key: cord-0877202-9u2eu6ue
authors: Clancy, Cornelius J; Nguyen, M Hong
title: Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA): Re-framing the debate
date: 2022-03-03
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac081
sha: 1448ac418de2790e16a5edf4d27c27feea7cb99a
doc_id: 877202
cord_uid: 9u2eu6ue

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has been reported in ~5%-10% of critically-ill COVID-19 patients. However, incidence varies widely (0%-33%) across hospitals, most cases are unproven, and CAPA definitions and clinical relevance are debated. We re-frame the debate by asking, what is the likelihood that patients with CAPA have invasive aspergillosis? We use diagnostic test performance in other clinical settings to estimate positive and negative predictive values (PPV, NPV) of CAPA criteria for invasive aspergillosis in populations with varying CAPA incidence. In a population with CAPA incidence of 10%, anticipated PPV/NPV of diagnostic criteria are ~30%-60%/≥97%; ~3%-5% of tested cohort would be anticipated to have true invasive aspergillosis. If CAPA incidence is 2%-3%, anticipated PPV/NPV are ~8%-30%/>99%. Depending on local epidemiology and clinical details of a given case, PPVs/NPVs may be useful in guiding antifungal therapy. We incorporate this model into a stepwise strategy for diagnosing and managing CAPA.

M a n u s c r i p t 2 Summary: We present a model by which clinicians can estimate the likelihood that critically-ill patients with coronavirus disease 2019 have invasive aspergillosis, using knowledge of local epidemiology and diagnostic test performance. We propose a stepwise approach to diagnostic and treatment decision-making. M a n u s c r i p t 4 Pulmonary aspergillosis is well-recognized among patients with severe coronavirus disease 2019 . 1, 2 Nevertheless, the incidence of COVID-19 associated pulmonary aspergillosis (CAPA) remains unclear. [3] [4] [5] Rates ranging from 0% to 33% have been reported in critically ill patients with COVID-19 at some hospitals. 2, 6 In general, CAPA incidence has been higher in reports from Europe than in those from North America. Discrepancies between studies may reflect differences in local epidemiology, environmental factors, treatment of COVID-19, thresholds for testing, disease definitions, diagnostic criteria and patient populations.

In studies that have retrospectively applied standardized CAPA definitions, pooled incidence of CAPA in intensive care units (ICUs) was 2% to 11%. 3,7-9,10-13 Only 2%

of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected decedents in autopsy studies published through September 2020 had histopathologic evidence of aspergillosis or other invasive mould infections;

incidence was also 2% among mechanically ventilated decedents. 4 Therefore, robust debate has arisen over the diagnosis of CAPA, its incidence and clinical relevance. 3, 5 In this paper, we re-frame the debate over CAPA Across guidelines, the major driver of diagnosis is detection of Aspergillus in respiratory tract samples by methods like culture, galactomannan detection or polymerase chain reaction (PCR). 14 These are not definitive diagnostic tests, as they do not distinguish between colonization and disease. 15 The preferred sample for testing, after respiratory tract tissue, is bronchoalveolar lavage (BAL) collected by bronchoscopy. 2 Bronchoscopies of patients with COVID-19 are safe using riskminimizing protocols, and they are now endorsed for diagnosing co-infections. 2, 16, 17 In general, detection of Aspergillus in BAL in absence of proven tissue invasion constitutes probable disease by consensus definitions, provided other criteria are also fulfilled. 2, 7, 10, 11 Respiratory samples like sputa, bronchial and tracheal aspirates, and nonbronchoscopic bronchial lavage (NBL) are employed in many CAPA studies, despite increased potential for upper airway microbial contamination and lack of validation for galactomannan testing or Aspergillus PCR. 2, 11, 18 Limited data suggest that performance of galactomannan detection in NBL may be comparable to that of A c c e p t e d M a n u s c r i p t 6 galactomannan or PCR in BAL. 11, 18 In the absence of other positive diagnostic markers, Aspergillus detection in non-BAL respiratory samples is supportive of possible disease. 2, 7, 10, 11 Blood cultures and serum galactomannan are insensitive for diagnosing pulmonary aspergillosis, but detection in at-risk hosts may reflect disseminated disease. 9 Beta-d-glucan detection in respiratory samples or serum cannot distinguish between Aspergillus, Candida or other fungi, and it is prone to false-positivity. A c c e p t e d M a n u s c r i p t 8 For populations in which 2%, 5% and 10% of patients fulfill criteria for CAPA, the anticipated incidence of true invasive aspergillosis is roughly 0.5% to 1%, 1% to 2% and 3% to 5%, respectively (across the range of BAL galactomannan performance in Table 1 ). These values are broadly in keeping with the 2% incidence of invasive mould infections from autopsy studies of mechanically ventilated patients dying with COVID-19. 4 Therefore, aggregate clinical and autopsy data on CAPA are largely in agreement; seeming discrepancies between results of antemortem and postmortem studies reflect that the latter, for the most part, have described a subset of the former with invasive disease [ Figure] . Based on these considerations, we propose definitions that may be useful in thinking about, and distinguishing between CAPA and invasive aspergillosis [ Table 2 ].

Combination testing has been proposed to improve diagnosis of CAPA, 11 contamination. The assumption that diagnostic test performance in critically-ill patients with COVID-19 is comparable to that in other populations is unproven.

How should clinicians approach the diagnosis and treatment of CAPA?

Antifungal treatment of probable and possible CAPA is endorsed by at least some consensus guidelines, 2 although it has not been associated with lower mortality in retrospective studies. In absence of clinical trial data, we recommend a six-step approach to diagnosing and managing CAPA [ Table 3 ].

In determining whether to treat a patient with CAPA, clinicians must decide upon the threshold likelihood of invasive aspergillosis that would trigger empiric antifungal therapy. Threshold PPVs or NPVs that justify treatment decisions for aspergillosis or other fungal infections are not firmly established. Data in immunosuppressed or critically ill patients suggest that antifungal prophylaxis is beneficial in preventing invasive fungal infections when baseline disease rates are ≥15% to 30%. 25 Hypothesizing that this target range encompasses a threshold for empiric treatment, we can identify settings in which likelihood of invasive aspergillosis (i.e., PPV) is expected to be above these values for patients with CAPA

[ Calculations such as those in Table 1 are starting points for interpreting diagnostic testing for aspergillosis, but they are useful only in context of all clinical data for a patient. In the end, the likelihood of disease and need for treatment is determined by A c c e p t e d M a n u s c r i p t 11 the clinician, not by any single test or criterion. Indeed, each piece of clinical information and data should be considered as its own "test", results of which increase or decrease the likelihood of invasive aspergillosis. Management of any patient, then, is shaped by combination of these results.

In most cases, it is infeasible to calculate a precise running tally of disease likelihood. Rather, clinicians can make qualitative assessments to guide decision

making. An example is: "This mechanically ventilated patient with COVID-19 who was treated with tocilizumab has worsening respiratory status and imaging. The work-up thus far is negative. Positive respiratory tract galactomannan increases the likelihood of invasive aspergillosis such that I am going to treat empirically. Negative respiratory tract galactomannan and fungal culture make invasive aspergillosis unlikely, so I am comfortable holding antifungal treatment even though the patient has some risk factors."

This article proposes a conceptual framework for approaching CAPA, which can also serve as a model for aspergillosis in other critically ill populations, including those with severe influenza or other respiratory viral infections. 26 M a n u s c r i p t 17 Many services are involved in care of critically ill patients with COVID-19. Engagement with and buy-in from services will improve compliance with protocols and treatment recommendations. Directed testing rather than routine surveillance testing will decrease false positives for aspergillosis 5. Determine thresholds to justify antifungal treatment Develop treatment protocols based on estimated PPVs and NPVs, using team approach Agree among clinical and stewardship services on likelihoods of aspergillosis that justify treatment, and how much potential antifungal over-treatment you are willing to tolerate 6. Individualize decisions in each patient Make treatment decisions for each patient by considering clinical data and case details

In each patient, clinical parameters (e.g., new findings, lack of alternative diagnoses, length of stay, etc.), radiography (e.g., new lesions) and laboratory data (e.g., higher values, repeat or multiple positive results, etc.) may refine assessments of disease likelihood and need for treatment

Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19

Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis

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Invasive mould disease in fatal COVID-19: a systematic review of autopsies

Navigating the uncertainties of COVID-19 associated aspergillosis (CAPA): A comparison with influenza associated aspergillosis (IAPA)

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A c c e p t e d M a n u s c r i p t 14 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 16 Table 1 . Anticipated positive and negative predictive values of CAPA diagnostic criteria for invasive aspergillosis CAPA has been diagnosed in 0 to 33% of critically ill COVID-19 patients in intensive care units (ICUs) at different hospitals. Optimal BAL galactomannan cut-offs for diagnosing invasive aspergillosis in patients with COVID-19 are not defined. 7, 11 Cut-offs and test performance in non-COVID-19 populations can be used to estimate positive and negative predictive values (PPV, NPV) for invasive aspergillosis in ICUs with various underlying burdens of CAPA (column 1). PPVs and NPVs within dark grey boxes are >30% and ≥97%, respectively. PPVs and NPVs within light grey boxes are 15%-30% and >99%, respectively. PPVs ≥15%-30% may be sufficiently high to justify empiric antifungal treatment, depending on constellation of clinical findings and other data in individual patients ( . In this group, CAPA is false-negative (FN) for IPA. It is plausible, but as yet unproven, that IPA in some patients is preceded by CAPA that represents Aspergillus colonization of the respiratory tract.