PMC:7377212 / 15020-21264 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7377212","sourcedb":"PMC","sourceid":"7377212","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7377212","text":"Diagnosis and risk of CAPA\nBearing these observations in mind, we argue that critically ill patients with COVID-19 and progressive features should be screened for CAPA. We acknowledge that acquiring and handling clinical samples for microbiology is very challenging given the Hazard Group 3 rating of the SARS-CoV-2 virus, alongside an overburdened critical care service [27].\nIdeally, screening for CAPA entails using a combination of computed tomography chest imaging and Aspergillus antigen tests on BAL and serum including GM ELISA or lateral-flow tests [28], or aspergillus PCR [29]. Whilst characteristic CT features of invasive aspergillosis such as nodules with halo sign were seen in 17.6% of severely ill COVID-19 patients, they were not confirmed to be IPA [30]. Given the lack of typical invasive aspergillosis features on CT in IAPA, the absence of classical findings such as cavitation should not be used to exclude CAPA; however, their presence can help support the diagnosis and reduce the burden of evidence placed on mycological investigations.\nIn a study of 26 ICU patients that were diagnosed with proven (non-CAPA/IAPA) IPA post mortem, serum GM had only 25% sensitivity in those that were not neutropenic (versus 70% in neutropenic patients) [31]. In contrast, BAL GM was 88–90% sensitive in both groups. In the IAPA study by Schauwvlieghe et al. [13] serum GM testing performed better with 20 (65%) out of 31 positive cases, however BAL GM remained superior at 67 (88%) out of 76 cases. In CAPA cases reported to date (table 1), BAL culture and GM had a sensitivity of 72.7% and 66.7%, respectively, but serum GM was positive in only six (21.4%) out of 28. Moreover, of the five cases of proven CAPA reported to date, four were serum GM negative (table 1) [8], indicating that serum GM test performance might be inferior in diagnosing CAPA. Therefore, bronchoscopy, including tracheobronchial inspection and BAL sampling for culture and GM should be the diagnostic gold standards whenever CAPA is suspected, providing this is compatible with local infection prevention and control guidance for aerosol-generating procedures. A positive BAL GM (index \u003e1.0) would be indicative of CAPA, whereas if the index is \u003c0.5 CAPA is much less likely [31]. A positive serum GM result (≥ 0.5) would be highly suspicious for CAPA but a negative result should not be used to exclude the diagnosis. Novel lateral-flow antigen tests may represent a locally implementable alternative to GM ELISA in the CL3 laboratory, but currently require validation in ICU patients without EORTC host factors including COVID-19 [28]. An Aspergillus-specific PCR test [29] may also be helpful and if positive could also lead to the application of molecular testing for the recognised markers of clinically or environmentally derived azole resistance [32].\nA (1–3)-β-D-glucan (BDG) test on a serum sample is an easily obtained, early screening test when there is a suspicion of IPA. Although performance might be superior to serum Aspergillus antigen testing for the detection of IPA in the ICU [33], BDG negativity cannot be used to rule out infection, with a 77% sensitivity determined across a heterogeneous population of invasive aspergillosis patients, and performance in CAPA as yet to be determined. BDG positivity can occur due to a number of reasons in this patient cohort, however serial positive tests increases specificity and should prompt a diagnostic work-up including computed tomography and bronchoscopy and testing for Aspergillus antigen as outlined above [34]. While initiating antifungal treatment pre-emptively based on BDG positivity may be an improvement on empirical therapy, every effort should be made to utilise other more specific diagnostic tests to complement the BDG result.\nCurrent guidelines advise against routine diagnostic bronchoscopy due to the risk of aerosol generation; recommending it only in patients in whom nasopharyngeal cultures are negative and BAL sampling will change clinical management [35]. In practice many patients with suspected CAPA undergo endotracheal sampling or non-directed BAL sampling only, and it is important that any case definition proposed for CAPA reflects this reality. To acknowledge this, we propose a screening and diagnostic algorithm for CAPA, which has clinical (respiratory) deterioration and/or positive aspergillus sputum, or tracheal aspirate culture as its entry point (figure 1). Although the host risk factors and clinical characteristics of CAPA are not yet understood, those individuals fulfilling the criteria for proven or probable aspergillosis [13, 14] should then be treated according to current guidelines [36, 37]. Importantly, now that adjunctive use of dexamethasone is likely to become widespread in the treatment of patients with severe COVID-19 [17], intensified screening for invasive aspergillosis is indicated to study the possible association between corticosteroid usage and CAPA.\nFIGURE 1 Proposed screening and diagnostic algorithm for coronavirus disease-2019 associated pulmonary aspergillosis (CAPA). BAL: bronchoalveolar lavage; BDG: (1–3)-β-D-glucan; TA: tracheal aspirate; Asp Ag: aspergillus antigen; AF: antifungal; IA: invasive aspergillosis; GM: galactomannan; EORTC: European Organization for Research and Treatment of Cancer; NBL: non-directed bronchoalveolar lavage; PCP: Pneumocystis pneumonia.Finally, the use of immunomodulatory drugs such as anakinra (recombinant interleukin-1Ra), tocilizumab (anti-interleukin-6) and Janus kinase inhibitors, currently undergoing trials for COVID-19, may also predispose patients to CAPA. There is also an increased risk of Aspergillus exposure for patients who are treated in hospital wards or makeshift “hospital” facilities that do not meet ICU specifications for appropriate room ventilation and air changes. It is also worth bearing in mind that pulmonary aspergillosis could develop into a chronic cavitary disease in a subset of patients, perhaps in those developing post-COVID-19 pulmonary fibrosis. For these reasons, clinicians following up patients manifesting chronic respiratory problems following their primary COVID-19 infection should bear in mind longer term fungal 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