Cytomegalovirus, herpes simplex virus, and Aspergillus species may form a self-reinforcing cycle with lung injury and immune dysregulation in patients with nonresolving acute respiratory distress syndrome, according to a narrative review published in European Respiratory Review.
Nonresolving acute respiratory distress syndrome (ARDS)—defined as persistent or worsening respiratory failure beyond 5 days following initiation of mechanical ventilation—is associated with high morbidity and mortality. Although persistent lung injury may stem from the initial insult, opportunistic infections have been identified in a substantial proportion of patients undergoing open lung biopsy. The review, by Lenn Maessen and colleagues, synthesizes evidence on the epidemiology, pathophysiology, diagnostic challenges, and knowledge gaps surrounding these infections, including in previously immunocompetent patients.
Methods
The researchers conducted two PubMed searches, last updated June 28, 2024, focusing on fungal and viral infections in ARDS. Abstracts were screened, and additional studies were identified from reference lists. The review was commissioned and peer reviewed.
Fungal Infections: Aspergillus in Viral-Induced ARDS
Invasive pulmonary aspergillosis is the most frequently studied fungal superinfection in nonresolving ARDS, particularly in ARDS secondary to severe viral pneumonia. Both influenza and COVID-19 are recognized as independent risk factors.
In cohorts with frequent bronchoalveolar lavage sampling, influenza-associated pulmonary aspergillosis (IAPA) and COVID-19–associated pulmonary aspergillosis (CAPA) can be identified in almost 20% of patients admitted to the ICU with severe viral pneumonia. Mortality in these patients approaches 50%, more than double that observed in patients without Aspergillus superinfection.
Timing differs between the two conditions: IAPA typically occurs early, often within 48 hours of ICU admission, whereas CAPA more commonly develops after approximately 1 week. The researchers suggest this difference may reflect a more pronounced impairment of antifungal immunity in influenza compared with COVID-19.
Other fungi—including Mucorales, Pneumocystis jirovecii, and Candida species—are less common causes of superinfection. In one prospective cohort study, no cases of invasive pulmonary candidiasis were identified on histopathology in 135 ICU patients with pneumonia, despite frequent detection of Candida in respiratory samples.
Pathophysiology
The review describes how the hyperinflammatory environment in ARDS facilitates fungal growth while impairing host defenses. Mechanisms include epithelial damage, depletion of alveolar macrophages, impaired phagocytic killing, reduced mucociliary clearance, and corticosteroid-associated immune suppression.
The antifungal immune response itself may also contribute to lung injury. Neutrophils targeting Aspergillus hyphae release reactive oxygen species, antimicrobial peptides, and neutrophil extracellular traps, which can exacerbate inflammation and impair gas exchange.
Viral Reactivations: CMV and HSV
Cytomegalovirus (CMV) and herpes simplex virus (HSV) establish lifelong latency and can reactivate under conditions common in the ICU, including mechanical ventilation, sepsis, corticosteroid therapy, and prolonged hospitalization.
Globally, HSV infection is common; the review cites estimates of about 67% for herpes simplex virus type 1 (HSV-1) in people younger than 50 years and about 13% for herpes simplex virus type 2 (HSV-2) in those aged 15 to 49 years. CMV seroprevalence is estimated at approximately 60% in high-income countries and up to 90% in low- and middle-income countries.
Reported incidence of pulmonary viral reactivation varies widely depending on patient selection, sampling methods, and diagnostic techniques. In studies using lower respiratory tract samples with polymerase chain reaction in mechanically ventilated patients, HSV positivity has been reported in 16% to 64% of patients, whereas CMV reactivation appears less frequent and tends to occur later.
The review emphasizes that blood testing may underestimate pulmonary CMV disease. Lung reactivation can precede blood reactivation, and bronchoalveolar lavage sampling has been shown to better reflect pulmonary infection.
Diagnostic Challenges
No gold standard exists for defining clinically significant pulmonary viral reactivation. Detection of viral DNA does not necessarily indicate active infection, particularly for HSV, which may represent local shedding or contamination in mechanically ventilated patients.
Similarly, diagnosing invasive pulmonary aspergillosis remains challenging. Serum galactomannan testing has limited sensitivity in non-neutropenic patients, whereas bronchoalveolar lavage–based testing—including culture, galactomannan, and polymerase chain reaction—is preferred. When bronchoscopy is not feasible, nonbronchoscopic respiratory samples may be used, although these approaches are less well validated and generally less accurate. Even with testing, distinguishing colonization from invasive disease remains difficult and may require tissue histology for confirmation.
Clinical Impact and Treatment
For fungal infections, observational data suggest a potential benefit of antifungal therapy in patients with IAPA or CAPA. First-line treatment typically includes mold-active azoles such as voriconazole, isavuconazole, or posaconazole, with liposomal amphotericin B as an alternative.
In contrast, the clinical impact of viral reactivation remains uncertain. A randomized controlled trial found that prophylactic-dose acyclovir did not increase ventilator-free days in mechanically ventilated patients with oropharyngeal HSV reactivation, whereas a meta-analysis suggested a possible survival benefit but was limited by bias and small sample sizes. No randomized trials have specifically evaluated treatment of pulmonary CMV or HSV reactivation in the lower respiratory tract.
Despite these uncertainties, the researchers noted that systematic assessment of viral reactivation may be warranted given the limited alternative treatable causes.
Interaction Between Fungal and Viral Infections
Emerging evidence suggests that fungal and viral infections may interact in ARDS. Preclinical data indicate that Aspergillus and CMV may act synergistically to impair host immune responses. Clinical studies have also reported higher rates of CMV reactivation and worse outcomes among patients with CAPA.
However, the complexity of these interactions and limitations in existing study designs make it difficult to establish causality.
Limitations and Knowledge Gaps
The researchers highlighted several methodological challenges in the literature, including variability in sampling methods, lack of standardized diagnostic thresholds, and biases in observational studies such as immortal time bias, which may affect interpretation of associations between infection and clinical outcomes. Corticosteroid use, a shared risk factor for both fungal infection and viral reactivation, further complicates interpretation.
Key priorities for future research include establishing clinically relevant viral load thresholds, identifying biomarkers to distinguish infection from colonization, and evaluating the role of antifungal and antiviral prophylaxis in high-risk patients.
Conclusion
Viral and fungal pathogens may exploit the hyperinflammatory environment and immune dysregulation in ARDS, contributing to persistent lung injury in patients with nonresolving disease. However, distinguishing clinically meaningful infection from colonization or viral shedding remains a major challenge.
Advances in diagnostic strategies and a deeper understanding of pathogen–host interactions may help improve management and outcomes in this high-risk patient population.
Disclosures
Study authors reported relationships with industry, including research funding, advisory roles, and speaker fees with pharmaceutical companies such as Pfizer, Gilead, and MSD. Several authors reported no conflicts of interest.
Source: European Respiratory Review
