Background and Objectives: With an increasing number of severe COVID-19 cases presenting with secondary fungal infections, this study aimed to determine the prevalence of fungal co-infections in severe COVID-19 patients across the six waves, identify the most common fungal pathogens associated with severe COVID-19, and explore any potential links between patient characteristics, therapeutic strategies, and the prevalence and type of fungal infection. Materials and Methods: A retrospective analysis was conducted on severe COVID-19 patients admitted to the Infectious Diseases and Pulmonology Hospital, "Victor Babes", Romania, between March 2020 and August 2022. Samples were collected from respiratory specimens, blood, and urine, after which a standard nucleic acid extraction protocol was employed. Patients were divided into groups with and without fungal infections, identified using multiplex PCR. The groups were compared based on demographic data, comorbidities, pandemic wave number, and clinical outcomes. Results: Out of 288 patients, 96 (33.3%) had fungal infections, with Candida spp. being the most common. Patients with fungal infections had higher rates of obesity (35.4% vs. 21.4%, p = 0.010) and a higher Charlson comorbidity index (CCI > 2) (37.5% vs 25.0%, p = 0.027). Ventilator use was significantly higher in the fungal infection group (45.8% vs. 18.8%; p < 0.001), as was ICU admission (39.6% vs. 26.6%; p = 0.024) and mortality (32.3% vs 12.0%; p < 0.001). The distribution of different fungal species varied across the pandemic waves, with no statistical significance (p = 0.209). The mortality risk notably increased with the degree of drug resistance (OR for three or more drug resistances = 6.71, p < 0.001). The second, fourth, and fifth pandemic waves were significantly associated with higher mortality risk (OR = 3.72, 3.61, and 4.08, respectively, all p < 0.001). Aspergillus spp. and Mucor spp. infections were significantly associated with increased mortality risk (OR = 4.61 and 6.08, respectively, both p < 0.001). Conclusions: Our study indicates a significant presence of fungal co-infections among severe COVID-19 patients that is associated with increased morbidity and mortality, particularly in patients with drug-resistant infections. These findings underline the necessity for comprehensive diagnostic approaches and tailored treatment strategies in managing COVID-19 patients, especially during specific pandemic waves and in patients with particular fungal infections. Further research is required to understand the implications of these co-infections and their management.

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