Abstract
Purpose of Review
This review discusses the connections between the gut-lung axis, gut and respiratory tract dysbiosis, and Candida bloodstream, oral, and respiratory infections in COVID-19 patients.
Recent Findings
COVID-19–related dysfunction in the intestinal barrier together with gut and lung dysbiosis played an important role in disease pathophysiology, which affected host immune homeostasis giving rise to prominent systemic and respiratory bacterial and fungal infections. Higher incidence of Candida bloodstream infections driven by accumulation of “classic” risk factors in severely ill COVID-19 patients was noted. Moreover, numerous C. auris outbreaks, characterized by high clonality of the strains, were reported from all around the world. Unlike other Candida species, C. auris colonization and infection cases most likely resulted from nosocomial transmission.
Summary
Infections due to Candida species in severely ill COVID-19 patients reflected the overall immune dysregulation and were largely driven by gut and respiratory tract dysbiosis.
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Introduction
The COVID-19 pandemic has wreaked a devastating impact on global health with mortality approaching 7 million people [1]. People at the highest risk of severe COVID-19 were those of advanced age and those with comorbidities including hypertension, diabetes, chronic heart, and renal diseases [2]. Approximately 5–6% of symptomatic infected patients developed atypical pneumonia requiring hospitalization with many of them progressing to the intensive care unit (ICU) with respiratory failure and a further subset developing a more lethal cytokine storm resulting in an acute respiratory distress syndrome (ARDS) requiring mechanical ventilation [3]. A hallmark of severely ill COVID-19 patients was the development of a profound immune dysfunction [4] promoting the emergence of opportunistic bacterial, fungal, and viral infections [5,6,7,8]. Bacterial infections were often manifested as secondary pneumonias, urinary tract infections, and sepsis and were closely associated with prolonged hospitalization, mechanical ventilation, and the presence of invasive medical devices [9,10,11]. Individuals with latent tuberculosis infection were at increased risk of developing active tuberculosis due to the immune system’s compromised state caused by COVID-19 [5•]. The extensive use of antibiotics for treatment and prophylaxis, well known to disrupt the normal gut microbiota, increased the risk for developing Clostridium difficile infections within the gastrointestinal (GI) tract [12]. COVID-19 patients were also at heightened risk for developing viral infections due to herpes simplex virus (HSV), cytomegalovirus (CMV), and other respiratory co-infections [10, 13].
In recent years, it has been recognized that patients with certain severe viral and bacterial respiratory tract infections, including influenza, tuberculosis, and those with chronic diseases like chronic obstructive pulmonary disease (COPD), are prone to invasive fungal infections [6]. Seriously ill hospitalized patients with COVID-19 displayed an array of known risk factors for invasive fungal infections including lung damage resulting in a need for oxygen therapy, profound immunosuppression, and monoclonal antibody and corticosteroid therapy [14, 15•]. Such patients have impaired immune function of proinflammatory cytokines like interleukins IL-6, IL-1, IL-12, tumor necrosis factor (TNF), and interferon gamma (IFNγ), which promote opportunistic fungal infections [16]. Hence, patients with severe COVID-19 were also prone to develop invasive fungal infections [15•], particularly those caused by Candida [17••], Mucorales, and Aspergillus species [18] resulting in COVID-19–associated pulmonary aspergillosis (CAPA) [19, 20], COVID-19–associated mucormycosis (CAM) [21], and COVID-19–associated candidiasis (CAC) [22]. The high prevalence of CAC was not surprising given immune and barrier dysregulation in the gut and lung [22]. CAC carried a higher mortality than candidemia in non-COVID-19 patients during the same period [6, 23•]. It is the importance of gut-lung axis, gut, and respiratory tract dysbiosis and resulting bloodstream, oral and respiratory infections during COVID-19 that is discussed in this review.
Gut-Lung Axis in COVID-19
The lower gastrointestinal tract contains a complex microbiome of bacteria, fungi, and viruses, which are largely kept in-check in healthy individuals through host and microbial interactions [24]. The intestinal mucosa is a critical component that serves as a functional barrier. However, a breach in host containment can turn harmless commensal organisms into disease-causing pathogens that have life-threatening consequences for a patient resulting in sepsis, bloodstream infection, hyper inflammatory state, and multisystem failures [25]. The intestinal immune system harbors over 80% of the total body’s lymphocyte population residing in intraepithelial, lamina propria, Peyer’s patches, and mesenteric lymph nodes. Peyer’s patches and mesenteric lymph form aggregates with the latter connected to lymphatic system via drainage channels. The Peyer’s patches in concert with epithelial cells help induce local immune responses by mediating antigen presenting cell/T-cell interactions and release of cytokines [26]. Gut microbiota and their metabolites shape a healthy balance of Th17 and Treg cells [27]. Growing evidence supports strong crosstalk between the gut microbiota and lung, likely through the same interactions that maintain host health/disease balance [28], and the term “gut-lung axis” was created to describe this phenomenon.
During COVID-19, severely ill patients developed profound immune dysregulation and were often treated with broad-spectrum antibiotics and anti-inflammatory drugs, e.g., corticosteroids and cytokine antagonists. The resulting gut microbiome dysbiosis was associated with translocation of bacteria into the blood [29, 30]. The gut has been described as a main driver of critical illness [31], which induces dysfunction in the intestinal barrier and its hyperpermeability enabling luminal microbiota and metabolites to escape. Colonizing organisms can traverse the barrier either via a transcellular pathway involving epithelial cells or through a paracellular path involving tight junctions between adjacent epithelial cells. Impaired epithelial barrier function is often observed in inflammatory diseases, cancer, and transplantation and is impacted by factors such immune dysfunction and treatment with corticosteroid, cytokine antagonists, and antibiotics, as well as high fat diets [32, 33].
Fungi residing in the gastrointestinal tract (gut mycobiome) play important roles in host immune homeostasis, metabolism, and infection prevention [34, 35]. Fungal dysbiosis in the gut is associated with numerous diseases, including inflammatory bowel disease [36], colorectal cancer [37], and asthma [38, 39]. It is now apparent that there is a strong association between the gut and respiratory health, which surfaced prominently with COVID-19 [28, 38]. The gut-lung connection has been demonstrated in human and murine studies with some lung diseases influenced by gut microbiome changes and vice versa [39]. Thus, it is not surprising, given the ability of SARS-CoV-2 to replicate in both the respiratory and digestive tracts [40], that gut mycobiome in COVID-19 patients was a focus of several studies. Lv et al. compared the gut mycobiome of COVID-19- and H1N1-infected patients and healthy individuals. They discovered that in infected patients (in the comparison to healthy controls), the fungal burden in the gut was higher and that the relative abundances of some fungi with important functions were lower, but those of several opportunistic pathogenic fungi were higher [41]. Zuo et al. specifically identified Candida albicans, Candida auris, and Aspergillus flavus proportions to be increased in COVID-19 patients’ gut [42••].
Similarly, lower respiratory tract dysbiosis with a shift to Candida species colonization and a decreased fungal diversity was noted in COVID-19 patients [43, 44••]. These data corroborate the notion of SARS-CoV-2–triggered disruption of lung immune homeostasis, leading to overgrowth of pathogenic bacteria and fungi, and inflammation.
Altogether, as summarized in Fig. 1, COVID-19-related dysfunction in the intestinal barrier together with gut and lung dysbiosis played an important role in disease pathophysiology, which affected host immune homeostasis giving rise to prominent systemic and respiratory bacterial and fungal infections [30, 45, 46].
Candida Respiratory Tract Colonization and Candida Pneumonia in COVID-19 Patients
Candida spp. are frequently isolated from respiratory specimens, especially from ICU patients receiving mechanical ventilation [47,48,49]. It was estimated that up to 20% of patients acquired tracheobronchial colonization with Candida spp. after 48 h of intubation and ventilation and that their percent increases with extended ventilation [48]. However, an understanding of the significance of Candida spp. detection from respiratory samples is complicated, as it can represent one of the four scenarios: (1) contamination, an artifact introduced during sampling; (2) commensalism, member of the normal microbiome; (3) colonization, noninfectious resident that is not a member of a normal microbiome; and (4) infection, etiologic agent of infection. The diagnosis of Candida pneumonia should be confirmed by histopathology [47, 50]. Moreover, the presence of Candida spp. in any respiratory specimen always needs to be interpreted within its clinical and microbiological context, especially since there is a growing body of evidence of Candida spp. impact on human health even in noninfectious settings [51].
Candida pneumonia is rare, but colonization of the lower respiratory tract with Candida spp. has been associated with longer duration of mechanical ventilation, increased risk of ventilator-associated pneumonia (VAP), increased length of intensive care unit (ICU) and hospital stay, and higher mortality in mechanically ventilated patients [48, 52,53,54,55,56]. Major risk factors for Candida spp. acquisition in the respiratory tract include (1) host factors (STAT1 and dectin-1 defective mutations); (2) iatrogenic conditions (broad-spectrum antibiotics, mechanical ventilation, radiation therapy); (3) immunosuppression (neutropenia, systemic immunosuppression, steroid use, HIV, diabetes mellitus, bone marrow or solid organ transplant); and (4) extraneous (prolonged hospital stay, ICU stay, burns) [51].
Patients with severe viral respiratory tract infections are well recognized to be at high risk for developing invasive fungal infections including pulmonary aspergillosis and mucormycosis [13, 21]. Influenza pneumonias often present with increased disease morbidity and mortality, and similar disease co-dependence was observed during COVID-19 [14]. In a population of 100 immunosuppressed COVID-19 patients, Candida species were recovered from 69% of bronchoalveolar lavage specimens. Indeed, Candida colonization with restricted species reflected dysbiosis of lung and gut microbiota, which correlated with acute respiratory distress syndrome among patients [57]. Candida colonization in such severely ill patients is typically not deemed to directly impact clinical outcomes and is more a reflection of generalized immune, barrier and microbiota dysfunction [14]. Yet, its contribution to the overall state of COVID-19, including ARDS and other clinically significant risk factors, needs to be better assessed [58].
In a 2018–2022 study from France, both the incidence and prevalence of detection of Candida spp. in respiratory specimens increased in COVID-19 pandemic. Moreover, the length of stay in the hospital, mechanical ventilation, diabetes, and the use of antibacterials were identified as independent risk factors of Candida airway colonization [59••]. In Iran, C. albicans was found in the respiratory specimens of COVID-19 patients, especially those with diabetes, malignancies, and kidney disorders [57]. Similarly, we found virus- and drug-induced immunosuppression, together with prolonged hospital stay and mechanical ventilation, to increase the susceptibility to Candida colonization in the COVID-19 patients in New Jersey, USA [60]. Additionally, results of a Belgian study pointed to biofilms formed on endotracheal tubes (ETT), as a reservoir of microorganisms that can cause secondary infections in mechanically ventilated patients [43].
COVID-19–related epithelial damage of the airways gives way to fungal invasion in the respiratory tract. Although the most common agents of infection are molds of Aspergillus and Mucor genera, Candida lung infections, including C. albicans pneumonia with lung abscess [61], post-COVID-19 fungal empyema thoracis due to C. glabrata [62], and post-COVID-19 C. glabrata pneumonia [63], were presumptively reported, but histopathological evidence was provided only in one case [61].
Oral Candidiasis
The human commensal Candida albicans is a normal component of the oral cavity microbiota, and the development of oral and esophageal thrush is often a hallmark indication associated with immune dysfunction among patients with cancer and HIV/AIDS [64]. During COVID-19, the oral cavity was also impacted in patients resulting in typical oral clinical manifestations associated with systemic immune dysfunction including white and erythematous plaques, blisters, necrotizing gingivitis, ulcerations, salivary gland alterations, gustatory dysfunction, and coinfections [65]. Furthermore, overgrowth of Candida species was exacerbated by virus-infected salivary glands which compromised the production of histatin-5, a family of histidine-rich cationic antimicrobial proteins that help maintain a healthy balance of Candida in the oral biome [65]. Candida was frequently encountered in sputum samples, exceeding 53% in some studies, and due to the prolonged and chronic use of antifungal, high levels of mono- and multidrug resistance among Candida species isolates were reported [66].
Invasive Candida Infections in COVID-19 Patients
COVID-19–associated Candida spp. superinfections quickly became recognized as complications of the severe disease with the first four cases (C. albicans, n = 3; C. glabrata, n = 1) reported in 99 patients hospitalized in Wuhan Jinyintan Hospital (China) from Jan 1 to Jan 20, 2020 [67]. Further studies reported an increased incidence of Candida bloodstream infections (candidemia) in COVID-19 patients (in comparison to patients without COVID-19), especially in the ICU settings (Table 1). However, results of Candida spp. clinical isolates genotyping revealed that such an increase was not characterized by an uncontrolled nosocomial transmission [60, 68, 69•], except for the spread of Candida auris (see the next section).
Reasons for the higher frequency of candidemia in COVID-19 patients are still not fully understood. Unlike COVID-19–associated pulmonary aspergillosis (CAPA), where hyperinflammation is thought to be the main predisposing mechanism [15•], COVID-19–associated candidemia (CAC) most likely results from a combination of concomitant “classic” risk factors, such as prolonged hospital stay, ICU stay, (poorly controlled) diabetes mellitus, use of broad-spectrum antibiotics, use of corticosteroids, presence and duration of CVC, mechanical ventilation, and parenteral nutrition (Table 1). Also, as already discussed, a path to infection most likely resulted from dysbiosis of the fungal gut microbiome, decreased fungal diversity, and a shift toward Candida colonization in SARS-CoV-2–infected patients. Additionally, pandemic-related issues in overwhelmed healthcare facilities (crowded hospital rooms, decreased staff-to-patient ratios, limited availability of personal protective equipment (PPE)), leading to breaches in infection control practices (deviations from catheter management policies, inappropriate use of PPE), were possible contributors to the increased number of Candida infections in COVID-19 patients [50, 68, 77].
In most reports, the predominant identified species was C. albicans (Table 1), but some healthcare institutions noticed a trend of increasing non-albicans clinical isolates over the years. For example, in Gregorio Marañón Hospital in Madrid, Spain, the proportion of isolates between 2020 and 2022 decreased in C. albicans (60.3% vs. 36.7%) and increased in C. parapsilosis (10.3% vs. 28.6%) and C. tropicalis (8.8% vs. 16.3%) [69•]. Uniquely in India, C. auris was found to be the most predominant agent of CAC [96, 97].
Since the beginning of the COVID-19 pandemic, experts debated whether it would result in increased prevalence of antimicrobial resistance, with Clancy, Buehrle, and Nguyen saying “yes” and Collignon and Beggs saying “no.” However, they did not make any specific predictions regarding antifungal resistance [98,99,100]. Regrettably, antifungal drug susceptibility of the CAC isolates was determined rarely (Table 1), complicating comprehensive assessment of the situation and trend analysis. Posteraro et al. reported development of echinocandin resistance upon caspofungin treatment in a fatal case of COVID-19–associated C. glabrata infection [101].
Mortality in CAC patients was in the 28 to 100% range, with some healthcare institutions reporting significantly higher mortality in COVID‐19 patients than non‐COVID‐19 patients [17, 23, 95].
Candida auris in COVID-19 Patients
Even before the COVID-19 pandemic, Candida auris had already established itself as one of the hot topics among infectious diseases experts. In 2019, it was named an urgent threat in the CDC’s Antibiotic Resistance (AR) Threats Report due to its antifungal drug resistance and easy transmission, often leading to nosocomial outbreaks [102]. In the initial months of the pandemic, it was speculated that COVID-19 patients, especially the ones receiving critical care, would establish a population highly vulnerable to colonization and infection by C. auris [103]. These predictions proved correct, and numerous C. auris outbreaks occurred in countries all around the world (Table 2), as well as single cases in Japan [104], Qatar [105], and Turkey [106] were reported. Moreover, broader temporal analyses performed in India [79], Israel [107], and the USA [108, 109] informed of a growing number of C. auris cases during pandemic years. New C. auris introductions into previously unaffected healthcare facilities were also described [107, 110, 111]. The pooled mortality rate of C. auris candidiasis from published studies was estimated to exceed 60% (64.7% [112], 67.849% [113]).
The outbreaks were characterized by high clonality of the strains [107, 110, 114, 115, 118,119,120, 125, 127, 132] supporting the notion of intrahospital transmission of C. auris. Prolonged hospital stays, high burden of severely sick patients, and challenges in the implementation of infection control practices (e.g., extended or incorrect use of personal protective equipment) during the COVID-19 pandemic are thought to be the main drivers of patients’ colonization with C. auris [96, 112, 127]. Lengthy lockdowns and travel restrictions most likely also contributed to the local spread pattern [114, 127].
Following the CDC guidance [134], echinocandins were used as first-line therapy in invasive C. auris cases [96, 97, 107, 110, 112, 114, 115, 118, 125, 126, 131], followed by amphotericin B [96, 112, 118, 125, 126, 131] and azoles [107, 110, 118, 125, 126]. Antifungal drug susceptibility (if determined) was clade-dependent with isolates of clade I (South Asian) showing almost uniform fluconazole resistance and high rates of amphotericin B resistance (Table 2). However, in Brazil, the researchers found unexpected low antifungal minimal inhibitory concentration (MIC) values and the absence of any resistance-conferring mutations in clade I isolates [114, 115]. Only a few studies identified molecular determinants of antifungal drug resistance in recovered C. auris clinical isolates. Well-known azole resistance-conferring mutations included Erg11 Y132F and K143R from India [97], Erg11 K143R and Tac1b A640V from Italy (120), Erg11 Y132F from Lebanon [123] and Qatar [127], and Erg11 V125A/F126L from the USA [131]. Moreover, previously reported echinocandin resistance-conferring Fks1 mutations S639F and S639Y were detected Qatari isolates [127].
COVID-19 patients who developed C. auris infection were often severely ill with the most prevalent comorbidities being hypertension, diabetes mellitus, and cardiovascular diseases [96, 97, 113, 114, 121, 122, 124, 125, 130, 131, 133]. Other risk factors, including mechanical ventilation, extensive antibiotic use, steroid treatment, and placement of indwelling devices, also contributed to the C. auris infection acquisition [79, 96, 97, 107, 111, 114, 115, 117, 118, 121, 122, 124,125,126, 131,132,133]. In some cases, C. auris infection occurred concurrently with bacterial superinfection, further complicating patient management [107, 114, 118, 120, 124,125,126, 129, 133].
Public health professionals have speculated on the role of COVID-19 pandemic-related logistical issues, including low PPE compliance due to anticipated/existing PPE shortages and relaxation of the measures to control C. auris due to the higher workload of healthcare workers, which would promote nosocomial transmission of C. auris. Recent experience has highlighted the urgent need for uninterrupted C. auris surveillance and containment efforts.
Conclusion
COVID-19 patients who progressed to severe disease with acute respiratory distress were notable for their associated immune dysfunction and increased risk for developing opportunistic invasive fungal infections, including the ones caused by Candida species. Additionally, many of severely ill COVID-19 patients were treated with broad‐spectrum antibiotics disrupting the normal intestinal flora composition [135] and corticosteroids enhancing Candida cells adhesion to the epithelial cells [136]. The resulting dysbiosis with promotion of Candida growth in the gastrointestinal and respiratory tracts with eventual translocation of Candida to the bloodstream system led to an increased number of Candida infections in COVID-19 patients. For commensal organisms like C. albicans and C. glabrata, which form a prominent reservoir in the gut, COVID-19 highlighted the importance of the gut-lung axis. While Candida in respiratory fluids of patients with pneumonia was associated with high mortality, it did not rise to the level of attributable mortality. Yet, such organisms almost certainly increased the body’s overall inflammatory state contributing to patient decline. Early and appropriate management of lung and gut dysbiosis should become a part of routine standard-of-care for such patients with the aim of preventing the progression toward invasive Candida infections.
Finally, the steady rise of C. auris colonization and infection cases among hospitalized COVID-19 patients is a cautionary tale, as this environmentally hearty and drug-resistant organism continues to prey on the chronically ill immunocompromised hosts. Active surveillance of patient body sites (axilla, groin, nares) and healthcare environment is critical for limiting transmission and preventing infections. Here, molecular diagnostics methods offer rapid and accurate detection of patient and surface colonization and can aid in implementation of infection prevention and control measures especially in case of patient transfers.
Change history
13 December 2023
A Correction to this paper has been published: https://doi.org/10.1007/s12281-023-00478-w
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This work was supported by NIH grant R01AI109025 to D.S.P.
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M.K. and D.S.P. wrote the manuscript text; M.K. prepared figures and tables.
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David S. Perlin receives funding from the U.S. National Institutes of Health (NIH) and contracts with Merck, Regeneron, and Pfizer. He serves on the advisory board for N8 Medical and holds patents on detection assays for fungi and their antifungal drug resistance. Milena Kordalewska declares that she has no conflict of interest.
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Kordalewska, M., Perlin, D.S. Candida in COVID-19: Gut-Lung Axis, Dysbiosis, and Infections. Curr Fungal Infect Rep 17, 263–280 (2023). https://doi.org/10.1007/s12281-023-00476-y
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DOI: https://doi.org/10.1007/s12281-023-00476-y