key: cord-0856403-d6vo7tb9
authors: Danion, François; Letscher-Bru, Valérie; Guitard, Juliette; Sitbon, Karine; Dellière, Sarah; Angoulvant, Adela; Desoubeaux, Guillaume; Botterel, Francoise; Bellanger, Anne-Pauline; Gargala, Gilles; Uhel, Fabrice; Bougnoux, Marie-Elisabeth; Gerber, Victor; Michel, Justin; Cornu, Marjorie; Bretagne, Stéphane; Lanternier, Fanny
title: Coronavirus Disease 2019-Associated Mucormycosis in France: A Rare but Deadly Complication
date: 2021-11-06
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab566
sha: 83287ab578a5de999b4b8875295569df3f867ea3
doc_id: 856403
cord_uid: d6vo7tb9

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus up to 95% in India), hematological malignancies (35% versus 1%), anatomical sites (12% versus >80% rhino-orbito-cerebral) and prognosis (88% mortality versus <50%).

We conducted a retrospective nationwide study on CAM. Our network of 59 French mycology laboratories, which covers most of the French territory, was requested to report CAM cases diagnosed from March 2020 to June 10, 2021 to the French National Reference Center for Invasive Mycosis and Antifungals (NRCMA) as part of its surveillance missions. Only cases occurring within the 3 months after COVID-19 diagnosis confirmed by a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 were included. Clinical data were recorded anonymously on a standardized case report form. Cases were classified as proven or probable according to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) criteria [5] , with the addition of diabetes mellitus (DM) and dexamethasone prescribed for COVID-19 as host factor and positive Mucorales PCR in serum, blood, or plasma as mycological evidence. Date of mucormycosis diagnosis was defined by the first positive sample for mucormycosis.

This report is part of the NRCMA official duties approved by the Institut Pasteur Internal Review Board (2009-34/IRB) in accordance with French Law. This investigation was considered to be a public health response and the necessity of written informed consent was waived. One case has already been published [6] .

From March 2020 to June 10, 2021, 17 patients from 11 centers developed CAM (Table 1 ). Sixteen (94%) patients were male and the median age was 64 (range 25-79). The median body mass index was 28 (range 19-37). During the same period, 473 353 patients have been hospitalized for COVID-19 in France [7] .

Among the 17 patients, 7 (41%) had classic EORTC/MSGERC host factors for invasive mold infections before COVID-19, including 1 with solid organ transplantation and 6 (35%) with hematological malignancies (HM) [5] . Overall, 4 (24%) patients had pre-existing DM. Three (18%) patients received immunosuppressive drugs, 2 (12%) received long-term corticosteroids, and 2 (12%) were currently having antineoplastic chemotherapy. Seven (41%) patients had no classic risk factors for mucormycosis before COVID-19.

Sixteen (94%) patients had severe COVID-19 requiring intensive care unit (ICU) care. Median time between first COVID-19 symptoms and ICU transfer was 7 days (range 0-86). Management of COVID-19 required corticosteroids for 13 (76%) patients, mainly dexamethasone, and tocilizumab for 2 (12%). Twelve (71%) patients had high-flow nasal cannula oxygen therapy, and 13 (76%) had invasive mechanical ventilation. Four (24%) patients developed DM induced by dexamethasone for COVID-19, meaning that overall 8 patients (47%) had DM. Four (24%) patients had diabetic ketoacidosis. Eleven (65%) patients had renal failure, 8 (47%) requiring dialysis.

Coronavirus disease 2019-associated mucormycosis was diagnosed a median of 24 days (range 8-90) after COVID-19 first symptoms, 12.5 days (range 1-49) after ICU hospitalization, and 16 days (range 1-49) after corticosteroid prescription. Coronavirus disease 2019-associated mucormycosis location was mainly pulmonary (n = 9; 53%), but it was also digestive (n = 3; 18%), rhino-orbito-cerebral (n = 2; 12%), or disseminated (n = 3; 18%). Twelve patients with a pulmonary location had a chest computed tomography scan evidencing a reversed halo sign in 1 patient (8%) with HM and neutropenia, consolidation in 10 (83%) patients, including 4 (33%) with a cavitation, and 1 with nodules.

Coronavirus disease 2019-associated mucormycosis was classified as proven in 5 (29%) patients and probable in 12 (71%). The culture grew Mucorales in samples from 11 (65%) patients (bronchoalveolar lavage [{BAL} n = 5] and tracheal aspirate and biopsy [n = 3, each]). Mucorales PCR assay (adapted from [8] in 7 centers, from [9] Mucorales was identified to the genera or species level by culture or species-specific PCR in 14 (82%) patients, mainly (n = 9, 64%) with Rhizopus (Rhizopus microsporus [n = 6; 43%], Rhizopus delamar [n = 2; 14%], and Rhizopus arrhizus [n = 1; 7%]), secondary (n = 4, 29%) with Rhizomucor (Rhizomucor pusillus, Rhizomucor miehei [1 each, 7%]), and with Lichtheimia spp in only 1 case (7%). All species identified from both culture and PCR were concordant. The cases of Rhizomucor occurred in 3 patients with HM and in 1 patient with pulmonary carcinoma.

Five (29%) patients developed COVID-19-associated aspergillosis (CAPA), a median of 2 days (−28 to 0) before CAM. All patients with CAPA and CAM died before week 12 of mucormycosis.

Five (29%) patients died before the diagnosis was made and did not receive any specific treatment. Twelve (71%) patients were prescribed liposomal amphotericin B (n = 10, 59%) or isavuconazole (n = 2, 12%). Three (18%) patients had surgery; 2 for rhino-orbito-cerebral mucormycosis and 1 for colonic perforation.

Global mortality was 76% (13 of 17) In this study, we reported 17 cases of CAM in France, the largest series from 1 country outside India [4, 10] . We observed a large spectrum of clinical presentations and host factors, and we showed evidence of high mortality (88%) by 12 weeks. These findings differ from our historical (2005-2007) series of 101 mucormycoses in France (RetroZygo) and from CAM reported in India [4, 10, 11] .

We compared this study with series of CAM and mucormycosis without COVID-19 from India and from the French RetroZygo study ( Table 2 ). The frequency of underlying DM was lower in this cohort than that recorded in CAM in India (60%-95%) [4, 9] . By contrast, the frequency of hematological malignancy in CAM was higher compared with India (35% vs 1%) [10] . Clinical spectrum was different, with more frequent pulmonary (53% vs 28%) and less frequent rhinoorbito-cerebral locations (12% vs 25%) in the current series versus the historical RetroZygo Study. The presentation clearly differed from India, where CAM mainly presents with rhinoorbito-cerebral locations (>80%) [10] . This difference could be explained by higher prevalence of DM in Indian patients.

Culture and/or histology were positive in 76% of patients, whereas diagnosis of CAM was based only on a positive Mucorales PCR in 4 patients (24%). The broad use of Mucorales PCR could partly explain the higher frequency of CAM in France compared with other European countries [3, 8] and of some locations, mainly pulmonary or digestive, compared with the previous French Retrozygo studies, in which PCR was not used [11] . Rhizopus microsporus was the most frequent species in this small series. It is likely that although Mucorales is present in the environment, the species recovered are influenced by the geographic area, as well as the anatomic site, and the underlying risk factors, explaining the differences in species distribution among studies independently of COVID [4] .

Twelve-week mortality was very high (88%) in our current CAM study, compared with the RetroZygo Study (44%), and with CAM in India (40%-50%) [4, 10, 11] . It is also higher than that reported for CAPA [1, 12] . This major difference might be partly explained by the higher frequency of pulmonary or disseminated presentations, which are classically associated with a poorer prognosis compared with rhino-orbito-cerebral locations. The severity of COVID-19 itself and the high proportion of patients hospitalized in the ICU might also account for these differences.

The differences in frequencies, comorbidities, anatomical location, and prognosis between our current series and CAM in India might be explained in part by a higher frequency of patients with DM in India [13] . Historically, there is a higher burden of mucormycosis in India. In addition to DM, we hypothesized that environmental and possibly genetic conditions might play a role in the occurrence of mucormycosis in this country independently of COVID-19. The addition of the COVID-19 pandemic, the broad use of dexamethasone, and the high frequency of DM lead to the so-called "black fungus threat" in India, which does not seem to be the case in France and other countries outside India.

Despite the multicenter design, the limitations of our study are the small number of cases and the retrospective design. However, epidemiological surveillance in France is based on a reliable and sustained collaboration between French mycologists and the NRCMA, which limits the risk of reporting bias.

Coronavirus disease 2019-associated mucormycosis has a high mortality in this study. Better knowledge, identification, and earlier treatments of CAM might help to improve the prognosis.

International studies are warranted to better understand and assess CAM.

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

ECMM and ISHAM. ECMM/ ISHAM recommendations for clinical management of COVID-19 associated mucormycosis in low-and middle-income countries

Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands

The Emergence of COVID-19

Associated Mucormycosis: Analysis of Cases From 18 Countries

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

Mixed mold infection with Aspergillus fumigatus and Rhizopus microsporus in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patient

COVID-19: point épidémiologique du 10 juin 2021. Available at

Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF)

PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue

Multicenter epidemiologic study of coronavirus disease-associated mucormycosis

A Global analysis of mucormycosis in France: the retrozygo study

Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study

When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis

Potential conflicts of interest. F. D. declares personal fees from Gilead outside the submitted work. F. L. declares personal fees from Gilead and F2G outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.