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Review
. 2021 Dec 11;7(12):1067.
doi: 10.3390/jof7121067.

A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA)

Simon Feys  1   2 , Maria Panagiota Almyroudi  3 , Reinout Braspenning  1 , Katrien Lagrou  2   4 , Isabel Spriet  5   6 , George Dimopoulos  7 , Joost Wauters  1   2
Affiliations
Review

A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA)

Simon Feys et al. J Fungi (Basel). .

Abstract

Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a severe fungal infection complicating critically ill COVID-19 patients. Numerous retrospective and prospective studies have been performed to get a better grasp on this lethal co-infection. We performed a qualitative review and summarized data from 48 studies in which 7047 patients had been included, of whom 820 had CAPA. The pooled incidence of proven, probable or putative CAPA was 15.1% among 2953 ICU-admitted COVID-19 patients included in 18 prospective studies. Incidences showed great variability due to multiple factors such as discrepancies in the rate and depth of the fungal work-up. The pathophysiology and risk factors for CAPA are ill-defined, but therapy with corticosteroids and anti-interleukin-6 therapy potentially confer the biggest risk. Sampling for mycological work-up using bronchoscopy is the cornerstone for diagnosis, as imaging is often aspecific. CAPA is associated with an increased mortality, but we do not have conclusive data whether therapy contributes to an increased survival in these patients. We conclude our review with a comparison between influenza-associated pulmonary aspergillosis (IAPA) and CAPA.

Keywords: COVID-19; COVID-19-associated pulmonary aspergillosis (CAPA); IAPA; aspergillosis; critical care; influenza; influenza-associated pulmonary aspergillosis; intensive care unit.

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Conflict of interest statement

S.F. is funded by a Research Foundation Flanders (FWO) PhD fellowship (11M6922N) and declares travel support from Pfizer. K.L. received consultancy fees from MRM Health, MSD and Gilead, speaker fees from FUJIFILM WAKO, Pfizer and Gilead and a service fee from Thermo Fisher Scientific. I.S. is supported by the Clinical Research Fund of UZ Leuven and served as a consultant to and has received unrestricted travel and research grants from Gilead Sciences, Merck Sharpe and Dohme Corp., Pfizer, Inc. and Cidara. G.D. declares advisory board participation (Pfizer, Gilead) and lecture fees from Gilead and Pfizer. J.W. has received investigator-initiated grants from Pfizer, Gilead and MSD and speakers’ and travel fees from Pfizer, Gilead and MSD. The other authors report no conflict of interest.

Figures

Figure 1
Figure 1
CAPA incidence along a time axis in prospective and retrospective studies with observational data. The time axis is according to the middle date of inclusion (which is the date in the middle, between the first and last day of inclusion in the study). Each dot represents a study. The color of the dot represents the criteria used in the study to diagnose CAPA, while the size of the dot is determined by the number of inclusions in the study. Studies without information on the time period of inclusion as well as case series are excluded from this figure. The partially retrospective/prospective study by Janssen et al. [16] is counted as a retrospective study. CAPA incidence is calculated per study for the combination of proven, probable, putative and possible CAPA cases. The middle date of inclusion is calculated as the date in the middle, between the start and end date of study inclusion.
Figure 2
Figure 2
Regional variation in number of inclusions and CAPA incidence in studies with observational data. Bar chart on the left shows the number of patients included in studies with observational data on CAPA, either per continent or per country. The maps on the right show the pooled CAPA incidence per country in studies with observational data. Only studies with exact information on the countries where patients were recruited were included in this figure [2,9,15,16,18,20,21,22,23,24,25,26,27,28,29,30,31,32,33,35,36,37,38,40,41,43,44,45,47,48,49,51,52,53,54,55,56,57,58,59]. CAPA incidence is calculated per study for the combination of proven, probable, putative and possible CAPA cases.
Figure 3
Figure 3
Selected risk factors among the studies in which these data were available. References of cited studies are: [9,16,17,18,21,23,26,31,32,33,37,38,41,44,47,51,54,56,57,59]. Only risk factors that were assessed by multiple studies with observational data are displayed, and only studies with assessments of at least two displayed risk factors are shown. The color indicates whether a significant association was found between CAPA and the risk factor in the study. Size of the dot indicates the number of inclusions in the study. Remarks: * For the study by Gangneux et al. [9], corticosteroids and tocilizumab were only significantly associated with the development of CAPA when combined. For those studies reporting a significant relationship between pulmonary disease and CAPA, this was COPD for Janssen et al. (only in the discovery cohort consisting of 519 patients) [16] and Wang et al. [57], pulmonary vascular diseases for Permpalung et al. [32], and chronic respiratory illness (not specified) for White et al. [47].
Figure 4
Figure 4
Comparison between IAPA and CAPA. Infograph on the similarities and differences between CAPA and IAPA. Both co-infections occur in ICU-admitted patients. Corticosteroids and anti-IL-6 therapy have been implicated in CAPA pathophysiology, while this is the case for corticosteroids and oseltamivir in IAPA. IAPA tends to occur earlier, more frequently and with more frequent angioinvasion than CAPA. Both lead to an increased mortality. Created with the aid of BioRender.com.
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