Aspergillosis Complicating Severe Coronavirus Disease

Kieren A. Marr; Andrew Platt; Jeffrey A. Tornheim; Sean X. Zhang; Kausik Datta; Celia Cardozo; Carolina Garcia-Vidal


Emerging Infectious Diseases. 2021;27(1):18-25. 

In This Article

Abstract and Introduction


Aspergillosis complicating severe influenza infection has been increasingly detected worldwide. Recently, coronavirus disease–associated pulmonary aspergillosis (CAPA) has been detected through rapid reports, primarily from centers in Europe. We provide a case series of CAPA, adding 20 cases to the literature, with review of pathophysiology, diagnosis, and outcomes. The syndromes of pulmonary aspergillosis complicating severe viral infections are distinct from classic invasive aspergillosis, which is recognized most frequently in persons with neutropenia and in other immunocompromised persons. Combined with severe viral infection, aspergillosis comprises a constellation of airway-invasive and angio-invasive disease and results in risks associated with poor airway fungus clearance and killing, including virus- or inflammation-associated epithelial damage, systemic immunosuppression, and underlying lung disease. Radiologic abnormalities can vary, reflecting different pathologies. Prospective studies reporting poor outcomes in CAPA patients underscore the urgent need for strategies to improve diagnosis, prevention, and therapy.


Invasive aspergillosis is frequently recognized in persons who have severe immunosuppression, especially that associated with hematologic malignancies and transplantation. It is characterized by hyphal invasion through bronchial or lower airway tissues, with potential vascular invasion and hallmark radiographic findings reflective of hemorrhage and necrosis. However, Aspergillus species cause a broader constellation of pulmonary disease, pathologically characterized by inflammatory disease in the airway and acute and chronic invasion, largely depending on host risks.[1] Much recent work has focused on describing epidemiology and significance of aspergillosis occurring after severe viral infections, especially influenza and coronavirus disease (COVID-19).

Aspergillosis associated with severe influenza virus infection (influenza-associated aspergillosis, IAA) was reported in 1951, when Abbott et al. described fatal infection in a woman with cavitary invasive pulmonary aspergillosis noted on autopsy.[2] Scattered reports appeared in thereafter; Adalja et al. summarized 27 cases in the literature during 1952–2011, which reported predominance after influenza A infection, associated lymphopenia, and occurring in persons of a broad age range (14–89 years), but with little underlying lung disease.[3] There were increased numbers of cases reported during and after the 2009 influenza A(H1N1) pandemic.[3–10] In 2016, Crum-Cianflone summarized 57 cases from literature; most (70%) were associated with H1N1 influenza.[11] Invasive aspergillosis was described, with complicating tracheobronchitis noted in 15.8%. Reported cases (68/128) during 1952–2018 were summarized by Vanderbeke et al..[12]

An increased understanding of IAA emerged from large cohort studies performed after 2015. One 7-year retrospective study in intensive care units (ICUs) in Belgium and the Netherlands reported rates varying from 14% in immunocompetent persons to 31% in immunocompromised persons.[13] Within the influenza-infected cohort, male sex, hematologic malignancy, high acute physiological assessment and chronic health evaluation II (APACHE II) score, and corticosteroid use were associated with IAA, whereas underlying diabetes was associated with lower risks. Cohort studies conducted in Canada, China, and Taiwan reported similar risk profiles and that incidence of disease varied according to season and viral epidemiology.[14–17] Despite these data, 2 recent survey studies reported that risk recognition is poor outside of countries in Europe.[18,19] Only 63% of critical care physicians responding to an international survey were familiar with IAA, and differences were notable between physicians in the United States (17%) and Europe (58%).[19] Similarly, a US Centers for Disease Control and Prevention–sponsored survey of infectious diseases practitioners reported that only 26% of 114 respondents were familiar with IAA.[18]

An increased number of reports described a similar syndrome associated with severe COVID-19.[20–45] In this study, we add to this literature, report 20 additional cases from 2 centers in Spain and the United States and provide a review of literature describing the emerging entity of COVID-19–associated pulmonary aspergillosis (CAPA).