Abstract
In 2019, severe acute respiratory syndrome caused by CoV-2 virus became a pandemic worldwide, being the fast spread of the disease due to the movement of infected people from one country to another, from one continent to another, or within the same country. Associated comorbidities are important factors that predispose to any fungal coinfections. Because of the importance of fungal infections in COVID-19 patients, the aim of this work was to collect data of the more encountered mycoses related to patients undergoing this disease. Aspergillosis was the first COVID-19-related fungal infection reported, being A. fumigatus the most frequent species for CAPA. Other fungal infections related include mainly candidiasis and mucormycosis, being Rhizopus spp. the more prevalent species found. Influenza-associated pulmonary aspergillosis is well documented; thus, similar complications are expected in severe forms of COVID-19 pneumonia. Therefore, in patients with COVID-19, it is important to take special attention to the surveillance and suspicion of fungal coinfections that might worsen the patient’s prognosis.
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Introduction
In 2019 in Wuhan, China, cases of unexpected pneumonia have emerged. The etiological agent of the disease that causes severe acute respiratory syndrome (SARS) is a virus belonging to Coronaviridae family, named coronavirus (CoV-2) [1]. The first was reported in 2002 (SARS-CoV) in China and in the Middle East, Saudi Arabia in 2012, (MERS)-CoV. Thus far, SARS-CoV-2 has become a pandemic worldwide, and until now (June 23rd 2021) over 179 million of infected people and over 3 million deaths have been reported representing an obit percentage of 2.1% [2]. The rapid spread of coronavirus disease was largely due to the movement by traveling of infected people from one country to another, from one continent to another, or within the same country.
Overall, the disease pattern ranged from asymptomatic, mild flu-like to severe respiratory distress. Associated comorbidities such diabetes, chronic obstructive pulmonary disease, immunocompromised conditions like corticosteroid, interleukin inhibitors or broad-spectrum antibiotic therapy, mechanical ventilation, long-term stay in intensive care unit stay, severe lung tissue damage, acute respiratory distress syndrome, use of catheters, immunological dysfunction, immune dysregulation characterized by decreased T cells including CD4 and CD8 cells, alveolar macrophages activity disturbed, cytokine storm, and lymphocytopenia are often seen [3,4,5,6]. Tomography findings are in mainly consisting of ground-glass opacities, nodular infiltrates and consolidations, bullous emphysema, interstitial change, halo sign, and reverse halo sign similar to what we see in patients with mucormycosis [7,8,9]. Clinical symptoms including cough, fever, dyspnea, and/or respiratory insufficiency are observed among many others [10].
These are indeed predisposing for any fungal coinfection, such as invasive aspergillosis (IA), disseminated candidiasis, endemic mycoses, phaeohyphomycosis, mucormycosis, or fusariosis, among others, even in the absence of classical well-defined host factors [6, 10, 11]. Prolonged use of corticosteroids is considered a risk factor for invasive fungal diseases [12]. The relation between COVID-19 and aspergillosis is known as CAPA (COVID-19-associated pulmonary aspergillosis). The criteria to classify patients with CAPA vary from those with risk factors for an IPA (invasive pulmonary aspergillosis), as considered by the EORTC [13], or those with other factors such as diabetes, obesity, or hypertension. Criteria based on AspICU algorithm [14] were also applied. Recently, a case definition for IAPA (influenza-associated pulmonary aspergillosis) was proposed by an expert panel to classify patients with CAPA, classified as putative aspergillosis rather than probable or proven [6]. In the IAPA case definition, host factors are not used because IAPA may develop in any patient with severe influenza. The European Society for Clinical Microbiology and International Society of Human and Animal Mycology recently published guidance to identify proven, probable, and possible CAPA [15]. Regardless of the definition, it is difficult to distinguish between infection and colonization.
It was reported that 14–30% of hospitalized patients diagnosed with COVID-19 develop a severe respiratory failure requiring intensive care admission. Invasive aspergillosis appeared at a range from 11 to 21 days after the onset of COVID-19 and affected up to 30% of intubated patients [16,17,18]. Some authors pointed to a mortality rate ranging from 15 to 30%, with less survival in patients with CAPA, compared with those without [1, 19,20,21,22,23,24]. The same trend has been previously observed for influenza-related aspergillosis [25].
In general serum galactomannan (GM) is negative, whereas bronchoalveolar lavage (BAL) GM antigen is reported positive at a percentage of 77.8, being hypothesized that patients have an airway invasive infection rather blood vessels invasion to cause release of galactomannan. Thus, wherever possible BAL GM should be performed, since it is more sensitive than in serum. However, due the high aerosolized risk, this procedure is avoided in COVID-19 patients, and tracheal secretions, for instance, are preferred [6, 15, 20, 26]. In one study, it was observed that Aspergillus tests from COVID-19 patients were similar to those with pneumococcal pneumonia but lower than those with influenza. Thus, it was concluded that in ICU, the specificity of tests is low and tests like pan-fungal B-D glucan should not be used, advising that a positive test for Aspergillus in COVID-19 should be interpreted with caution [27].
COVID-19-associated mucormycosis will be further discussed. This is an infection that is worldwide distributed and has no predilection for a particular country. The large number of reported cases from India is link to possess a high burden with 77 million people with diabetes and another 36.5 million with prediabetes which are a high-risk condition, worsen, if is being uncontrolled, for suffering, particularly, rhino-orbital-cerebral mucormycosis [28, 29].
Treatment with interleukin inhibitors or tocilizumab (monoclonal antibody), which was used as therapy in COVID patients [30, 31], could also potentially increase the risk of other fungal infections, such those, among others, caused by Candida spp., Histoplasma spp., or Pneumocystis jirovecii [32]. Candidemia has been reported in 2.5–6.9% of COVID-19 patients in the ICU, mainly catheter-related infections and often with unfavorable outcomes [33, 34].
Considering all, the objective of this work was to collect data on the more encountered mycoses related to patients undergoing COVID-19. Although there are reviews related to this topic, all are, in general, treated separately. Thus, an updated data considering this information altogether can be found in this single review.
Methods
We searched in Pub Med and Google Scholar database for eligible studies published until May 31th 2021 for COVID-19-related fungal infections, using the key words “COVID-19” AND, “CAPA,” “COVID-19” AND “fungal infections,” “COVID-19 pneumonia,” “COVID-19” AND “Candida” OR candidiasis, “COVID-19” AND “Aspergillus” OR aspergillosis, “COVID-19” AND “Mucormycosis” OR Post “COVID-19” fungal infections, “COVID-19” AND “Cryptococcus,” “COVID-19” AND “Pneumocystis,” “COVID-19” AND “Histoplasma” OR Histoplasmosis OR endemic mycosis. A total of 160 articles were identified through the initial database search. We excluded 32 articles including four reviews, two research letters, and the remain ones for lack of the information we needed or publications that did not report primary data. After the removal of duplicated items and screening based on title and abstract, 134 articles were assessed for eligibility. Sixty-three were related to COVID-19 and invasive pulmonary aspergillosis and definitions of probable, proven, or putative according with the author definition criteria selection, including 36 articles of clinical case description of CAPA related. Thirty-seven publications were related to cases of mucormycosis and twenty-six to other fungal infections, including candidiasis, yeast non-Candida infections, pneumocystosis, and endemic mycosis. We collected data on epidemiology (age, gender, comorbidities), diagnostic methods, fungi isolated, antifungal indicated therapy, and clinical outcomes that are presented in the corresponding tables. We restricted our search to works published in the English language.
Results
Overall, 178 cases of CAPA were published. Mortality was reported in 88 cases; survivors in 80 and 10 were not specified. The main comorbidities reported were DBT, ATH, obesity, and COPD. A total of 163 Aspergillus species were recovered distributed as follows: A. fumigatus (130), following by A. flavus (15), A. niger (5), A. terreus (4), A. nidulans (2,) and one strain of A. ochraceus, A. calidoustus, A. awamorii, A. citrinoterreus, and A. penicilloides. A. fumigatus was generally susceptible to all drugs, except in 3 reports in which the TR34L98H resistance mutation in the cyp51A gene was found, associated with azole resistant [35,36,37]. Voriconazole was the drug most used, following by amphotericin. All data is detailed in Table 1.
Mucormycosis reported cases were 158, mainly related to uncontrolled diabetes. The isolation from different samples includes Mucor spp. (4), Rhizopus spp. (16), R. oryzae (4), R. azygosporus (1), R. arrhizus (1), R. microsporus (4) Lichtheimia spp. (2), and L. ramosa (1). In cases diagnosed by histology only or those from which no isolation from culture was available, it was named as mucormycosis or Mucorales (125). Forty-eight deaths and eighty-two survivors were reported. Amphotericin liposomal formulation and deoxycholate were the most antifungal drugs used. All data is detailed in Table 2.
Fungemia due to Candida species was reported in 149 cases. The mortality was high, but not accurate percentage could be calculated, due non-reported data in 17 cases. Forty-four patients died and 23 survived. The most frequent species isolated from blood cultures were C. albicans (64), C. auris (51), C. glabrata (17), C. tropicalis (9), C. parapsilosis (6), C. dubliniensis (6), C. orthopsilosis (1), and C. krusei (renamed as Pichia kudriavzevii) (2). Non-Candida yeasts seen were Trichosporon asahii (6), Saccharomyces cerevisiae (2), Rhodotorula mucilaginosa (1), and C. neoformans (2). Histoplasmosis, coccidioidomycosis and paracoccidioidomycosis cases were 4, 2, and, 1, respectively. P. jirovecii was reported in two cases. All data is detailed in Table 3.
Only one case of pulmonary fusariosis classified as putative, due by F. proliferatum in an immunocompetent patient, was reported [112]. There are six reports in which mix isolations were described. One describes a pulmonary mucormycosis diagnosed by biopsy, in which from bronchoalveolar lavage A. flavus, A. niger, C. albicans, C. glabrata, and C. krusei were found [113]. In another study, R. arrhizus plus A. fumigatus were isolated from a lung of a patient suffering from COVID-19 [114]. In a patient with a history of pulmonary embolism treated with corticosteroids, R. microsporus plus A. fumigatus were found [42]. In one patient with lymphoma, R. microsporus plus A. fumigatus were isolated from bronchoalveolar lavage [115]. Other report showed in a patient with diabetes and leukemia, A. fumigatus isolated from BAL, and after some days, isolation of R. microsporus was detected, and in other patient with no underlying disease, treated with corticosteroids, A. fumigatus was first isolated and days after L. ramosa [81]. Other report of fatal COVID-19-associated pulmonary aspergillosis described a mix fungi isolation from respiratory tract secretions. A. niger plus C. albicans were isolated from a patient with diabetes, hepatitis B, and hypertension, whereas A. terreus plus C. albicans were isolated from an otherwise healthy patient [116].
Discussion
The use of steroids, such as dexamethasone to modulate immune-mediated organ damage, interleukin inhibitors, and broad-spectrum antibiotics for the management of COVID-19, could exacerbate preexisting comorbidities and enhance the chances of new onset of fungal infections as was above discussed. Due to the high incidence of influenza-associated pulmonary aspergillosis, it seems natural to expect similar complications in severe forms of COVID-19 pneumonia. The incidence of fungal infections in SARS 2003 was 14.8–33% and the mortality rate 25–73.7% [117]. Besides, reports of severe influenza pneumonia complicated by fungal infections were published [118].
It is important to mention that the development of any fungal coinfection is highly expected in colonized patients, given the characteristics of the coronavirus disease. Therefore, taking into consideration, previous risk factors seem necessary, indicating whether coinfections might worsen the patient’s prognostic values. Mortality in patients with COVID-19 and CAPA has been seen to increase compared to COVID-19 patients without CAPA [19]. The high mortality in CAPA patients could be related with critically ill COVID-19 individuals that require mechanical ventilation, who were mostly elderly and had significant co-existing chronic comorbidities [116].
Despite all this, the mortality rate is also high in non-COVID-19 patients at risk such as those with underlying neutropenia with IPA, if treatment is not initiated on time or whether the underlying disease conditions do not improve [119]. Thus, it could be reasonable that an adequate treatment for COVID-19 could have a positive impact on the absence of improvement in the evolution of IPA. Patients with COVID have chronic obstructive pulmonary disease (COPD) for which the association with aspergillosis is well known or asthma/corticoid therapy that are also known risk factors for Aspergillus colonization. Thus, COVID-19 might be a risk factor for aspergillosis, and the underlying pulmonary conditions may favor COVID-19-associated aspergillosis [120]. Corticosteroids treatment, as is indicated in severe COVID-19 patients, increases 3 times the risk to develop invasive fungal infections in comparison to other patients who do not receive steroids [121]. Some reports highlight the need to monitor pneumatoceles that might predispose to pneumothorax and/or cavitary lesions that could be complicated with coinfections like aspergillosis, even in the recovery phase of COVID-19 [57, 122].
Other fungal infection such as candidiasis could be expected due the aforementioned conditions that predispose for suffering a fungemia, being an important issue to be considered. Diseases such as diabetes or severe COVID-19 seem to alter the intestinal barrier function that facilitates Candida translocation, allowing the gut microbiota like Candida species, to reach the bloodstream and then disseminate systemically [123]. The estimated mortality due to invasive candidiasis is 19–40% [124], being even higher among ICU patients, around 70% [125]. Cases of fungemia due to C. albicans and non albicans in COVID patients were reported in several publications. The reported cases of C. auris sound alarming, due the association of COVID-19 with an emerging pan-resistant yeast [34]. However, its sensitivity to antifungal agents should be studied and suspected according to the epidemiological setting. In Brazil, all C. auris were reported as susceptible to azoles, amphotericin, and echinocandins [95]. Some cases have been seen that appeared in colonized patients when they moved from non-COVID-19 rooms to COVID-19 rooms [97]. However, in a report by the CDC evaluating strains originating worldwide, more than 70% of the C. auris isolates were resistant to fluconazole. In the USA, resistance of C. auris isolates was about 90% for fluconazole, 30% for amphotericin B, and less than 5% for echinocandins. These proportions may include multiple isolates from the same individuals and may change as more isolates are tested [126].
No least is the report of C. glabrata pan-echinocandin resistant infection [92]. In Colombia, fungemia due to non-C. albicans was 78.94%, including C. auris [98]. In India, a high percentage of C. auris isolated from blood were resistant to fluconazole, voriconazole, flucytosine, and amphotericin [34]. In a study performed in Minas Gerais, Brazil, from 212 patients, Candida species were isolated in 98.2%, mostly from tracheal aspirate. The authors described a mortality rate of 90.5% and 76.3% in cases related to Candida non-albicans and C. albicans, respectively [91]. Candida was also related to oropharyngeal candidiasis (OPC), infecting old people with cardiovascular diseases and diabetes due to the weaker immune functions of these patients. CoV-2 as HIV virus produce T lymphocytes consumption [40]. Besides, elderly patients have lower activity levels of protective salivary innate defenses [127]. Fungemia by other yeasts such Trichosporon and Saccharomyces cerevisiae/boulardii was reported [98, 103]. This last is used in ICU patients as a probiotic for treatment of diarrheal disorders [128].
Moreover, it is not surprising to isolate Mucorales, since many patients with COVID-19 suffer from diabetes mellitus as their underlying disease that alters the body’s immunological response enhancing fungal proliferation and diminishing the phagocytic capacity of host immune cells [129]. Besides, corticosteroids have other side effects such as blunting the action of insulin with the increment of blood glucose. This hyperglycemic effect is magnified in diabetic patients and can lead to ketoacidosis [130]. In addition, the ketone reductase enzyme in Rhizopus organisms allowing them to thrive in high glucose and acidic conditions, being the reason for the stimulated growth of these organisms in those patients [131]. It is known that in patients with ketoacidosis, rhino-orbital-cerebral mucormycosis can develop, regardless of whether the patient is undergoing a COVID-19 infection. Mucormycosis without concomitant COVID-19 infection has a mortality rate ranging from 40 to 80% [9]. Severe immunocompromised from untreated diabetes made the patients be susceptible to contract both mucormycosis and COVID-19 [4, 61]. In general, uncontrolled diabetes was the main risk factor [67]. The mortality rate appears to reach 100% when both diseases are associated [113]. Besides, it is very important that ophthalmologists suspect the possible orbital infarction syndrome secondary to mucormycosis in these patients [69]. In one report, loss of vision was observed in 66% and orbital exenteration in 38% of the patients analyzed [28].
However, some cases of patients with diabetes without ketosis are reported [29, 70], as well some with non-underlying condition, suggesting a COVID-19 as risk factor due to steroids or interleukin inhibitor therapies [73, 83]. It is important to note that although corticosteroid therapy helps for the treatment of the severe form of COVID, when comorbidities such as diabetes or other immunosuppression factors exit, can be harmful. Steroids can exacerbate hyperglycemia. Therefore, close monitoring hospitalized patients and after discharged should be take into account for possible complications of post-COVID-19 fungal infections such the cases of mucormycosis that have been described [70, 71, 82, 85]. Thus, diagnosis of mucormycosis requires clinical observations, images, histopathologic findings, fungal culture, and surgical debridement which seem to improve patient survival. However, no growth happens very frequently, being important to consider the proper clinical context for suspicion. The risk of Pneumocystis pneumonia increases significantly with severe CD4 lymphocytopenia [132]. This is the case of HIV patients, and also this scenario occurs with COVID-19 infection. Thus, patients without other underlying factors might suffer of pneumocystosis as has been reported [111].
SARS-CoV-2 and endemic mycoses have overlapping risk factors. Coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis have been reported. There is a lack of information if severity of COVID and endemic mycosis can be influenced one by the other. It is possible that the fungus stays in a latent stage and be reactivated due to coronavirus disease related to immune dysregulation. In areas where these fungi are endemic, awareness should be taken [102, 104, 107, 108].
The frequency of COVID-19 in AIDS is not higher than the frequency of COVID-19 in the general population [133, 134]. There are reported cases of COF or other infections in HIV/COVID-19-positive patients. However, we do not think it is unexpected, since patients with CD4 < 100 generally present COF to different Candida species, endemic diseases, or cryptococcosis. We think that these are HIV-positive patients, with low CD4s susceptible for suffering marker diseases and who were infected with COVID-19. This thought is in agreement with the favorable outcome of HIV/COVID/histoplasmosis case patients in whom not lung damage was observed and no ICU was required [108]. The course and presentation of the reported cases do not vary from those negative COVID-19. Those cases should be taken into account to indicate the appropriate treatment but might not be taken as a separate entity. Nevertheless, the true role of the SARS-CoV-2 virus in HIV patients remains to be fully elucidated.
Conclusion
This review aimed to summarize all the main published reports of COVID-19-associated fungal infections identified by different methodologies, among which A. fumigatus can be considered the most prevalent species reported for CAPA. However, it is difficult to compare the different published studies since not all medical centers use the same criteria to define CAPA, reason for which is needed to find consensus on these definitions. The diagnosis is complicated because serum GM is generally negative, with BAL being the most sensitive sample, but it is difficult to perform due to the risk it represents. Cultures are not very profitable either and PCR is not always useful or available. The suspicion and searching for fungal infections, whether of yeast, hyaline, or pigmented fungi, should be taken into account to indicate the appropriate treatment and improve the patient’s prognosis. In addition, it is of paramount importance to make physicians aware of the fact that invasive fungal infections might occur after patients with COVID-19 have been discharged, particularly those with predisposing conditions, such uncontrolled diabetes related with mucormycosis. This entity has been relevant in recent days, due to the indiscriminate increase in reported cases, especially in India. Therefore, it is mandatory to establish an exhaustive patient follow-up and combine different methodologies of laboratory diagnosis, images, and clinical suspicion related to any fungal infection-COVID-19 related.
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Acknowledgements
R.G.V. and S.M.R. are grateful to Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación of Argentina (PICT-2018-03781). The work of S.S. was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center, Department of Laboratory Medicine.
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Vitale RG, Romero SM, Giudicessi SL, Seyedmousavi S, and Afeltra J. The first draft of the manuscript was written by Vitale RG, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Vitale, R.G., Afeltra, J., Seyedmousavi, S. et al. An overview of COVID-19 related to fungal infections: what do we know after the first year of pandemic?. Braz J Microbiol 53, 759–775 (2022). https://doi.org/10.1007/s42770-022-00704-6
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DOI: https://doi.org/10.1007/s42770-022-00704-6