nonresolving ARDS is defined by persistent or worsening respiratory failure beyond 5 days of mechanical ventilation and is associated with high mortality. Opportunistic infections, including invasive pulmonary aspergillosis and viral reactivations, have been identified in a substantial proportion of these patients, even among those previously immunocompetent. Influenza and COVID-19 are recognized risk factors for fungal superinfections, with Aspergillus species being the most studied. Viral reactivations of latent CMV and HSV are common in ICU settings due to factors such as mechanical ventilation, sepsis, and corticosteroid therapy.

Data Highlights

Infection Type	Incidence in ICU Patients with Severe Viral Pneumonia	Mortality Rate	Timing of Onset
Influenza-associated Pulmonary Aspergillosis (IAPA)	~20%	~50%	Within 48 hours of ICU admission
COVID-19–associated Pulmonary Aspergillosis (CAPA)	~20%	~50%	Approximately 1 week after ICU admission
HSV Positivity in Mechanically Ventilated Patients	16%–64%	Not specified	Variable
CMV Reactivation	Less frequent than HSV	Not specified	Tends to occur later than HSV

Key Findings

Invasive pulmonary aspergillosis occurs in nearly 20% of ICU patients with severe viral pneumonia, with mortality rates around 50%, more than double that of patients without Aspergillus superinfection.
IAPA typically develops early (within 48 hours), while CAPA tends to occur about one week after ICU admission, possibly due to differences in antifungal immunity impairment.
Viral reactivations of CMV and HSV are common in ICU patients, with HSV detected in 16% to 64% of mechanically ventilated patients; CMV reactivation is less frequent and occurs later.
Diagnostic challenges exist due to lack of gold standards; viral DNA detection does not always indicate active infection, and distinguishing colonization from invasive fungal disease often requires histology.
Antifungal therapy with mold-active azoles or liposomal amphotericin B shows potential benefit in IAPA and CAPA, whereas evidence for antiviral treatment impact on viral reactivation outcomes remains inconclusive.
Emerging evidence suggests synergistic interactions between fungal and viral infections, such as Aspergillus and CMV, which may worsen immune dysfunction and clinical outcomes in ARDS.

Clinical Implications

Clinicians should maintain a high index of suspicion for fungal superinfections and viral reactivations in patients with nonresolving ARDS, especially those with severe viral pneumonia. Early and appropriate diagnostic sampling, including bronchoalveolar lavage, is critical to guide targeted antifungal therapy. Although antiviral treatment benefits are uncertain, systematic assessment of viral reactivation may be warranted given limited alternative treatable causes in this population.

Conclusion

Viral and fungal infections play a significant role in the pathogenesis and poor outcomes of nonresolving ARDS by perpetuating lung injury and immune dysregulation. Improved diagnostic strategies and targeted therapies are essential to address these infections and potentially improve patient prognosis.