Prevalence of invasive yeast infections in a COVID-19 intensive care unit in northeastern BrazilAbstract
The COVID-19 pandemic has caused a global crisis, overwhelming hospitals and intensive care units (ICU) and leading to an increase in nosocomial infections due to prolonged hospitalization and other risk factors. The present study evaluated the prevalence of secondary fungal infections in critically ill patients with COVID-19. This is a retrospective, single-center study conducted in a hospital in northeastern Brazil, which evaluated 1,364 medical records of patients admitted to a COVID-19 ICU during 2020 and 2021. A total of 327 pathogenic yeasts were isolated from 132 (40.4%) respiratory, 70 (21.4%) blood, 124 (37.9%) urine, and one (0.3%) surgical wound samples. Fungal infections were diagnosed in the intermediate (5 to 12 days) or late (≥12 days) stage of hospitalization. The most frequent yeast isolated from critically ill COVID-19 patients was Candida albicans [126 (67.7%) and 60 (42.6%)], followed by Candida tropicalis [25 (13.4%) and 39 (27.7%)]. Candida parapsilosis isolates increased 5.7-fold in 2021 [40 (28.4%)] compared to 2020 [7 (3.8%)]. The least frequently isolated in 2020 and 2021 were Nakaseomyces glabratus [4 (2.2%) and 1 (0.7%)], and Pichia kudriavzevii, which was isolated only in 2021 (1 (0.7%)). During the study period, a decrease in susceptibility to antifungals was observed: susceptibility to voriconazole reduced from 100 to 77.2%, to flucytosine from 99.4 to 78.8%, and to micafungin from 99.4 to 83.6%. The changes in the frequency of species causing secondary infections in critically ill COVID-19 patients and susceptibility to the antifungals indicate the need for early and adequate diagnosis to minimize negative outcomes.
COVID-19; Intensive care unit; Fungal infections; Candida; Antifungal susceptibility
Introduction
Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who developed coronavirus disease 2019 (COVID-19) in its most severe form usually required intensive care unit (ICU) support and were treated with broad-spectrum antimicrobials as well as invasive ventilatory support, which resulted in increased exposure and risk of secondary infections caused especially by nosocomial pathogens and associated with a high mortality rate among COVID-19 patients (1).
Immune system dysregulation, corticosteroid treatment, and prolonged hospitalization of severe COVID-19 patients may favor the development of secondary infections (2). Opportunistic lung infections have nonspecific symptoms, such as cough, dyspnea, shortness of breath, and fever, which are also common in COVID-19. Therefore, the diagnosis and treatment of these diseases are challenging. Secondary infections also increase the risk of adverse outcomes for patients (3).
Among fungi, Candida species are pathogens that cause secondary infections with high morbidity and mortality rates on a global scale (4). Invasive candidiasis is an important healthcare-associated infection. It can occur independently or concomitantly, being difficult to diagnose, since colonization with Candida species usually precedes most infections that occur in critically ill patients admitted to the ICU (5).
Although clinical and epidemiological data on the impact of secondary fungal infections in severe COVID-19 patients remain limited in some countries and regions (5,6), previous studies have demonstrated that fungemia occurs as secondary infection in COVID-19 (1,3,7), as well as invasive Candida infections that were described in COVID-19 patients in the ICU (8). Another factor of concern is the frequently reported antifungal resistance in hospitalized COVID-19 patients. Consequently, the identification and proper diagnosis of secondary fungal infections associated with COVID-19 are essential, as it has a significant impact on the treatment and evolution of patients, especially those in critical condition (5,9).
Thus, this study aimed to investigate the frequency of secondary fungal infections and the antifungal susceptibility profile in critically ill COVID-19 patients in an ICU of a private tertiary hospital in the Brazilian state of Paraíba, a low-income region, from March 2020 to December 2021.
Material and Methods
Setting and study design
This was a retrospective single-center study, in which secondary yeast infections were evaluated in critically ill adult patients diagnosed with COVID-19 admitted to the ICU of a private tertiary hospital in João Pessoa, Paraíba, Brazil, from March 2020 to December 2021. The diagnosis of COVID-19 was carried out according to the guidelines of the World Health Organization (WHO) and the guidelines of the Brazilian Ministry of Health (10,11). COVID-19 was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) using oropharyngeal and nasopharyngeal samples (12). Yeast infection was defined based on clinical evaluation and laboratory parameters. Microbial identification and antimicrobial susceptibility tests were performed using the Vitek® 2 Compact automated identification system (bioMérieux, software version 8.01, France). This study was approved by the Research Ethics Committee of the Universidade Federal da Paraíba (CAAE: 59777522.8.0000.8069).
Data collection and participants
Patient data were obtained through an electronic system, which contains prospectively collected structured data for all ICU admissions (Epimed Monitor®, Brazil). Demographic data such as age, gender, periods of hospital admission, ICU admission and outcome (discharge or death), clinical data, and microbiological results were collected. Adult patients with a confirmed diagnosis of COVID-19 by RT-PCR and a positive fungal culture during the hospitalization period were included in the study. Patients who were discharged or died within less than 72 h from the date of admission to the ICU or those whose medical records had incomplete information were excluded from the study. Patients who did not have a confirmed diagnosis of COVID-19 or did not have positive fungal culture during their ICU stay were also excluded from the study. Among 1,364 patients with severe COVID-19 admitted to the ICU, 207 were eligible for the study, of which 112 patients were admitted to the ICU in 2020 and 95 patients in 2021. A total of 327 positive cultures for yeast were identified in 132 isolates from the respiratory tract, 70 from bloodstream, 124 from the urinary tract, and one from a surgical wound (Figure 1).
Study flowchart. *One patient had a positive culture for Candida tropicalis isolated from a surgical wound.
Statistical analysis
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, IBM, USA) software version 20 for macOS, using descriptive and correlational statistics and relative and absolute frequencies. Fisher's exact test was used to compare categorical variables, ANOVA for quantitative variables, and linear regression to determine relative risks. The comparison of data between 2020 and 2021 was made with the Mann Whitney U test for non-normally distributed data.
Results
Population characteristics
Among 1,364 patients with severe COVID-19 admitted to the ICU during 2020 and 2021, 15.1% (207/1,364) were eligible for the study (Figure 1). Yeast infection occurred in 54.6% (113/207) male and 45.4% (94/207) female patients, with a median age of 68 years (IQR 58-78). The median time from hospital admission to ICU admission was 2 days (IQR 0-4). The median length of stay in the ICU was 18 days (IQR 12-25), while the total length of hospitalization was 26 days (IQR 18-40) (Table 1).
Of all included patients, 86% (178/207) had underlying medical conditions, including systemic arterial hypertension (SAH, 75.2% (134/178)), diabetes mellitus (DM, 45.5% (81/178)), and obesity (18%, 32/178). Only 1 (0.56%) patient had a history of previous pneumonia in the last 12 months and 11 (6%) patients had severe chronic obstructive pulmonary disease (COPD). Regarding the outcome, 31.4% (65/207) patients were discharged, while 68.6% (142/207) patients died, of which 86.6% (123/142) had underlying diseases: 76.4% (94/123) had SAH, 45.5% (56/123) had DM, and 14.6% (18/123) had obesity. Additionally, 7.3% (09/123) patients who died had a diagnosis of severe COPD. Cultures from the respiratory and urinary tract, which have a quantitative standard, were considered when the number of colony forming units (CFUs) were consistent with infection.
Secondary yeast infections in severe COVID-19 patients
Candida species were isolated in 327 samples from COVID-19 patients in the ICU. Candida albicans was the most prevalent fungus in critically ill COVID-19 patients among anatomic sites (respiratory tract, bloodstream, and urinary tract). C. albicans was isolated in 67.7% of the samples in 2020 and in 42.6% of the samples in 2021, while Candida tropicalis was isolated in 13.4% of the samples in 2020 and in 27.7% of the samples in 2021. Other Candida species isolated in 2020 were Candida parapsilosis (3.8%) and Nakaseomyces glabratus (previously Candida glabrata) (2.2%) and in 2021 C. parapsilosis (28.4%), N. glabratus (0.7%), and Pichia kudriavzevii (previously Candida krusei) (0.7%). In 2020, 12.9% of the isolates were identified only at the genus level as Candida spp. (Table 2).
Overall, 40.4% (132/327) of yeast isolates were obtained from respiratory samples (endotracheal aspirate and bronchoalveolar lavage) (Table 3). The most common fungal species isolated were C. albicans (47.8%; 89/132), C. tropicalis (43.8%; 28/132), and C. parapsilosis (8/132; 17%). In the blood culture, Candida species were detected in 21.4% (70/327) of the samples. C. albicans was the most common cause of bloodstream infections, corresponding to 15.1% (28/70) of these infections, followed by C. parapsilosis (44.7%; 21/70) and C. tropicalis (20.3%; 13/70). A total of 124 (37.9%; 124/327) yeast isolates were identified in urine samples, C. albicans was present in 37.1% (69/124) of the samples, followed by C. tropicalis (34.4%; 22/124) and C. parapsilosis (38.3%; 18/124) (Table 3).
Prevalence of fungal infections diagnosed at different isolation sites in critically ill COVID-19 patients in the ICU.
None of the infections were diagnosed in the initial stage (1 to 5 days in ICU). All infections were diagnosed between the intermediate (5 to 12 days) or late (≥12 days) stage of ICU admission. Of all episodes of respiratory infection, the median time to diagnosis was eight days. Among the species, C. albicans was the fastest identified microorganism with a median time of eight days, while C. parapsilosis identification was delayed with a median time of 15 days and this species was only isolated in 2021 (Table 3).
Regarding fungemia, the overall median time to diagnosis was 11 days. C. albicans was identified in a median time of 13 days in 2020 and eight days in 2021. C. tropicalis and C. parapsilosis were identified in blood cultures only in 2021, with a median time of nine and 12 days, respectively. The two isolates of N. glabratus had the longest time to diagnosis, 19 days in 2020 and 34 days in 2021 (Table 3).
Urinary tract infections were identified in a median time of 11 days. Analyzing the species, N. glabratus was only identified in 2020, with a shorter median time (7 days) than other species, while C. parapsilosis identification in the urinary tract had the longest time to diagnosis, 15 days in 2020 and 23 days in 2021. P. kudriavzevii was isolated in only one sample with 39 days to its identification.
Antifungal susceptibility profile of yeasts isolated from severe COVID-19 patients
Table 4 shows the susceptibility of Candida isolates to the antifungal tested. C. albicans showed reduced susceptibility to voriconazole (S=88.3%). C. tropicalis showed reduced susceptibility to micafungin (S=71.7%), but it was susceptible (S=100%) to the other antifungals evaluated. C. parapsilosis showed a lower susceptibility rate to flucytosine (S=76.9%) and voriconazole (S=80.9%). N. glabratus showed reduced susceptibility to caspofungin (S=66.7%) and micanfungin (S=75%). P. kudriavzevii was susceptible (S=100%) to micafungin and voriconazole. All clinical isolates of C. albicans, C. tropicalis, C. parapsilosis, and N. glabratus were susceptible to amphotericin B (S=100%) (Table 4).
Antifungal susceptibility profile of Candida isolates from critically ill COVID-19 patients.
There was a reduction in the susceptibility of the antifungals tested from 2020 to 2021 (Table 5). Among the antifungals that showed a significant reduction in their efficacy, voriconazole was 100% effective in 2020 and 77.2% effective in 2021, flucytosine efficacy was reduced from 99.4% in 2020 to 78.8% in 2021, and micafungin decreased from 99.4% in 2020 to 83.6% in 2021 (Table 5).
Antifungal susceptibility profile of Candida isolates from critically ill COVID-19 patients in 2020 and 2021.
Discussion
Invasive yeast infections have become a concern in critically ill patients (1). This study investigated secondary fungal infection in severe COVID-19 patients in an ICU of a private hospital in Northeast Brazil, a tropical and low-income region, during 2020 and 2021. The results obtained were similar to those from the study by de Medeiros et al. (13), which analyzed the prevalence and distribution of Candida species in hospitalized patients in the Northeast region between 2011 and 2016, before the COVID-19 pandemic. We found that C. albicans was the most prevalent species of candidiasis in the region, demonstrating the stability of these microorganisms in their pathogenic capacity. C. albicans was the most prevalent in respiratory, urinary, and blood samples from COVID-19 patients, followed by C. tropicalis, C. parapsilosis, N. glabratus, and P. kudriavzevii.
Patients with COVID-19 may also suffer from infections that are not directly related to respiratory impairment (14). In our study, three types of secondary yeast infections were found in the following order of prevalence: respiratory tract, urinary tract, and bloodstream infection. The use of invasive medical devices in critically ill patients may explain why the respiratory and urinary tracts were the most common anatomical sites among the diagnosed secondary infections. Indeed, colonization followed by infection with Candida species is common in patients treated with long-term invasive mechanical ventilation (15).
Zhang et al. (16) evaluated samples from 38 critically ill COVID-19 patients and found secondary infections in 57.89% (22/38) of these, including respiratory infections (21/38), bloodstream infections (13/38), and urinary infections (7/38). Riche et al. (17) observed a 10-fold increase in the frequency of fungemia at two medical centers in Brazil in patients with COVID-19. Previous studies observed that C. albicans is the most frequent agent of fungemia in COVID-19 patients (8,18). Our data also demonstrated that C. albicans was the most frequently found microorganism, being predominant in all the evaluated anatomical sites.
In the present study, the isolates were mostly obtained during the middle and late stages of ICU admission. The long-term impact of secondary fungal infections, especially among critically ill patients requiring invasive mechanical ventilation or immunomodulatory therapies, is still little discussed. However, it has become a worrisome issue since data from influenza outbreaks suggest that late invasive fungal infection may lead to adverse outcomes (6,19).
The gold standard detection test for bloodstream yeast infections is blood culture; however, this method has limitations due to low sensitivity and delayed time for microorganism detection. Clancy et al. (20) reported that approximately 50% of candidiasis cases cannot be detected by blood cultures. The limitation in sensitivity is due in part to the reduction of the Candida cells’ viability. Another factor associated with the difficulties of detecting these microorganisms is the mechanisms of pathogenicity and the different species of the genus Candida associated with bloodstream infection (21). In our study, the isolates at the Candida spp. genus level presented an elevated median time to positivity (42 days). Isolates of N. glabratus are associated with a longer time to positivity compared to C. albicans (20). Here, the median time to N. glabratus positivity was three times longer compared to the median time to C. albicans positivity.
Furthermore, C. albicans, C. tropicalis, C. parapsilosis, N. glabratus, C. dubliniensis, and P. kudriavzevii were also found to cause secondary infections in severe COVID-19 patients. Patients who tested positive for Candida spp. stayed longer in the ICU and had higher mortality rates (22). Our findings showed that the prevalence of C. parapsilosis isolates in severe COVID-19 patients increased 5.7-fold in 2021 compared to 2020, demonstrating a change in the frequency of Candida species during the two years of this study.
N. glabratus infection is more frequent in the elderly population than in young adults. This species is associated with fungemia in patients with advanced age suffering from acute respiratory distress syndrome (ARDS) (20,23). N. glabratus was linked to a fatal bloodstream infection in a type 2 diabetes patient diagnosed with COVID-19. After 13 days of treatment with caspofungin, the isolate of N. glabratus showed resistance to echinocandin, and the patient died of septic shock in the ICU (23). In the present study, N. glabratus was related to two cases of secondary bloodstream infection and three cases of secondary urinary tract infection in critically ill COVID-19 patients, while this yeast was not identified in secondary respiratory tract infection.
C. tropicalis is commonly isolated from patients with neutropenia and hematologic malignancy in developed countries. In Latin America, C. tropicalis ranks second after C. parapsilosis (24). Among the cultures analyzed in the hospital of the present study, a higher frequency of C. tropicalis was found in 2020 compared to C. parapsilosis, although in 2021 the frequency of C. tropicalis and C. parapsilosis were very similar in severe COVID-19 patients. Indeed, C. parapsilosis is often isolated from the hands of healthcare workers and inanimate surfaces in the ICU. C. parapsilosis is more frequent in southern Europe, Australia, and Latin America, while in Brazil it is the most frequently found non-C. albicans yeast species (24,25).
Other studies have shown that secondary infections may lead to lower survival rates, as viral pneumonia and secondary infections are mutually reinforcing factors in the progression of COVID-19 (16,26). Furthermore, severe COVID-19 has been associated with comorbidities. SAH, DM, and obesity are diseases considered risk factors for the development of the severe form and mortality in patients with COVID-19 (27,28). Comorbidities were described in 86.6% (123/142) of the patients who died. This may have been a determining factor for mortality since studies describe the relationship between comorbidities and lower patient survival (27- 29). In addition, secondary yeast infections are often associated with mortality, especially in critically ill patients (21), and fungal co-infection was associated with a high fatality rate in COVID-19 patients in the ICU (30).
Currently, the main challenges in antifungal therapy in developing countries include delayed therapy initiation due to late diagnosis and prescription, use, and inadequate duration of antifungal treatment. The overuse of antifungal agents increases the resistance of opportunistic pathogens. Therefore, proper antifungal dosages are necessary to ensure treatment success (31,32). Amphotericin B remains one of the main antifungals used for therapy. The excellent performance of amphotericin B in the clinical isolates identified in the study confirms its fungicidal capacity against opportunistic yeasts (33).
Amphotericin B resistance in Candida spp. is still poorly described, and the decreased susceptibility to this antifungal is less prevalent in strains of this genus compared to other classes of antifungals, such as azoles or echinocandins (31,34). The present study detected a reduction in the susceptibility of C. parapsilosis to the azoles used compared to the other identified species. Although azoles (especially fluconazole and voriconazole) are the treatment of choice for invasive C. parapsilosis infections, studies demonstrate an increase in rates of hospital outbreaks due to azole-resistant C. parapsilosis, which may be caused by previous use of fluconazole or other antibiotics, in addition to a clonal spread of isolates in the hospital, leading to increased fungal resistance (35,36). In Latin America, fluconazole is the most widely used antifungal agent for the primary therapy for fungemia (24).
The prevalence of C. parapsilosis was increased in 2021 compared to 2020. This may be related to reduced susceptibility to antifungals, indicating likely transmission within the hospital. The increased prevalence of C. parapsilosis is worrisome and poses a threat to critically ill patients, mainly due to the potential risk of resistance to the antifungals of choice, as previously described (22).
Another important finding was the diminished susceptibility of N. glabratus to echinocandins, a class of first choice antifungals that has a good fungicidal effect on Candida species. All echinocandins have high efficiency and a good safety profile. However, increasing azole resistance in recent years has created considerable selective pressure for the development of multidrug resistance. Candida species other than C. albicans have shown reduced sensitivity or even intrinsic resistance to azoles and echinocandins. This emerging resistance, specifically in N. glabratus, suggests that overuse of these agents may eventually lead to decreased efficacy of these antifungals (37,38). It is important to emphasize that antifungal resistance and antimicrobial resistance in general should be addressed in the context of understanding local patterns of antimicrobial resistance and prescription, since these are interconnected and can lead to differences in resistance in different geographic regions (25).
The neglect of the dissemination of candidiasis, as well as the carrier strains that are determinants of resistance, in the northeast of Brazil, is confirmed by the scarcity of studies that report the phenotypic profile of strains of the genus Candida in this region, as well as the lack of epidemiological studies on the distribution of infections by this microorganism in the target state of the present study, which comprises one of the regions with the least progress in laboratory diagnosis in the country (13,39,40). Thus, a thorough analysis of clinical epidemiology is needed to provide information on epidemiological changes in the distribution of yeast species and the risk of co-infections by these microorganisms.
Finally, the limitations of the study included the fact that the patients were from only one hospital; thus, the generalization of the results may be limited. New studies with larger samples are important to elucidate the frequency and resistance patterns of secondary fungal infection in patients with COVID-19 in different regions of Brazil.
In conclusion, this study identified the epidemiological shift in the distribution of yeast species and the reduced susceptibility to antifungals. The findings reinforced the need for controlling spread and improving rapid detection and treatment since a high mortality rate was observed in severe COVID-19 patients with secondary yeast infections.
Acknowledgments
We acknowledge the Federal University of Pernambuco and the Federal University of Paraiba for supporting the development of this work.
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Funding
This study was supported by PROAP/UFPE/CAPES (Coordination for the Improvement of Higher Education Personnel, Brazil) and by Financiadora de Estudos e Projetos/Ministério da Ciência, Tecnologia e Inovação (FINEP/MCTI) (process number 01.20.0026.03).
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