key: cord-0925372-mralkanx
authors: Chong, Woon H.; Neu, Kristoffer P.
title: The Incidence, Diagnosis, and Outcomes of COVID-19-associated Pulmonary Aspergillosis (CAPA): A Systematic Review
date: 2021-04-21
journal: J Hosp Infect
DOI: 10.1016/j.jhin.2021.04.012
sha: 0dd46e05d5d412e6c9dacf765782caa35a11538a
doc_id: 925372
cord_uid: mralkanx

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is defined as invasive pulmonary aspergillosis occurring in COVID-19 patients. OBJECTIVE: The purpose of this review is to discuss the incidence, characteristics, diagnostic criteria, biomarkers, and outcomes of hospitalized patients diagnosed with CAPA. METHODS: A literature search was performed through Pubmed and Web of Science databases for articles published up to March 20th, 2021. RESULTS: In 1,421 COVID-19 patients, the overall CAPA incidence was 13.5% (ranging 2.5-35.0%). The majority required invasive mechanical ventilation (IMV). The time to CAPA diagnosis from illness onset varied between 8.0-16.0 days. However, the time to CAPA diagnosis from ICU admission and IMV initiation ranged between 4.0-15.0 days and 3.0-8.0 days. The most common diagnostic criteria were the modified AspICU-Dutch/Belgian Mycosis Study Group and IAPA-Verweij et al. 77.6% of patients had positive lower respiratory tract cultures, other fungal biomarkers of BAL and serum galactomannan were positive in 45.3% and 18.2% of patients. The CAPA mortality rate was high at 48.4%, despite the widespread use of antifungals. Lengthy hospital and ICU LOS ranging between 16.0-37.5 days and 10.5-37.0 days were observed. CAPA patients had prolonged IMV duration of 13.0-20.0 days. CONCLUSION: The true incidence of CAPA likely remains unknown as the diagnosis is limited by the lack of standardized diagnostic criteria that rely solely on microbiological data with direct or indirect detection of Aspergillus in respiratory specimens, particularly in clinical conditions with a low pretest probability. A well-designed, multi-center study to determine the optimal diagnostic approach for CAPA is required.

examine and discuss the incidence of secondary IPA in COVID-19 patients defined as COVID-19-associated pulmonary aspergillosis (CAPA), clinical characteristics, diagnostic criteria, biomarkers, and associated outcomes based on the evidence available in the current literature.

This systematic review was conducted and presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ethical approval and informed consent were not required for this study as it was a systematic review of previously published studies.

A literature search was performed through Pubmed and Web of Science databases for articles published, using the keywords of "coronavirus disease 2019 (COVID- 19) ," "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)," "COVID-19-associated pulmonary aspergillosis (CAPA)," "fungal infections," "secondary infections," "fungal pneumonia," "mycosis," "Aspergillosis," "Aspergillus," and "invasive pulmonary aspergillosis (IPA)." All specified keywords were combined using the "OR" operator and "AND" operator for searching the literature. Moreover, to detect additional studies, any cited references were reviewed to identify relevant literature that met our inclusion criteria.

Articles that met the following criteria were included in our study: 1) observational studies that described the incidence, clinical characteristics, biomarkers, and outcomes of IPA in hospitalized adults with COVID-19 infections; 2) articles where the diagnosis of CAPA was made using several well-established diagnostic criteria (Table 1) that had been described in the current literature involving AspICU [13] , CAPA-European Excellence Center for Medical Mycology (ECMM) [14] , Modified AspICU Gangneux et al. [15] , Modified AspICU Dutch-Belgian Mycosis J o u r n a l P r e -p r o o f Study Group [10] , influenza-associated pulmonary aspergillosis (IAPA) criteria- Verweij et al. [16] , or European Organization for Research and Treatment of Cancer/Invasive Fungal

Mycoses Study Group (EORTC/MSG) [17] ; 3) studies in which the diagnosis of COVID-19 was made by reverse transcriptase-polymerase chain reaction (RT-PCR) in all cases from respiratory tract specimens that include nasal and pharyngeal swabs, sputum, ETA, and BAL; and 4) articles published between January 1st, 2020 to March 20th, 2021 in peer-review journals.

The exclusion criteria were specified as follows: 1) articles that do not meet or described specific diagnostic criteria for CAPA diagnosis ( Table 1 ) that could represent colonization or had coexisting bacterial and/or (non-Aspergillus) fungal microorganisms simultaneously identified from the LRT specimens and/or blood cultures; 2) articles with less than 18 patients (defined as case series) and/or case reports; 3) articles involving COVID-19 patients less than 18 years of age; 4) articles where pulmonary aspergillosis was concurrently diagnosed with other microorganisms such as bacterial and/or viral from similar respiratory tract cultures; and 5) articles describing aspergillosis obtained from non-respiratory tract cultures.

Two researchers (WC and KN) independently screened the titles and abstracts, and reviewed the full texts of articles to identify studies that evaluated the incidence, clinical characteristics, diagnostic criteria, biomarkers, and associated outcomes of hospitalized COVID-19 patients J o u r n a l P r e -p r o o f diagnosed with CAPA. Any disagreements were resolved by discussion. The extracted data from full texts of included studies was added into a standardized Excel (Microsoft Corporation) form.

All included studies' characteristics and outcomes were analyzed in Table 3 involving: study design (e.g., retrospective or prospective; cross-sectional, case-control, or cohort; single-or multi-center); month/year; country; the number of patients; the age of the patient (e.g., mean +/standard deviation or median [interquartile range] years); incidence of CAPA; incidence of proven CAPA; time to diagnosis of CAPA; mortality; length of hospitalization; patients requiring IMV; and the median days of IMV. In Table 4 , diagnostic evaluation and antifungal therapies were summarized comprising of: positive lower respiratory tract cultures (LRTC); aspergillus species (spp.); CAPA diagnostic criteria; EORTC host risk factors; positivity of serum galactomannan (GM), BAL GM, and serum beta-D-glucan (BDG); therapeutic antifungals received.

Two researchers performed quality assessments using the Newcastle-Ottawa Scale (NOS), containing nine items, for the cohort and case-control studies. In NOS, the total score ranged from 0 to 9 and was categorized into three groups: Low quality "0-3", moderate quality "4-6", and high quality "7-9". [18] During the quality assessment of the included studies, any disagreements were resolved by discussion.

J o u r n a l P r e -p r o o f hospitalized adult COVID-19 patients diagnosed with CAPA were critically ill and required ICU admission and IMV at the time of diagnosis, excluding observational studies by Nasir et al. [19] A small retrospective cohort study by Rutsaert et in 239 patients using the modified AspICU-Dutch/Belgian Mycosis Study Group criteria. [24] J o u r n a l P r e -p r o o f Time to CAPA Diagnosis:

According to 14 observational studies (Table 3) , the overall time to CAPA diagnosis from the onset of COVID-19 symptoms ranged between 8.0 to 16.0 days. The time to CAPA diagnosis from ICU admission and after IMV initiation ranged between 4.0 to 15.0 days and 3.0 to 8.0 days, respectively.

The most common diagnostic criteria used ( [13] , CAPA-ECMM [14] , and modified AspICU-Gangneux et al., [15] to diagnose CAPA.

The CAPA diagnosis was made using LRTCs in 77. 6 In terms of fungal biomarkers used to assist with CAPA diagnosis, two different biomarkers were described involving GM and BDG. GM was obtained either from serum or BAL with a cut-J o u r n a l P r e -p r o o f off of 0.5 and 1.0 optimal density index (ODI) used, respectively ( 

The hospital mortality observed among the 192 patients diagnosed with CAPA was highly variable, with an overall mortality rate of 48.4% (93/192) and ranging between 22.2% to 100% (Table 3) . According to 12 studies, the overall hospital and ICU length of stay (LOS) ranged between 16.0 to 37.5 days and 10.5 to 37.0 days. In four studies, the mean duration of IMV requirement ranged between 13.0 to 20.0 days. 89.5% (17/19) of studies described the antifungal therapies received by CAPA patients that were predominantly voriconazole. Other antifungal therapies used were amphotericin B, anidulafungin, caspofungin, and isavuconazole (Table 4) .

No patients diagnosed with CAPA were on antifungal prophylaxis in all included studies.

J o u r n a l P r e -p r o o f

The overall incidence of CAPA is 13.5% and ranged between 2.5-35.0%, among 1,421 COVID-19 patients included. Generally, patients diagnosed with CAPA were critically ill and required IMV, although few had pre-existing EORTC risk factors. The mean age of CAPA patients Six observational studies reported an incidence of CAPA exceeding 20% among hospitalized COVID-19 patients, and five of these studies had a small sample size of fewer than 42 patients observed (Table 3) . [20] [21] [22] [23] 28 ] Among these five studies described, Bartoletti et al. routinely performed serial samplings of BAL in a large sample size of 108 critically ill COVID-19 patients J o u r n a l P r e -p r o o f on the day of ICU admission, day seven after requiring IMV, and at the time of clinical deterioration, which likely contributed to the high observed CAPA incidence of 27.7%. [22] A prospective study by Alanio et al. reported a CAPA incidence of 33.3% among 27 COVID-19 patients requiring IMV in which bronchoscopy with BAL was performed routinely on day three post-intubation. [21] According to two observational studies by Lahmer et al. and Van Biesen et al., the high incidence of CAPA at 21.4% and 34.4%was due to a non-directed BAL approach used to minimize aerosolization and routinely performed within two days of ICU admission. [23, 29] The non-directed BAL approach consists of advancing 12-French suction catheter via a closed-circuit until bronchial wedging is achieved, followed by lavage. Rutsaert et al. also described an elevated incidence of CAPA (35%) in their study in which routine bronchoscopy with BAL culture and GM testing was performed for indications of atelectasis and worsening clinical status among critically ill COVID-19 patients. [20] Furthermore, any suspicious tracheobronchial lesions concerning for Aspergillus tracheobronchitis were biopsied via bronchoscopy in that study. Therefore, the high CAPA incidence was at least partially explained by the frequent invasive BAL sampling approach across these five studies.

As the clinical course of COVID-19 demonstrates many features shared with severe influenza infection that include ARDS, lymphocytopenia, sepsis, and cytokine storm leading to multiorgan failure, it is reasonable to suspect that patients with severe COVID-19 may be similarly susceptible to IPA. [30] The clinical state of immunosuppression and underlying influenzarelated acute respiratory failure is an independent risk factor for IPA. [10, 31] When compared to critically ill adult patients being treated for influenza-related acute respiratory failure, several multi-center retrospective studies reported an overall incidence of influenza-associated J o u r n a l P r e -p r o o f pulmonary aspergillosis (IAPA) amounting to 16-19% . [10, 31] In influenza patients who are immunocompromised, the incidence of IAPA increased up to 32% from 14% in immunocompetent influenza patients. Critically ill patients with influenza-related respiratory failure have also been observed to have a 5.2-fold increased risk of contracting IAPA. [10] The evidence of IPA has also been found in 7.1-12.5% of autopsy series in SARS patients. [7] [8] [9] The diagnosis of CAPA from the onset of COVID-19 symptoms, ICU admission, and after initiation of IMV was highly variable. For the diagnosis of secondary bacterial pulmonary infections among COVID-19 patients, the time to diagnosis is 10 days (ranged 2-21 days) from hospital admission and 9 days (ranged 4-18 days) after ICU admission but can occur as rapidly within five days after initiation of IMV. [2, 3, 32] Conversely, in critically ill adult patients with influenza-related acute respiratory failure, the median onset of IPA was three days after ICU admission. [10, 31] The suspicion for secondary pulmonary infections typically arises when there is a sudden deterioration in the patient's clinical status or worsening chest imaging findings that cannot be explained by the underlying illness when managing critically ill COVID-19 patients.

In the setting of this ongoing pandemic, clinicians' reluctance to perform BAL and rely on sputum and ETA specimen is not surprising and likely explained the delay in diagnosis of secondary bacterial and fungal pulmonary infections in COVID-19 patients compared to critically ill influenza patients.

There are multiple diagnostic criteria used for clinical decision-making in determining the probability of CAPA among the 19 observational studies included. These diagnostic criteria are a composite of host factors/clinical features, radiological findings, and mycological results J o u r n a l P r e -p r o o f described in Table 1 . Historically, EORTC/MSG criteria are used to classify patients who are immunocompromised into proven, probable, or possible aspergillosis while heavily reliant on characteristic radiological features of IPA that can be helpful to distinguish from COVID-19

pneumonia. [17] The diagnosis of IPA in critically ill patients can be challenging as the EORTC/MSG criteria is not necessarily applicable in the ICU setting or validated in immunocompetent patients, including COVID-19 patients, where many lack the typical host factors and often have less specific radiological features, especially in the presence of diffuse lung infiltrates from acute respiratory distress syndrome (ARDS). [17, 22] The EORTC/MSG diagnostic criteria were not used despite 36.8% of observational studies reporting COVID-19 patients with pre-existing EORTC host risk factors (Table 4 ), although this comprises 12.5% of patients diagnosed with CAPA. For patients with no underlying immunosuppressive comorbidities and in the ICU setting, the AspICU algorithm has emerged as the diagnostic criteria used to distinguish IPA into proven or putative from Aspergillus colonization in patients who are critically ill. [13] Putative AspICU diagnosis requires the presence of Aspergilluspositive LRT cultures (entry criterion) with compatible clinical, radiological, and mycological findings described in Table 1 . More recently, several expert consensuses have proposed a modified case definition of CAPA from the AspICU algorithm, based on the addition of GM biomarker from serum or BAL specimens, irrespective of results of BAL cultures termed CAPA-ECMM [14] , Modified AspICU-Dutch/Belgian Mycosis Study Group [10] , and Influenzaassociated Pulmonary Aspergillosis (IAPA)-Verweij et al.. [16] A BAL PCR testing for Aspergillus species has even been proposed as part of mycological criteria not only in EORTC//MSG but also in CAPA-ECMM and Modified AspICU-Gangneux et al. [14, 15, 17] J o u r n a l P r e -p r o o f [24] Therefore, the many CAPA definitions provided have enabled clinicians to utilize a strategic approach to identify and classify CAPA in critically ill COVID-19 patients. It also provides a framework for early diagnosis and possibly allows prompt treatment initiation, which may confer a survival benefit. In the prospective study by Alanio et al., the reported incidence of CAPA was 33% (9/27); however, five out of nine CAPA patients had positive BAL culture but negative BAL/serum GM suggesting a lack of tissue invasion. [21] Undeniably, 60% (3/5) of these COVID-19 patients were not treated with antifungals and survived. Several other diagnostic criteria have been suggested to allow early screening and diagnosis of CAPA, specifically in critically ill patients; yet, these criteria have not been validated in any studies. [30, 35, 36] J o u r n a l P r e -p r o o f Consequently, as the diagnostic criteria of CAPA continue to evolve during this current pandemic, large, prospective, multi-center validation studies are required to determine which diagnostic CAPA criteria are most pragmatic or needed to be refined.

In the setting of this ongoing pandemic, the reluctance of clinicians to perform invasive diagnostic procedures such as BAL and over-reliance on sputum and ETA specimen is not unexpected. Elevated serum levels of procalcitonin and higher neutrophil to low lymphocyte ratio from dysregulated immune response have been suggested to predict secondary bacterial infection in critically ill COVID-19 patients. [37] However, these findings do not apply during the evaluation of suspected CAPA or invasive fungal disease. [35] Therefore, systematic screening using a combination of biomarkers such as serum and BAL GM is essential to assist with the diagnosis of CAPA and has since been included as part of the CAPA-ECMM [14] , modified diagnostic CAPA criteria used involving Modified AspICU-Gangneux et al. [15] , Modified AspICU-Dutch/Belgian Mycosis Study Group [10] , and Influenza-associated Pulmonary Aspergillosis (IAPA)-Verweij et al. [16] , given the poor specificity (20-50%) of a positive Aspergillus culture identified in sputum and ETA, that may represent colonization. [38] BAL GM, when performed, has an observed 90% sensitivity and 94% specificity for diagnosing proven or probable IPA according to the EORTC/MSG criteria. [39] However, in nonimmunocompromised critically ill patients who do not have the typical host factors meeting EORTC/MSG criteria (Table 1) , BAL GM ODI of more than 0.5 cutoffs had 76% sensitivity and 81% specificity in diagnosing IPA. [40] Therefore, BAL PCR has been increasingly used to assist with the diagnosis of CAPA in 42.9% of observational studies included (Table 3 ) with a reported sensitivity of 80% and specificity of 93% in non-neutropenic critically ill patients. [41] Using the J o u r n a l P r e -p r o o f Modified AspICU-Dutch/Belgian Mycosis Study Group criteria, a BAL GM will return positive in 92% cases using an index of more than 0.5 cutoffs for diagnosing IAPA. [10] The use of BAL PCR may allow early CAPA diagnosis; however, this was not observed in the study by Gangneux [20] This finding further supports the notion that BAL GM is a more sensitive biomarker for IPA than serum GM, especially in those with non-angio-invasive CAPA. The specificity of serum BDG to distinguish between IPA to those with Aspergillus colonization has been shown to be as high as 86%, with two consecutive positive results. [53] Yet, the role of serum BDG in supporting the diagnosis of CAPA remains uncertain due to the scarcity of the tests being performed in the limited literature available. Lung biopsy remains the gold standard to confirm the diagnosis of proven CAPA, regardless of diagnostic criteria used (Table 1) , by revealing evidence of hyphae invasion and damage of lung tissue but generally avoided due to its associated risk, especially in ventilated COVID-19 patients. Again, a small retrospective study by Rutsaert et al. was the only study that performed routine bronchoscopy-guided biopsies of any suspicious tracheobronchial lesions, which likely explained the high incidence and proven CAPA diagnosis observed. [20] Moreover, it is not unusual for the diagnosis of proven CAPA to be confirmed during postmortem examination, which was seen in several studies. [52, 54] The difficulties in CAPA diagnosis are further outlined in a study by Blaize et al., where both LRT culture and serum biomarkers were initially negative but repeat LRT cultures eventually returned positive after the patient's death. [54] In order to J o u r n a l P r e -p r o o f optimize microbiological and molecular diagnostics to better improve protection strategies for vulnerable patient groups, bronchoscopy, including tracheobronchial inspection and BAL sampling for culture, PCR, and GM, should be part of the diagnostic gold standards whenever CAPA is suspected, providing local infection prevention and control guidance for aerosolgenerating procedures can be adhered.

Critically ill ARDS patients with putative IPA diagnosis are shown to have significant mortality (OR 9.58; 95% CI 1.97-46.52; P = 0.005) while Aspergillus colonizers are not. [13, 55] The increased awareness of the high mortality rate observed in severe viral pneumonia such as SARS and IAPA has generated concerns relating to CAPA, especially in critically ill COVID-19 patients. One may even hypothesize that CAPA, which appears to be almost exclusively suggesting that patients are likely to be colonized despite meeting Modified AspICU-DB criteria that suggest actual infection. [21] Although antifungals are safe and effective, even as prophylaxis in immunocompromised patients, drug interactions, adverse effects, costs, and capability to measure drug levels are always of concern, especially in critically ill patients with healthcare systems already stretched to the limit. Moreover, countries with lower socioeconomic status are likely to have inadequate resources available to diagnose and treat patients with CAPA. This can very well explain the low incidence of CAPA (10% and less) observed in developing countries (e.g., Mexico and Pakistan), although mortality rates observed were similar. [19, 27] Better studies are required to confirm this hypothesis.

Several possible limitations explain why the incidence of CAPA varied widely from 2.5% to 35% across studies included in our review (Table 3) 1. Representatives of the exposed cohorts.

2. Selection of the non-exposed cohorts 3. Ascertainment of exposure. J o u r n a l P r e -p r o o f

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J o u r n a l P r e -p r o o f [18] performed for 19 cohort studies.1. Representatives of the exposed cohorts.2. Selection of the non-exposed cohorts 3. Ascertainment of exposure. 

Prospective Cohort * * * * N/A * * * 7

Prospective Cohort * * * * ** * * * 9Chauvet et al. [26] Retrospective Cohort * * * * ** * * * 9Delliere et al. [25] Retrospective Cohort * * * * ** * * * 9

Prospective Cohort * * * * N/A * * * 7

Prospective Cohort * * * * ** * * * 9

Retrospective Cohort * * * * N/A * * * 7

Retrospective Cohort * * * * N/A * * * 7

Prospective Cohort * * * * ** * * * 9Lamoth et al. [42] Retrospective Cohort * * * * N/A * * * 7

Prospective Cohort * * * * ** * * * 9

Retrospective Cohort * * * * ** * * * 9Nasir et al. [19] Retrospective Cohort * * * * N/A * * * 7

Retrospective Cohort * * * * * * * * 8

Retrospective Cohort * * * * N/A * * * 7Van Arkel et al. [62] Retrospective Cohort * * * * * * * * 8

Retrospective Cohort * * * * ** * * * 9Velez Pintado et al. [63] Retrospective Cohort * * * * * * * * 8

Retrospective Cohort * * * * ** * * * 9