Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis
Authors: Kauser Jabeen, Joveria Farooqi, Muhammad Irfan, Syed Ahsan Ali, David W Denning
Journal: The Lancet Infectious Diseases (2021)

We read with interest the ECMM/ISHAM consensus criteria for COVID-19-associated pulmonary aspergillosis (CAPA), but noted with concern its limited applicability to resource-limited settings.1Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.Lancet Infect Dis. 2020; (published online Dec 14.)https://doi.org/10.1016/S1473-3099(20)30847-1Summary Full Text Full Text PDF PubMed Scopus (539) Google Scholar Multiple studies indicate that approximately 20% of severely ill patients with COVID-19 develop invasive aspergillosis if a diagnosis is actively sought.2Arastehfar A Carvalho A van de Veerdonk FL et al.COVID-19 associated pulmonary aspergillosis (CAPA)—from immunology to treatment.J Fungi (Basel). 2020; 6: 91Crossref PubMed Scopus (269) Google Scholar Pakistan was among the first countries to report CAPA in critically ill patients with COVID-19 using AspICU criteria.3Nasir N Farooqi J Mahmood SF Jabeen K COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: an observational study from Pakistan.Mycoses. 2020; 63: 766-770Crossref PubMed Scopus (125) Google Scholar After an initial report of five putative CAPA cases from March to April, 2020, at our institute, within 2 months 12 more putative CAPA cases were identified. The largest series of CAPA cases include data from four low-income and middle-income countries (LMICs).4Salmanton-García J Sprute R Stemler J et al.COVID-19-associated pulmonary aspergillosis: March–August 2020.Emerg Infect Dis. 2021; (published online Feb 4.)https://doi.org/10.3201/eid2704.204895Crossref PubMed Scopus (177) Google Scholar In these and other LMICs, very few clinical laboratories do fungal PCR or expensive serology-based tests such as galactomannan and β-D-glucan. Similarly, due to hazards related to aerosol production, bronchoscopic or non-bronchoscopic lavage procedures are rarely done. At our institute from July to December, 2020, 490 tracheal aspirates were sent for culture, compared with only two bronchial lavage samples from COVID-19 patients. Therefore, despite having substantial CAPA burden in our centre, none of the patients in retrospect could be categorised into any of the three grades of proven, probable, or possible, as suggested by Philipp Koehler and colleagues.1Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.Lancet Infect Dis. 2020; (published online Dec 14.)https://doi.org/10.1016/S1473-3099(20)30847-1Summary Full Text Full Text PDF PubMed Scopus (539) Google Scholar A very restricted disease categorisation is concerning as it will lead to underrecognition of this important complication in patients with COVID-19, not only for surveillance but also for their management. On the basis of better inclusivity of patients too hypoxic to undergo bronchoscopy and applicability to low-resource settings, we propose that endotracheal aspirates be added to the appropriate specimens for diagnosis. These may be cultured in high volume (0·5–1·0 mL) for better fungal yield5Vergidis P Moore C Rautemaa-Richardson R Richardson M High-volume sputum culture for the diagnosis of pulmonary aspergillosis.Open Forum Infect Dis. 2017; 4: S609Crossref Google Scholar and in settings where galactomannan is available be validated for detecting the aspergillus antigen. High-volume culture on Sabouraud dextrose agar in our laboratory increased yield of moulds from 15% to 72% in 133 lower respiratory samples (tracheal aspirates, bronchial lavages, and sputa). However, cultures positive for Aspergillus spp must be interpreted strictly within each clinical context to prevent overdiagnosis. We have begun to validate aspergillus galactomannan in endotracheal aspirates for patients with CAPA. So far, in 15 patients with CAPA and 15 without, we have found a sensitivity and specificity of 93·3% and 60·0%, respectively, at a galactomannan index of 1·414 (appendix). These data, and those from a study by Roman-Montes and colleagues,6Roman-Montes ACM Martinez-Gamboa A Diaz-Lomelí P et al.Accuracy of galactomannan testing on tracheal aspirates in COVID-19-associated pulmonary aspergillosis.Mycoses. 2020; (https://dx.doi.org/10.1111%2Fmyc.13216 published online Nov 20.)PubMed Google Scholar highlight the need for expanded datasets. More flexible diagnostic criteria might be warranted for a common complication of a pandemic, incorporating simpler approaches on difficult-to-obtain samples, including high-volume culture and aspergillus antigen on tracheal aspirates. DWD reports holding founder shares in F2G; acting as a consultant to Pulmatrix, Pulmocide, Zambon, iCo Therapeutics, Mayne Pharma, Biosergen, Bright Angel Therapeutics, Cipla, and Metis; being paid for talks on behalf of Dynamiker, Hikma, Gilead, Merck, Mylan, and Pfizer; and being a longstanding member of the Infectious Diseases Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology, and Infectious Diseases Aspergillosis Guidelines group. All other authors declare no competing interests. Download .pdf (.18 MB) Help with pdf files Supplementary appendix Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidanceSevere acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. Full-Text PDF Diagnostic dilemma in COVID-19-associated pulmonary aspergillosisWe thank the community for rapid recognition and characterisation of COVID-19-associated pulmonary aspergillosis (CAPA), increasingly observed in people with severe SARS-CoV-2 infection. Consistent with previous efforts to standardise definitions for invasive fungal infections,1–3 Philipp Koehler and colleagues4 propose new definitions for CAPA and provide management recommendations. We have questions and concerns for feedback. Full-Text PDF Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis – Authors' replyWe thank Nitipong Permpalung and colleagues and Kauser Jabeen and colleagues for their thoughtful remarks on the 2020 ECMM/ISHAM consensus criteria on COVID-19-associated pulmonary aspergillosis (CAPA).1 We acknowledge that the proposed definitions have shortcomings due to the recent and rapid emergence of CAPA limiting validation studies in this patient population. However, up to publication of these consensus definitions, CAPA cohort studies had used numerous case definitions, including EORTC/MSGERC (for immunocompromised patients), AspICU, modified AspICU, modified Influenza-Associated Pulmonary Aspergillosis (IAPA), and modified IAPA expert case definition, illustrating the urgent need for standardisation2 and recognition of secondary fungal infections as an issue in future WHO COVID-19 clinical research recommendations. Full-Text PDF