Invasive Aspergillosis Is an Independent Predictor of Mortality in Mechanically Ventilated Patients with SARS-CoV-2 Infection
By Vibhu Sharma, MD
Associate Professor of Medicine, University of Colorado, Denver
SYNOPSIS: This multicenter cohort study found a high incidence of invasive aspergillosis in mechanically ventilated patients with SARS-CoV-2 pneumonia.
SOURCE: Bartoletti M, Pascale R, Cricca M, et al. Epidemiology of invasive pulmonary aspergillosis among intubated patients with COVID-19: A prospective study. Clin Infect Dis 2021;73:e3606-e3614.
The authors reported the results of a multicenter cohort study consisting of ventilated patients with acute respiratory distress syndrome related to SARS-CoV-2 infection and the incidence of COVID-associated pulmonary aspergillosis (CAPA). Patients were screened for invasive pulmonary aspergillosis (IPA) at four Italian intensive care units and were enrolled between February and April 2020. Screening procedures included bronchoalveolar lavage (BAL) on admission, one week from the day of admission, or at any time due to worsening of respiratory failure, new fever, or increased respiratory secretions. Samples were sent for galactomannan (GM) and fungal cultures. BAL specimens that were positive for GM were subsequently analyzed for the presence of Aspergillus species using real-time polymerase chain reaction (RT-PCR). Serum GM was sent simultaneously. CAPA was diagnosed if BAL GM was > 1, serum GM > 0.5, cultures were positive for Aspergillus, or a new cavitary opacity was seen. Among patients screened, BAL GM was > 1 on admission in 13% and on a subsequent sample in an additional 13%. Clinical evidence of aspergillosis (e.g., tracheobronchial ulcers or plaques) was found in 5%. Based on consensus criteria, probable CAPA was diagnosed in 28%, a median of eight days after intubation, and a median of two weeks after disease onset. Serum GM had poor sensitivity, specificity, and positive and negative predictive values; only one patient had a serum GM > 0.5. Cultures were positive for Aspergillus species in 18%.
Mortality among patients with probable CAPA was higher, and an initial positive test for BAL GM was associated with higher mortality. Mortality increased as measured levels of GM in BAL fluid increased. No single clinical criterion (e.g., presence or absence of fever, cough, increasing dyspnea) or laboratory parameter (e.g., C-reactive protein, lactate dehydrogenase [LDH] levels, white blood cell with differential count) differentiated between probable CAPA and no CAPA. No single drug class used to treat SARS-CoV-2 infection was associated with an increased risk of CAPA except steroid therapy. Only 50% of patients were treated with antifungals (voriconazole). Treatment was associated with a trend toward survival and a downtrend in GM levels.
COMMENTARY
This study underlines both the difficulty in diagnosing IPA and the need to sample the lower respiratory tract to diagnose it confidently. CAPA typically is considered in the setting of clinical or radiologic worsening in a patient with COVID-19 pneumonia, and presentations may include recrudescent fever, persistent fever after 72 hours of adequate antibiotic therapy, and worsening respiratory failure despite adequate ventilatory support and antibiotic therapy. It will be evident to clinicians who care for patients with COVID-19 pneumonia that these clinical characteristics have poor positive predictive value for the diagnosis of CAPA, underlining the need for further investigation.
Cultures of Aspergillus in BAL fluid may be negative in up to 42% of cases eventually proven to be IPA.1 Further complicating matters is the difficulty with interpretation of Aspergillus cultures that may represent colonization. These difficulties with diagnosis of IPA in the critical care setting prompted a consensus definition of IPA to include proven IPA and probable IPA.2 Proven IPA was defined as either histopathologic, cytopathologic, or direct microscopic evidence of hyphae compatible with Aspergillus species in a biopsy specimen, or aspirate or culture of Aspergillus species from a normally sterile site. The definition of probable IPA in the critical care setting includes at least one of the following: cytology or microscopy showing Aspergillus species in a lower respiratory tract specimen; GM index > 0.5 in serum and/or > 0.8 in BAL fluid; radiologic findings consistent with invasive fungal disease (e.g., halo sign); one of a list of predisposing host factors, including use of prednisone > 20 mg/day or other immunosuppressants (e.g., mTOR inhibitors, tumor necrosis factor [TNF] antagonists, ibrutinib/nucleoside analogs), a neutrophil defect, history of structural lung disease, decompensated cirrhosis, human immunodeficiency virus, stem cell and solid organ transplant, and severe viral pneumonia due to coronavirus disease or influenza.
It is important to obtain BAL fluid GM levels to enhance diagnostic certainty while recognizing that the test is not specific for Aspergillus species and may be positive in the setting of infections with other molds, including Histoplasma and Cryptococcus infections.3 Serum GM has poor sensitivity (42%), specificity, and positive and negative predictive values. BAL GM has a higher sensitivity and specificity (88% and 87%, respectively).4 With newer techniques, false-positive assays due to administration of piperacillin/tazobactam or PlasmaLyte are no longer concerns. False-positive tests may be seen in patients ingesting food items that may contain galactomannan (e.g., ice pops, soy protein). Importantly, the sensitivity of the GM test is reduced substantially in those patients already being treated with antifungals for disease prophylaxis or treatment.3
This study provides an epidemiologic perspective to IPA in the setting of COVID-19 pneumonia and suggests that the utility of a serum GM test is low, and a BAL GM should be obtained when suspicion for IPA is high. It is important to review the working definitions of proven and probable IPA as they apply to the critically ill to maximize diagnostic certainty, especially since treatment seems to be associated with reduced mortality.
REFERENCES
- Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012;186:56-64.
- Bassetti M, Azoulay E, Kullberg BJ, et al. EORTC/MSGERC definitions of invasive fungal diseases: Summary of activities of the Intensive Care Unit Working Group. Clin Infect Dis 2021;72(Suppl 2):S121-S127.
- Mercier T, Castagnola E, Marr KA, et al. Defining galactomannan positivity in the updated EORTC/MSGERC consensus definitions of invasive fungal diseases. Clin Infect Dis 2021;72(Suppl 2):S89-S94.
- Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: A tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med 2008;177:27-34.
This multicenter cohort study found a high incidence of invasive aspergillosis in mechanically ventilated patients with SARS-CoV-2 pneumonia.
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