key: cord-0869381-jk8wzcbx
authors: Pasquier, Grégoire; Bounhiol, Agathe; Robert Gangneux, Florence; Zahar, Jean‐Ralph; Gangneux, Jean Pierre; Novara, Ana; Bougnoux, Marie‐Elisabeth; Dannaoui, Eric
title: A review of significance of Aspergillus detection in airways of ICU COVID‐19 patients
date: 2021-07-01
journal: Mycoses
DOI: 10.1111/myc.13341
sha: 8fd7f7d62ad75f46d78609635223589490ed3628
doc_id: 869381
cord_uid: jk8wzcbx

It is now well known that patients with SARS‐CoV‐2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS‐CoV‐2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID‐19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non‐surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.

respiratory viral infection, SARS-CoV-2 infection may also be a risk factor for IPA. More and more cases in the literature report the presence of Aspergillus in airway specimens, for which the diagnosis of IPA seems unclear. There are several difficulties for the diagnosis: symptomatology is often atypical in ventilated intubated patients, and the radiological aspects are difficult to differentiate from those of SARS-CoV-2 pneumonia.

The first studies reported a widely variable incidence ranging from 2.4% 3 to 35% 4 depending on the screening protocols and used definition of IPA. Indeed, aspergillosis definitions were not consensual and were not necessarily in agreement with the definition of IPA in haematology. 5, 6 As a reminder, the definition of IPA in ICU still remains non-consensual and unclear. 7 It is only recently that IPA definitions specifically, in the context of COVID-19, have been proposed.

One of the major issues is the significance of Aspergillus detection (culture, galactomannan antigen (GM) or specific PCR) in airways from intubated COVID-19 patients (colonisation or IPA) and thus the indication for an antifungal treatment. In an attempt to clarify this issue, we analysed all published cases of Aspergillus colonisation and IPA in ICU COVID-19 patients until 1 October 2020. Comparison of treated and non-treated patients allowed us to highlight the criteria leading the clinicians to a non-treatment decision. Comparison of survivor and non-survivor groups underlined the criteria associated with mortality that should help for treatment decision.

We performed a review of literature until the 1 October 2020 on Pubmed database with the MeSH terms: "Aspergillosis" and "COVID" (Figure 1 , Flow chart). Inclusion criteria were the description of SARS-CoV-2-infected patients in ICU under mechanical ventilation (35 publications 

A systematic review of the literature allowed us to select 35 studies ( Figure 1 ), published between January 2020 and the 1 October 2020, gathering data from 182 COVID-19-associated pulmonary aspergillosis (CAPA) patients and 49 patients with Aspergillus colonisation In order to analyse the criteria used for the decision of antifungal treatment, we selected the 28 publications for which individual data were available ( Figure 1 , Table S1 ). One hundred and thirty-four patients with CAPA or Aspergillus colonisation were included in these 28 studies (Table 2 ). Eleven CAPA patients were not treated because of pre-or post-mortem aspergillosis diagnosis and were thus excluded from the analysis. We compared the treated CAPA group (n = 96) vs the non-treated group with CAPA or Aspergillus colonisation (n = 27). Clinical decision not to initiate an antifungal treatment F I G U R E 1 Flow chart was associated with a younger age (59.1 vs 68.8 years, p = .001) and a diagnosis based on a unique microbiologic criterion (culture, respiratory marker or blood marker) (81.5% vs 33.3%, p < .001), particularly on a unique respiratory marker (44.4% vs 11.5%, p < .001).

In the non-treated group, positivity rates of Aspergillus isolation in culture (P =.006), of GM in non-BAL respiratory samples (p = .03) and of Aspergillus specific PCR in blood (p < .001) and in respiratory samples (p = .01) were significantly lower than in the treated group in univariate analysis. These results were confirmed in multivariate analysis except for Aspergillus isolation in culture (Table S2) . We TA B L E 1 Review of the 35 studies reporting COVID-19-associated pulmonary aspergillosis cases (CAPA) or respiratory Aspergillus colonisation in ICU COVID-19 patients noted that a combination of positive culture and positive marker in respiratory sample was more frequent in the treated group (35.4% vs 11.1%, P =.02) ( Table 2 ). Moreover, Aspergillus specific blood markers (GM and PCR) were more often positive in treated patients (p = .02).

Interestingly, among Aspergillus species, A niger was more common in non-treated group (20% vs 2.6%, p = .03) and thus was more frequently considered as a contaminant. Concerning radiological data, although CT-scan results were reported only for 34 patients, the presence of typical aspergillosis imaging was correlated with the decision to treat (p < .001, data not shown). Besides, decision of non-treatment was not associated with an over-mortality (18.5% of fatality rate in non-treated group vs 56.3% in treated group,

The overall mortality rate was 52.2% (70/134). In order to compare characteristics of survivor (n = 64) and non-survivor (n = 70) patients, we analysed the underlying diseases, the microbiological data and the antifungal treatment (Table 3) . Non-survivor patients were older (70.8 vs 62.5 years, p < .001), were more likely to have chronic respiratory diseases (33.9% vs 11.8%, p = .009) and chronic obstructive pulmonary disease (COPD) (17.7% vs 2%, p = .01) in univariate analysis. However, the multivariate analysis did not confirm the positive association between COPD and mortality (Table S3) Table 2 ). A short and long bar represent a retrospective and prospective study, respectively. The three yellow bars represent the global prevalence in ICU non-COVID-19 and non-Influenza patients (0.3%-6.9%). 18, 51, 52 The three red bars represent the prevalence in the group of ICU patients with severe influenza (16%-23%). 10 Nevertheless, some differences appeared between IAPA and CAPA.

More patients fulfilled the EORTC host factor criteria in IAPA (43% according to Schauwvlieghe et al. 10 ) than in CAPA (6.3% in this study).

The mean delay between admission in ICU and the mycological diagnosis seems to be shorter in IAPA (2-3 days 22 ) than in CAPA (9.5 days in this review). Finally, very few cases of tracheobronchitis form of aspergillosis 4 were described among CAPA compared with IAPA. 19 To decipher the risk factors for and characteristics of CAPA, it would be of major interest to design a study comparing COVID patients with non-COVID patients, in the same ICUs and same time period.

There are some limitations in the present review as many individual data were missing, especially concerning COVID-19 treatments that could increase the occurrence of CAPA. Particularly, corticosteroids are a known risk factor for IPA in ICU patients, 18 

Data sharing not applicable -no new data generated.

Eric Dannaoui https://orcid.org/0000-0002-2817-3830

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A review of significance of Aspergillus detection in airways of ICU COVID-19 patients