Summary Background: The COVID-19 pandemic has exposed patients to severe secondary fungal infections, exacerbating clinical outcomes and devastating impact. This study conducts a systematic review with meta-analysis of secondary fungal infections (SFIs) associated with COVID-19 considering various significant parameters, such as the frequency of SFIs across the globe, species shift, gender-specific infection rates, the significance of medical history, efficacy of steroid and antifungal, treatment outcomes (mortality rate), and fungal-polymicrobial mortality analysis. Methods: A literature search was conducted on COVID-19-related fungal infection studies (2020-2024) from SCOPUS and PUBMED databases, excluding preprints. The systematic data extraction captured the PMCID, country, patient demographics (age and gender), clinical outcomes, associated pathogens, medical history, and treatment details. Findings: The global meta-analysis of COVID-19-associated SFIs yielded 10,700 cases across 58 countries, exhibiting a significant male predominance (65.6% vs. 34.3% female). Aspergillus spp., Candida spp., and Mucorales spp. emerged as the primary fungal pathogens. The predominant six countries marking 80 % of global cases include India (46.8 %), Italy (10 %), Iran (9.4 %), France (5.1 %), Spain (4.3 %), and Egypt (4.1 %). Complication rates revealed CAM as the most prevalent (59.2%), with a 28% mortality rate. CAC (21.6%) and CAPA (19.1%) had substantially higher mortality rates, at 54% and 58%, respectively. Specific populations were highly affected, including individuals with diabetes were prone to CAM, those undergone catheterization were at increased risk of CAC, and individuals with respiratory diseases or without prior medical history were susceptible to CAPA. In both CAC and CAPA, the species shift towards the non-albicans spp. and non-fumigatus spp., associated with higher mortality. In addition, polymicrobial infection with fungal pathogens (Aspergillus spp., Candida spp., Mucorales spp.) and Multi-bacteria ( K. pneumoniae, P. aeruginosa, E. coli, S. aureus) also increased the mortality rate. Effective treatments were identified, including combining caspofungin with corticosteroids for CAC, voriconazole with dexamethasone for CAPA, and AmBisome monotherapy for CAM. Interpretation: In SFIs populations, CAM prevailed in high-density areas with relatively lower mortality rates, whereas CAC and CAPA exhibited higher mortality rates. Notably, polymicrobial infections significantly increased mortality across all SFIs. Underlying medical conditions primarily influenced the type of fungal pathogen, but treatment outcomes varied. Azole drugs and Amphotericin-B were ineffective against Candidiasis, except for caspofungin's limited susceptibility. Voriconazole and AmBisome demonstrated efficacy against Aspergillosis and Mucormycosis, respectively. Additionally, steroid administration proved life-saving in CAPA and CAC cases, yet remained ineffective in CAM.
