SYNOPSIS Aspergillosis Complicating Severe Coronavirus Disease Kieren A. Marr, Andrew Platt, Jeffrey A. Tornheim, Sean X. Zhang, Kausik Datta, Celia Cardozo, Carolina Garcia-Vidal describing epidemiology and significance of aspergil- Aspergillosis complicating severe influenza infection losis occurring after severe viral infections, especially has been increasingly detected worldwide. Recently, coronavirus disease–associated pulmonary aspergil- influenza and coronavirus disease (COVID-19). losis (CAPA) has been detected through rapid reports, Aspergillosis associated with severe influenza primarily from centers in Europe. We provide a case virus infection (influenza-associated aspergillosis, series of CAPA, adding 20 cases to the literature, with IAA) was reported in 1951, when Abbott et al. de- review of pathophysiology, diagnosis, and outcomes. scribed fatal infection in a woman with cavitary in- The syndromes of pulmonary aspergillosis complicating vasive pulmonary aspergillosis noted on autopsy (2). severe viral infections are distinct from classic invasive Scattered reports appeared in thereafter; Adalja et al. aspergillosis, which is recognized most frequently in summarized 27 cases in the literature during 1952– persons with neutropenia and in other immunocompro- 2011, which reported predominance after influenza mised persons. Combined with severe viral infection, A infection, associated lymphopenia, and occurring aspergillosis comprises a constellation of airway-inva- in persons of a broad age range (14–89 years), but sive and angio-invasive disease and results in risks as- sociated with poor airway fungus clearance and killing, with little underlying lung disease (3). There were including virus- or inflammation-associated epithelial increased numbers of cases reported during and af- damage, systemic immunosuppression, and underlying ter the 2009 influenza A(H1N1) pandemic (3–10). In lung disease. Radiologic abnormalities can vary, reflect- 2016, Crum-Cianflone summarized 57 cases from ing different pathologies. Prospective studies reporting literature; most (70%) were associated with H1N1 poor outcomes in CAPA patients underscore the urgent influenza (11). Invasive aspergillosis was described, need for strategies to improve diagnosis, prevention, with complicating tracheobronchitis noted in 15.8%. and therapy. Reported cases (68/128) during 1952–2018 were sum- marized by Vanderbeke et al. (12). nvasive aspergillosis is frequently recognized in An increased understanding of IAA emerged Ipersons who have severe immunosuppression, es- from large cohort studies performed after 2015. One pecially that associated with hematologic malignan- 7-year retrospective study in intensive care units cies and transplantation. It is characterized by hyphal (ICUs) in Belgium and the Netherlands reported invasion through bronchial or lower airway tissues, rates varying from 14% in immunocompetent per- with potential vascular invasion and hallmark radio- sons to 31% in immunocompromised persons (13). graphic findings reflective of hemorrhage and ne- Within the influenza-infected cohort, male sex, he- crosis. However, Aspergillus species cause a broader matologic malignancy, high acute physiological as- constellation of pulmonary disease, pathologically sessment and chronic health evaluation II (APACHE characterized by inflammatory disease in the airway II) score, and corticosteroid use were associated with and acute and chronic invasion, largely depending IAA, whereas underlying diabetes was associated on host risks (1). Much recent work has focused on with lower risks. Cohort studies conducted in Can- ada, China, and Taiwan reported similar risk pro- Author affiliations: Johns Hopkins School of Medicine, Baltimore, files and that incidence of disease varied according Maryland, USA (K.A. Marr, J.A. Tornheim, S.X. Zhang, K. Datta); to season and viral epidemiology (14–17). Despite National Institutes of Health, Bethesda, Maryland, USA (A. Platt); these data, 2 recent survey studies reported that risk Hospital Clinic of Barcelona, Barcelona, Spain (C. Cardozo, recognition is poor outside of countries in Europe C. Garcia-Vidal) (18,19). Only 63% of critical care physicians respond- DOI: https://doi.org/10.3201/eid2701.202896 ing to an international survey were familiar with 18 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 1, January 2021 Aspergillosis Complicating Coronavirus Disease IAA, and differences were notable between physi- and Hospital Clinic of Barcelona (Table, https:// cians in the United States (17%) and Europe (58%) wwwnc.cdc.gov/EID/article/27/1/20-2896-T1. (19). Similarly, a US Centers for Disease Control and htm). Demographics mirrored those described for Prevention–sponsored survey of infectious diseases poor overall outcomes; advanced age and underly- practitioners reported that only 26% of 114 respon- ing diseases of hypertension and pulmonary disease dents were familiar with IAA (18). predominated. Two patients had an underlying im- An increased number of reports described a munosuppressive disease. The most common im- similar syndrome associated with severe COVID-19 munosuppressing agents associated with CAPA in- (20–45). In this study, we add to this literature, report cluded systemic or inhaled steroids, most frequently 20 additional cases from 2 centers in Spain and the for adjunctive management of COVID-19 related United States and provide a review of literature de- inflammatory disease. CAPA was recognized a me- scribing the emerging entity of COVID-19–associated dian of 11 days after symptom onset and 9 days after pulmonary aspergillosis (CAPA). ICU admission. Most of these patients were hospital- ized during stages characterized by inflammation or Methods acute respiratory distress syndrome or afterwards, with lung injury, in the ICU and required respira- Case Series tory support. Thus, WHO ordinal classifications at Cases of CAPA were identified during March–June CAPA diagnoses were ≥5 (46). 2020 at Johns Hopkins University (Baltimore, MD, In cases for which CT scans were performed, USA) and Hospital Clinic of Barcelona (Barcelona, radiographic reports generally described a mixture Spain) by review of microbiologic and infectious dis- of findings attributable to the virus (ground glass eases consult data, with approval of the institutional opacities and crazy-paving), findings consistent review boards of both institutions. Cases were defined with airway inflammation and mucous plugging as recovery of Aspergillus species from respiratory flu- (bronchiectasis, airway wall thickening and irregu- ids (tracheobronchial secretions, sputum, bronchoal- larity, bronchiectasis), and radiographic findings veolar lavage [BAL]) or positive (index ≥1) serum or consistent with airway-invasive disease (consolida- BAL markers, identified with work-up for possible tions, tree-in-bud nodules) (Table; Figure 1). In some secondary pneumonia, typically clinically indicated cases, larger nodules with necrosis and cavitation with new fever or respiratory decompensation with were noted. Although nodular necrosis with cavita- new focal infiltrates on chest radiograph or comput- tion was described, no radiographic reports high- ed tomography (CT) scan. Results for a Fungitell β-D lighted findings that are classically associated with Glucan Assay (https://www.fungitell.com) were re- angioinvasive disease (ground glass attenuation de- ported when available but did not suffice to establish scribed as halos) (47). case diagnosis; 60 pg/mL was considered intermedi- Bronchoscopy was rare, and diagnosis was most ate and ≥80 pg/mL was considered positive. Neither frequently supported by tracheal aspirate culture; center used PCR-based testing for fungal infections few patients had positive serum biomarkers. Seven- during this period. Charts were reviewed to sum- teen (85%) cases were identified by positive culture; marize demographic, clinical, and outcomes data, most (12/17, 71%) were identified by detection of including day of hospitalization and ICU admission A. fumigatus. Although rarely used, results of Fung- relative to reported onset of symptoms. World Health itell β-D glucan assays were more frequently positive Organization (WHO) ordinal scale scores (0–8) at di- compared with serum galactomannan assays. All but agnosis of CAPA were estimated (46). 2 patients were given intravenous antifungal drugs, which included voriconazole, posaconazole, or li- Analyses posomal amphotericin B. One patient (#2) was not We calculated descriptive statistics for all data. These treated for findings of a nodule and positive serum values are shown as frequencies, means (±SD), medi- galactomannan result, was extubated, and survived. ans (with ranges), and proportions. Another patient (#12) had diagnosis of CAPA estab- lished 1 day before death and never received antifun- Results gal therapy. Characteristics of Cases Synopsis of Literature Patient-level data were compiled in cases recognized Evidence of secondary aspergillosis developing before June 2020 at Johns Hopkins Medical Center in persons infected with severe acute respiratory Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 27, No. 1, January 2021 19 SYNOPSIS Figure 1. Representative computed tomography (CT) scans for 9 patients with aspergillosis complicating severe viral pneumonia in patients with coronavirus disease. Scans were obtained at or around diagnosis of coronavirus disease–associated pulmonary aspergillosis in this series of patients, described in the Table (https://wwwnc.cdc.gov/EID/article/27/1/20-2896-T1.htm).