Background: Patients with severe COVID-19 have clearly emerged as a population with a high risk of invasive fungal infections (IFI). However, the prevalence of IFI has not yet been assessed in large populations of mechanically ventilated COVID-19 patients. We aimed to determine the prevalence, risk factors, and mortality associated with IFI in mechanically ventilated COVID-19 patients in the ICU.Methods: We performed a national multicenter observational cohort study among 18 French ICUs and enrolled 576 mechanically ventilated COVID-19 patients. Patients were systematically screened for fungi once/twice a week during the period of mechanical ventilation up to ICU discharge. The trial is registered at ClinicalTrials.gov, NCT04368221. Findings: In total, 509 patients with > 3 screening samples were analyzed (mean age of 59·4 years, 78·6% male). The prevalence, as declared by the local investigators, was 11·2% (57/509) for putative invasive pulmonary aspergillosis (IPA), and 14·9% (76/509) and 4·7% (24/509) for probable and possible COVID-19-associated pulmonary aspergillosis (CAPA), respectively, using the recently published CAPA definitions. Patients with CAPA were significantly older and more frequently received the combination of dexamethasone and anti-IL6 treatment. Thirty-eight (7·5%) patients experienced one or more other IFIs: 32 candidemia (6·3%), six mucormycosis (1·2%), and one fusariosis. Multivariate analysis of factors associated with death for the 509 patients showed three significant factors: age >62 (HR: 1·70 [95% CI 1·25-2·30]), solid organ transplantation (2·44 [1·52-3·92]), and probable CAPA (1·48 [1·05-2·08]). Severity scores were significantly higher for CAPA and mortality was significantly higher in cases of probable and possible CAPA than no CAPA: 61·8%, 45·8%, and 31·3%, respectively ( p<0·0001 ).Interpretation: This study shows the high prevalence of invasive aspergillosis and candidemia associated with a high mortality rate in mechanically ventilated COVID-19 patients. These findings highlight the need for active surveillance for fungal pathogens in severe COVID-19 patients.Clinical Trial Registration Details: The trial is registered at ClinicalTrials.gov, NCT04368221.Funding Information: Pfizer Inc., NY, USA.Declaration of Interests: submitted work. ED reports grants and non-financial support from MSD, grants and non- financial support from Gilead, non-financial support from Pfizer, non-financial support from Astellas, outside the submitted work. AF reports personal fees and non-financial support from MSD, grants from Janssen, personal fees and non-financial support from Gilead, non-financial support from Pfizer, outside the submitted work. C-EL reports personal fees from Carmat, personal fees from Merck, personal fees from Biomérieux, personal fees from Thermofischer Brahms, personal fees from Bayer Healthcare, personal fees from Faron, outside the submitted work. FB reports grants from Astellas, personal fees from MSD, non-financial support from Pfizer, non-financial support from MSD, non-financial support from Astellas, outside the submitted work. J-FT reports personal fees from Pfizer, personal fees from Merck, personal fees from Astellas, personal fees from Gilead, outside the submitted work. FP reports non-financial support from Gilead, non-financial support from Pfizer, outside the submitted work. EC reports personal fees from Gilead, personal fees from Baxter, personal fees from Sanofi-Genzyme from null, outside the submitted work. AA reports personal fees from Pfizer, personal fees from Gilead, outside the submitted work. MC reports grants from Pfizer, outside the submitted work. JM reports non-financial support from Gilead, outside the submitted work. SE reports grants, personal fees and non-financial support from Aerogen Ltd, grants, personal fees and non-financial support from Fisher & Paykel, outside the submitted work. GV reports grants and personal fees from BioMérieux, grants from SOS Oxygène, grants from Janssen, outside the submitted work. JM reports other from Pfizer, other from Gilead, outside the submitted work. J-RZ reports grants, personal fees and other from MSD, personal fees from Novartis, personal fees from Pfizer, outside the submitted work. M-EB reports grants from Pfizer during the conduct of the study; grants and non-financial support from GILEAD and from Pfizer, non-financial support from MSD outside the submitted work. Other authors report no disclosures.Ethics Approval Statement: The MYCOVID study was conducted in full concordance with the principles of the Declaration of Helsinki and the laws, and regulations of France. This study was approved by the French authorities (Comité Consultatif sur le Traitement de l'information en matière de Recherche dans le domaine de la Santé, and Commission Nationale de L'Informatique et des Libertés). According to French policy, a non-opposition statement was obtained for all included patients signifying that all received written detailed information about the objectives of the study and were free to request withdrawal of their data at any time. The study protocol was reviewed and approved by the ethics committee of Rennes University Hospital, Rennes, France (Approval no. 20.56).
Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to atovaquone selective pressure have been identified on cytochrome b (CYB) gene of P. jirovecii. It was recently shown that atovaquone prophylaxis can lead to the selection of specific P. jirovecii CYB mutants potentially resistant to atovaquone among organ transplant recipients. In this context, our objectives were to provide data on P. jirovecii CYB mutants and the putative selective pressure exerted by atovaquone on P. jirovecii organisms in France. A total of 123 patients (124 P. jirovecii specimens) from four metropolitan hospitals and two overseas hospitals were retrospectively enrolled. Fourteen patients had prior exposure to atovaquone, whereas 109 patients did not at the time of P. jirovecii detection. A 638 base-pair fragment of the CYB gene of P. jirovecii was amplified and sequenced. A total of 10 single nucleotide polymorphisms (SNPs) were identified. Both missense mutations C431T (Ala144Val) and C823T (Leu275Phe), located at the Qo active site of the enzyme, were significantly associated with prior atovaquone exposure, these mutations being conversely incidental in the absence of prior atovaquone exposure (P < 0.001). Considering that the aforementioned hospitals may be representative of the national territory, these findings suggest that the overall presence of P. jirovecii CYB mutants remains low in France.The mutations C431T (Ala144Val) and C823T (Leu275Phe) at the cytochrome b (CYB) active site of Pneumocystis jirovecii are associated with patient prior exposure to atovaquone. Conversely, these mutations are incidental in the absence of exposure. Overall, the presence of P. jirovecii CYB mutants remains low in France.
ABSTRACT This article describes positive (1→3)-β- d -glucan levels in serum from infants with primary Pneumocystis infection and from immunosuppressed patients with Pneumocystis pneumonia (PCP) and negative levels in serum from patients colonized by Pneumocystis jirovecii . Glucan detection is a complementary tool for the diagnosis of the diverse clinical presentations of P. jirovecii infection.
Although trimethoprim-sulfamethoxazole is the more efficient drug for prophylactic and curative treatment of pneumocystosis, atovaquone is considered a second-line prophylactic treatment in immunocompromised patients. Variations in atovaquone absorption and mutant fungi selection after atovaquone exposure have been associated with atovaquone prophylactic failure. We report here a Pneumocystis jirovecii cytochrome b (cyt b) mutation (A144V) associated with such prophylactic failure during a pneumocystosis outbreak among heart transplant recipients. Analyses of clinical data, serum drug dosage, and molecular modeling of the P. jirovecii Rieske–cyt b complex were performed to investigate these prophylactic failures. The cyt b A144V mutation was detected in all infected, heart transplant recipient patients exposed to atovaquone prophylaxis but in none of 11 other immunocompromised, infected control patients not treated with atovaquone. Serum atovaquone concentrations associated with these prophylactic failures were similar than those found in noninfected exposed control patients under a similar prophylactic regimen. Computational modeling of the P. jirovecii Rieske–cyt b complex and in silico mutagenesis indicated that the cyt b A144V mutation might alter the volume of the atovaquone-binding pocket, which could decrease atovaquone binding. These data suggest that the cyt b A144V mutation confers diminished sensitivity to atovaquone, resulting in spread of Pneumocystis pneumonia among heart transplant recipients submitted to atovaquone prophylaxis. Potential selection and interhuman transmission of resistant P. jirovecii strain during atovaquone prophylactic treatment has to be considered and could limit its extended large-scale use in immucompromised patients.
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