COVID-19-associated mucormycosis in India: Why such an outbreak?

An unprecedented mucormycosis outbreak occurred in India during the second COVID-19 wave in spring 2021. COVID-19-associated mucormycosis (CAM) was observed, mainly rhino-orbito-cerebral mucormycosis (ROCM), in patients with poorly controlled diabetes and treated with inappropriate doses of glucocorticoids. The aim of this mini-review was to compare the characteristics of the CAM epidemic in India with (i) mucormycosis cases before the COVID-19 pandemic and (ii) CAM in the rest of the world (particularly in France) in order to identify the reasons for this outbreak. In India, the major mucormycosis epidemiologic change during the COVID-19 pandemic was an increase in the percentage of patients treated with corticosteroids who developed CAM. Compared with the rest of the world, India reported a higher mucormycosis incidence even before the COVID-19 pandemic. Moreover, in India, patients with CAM were more likely to have diabetes mellitus and ROCM; conversely, mortality rates were lower. The reasons for such a localized epidemic in India have remained unclear, but some hypotheses can be put forward, particularly the combination of high prevalence of uncontrolled diabetes mellitus and frequent indiscriminate corticosteroid utilization in a country that already had a high mucormycosis burden before the COVID-19 pandemic.

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29-2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

Aspergillus detection in airways of ICU COVID-19 patients: To treat or not to treat?

It is now well known that patients with severe COVID-19 are at risk for developing invasive pulmonary aspergillosis (IPA). Nevertheless, the symptomatology of IPA is often atypical in mechanically ventilated patients and the radiological aspects of SARS CoV-2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in respiratory tract samples (detected by culture, galactomannan antigen, or specific PCR) is not yet fully understood. Here we report two cases of intubated and mechanically ventilated ICU patients with SARS-CoV-2 pneumonia, in whom Aspergillus was detected in respiratory samples, who had a favorable outcome in the absence of antifungal treatment. These two cases highlight the difficulty of using the new definitions of COVID-19 associated pulmonary aspergillosis for routine management of patients.

A review of significance of Aspergillus detection in airways of ICU COVID-19 patients.

It is now well known that patients with SARS-CoV-2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS-CoV-2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID-19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non-surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.