








key: cord-290490-u3mkfvxw
authors: Armstrong-James, Darius; Youngs, Jonathan; Bicanic, Tihana; Abdolrasouli, Alireza; Denning, David W.; Johnson, Elizabeth; Mehra, Varun; Pagliuca, Tony; Patel, Brijesh; Rhodes, Johanna; Schelenz, Silke; Shah, Anand; van de Veerdonk, Frank L.; Verweij, Paul E.; White, P. Lewis; Fisher, Matthew C.
title: Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA)
date: 2020-07-23
journal: Eur Respir J
DOI: 10.1183/13993003.02554-2020
sha: 
doc_id: 290490
cord_uid: u3mkfvxw

Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.

The SARS-CoV-2 (COVID- 19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities (1) . Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (2) . Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy (3) . However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.

Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) (4, 5) and Middle East Respiratory Syndrome (MERS-CoV) (6) . From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail (2) and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region (7) . More recently, retrospective case series from Belgium (8), France (9) , The Netherlands (10) and Germany (11) have reported evidence of CAPA in an alarming 20-35% of mechanically ventilated patients.

Influenza-associated pulmonary aspergillosis (IAPA) presents a known risk to critically unwell patients with influenza (12) (13) (14) and the clinical course of COVID-19 shows many features that are shared with severe influenza infection. These include ARDS, lymphopenia, bilateral pulmonary infiltrates, systemic pro-inflammatory cytokine responses and sepsis leading to multiple organ failure (14, 15) . It is therefore reasonable to suspect that patients with severe COVID-19 may be similarly susceptible to IA. Corticosteroid use is an important acquired immunological risk factor for IAPA (16) and, during the SARS-2003 epidemic, there were case reports of patients developing SARS-associated IA after corticosteroid use (5) . Corticosteroid use has been reported in hospitalised patients with COVID-19

(1) and may further contribute to the risk of CAPA. Importantly, the recent finding by the UK RECOVERY trial (ISRCTN50189673) (17) of a one-third mortality reduction conferred by dexamethasone in ventilated patients with Covid-19, while leading to a crucial new therapeutic avenue, may increase the risk of patients acquiring CAPA and emphasises the need for enhanced fungal surveillance. Table 1 summarises individual patient-level data in 33 cases of CAPA that have been reported to date. The median age of cases is 70 (IQR 57-75), of whom only 2 (6%) had an EORTC host factor. Of these 16 (48%) had exposure to inhaled or systemic corticosteroids, 10 (30%) diabetes and 9 (27%) underlying chronic lung disease; chronic obstructive pulmonary disease (n=5), asthma (n=3), bullous emphysema (n=1), pulmonary fibrosis (n=1) and post-radiotherapy for non-small-cell lung cancer IA is difficult to diagnose in critically unwell patients without traditional host factors because radiological changes are usually non-specific (e.g. infiltrates, consolidation or nodules), with features such as halo sign, air-crescent sign or cavitation being rare (19) . Table 1 were 'proven', 11 'putative' and 17 might be considered putative but with caveats which have been described in the table. For example, in many cases a tracheal aspirate, rather than BAL, provided the only mycological evidence of IA (in the absence of tracheobronchitis/cavitation). There should therefore be caution about over-estimating the incidence of CAPA from such case series, which may include some patients with Aspergillus colonisation or contamination only. In the study by Alanio et al. (9) which reported evidence of CAPA in 9/27 (33%) of ventilated patients who underwent BAL/ tracheal aspirate (TA), one case was defined based on on a BAL GM of 0.89 (below the usual cut-off of 1.0), two based on TA rather than BAL culture, one based on a serum GM of 0.51 (cut-off being 0.50) and in four cases BAL culture was positive but BAL GM negative, which suggests a lack of tissue invasion. Indeed, of seven cases that were not treated with antifungals, five survived. Accordingly, larger, prospective, multi-site studies are needed to refine the AspICU criteria for patients with COVID-19, as well as to estimate incidence and the impact of CAPA on survival (20, 21) .

Bearing 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 (HG3) rating of the SARS-CoV-2 virus, alongside an overburdened critical care service (22) .

Ideally, screening for CAPA entails using a combination of CT chest imaging and Aspergillus antigen tests on BAL and serum including galactomannan (GM) ELISA or lateral-flow tests (23), or Aspergillus PCR (24) . Whilst characteristic CT features of IA such as nodules with halo sign were seen in 17.6% of severely ill COVID-19 patients, they were not confirmed to be IPA (25) . Given the lack of typical IA 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.

In 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 (vs 70% in neutropenic patients) (26) . 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 20/31 (65%) of cases positive, however BAL GM remained superior at 67/76 (88%). 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 6/28 (21.4%). 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 >1.0) would be indicative of CAPA, whereas if the index is <0.5, CAPA is much less likely (26) . 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 (23) . An Aspergillusspecific PCR test (24) 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 (27) .

there is a suspicion of IPA. Although performance might be superior to serum Aspergillus antigen testing for the detection of IPA in the ICU (28), BDG negativity cannot be used to rule out infection, with a 77% sensitivity determined across a heterogeneous population of IA 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 CT and bronchoscopy and testing for Aspergillus antigen as outlined above (29) . While initiating antifungal treatment pre-emptively based on of 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.

Current 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 (30) . 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 (31, 32) . 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 IA is indicated to study the possible association between corticosteroid usage and CAPA.

Finally, the use of immunomodulatory drugs such as Anakinra (recombinant IL-1Ra), Tocilizumab (anti-IL6) and Janus kinase (JAK) inhibitors, currently undergoing trials for COVID19, 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-COVID19 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 complications.

Fungal infections present an additional threat in the challenging task of managing COVID-19 patients in outbreak conditions. The pandemic of SARS-CoV-2 virus will undoubtedly involve CAPA, and the use of immunomodulatory therapy and impact of overburdened critical care services during this pandemic may exaggerate its impact. More research is needed on the epidemiology and diagnosis of CAPA in patients with COVID-19, a need that is partially met as ongoing prospective multi-site clinical studies are extended to include this cohort (e.g. AspiFlu (20) ) or are launched (CAPA (21)) in response to pandemic COVID-19. 

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Bacterial and fungal co-infection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing

Pulmonary pathology of severe acute respiratory syndrome in Toronto

Fatal aspergillosis in a patient with SARS who was treated with corticosteroids

The emergence of the Middle East respiratory syndrome coronavirus

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Van Regenmortel N. COVID-19-associated invasive pulmonary aspergillosis

Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19

COVID-19 Associated Pulmonary Aspergillosis

Shimabukuro-Vornhagen A. COVID-19 associated pulmonary aspergillosis

Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study

Dutch-Belgian Mycosis study g. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study

Dutch Mycoses Study G. Influenza-Associated Aspergillosis in Critically Ill Patients

Recovery: Randomised Evaluation of Covid-19 Therapy

Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients

Aspergillosis in patients with severe influenza or coronavirus

Dutch-=Belgian Mycosis Study Group: CAPA

Guidance: COVID-19 safe handling and processing for samples in laboratories

Lateral Flow Assays for the Diagnosis of Invasive Aspergillosis: Current Status

Diagnosis of aspergillosis by PCR: Clinical considerations and technical tips

Coronavirus Disease 2019 (COVID-19): Role of Chest CT in Diagnosis and Management

Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients

Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use?

Comparison of 1,3-beta-dglucan with galactomannan in serum and bronchoalveolar fluid for the detection of Aspergillus species in immunosuppressed mechanical ventilated critically ill patients

Beta-Dglucan detection as a diagnostic test for invasive aspergillosis in immunocompromised critically ill patients with symptoms of respiratory infection: an autopsy-based study

The Use of Bronchoscopy During the COVID-19 Pandemic: CHEST/AABIP Guideline and Expert Panel Report

Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clinical microbiology and infection : the official publication of the

COVID-19 Associated Pulmonary Aspergillosis

Invasive pulmonary aspergillosis in severe COVID-19 pneumonia

Fatal invasive aspergillosis and coronavirus disease in an immunocompetent patient

Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19

Invasive pulmonary aspergillosis complicating COVID-19 in the ICU -A case report

COVID-19-associated invasive pulmonary aspergillosis

COVID-19 Associated Pulmonary Aspergillosis

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Invasive pulmonary aspergillosis complicating SARS-CoV-2 pneumonia: A diagnostic challenge

Under EORTC criteria without histological evidence of 'proven' IPA a patient host factor (e.g. recent neutropenia, haematological malignancy) is required to meet the 'probable'/'possible' definition. Corticosteroids must be given at ≥0.3 mg/kg for ≥3 weeks to classify as a host factor. 

