Clinical Features and Mortality of COVID-19-Associated Mucormycosis: A Systematic Review and Meta-Analysis

ABSTRACT

Rationale. Invasive fungal infection secondary to the coronavirus disease 2019 (COVID-19) has been increasing. Whereas COVID-19-associated pulmonary aspergillosis has been shown to be associated with high mortality, less is known about COVID- 19-associated mucormycosis (CAM). The overall mortality of non-COVID-19 mucormycosis ranges from 20% to 100%, depending on the infection site. Delayed diagnosis, neurological symptoms, and pre-existing malignancies are associated with worse outcomes. Herein, our study aimed to elucidate the characteristics, risk factors, and outcomes of CAM. Methods. We searched all observational studies reporting CAM through PubMed and EMBASE on September 13th, 2021. Case reports, case series, and observational studies without clearly documented diagnostic criteria for COVID-19 or mucormycosis were excluded. We collected data on the comorbidities, initial symptoms, site of infection, treatment for COVID-19, frequency of orbital exenteration, and mortality. One-group meta-analyses were performed for the potential risk factors, orbital exenteration, and mortality. Results. Our systematic review identified 32 eligible observational studies. The largest number of studies were conducted in India, followed by Egypt, Iran, and Turkey. A total of 4,463 patients were included in the analysis. The most common initial presentation was ocular symptoms 78%, followed by facial 48%, nasal 21%, constitutional 12%, oral 4.4%, neurological 1.1%, and others 0.4%. Diabetes mellitus (DM) and glucocorticoid therapy were present in 81% (95% CI, 76-86;I2=96%) and 79% (95% CI, 75-84;I2=91%), respectively. Among those with DM, the percentage of newly-diagnosed DM was 30% (216/711). Diabetic ketoacidosis, malignancy, and immunosuppression were found in 4.9% (165/3353), 0.7% (25/3471), and 0.6% (18/2921), respectively. Regarding the outcomes, orbital exenteration was performed in 17% (95% CI, 13-21;I2=83%) of the patients. Pooled estimate of mortality of CAM was 29% (95% CI, 22-36;I2=94%). Conclusion. The most prevalent type of CAM was rhino-orbital-cerebral mucormycosis. In addition to DM, severe hyperglycemia and immune dysregulation provoked by excessive corticosteroid therapy may have played a critical role in the recent rise of mucormycosis cases among COVID-19 patients. This systematic review and meta-analysis revealed a high frequency of orbital exenteration and mortality. The development of CAM can be associated with poorer prognoses in COVID-19 patients. Keeping the possible risk factors in mind and paying attention to the usual clinical presentation will be crucial to suspect CAM as early as possible.