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Incidence and Outcomes of Invasive Pulmonary Aspergillosis in Critically Ill Patients with COVID-19: A Systematic Review and Meta-Analysis

Saikat Mitra, Ryan Ruiyang Ling, Sajeev Arvind Mahendran, Megan Ruien Ling, Ashwin Subramaniam, Kiran Shekar, Chuen Seng Tan, Suei Nee Wong, Jyoti Somani, Graeme MacLaren, Kollengode Ramanathan

Background: Recent reports of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) have raised concerns about fungal super-infections in critically ill patients with COVID-19. However, true incidence of CAPA is difficult to estimate given the challenges of diagnosing invasive pulmonary aspergillosis as well as the heterogeneity in case definitions.

Methods: We conducted a systematic review of literature (through 31st December 2021) for relevant studies reporting on the CAPA incidence in critically ill COVID-19 patients. Random effects meta-analyses were conducted. Risk of bias and certainty of evidence were assessed using the appropriate Joanna Briggs Institute checklists and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach respectively. The primary outcome was the overall incidence of CAPA. Secondary outcomes included CAPA-associated mortality, ICU length of stay, duration of invasive mechanical ventilation, and the time between COVID-19 symptoms and CAPA diagnosis.

Results: Of 53 observational studies (11,013 adult COVID-19 patients), 1097 patients had CAPA; the pooled incidence of CAPA was 13.0% (95%-CI: 8.7%-18.0%), albeit with publication bias (p_egger=0.002) and the pooled mortality was 63.4% (95%-CI: 56.2%-70.4%). Patients with CAPA were older (+3.1 years (95%-CI: 1.3-4.9, p=0.0006) with significantly increased mortality (Risk Ratio: 2.13 (95%- CI: 1.80-2.52, p<0.0001) compared to COVID-19 patients without CAPA. Meta-regression analysis found that corticosteroids and/or hypertension were potential risk factors for CAPA

Conclusion: Critically ill patients with COVID-19 are vulnerable to develop CAPA with considerably high mortality rates; patients with hypertension and those treated with corticosteroids as an adjuvant therapy appear to be at higher risk of CAPA.