key: cord-0941026-2w5m6c96 authors: Dupont, Damien; Menotti, Jean; Turc, Jean; Miossec, Charline; Wallet, Florent; Richard, Jean-Christophe; Argaud, Laurent; Paulus, Sylvie; Wallon, Martine; Ader, Florence; Persat, Florence title: Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19) date: 2020-09-10 journal: Med Mycol DOI: 10.1093/mmy/myaa078 sha: a1868f4cacbb0420486333a7b7e71656e4991dc2 doc_id: 941026 cord_uid: 2w5m6c96 Occurrence of putative invasive pulmonary aspergillosis was screened in 153 consecutive adult intensive care unit (ICU) patients with respiratory samples addressed for mycological diagnosis during a 6-week period at the emergence of coronavirus disease 2019 (COVID-19) pandemic. Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) was observed for 106 patients (69.3%). Nineteen of them (17.9%) with positive Aspergillus results were considered as having putative invasive pulmonary aspergillosis. These observations underline the risk of pulmonary aspergillosis in COVID-19 patients, even in patients not previously known to be immunosuppressed, advocating active search for Aspergillus infection and prompt antifungal treatment. Standardized surveillance protocols and updated definitions for ICU putative invasive pulmonary aspergillosis are needed. LAY ABSTRACT: Adult ICU patients with respiratory samples addressed for mycological diagnosis were screened during the emergence of COVID-19 pandemic. Positive SARS-CoV-2 PCR was observed for 106 patients, nineteen of them (17.9%) having aspergillosis. This underlines the risk of aspergillosis in COVID-19 patients. During the coronavirus disease 2019 (COVID-19) pandemic, a risk of secondary pulmonary infections, including aspergillosis, was mentioned in patients suffering from acute respiratory distress syndrome (ARDS). 1 This was congruent with the well-established risk of invasive pulmonary aspergillosis (IPA) in patients with severe influenza. 2,3 A prospective study was conducted in Lyon teaching Hospitals, in order to estimate the occurrence of IPA and describe patient characteristics. Patients were included from March 1 to April 11, during the period of active circulation of the virus in this area in France, in adult patients admitted to five intensive care units (ICU) for whom at least one sample was sent to the mycology laboratory. Patients with only sputum samples were excluded. Lower respiratory tract samples (LRT) including Broncho-Alveolar Lavage (BAL), Endo-Tracheal Aspiration (ETA), and Bronchial Aspiration (BA) received at the Mycology laboratory from Hospices Civils de Lyon (HCL) intensive care unit (ICU) adult patients during this 6-week period were processed according to standard mycological procedures. Calcofluor direct examination (Becton-Dickinson, Franklin Lakes, NJ, USA) and cultures on Can2 and Sabouraud mycological media (bioMérieux, Marcy l'Etoile, France) were performed. Identification was obtained by MALDI-TOF (VITEK ® MS, bioMérieux). Additionally, serum and/or BAL galactomannan (GM) Aspergillus antigen was performed by ELISA (Platelia TM Aspergillus antigen, BioRad, Marnes, France), with a cut-off index of 1 as recently recommended. 2, 4 We collected results of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR in respiratory samples (nasopharyngeal, tracheal aspirate and/or BAL samples) from all included patients, independently. Clinical characteristics (Table 1) were retrieved from the medical record database. Ethical clearance was granted as part of the HCL Global COVID Research Initiative: patients were informed that their clinical and biological data could be used for research purposes; no patient opposed. Putative IPA definition cases followed the AspICU criteria (Aspergillus positive culture on respiratory samples from at risk patient with abnormal pulmonary imagery), 5 with inclusion of BAL GM results. 2,4 COVID-19 diagnosis was considered as a risk factor, as previously reported by Koehler et al. 6 Among the 153 patients screened for fungal infection, i) 106 had a positive SARS-CoV-2 PCR result during the study period (69.3%), ii) Twenty-three patients had at least one microbiological finding evocative of putative IPA: a positive Aspergillus culture (n = 19), a positive GM assay in BAL (n = 6), or both (n = 2). Blood GM test was performed for 12 patients among these 23 patients. Only one was positive (index: 2.41), associated with a positive LRT culture. Sex ratio was 3.6 (18 males/5 females). Median age was 69 [62, 73] years. Positive samples for Aspergillus detection were sent 6 days [1, 9] after the start of ventilation. Mycological positive results were given to clinicians from 12 [7.25, 15] days after ICU admission. Among the 23 patients with microbiological findings consistent with putative IPA, 19 patients had a positive SARS-CoV-2 PCR, in the context of classical clinical symptoms (fever, cough, dyspnea, myalgia or headaches). Four patients had putative IPA with repeatedly negative SARS-CoV-2 PCR. These four patients died during their ICU stay. One had risk factor for aspergillosis (COPD). All had concurrent fungal (Pneumocystis jirovecii pneumoniae (n = 2), mucormycosis (n = 1), and candidemia (n = 1)), bacterial or viral infections. Characteristics of the 19 patients are summarized in Table 1 . Fifteen presented lymphocytopenia at admission. The most frequent underlying diseases was arterial hypertension (n = 7; 36.8%) and type-2 diabetes mellitus (n = 7; 36.8%). Three had recent history of malignancy (follicular lymphoma, n = 1; colon cancer, n = 1; urothelial carcinoma, n = 1), not considered as risk factors for IPA by EORTC/MSG. 4 Seven patients received steroids, six for hemodynamic or renal failures and one for COVID-19 treatment (methylprednisolone 40 mg bid). No patient received steroid at dose and length of treatment considered as as risk factor for IPA. 4 Three patients (no 6, 15, 16) received hydroxychloroquine for 10, 5, and 2 days, respectively. Respiratory risk factors were reported for seven patients, three of them having two risk factors: COPD (n = 4; 21.1%), asthma (n = 4; 21.1%), or a history of tuberculosis (n = 2; 10.5%). The remaining 12 patients had no identified risk factors for Aspergillus infection. All patients suffered from either mild (n = 2), moderate (n = 13), or severe (n = 4) ARDS at the time of sampling (Berlin definition), 7 all requiring invasive mechanical ventilation and prone positioning. Radiological features revealed ground glass opacities typical of COVID-19 lesions, with condensation (n = 13; 68.4%) and pulmonary embolism (n = 5; 26.3%). Nine patients presented other computed tomography (CT) scan features: emphysema (n = 5; 26.3%), cavitation (n = 2; 10.5%), nodule (n = 2; 10.5%), bronchiectasis (n = 2; 10.5%) and secondary infection signs (n = 5; 26.3%). LRT cultures yielded Aspergillus fumigatus in 14 of the SARS-CoV-2 patients and other Aspergillus species for two patients. According to the ICU-IPA definition, our patients may be considered with putative IPA, if the viral infection is considered as a risk factor. Nine patients were given voriconazole for at least 48 hours. Although not significant, there was a trend towards a lower mortality rate at 42 days after mycological diagnosis in antifungal-treated patients (3 deaths/9; 33.3%), compared to untreated patients (5 deaths/10; 50%). This study reports a series of 19 putative IPA among 106 ICU patients with COVID-19 (17.9%) and provides three important findings. First, it highlights that severe SARS-CoV-2 infection should be considered as a risk factor for IPA, as recently reported. 6, 8, 9 Second, this higher risk for IPA occurs even in patients not previously known to be immunosuppressed, as reported with flu patients. Indeed, in our series, only three patients out of 19 presented with a previous history of cancer. Interestingly, respiratory risk factors classically associated with the presence of Aspergillus in the airway, such as COPD, asthma or previous history of tuberculosis, were reported for seven patients. Third, these observations highlight the need to monitor specifically COVID-19 ICU patients for IPA, since the association of these two pathogens is emerging. Further data are required to assess to what extend IPA worsens patients prognosis. 10 BAL, if possible, should be used for standard mycological culture and GM detection on the rationale that the deeper the sample, the higher the probability of IPA. Koehler et al. 6 recommended GM detection in ETA as well, however ETA is not validated by the manufacturer. Also, GM detection is more sensitive in BAL than in blood in non-neutropenic patients who are more likely to have a non angioinvasive IPA, as opposed to neutropenic patients. 11, 12 Monitoring blood antibody levels might still be of interest in patients who are mildly immunocompromised and/or have underlying respiratory diseases. Aspergillus PCR assay on LRT samples may also be proposed to increase diagnostic sensitivity. 10 Since the EORTC-MSG consensus criteria for IPA in immunocompromised patients are inappropriate for ICU patients, 4,13 a specific definition is needed for these patients. 14 COVID-19 and other viral infections associated with ARDS might be considered as a host risk factor in ICU by analogy with flu infection. 2 Noteworthy, more precise other criteria, particularly mycological criteria (number or nature of the respiratory samples) are needed since the putative IPA classification used in this study might have led to an excess of IPA, compared to chronic pulmonary aspergillosis and Aspergillus colonization of the respiratory tract. 15 An updated definition and standardized diagnostic procedures would then benefit patients and serve as a basis for optimizing clinical management and assessing treatment efficacy. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study Invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients COVID-19 associated pulmonary aspergillosis Acute respiratory distress syndrome: The Berlin definition High prevalence of putative invasive pulmonary aspergillosis in critically ill COVID-19 patients COVID-19 associated pulmonary aspergillosis Invasive fungal diseases during COVID-19: we should be prepared Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid samples from patients with nonneutropenic invasive pulmonary aspergillosis The strategy for the diagnosis of invasive pulmonary aspergillosis should depend on both the underlying condition and the leukocyte count of patients with hematologic malignancies Aspergillosis in the ICU: the new 21st century problem? Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project Diagnosing COVID-19-associated pulmonary aspergillosis The authors thank Michelle Grange for English editing of the manuscript. J.M. has received a research grant outside the submitted work from MSD and aid for attending symposia from Gilead, MSD, Pfizer and Roche Diagnostics; F.P. has received aid for attending symposia from Gilead and Pfizer. All other authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.