Epidemiology of fungal infection in COVID 19 in Spain during 2020 and 2021: a nationwide study | Scientific Reports – Nature.com

This is a retrospective study of COVID-19 hospitalized patients in Spain during 2020 and 2021 with a nosocomial fungal coinfection. To the best of our knowledge, this is the first study analyzing fungal coinfection at a national level in hospitalized patients with COVID-19 in Spanish population. We found that (i) The incidence of fungal coinfections in patients with COVID-19 was 1.41%, (ii) Patients with fungal coinfection had a longer general hospital stay, higher ICU admission, mortality and stay, as well as and a greater need for mechanical ventilation, (iii) The respiratory tract was the most frequent site of infection, followed by the genitourinary tract, (iv) Risk factors for the development of fungal infection included surgery, sepsis, age, male sex, obesity and chronic obstructive pulmonary disease.

Previous studies analyzing the association between fungal coinfections and SARS-CoV-2, reported highly variable incidences, ranging from 0.70% in a study by Garca-Vidal8 to 26.70% in another study by White23. In our study, the incidence found was 1.41%, which is within the lower range of the previously described incidences. Estimating the coinfection rate in all COVID-19 cases is a challenging task as not all patients undergo sequential testing for coinfection. Also, this disparity could be attributed to the different methodologies used in these studies (case series, retrospective studies, prospective studies) with varying numbers of patients, and conducted in different populations.

Critically ill patients have a higher risk of developing coinfections. These patients exhibit increased levels of pro-inflammatory and anti-inflammatory markers, elevated cytokine levels, and reduced CD4+and CD8+lymphocyte levels10,24. These conditions, along with invasive procedures performed in the ICU25, and prolonged hospital stays26, increased the risk of developing fungal coinfections. In our study, patients with fungal coinfection had longer hospital stay, higher risk of death, increased ICU admission, and longer duration of ICU stay.

Furthermore, the most commonly fungal microorganisms found in the population studied, were Candida and Aspergillus that have been previously described2,27. In our cohort, the most frequent site of infection was the respiratory tract. This could be explained by the destruction of the respiratory tract epithelium and suppression of the immune response in the site after viral infections. Also, the antibiotic treatment and the microbiota alteration, may lead to the emergence of fungal infection13. The second most frequent site of infection was the genitourinary tract. This could be attributed to the presence of risk factors in COVID-19 patients that promote the occurrence of fungal infections in the urinary tract, such as renal failure, advanced age, diabetes, cancer, and immune system disorders28.

Multiple factors have been associated with the risk of fungal coinfection in COVID-19 patients, such as admission to the ICU, high-dose steroid administration, presence of diabetes mellitus, COPD, among other15,29,30. In our study, the main risk factors described were surgery, sepsis, obesity, advanced age, men gender, and COPD.

Surgery, especially abdominal surgery, causes damage to the body's natural barrier, which can favor gastrointestinal translocation and lead to Candida infection, as Candida often colonizes the intestines31. This risk factor has not been described in previous studies conducted in COVID-19 patient groups, but in the literature, different risk assessment scales analyze the main risk factors for developing invasive fungal infection in non-COVID-19 patients, such as the scale developed by Len et al.32, where surgery was identified as a significant risk factor, consistent with our study findings. This is the first time that surgery has been described as a risk factor for the development of aspergillosis in patients with SARS-CoV-2. The presence of surgery as a risk factor for the development of aspergillosis in patients with SARS-CoV-2 may not have been previously identified due to the lack of information on surgical procedures in previous studies or because this variable was not considered in those studies. Therefore, further research and data collection are required to better understand the relationship between surgery and fungal infections in COVID-19 patients.

Sepsis and the presence of multiorgan dysfunction further contribute to the occurrence of superinfections due to the immunosuppressive state they induce. Patients with sepsis and multiorgan failure have multiple risk factors for developing fungal infections, such as antibiotic administration, invasive therapeutic strategies33, sepsis-induced immunosuppression34, and intestinal barrier dysfunction35. The presence of sepsis was a significant risk factor for Aspergillus spp. infection in COVID-19 patients, which is consistent with the findings of the meta-analysis by Chong et al.36.

Obese patients have an increased risk of bacterial, viral, and fungal infections37,38 due to the inflammatory state they experience, which leads to elevated proinflammatory cytokines and favors the development of chronic inflammation. Additionally, obese patients often require invasive mechanical ventilation, which further contributes to the development of superinfections39.

We observed that age was independently associated with an increased incidence of fungal infection. Advanced age is a known risk factor for infections due to immunosenescence, which results in reduced activation of the immune system (increased immature T lymphocytes, altered CD4+/CD8+T cell ratio, and decreased immune response), thus promoting the occurrence of infections40,41.

We report that fungal coinfection was more frequent in men than in women. This higher risk in males could be influenced by hormonal factors, genetic factors leading to differences in immune response, or even genetic polymorphisms.

In this research, the presence of COPD was identified as a risk factor for the development of Aspergillus spp. infection in COVID-19 patients, that do not present in patients with invasive candidiasis. This could be explained by the fact that Aspergillus spp. spores are normally cleared by the ciliary action of the respiratory epithelium, but in COPD patients (as in those infected with SARS-CoV-2), this ciliary clearance is impaired, facilitating the invasion of the bronchial mucosa and lung parenchyma42. Additionally, COPD patients often receive inhaled corticosteroid treatment, which can reduce immune activity and predispose them to fungal infection.

Our study presents certain limitations due to its retrospective design, relying on data obtained from the Spanish MBDS. As with any retrospective analysis, there is a possibility of under-coding of variables, leading to incomplete or inaccurate information. This could introduce potential bias and affect the robustness of our findings. Furthermore, the lack of coding for certain analytical variables and multiple admissions of the same patient might have influenced the precision and completeness of our results. Despite the limitations, our study possesses notable strengths. Foremost among these is the substantial sample size, which confers high statistical power and enhances the reliability of our analyses. The extensive dataset enabled us to provide a comprehensive and representative perspective on the epidemiological landscape of fungal co-infections in patients with COVID-19 within the Spanish population. This large-scale approach contributes to a more nuanced understanding of the prevalence and characteristics of fungal infections in this specific context.

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Epidemiology of fungal infection in COVID 19 in Spain during 2020 and 2021: a nationwide study | Scientific Reports - Nature.com