Clinical data analysis of 86 patients with invasive infections caused by Malassezia furfur from a tertiary medical center and 37 studies

Abstract

Objective:

Malassezia furfur (M. furfur) is a lipophilic, conditionally pathogenic yeast that mainly causes skin infections, but the reports of related invasive infections are increasing. The aim of this study is to provide clinical data to assist physicians in the management of patients with invasive infections caused by M. furfur.

Methods:

A case of pulmonary infection caused by M. furfur in a hematopoietic stem cell transplant patient for aplastic anemia was reported. In addition, the literature on invasive infection by M. furfur published in PubMed and Web of Science in English until 31 July 2022 was reviewed.

Results:

Clinical data analysis of 86 patients (from 37 studies and our case) revealed that most of them were preterm (44.2%), followed by adults (31.4%). M. furfur fungemia occurred in 79.1% of the 86 patients, and 45 of them were clearly obtained from catheter blood. Other patients developed catheter-related infections, pneumonia, peripheral thromboembolism, endocarditis, meningitis, peritonitis and disseminated infections. Thirty-eight preterm infants had underlying diseases such as very low birth weight and/or multiple organ hypoplasia. The remaining patients had compromised immunity or severe gastrointestinal diseases. 97.7% of patients underwent invasive procedures and 80.2% received total parenteral nutrition (TPN). Fever, thrombocytopenia and leukocytosis accounted for 55.8%, 38.4% and 24.4% of patients with M. furfur invasive infections, respectively. 69.8% of the patients received antifungal therapy, mainly amphotericin B (AmB) or azoles. Of 84 patients with indwelling catheters, 58.3% underwent the removal of catheters. TPN were discontinued in 30 of 69 patients. The all-cause mortality of 86 patients was 27.9%.

Conclusions:

M. furfur can cause a variety of invasive infections. These patients mostly occur in premature infants, low immunity and severe gastrointestinal diseases. Indwelling catheters and TPN infusion are major risk factors. AmB, l-AmB and azoles are the most commonly used agents, and simultaneous removal of the catheter and termination of TPN infusion are important for the treatment of M. furfur invasive infections.

Introduction

Malassezia are yeast species belonging to Basidiomycota, Ustilaginomycotina, and class Malasseziomycetes, which are commonly found on the skin surfaces of human body and other warm-blooded animals (Theelen et al., 2021). Currently, the Malassezia genus comprises 18 species with numerous functionally distinct strains based on morphology, microstructure, physiological biochemistry and molecular biology (Vijaya Chandra et al., 2021). As a conditionally pathogenic fungus, it is well known for causing a variety of skin diseases such as tinea versicolor, seborrheic dermatitis/dandruff, atopic dermatitis, folliculitis and psoriasis (Abdillah and Ranque, 2021). Besides these skin disorders, invasive infections caused by Malassezia have been increasingly reported in recent years.

Malassezia furfur (M. furfur) is the most encountered species from bloodstream infections in the Malassezia genus, followed by M. pachydermatis and M. sympodialis, especially in premature neonates and immunocompromised hosts (Rhimi et al., 2020). Apart from fungemia, pneumonia, peritonitis, meningitis and disseminated infection caused by M. furfur have been continuously reported worldwide in recent years (Shek et al., 1989; Johnson et al., 1996; Rosales et al., 2004; Baker et al., 2016). However, the epidemiology of these infections caused by M. furfur has not been well investigated. Due to its lipid-dependent nature, M. furfur infections are likely to be underestimated in routine clinical cultures (Theelen et al., 2018). The non-specific clinical manifestations of these infections make the diagnosis of M. furfur even more difficult.

Here, we describe a case of pulmonary infection caused by M. furfur in a patient undergoing hematopoietic stem cell transplantation (HSCT) for aplastic anemia (AA). As the largest tertiary medical center in the region, M. furfur is isolated from respiratory specimen for the first time in our hospital, which arises our great interest. In order to improve the understanding of M. furfur among clinicians and laboratory personnel, this article reviews the cases of invasive infections caused by it. In addition, the latest advances in the pathogenesis, diagnosis and treatment of M. furfur invasive infections were summarized and discussed.

Materials and methods

Case presentation

A 17-year-old male underwent HSCT in our hematology department 7 months ago for AA. Immunosuppressant and hormone therapy were routinely administered after transplantation. The patient developed fever 3 days before admission, and a chest computed tomography (CT) examination at the local hospital indicated severe infection of both lungs. At admission, laboratory tests revealed a normal white blood cell count (WBC) but with a markedly reduced platelet count (56×10⁹/L) and low hemoglobin (105 g/L). His C-reactive protein (CRP) was markedly elevated (52.1 mg/L), and the level of galactomannan was normal. Multi-row CT chest scan showed multiple patchy ground-glass shadows in the lower lobe of both lungs, considering the possibility of infectious lesions.

Blood cultures drawn from peripheral vein and central venous catheter (CVC) were negative. No abnormality was observed in sputum culture. Due to the aggravation of infection, bronchoscopy with bronchoalveolar lavage was performed. After centrifugation of bronchoalveolar lavage fluid (BALF), gram staining and Gomori methenamine silver (GMS) staining revealed some bottle-shaped and budding yeast cells (Figures 1A, B). The BALF was cultured to sabouraud dextrose agar (SDA) and columbia blood agar medium and incubated at 35°C. Dust-like colonies grew on the SDA after 3 days of incubation (Figure 2A) but not on blood agar. After 5 days of culture, small creamy and fragile colonies were observed on SDA plate (Figure 2B). Gram staining of the colonies showed a culster of budding yeast cells, with a collarette-like structure seen at the junction between the budding and the mother spore (Figure 1C). The colonies were transferred to another SDA and CHROMagar™ Candida covered with a thin layer of sterile olive oil for subculturing. After 3 days of incubation, the morphology of colonies on the SDA covered with olive oil (Figure 2C) were cheese-colored, raised, smooth or rough, and pink on CHROMagar™ Candida covered with olive oil (Figure 2D). The colonies were identified as M. furfur by Vitek 2 Compact microbial identification system (BioMérieux) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) with a 99.9% confidence level. Furthermore, the second-generation sequencing results of BALF showed that the number of sequences of M. furfur was as high as 5830.

Figure 1

Figure 2

Originally, pneumocystis carinii infection was highly suspected clinically, given the patient’s condition. Biapenem, sulfamethoxazole-trimethoprim and caspofungin were administered as anti-microbial therapy. When the pathogen was confirmed as M. furfur, caspofungin was replaced with voriconazole (VOR, 200mg every 12 hours) for antifungal treatment. After 14 days of treatment, the patient had no fever, and the symptoms of chest distress and asthma were improved. The results of chest CT reexamination showed that the infection was better than before. The patient was transferred from the intensive care unit to the hematology department and continued oral VOR (200mg twice daily) for 14 days. At follow-up 3 months later, the patient continued to show clinical improvement with no signs of infection.

Literature review

We conducted literature searches in PubMed and Web of Science, and the literature was published until 31 July 2022. The query was ‘Malassezia furfur’, and article type choosed ‘Case report’. All relevant, available full texts published in English were extracted and the details of clinical data were retrieved.

Results

A total of 37 articles including 85 patients were obtained through retrieval (Figure 3) and included in the data analysis together with the case of this study. The clinical data of 86 patients with M. furfur invasive infections were shown in Table 1. The geographic distribution, demographic characteristics, site of infection, underlying disease, clinical feature, laboratory data, treatment and patient outcome were summarized and analyzed.

Figure 3

The majority of 86 patients in this study were reported from USA with 68 patients (80%), 6 from Belgium, 3 each from China and Portugal, 2 in Australia, and 1 each from France, UK, Italy and Japan. 79.1% of the patients were isolated from the blood culture, of which 45 were definitely drawn from catheter blood. In addition, mycotic thrombosis around the indwelling catheter tip or leading to catheter occlusion, peripheral thromboembolism, pneumonia, endocardial neoplasms, meningitis, peritonitis, pulmonary vasculitis, inflammation of alveolar, bronchial and bronchiolitis, and disseminated infections (spread to heart, kidney, liver, spleen and pancreas) caused by M. furfur were reported.

62.0% were male in 79 patients with known gender. The majority of 86 patients were premature neonates (44.2%), followed by adults older than 18 years (31.4%) and infants younger than 1 year (12.8%). Among 38 premature infants, 78.9% were less than 32 weeks of gestational age and all had very low birth weight (VLBW, birth weight was less than 1500g). These premature infants were born with multiple organ hypoplasia. In addition, 12 patients had hematological malignancy and half of which underwent stem cell transplantation (SCT), and 11 patients had solid malignant tumor. Other patients reported in the literature presented with a variety of underlying diseases such as Crohn’s disease, Hirschsprung disease, short bowel syndrome, bowel surgery, and HIV infection.

97.7% of patients underwent invasive procedures, and predominantly with central venous access devices (CVADs). All 38 premature infants had CVADs and received total parenteral nutrition (TPN). Among the 48 patients of non-premature infants, 31 patients (64.6%) received intralipid emulsions, and 20 of them were statistically found to be caused by feeding intolerance, gastrointestinal disease and/or intestinal resection. The most common presentations were fever (55.8%), bradycardia (15.1%), apnea (14.0%), and respiratory distress (8.1%). Laboratory examination showed thrombocytopenia in 38.4% patients and leukocytosis in 24.4% patients. Leukopenia was found in 15 patients, and further analysis revealed that 6 of them were premature, and the other 9 had immunodeficiency disease or had received chemoradiotherapy or SCT for malignancy.

69.8% of the patients received anti-microbial therapy. Of 84 patients with indwelling catheters, 58.3% underwent the removal of catheters. Parenteral lipid emulsions were discontinued in 30 of 69 patients. Amphotericin B (AmB) or liposomal-AmB (l-AmB) was the most commonly used antifungal agent, accounting for 76.7% (46/60). 17 patients were treated with azole drugs, most of which were combined with AmB or sequential therapy. Of the 26 patients who did not receive antifungal therapy, 80.8% had catheters removed (partially simultaneous termination of TPN) and 34.6% terminated TPN. The all-cause mortality of 86 patients was 27.9%. Among the 24 patients who died, 15 cases of bacteremia, 5 of pneumonia and 4 of disseminated infection were caused by M. furfur. All deaths had CVADs, and 20 patients received TPN infusion. There were 22 deaths that were treated with antifungal therapy, 17 of which were treated with AmB or l-AmB. Only 6 of these 22 patients had the catheter removed.

Discussion

The overall incidence of invasive fungal infection (IFI) was approximately 6 cases per 100 000 persons per year, with a mortality of 27.6% (von Lilienfeld-Toal et al., 2019). Recent studies have reported higher morbidity and mortality in neonates and immunocompromised patients, especially those with cancer and stem cell or solid-organ transplant (Bassetti et al., 2021; Puerta-Alcalde and Garcia-Vidal, 2021; Weimer et al., 2022). Candida and Aspergillus were generally considered to be the most common pathogens of invasive fungal disease (IFD). However, increasingly emerging opportunistic fungal (such as Malassezia) infections were being recognized and might play an important role in IFD (Miceli et al., 2011). The majority of invasive infections caused by Malassezia genus reported in recent years were associated with the lipid-dependent M. furfur. A 12-month study of fungal bloodstream infections in critical care patients showed a higher prevalence of M. furfur (2.1%) than candida spp. (1.4%) in patients with very complex underlying diseases or premature infants (Iatta et al., 2014). The severity of invasive infection caused by M. furfur could range from localized organ infection to fulminant fungemia with death (Devlin, 2006). Due to improper diagnosis, invasive infections caused by M. furfur were likely to be underestimated. In this study, we provided an overview of the epidemiology, risk factors, pathogenesis, clinical feature, diagnosis, treatment and clinical outcome of M. furfur invasive infections.

Several retrospective studies found that host immunosuppression played a dominant role in the development of IFI (Jenks et al., 2020). Congenital immune deficiency, prolonged neonatal intensive care units (NICU) stay, multiple courses of antibiotics and surgical treatment might increase the risk of M. furfur infection in premature infants. M. furfur colonization has been reported to occur in rates of 36.8% to 64% of infants hospitalized in NICU (Nguyen et al., 2001). Furthermore, there has been a nosocomial outbreak of systemic M. furfur infection in neonatal nurseries, with evidence of human-to-human transmission (Devlin, 2006). The presence and duration (>10 days) of granulocytopenia, treatment with glucocorticoids, chemoradiotherapy, and exposure to broad-spectrum antibiotics that caused changes in endogenous microbiota might be predisposing conditions for M. furfur infection. Limon et al. found that Malassezia was strongly associated with the inflammatory bowel disease, especially Crohn’s disease (Limon et al., 2019). In addition, Malassezia probably colonized internal organs in immunocompromised HIV patients (Abdillah and Ranque, 2021). The correlation of M. furfur infection with these underlying diseases deserved further investigation.

The risk of opportunistic fungal infection was increased by invasive procedures such as deep venous catheterization, mechanical ventilation and percutaneous drainage that breached the skin barrier and served as a port of entry and a nidus for pathogen infection (Jenks et al., 2020). Biofilms formation of M. furfur played an important role in its pathogenesis. It underwent multistep growth processes, including contacting with suitable substrates, adhesion to the biotic or abiotic surface by reversible hydrophobic interactions, production of polysaccharide material, biofilms maturation and dissemination (Inigo and Del Pozo, 2018). The correlation between hydrophobicity, adherence and biofilms formation in M. furfur species was examined and confirmed, as reported by other authors for Candida albicans (Borghi et al., 2011; Vavala et al., 2013). Human tissues, indwelling medical devices, other implanted foreign bodies and mucosal surfaces provided the substrate for biofilms colonization and infection (Boisvert et al., 2016). Once adhered to the surfaces, pathogens were extremely difficult to be eradicated, leading to a large number of nosocomial infections. The increased use of medical devices such as catheters and prosthetics contributed to the recurrent invasive infections and increased mortality rates among patients (Lagree and Mitchell, 2017).

Malassezia yeasts could produce a variety of enzymes, such as lipases and phospholipases that utilized lipids and proteases that utilized proteins (Vijaya Chandra et al., 2021). These enzymes might play complex roles in the human hosts, on one hand were involved in the pathogenesis, and on the other hand had a protective function (Rhimi et al., 2020). Studies found that M. furfur strains causing fungemia showed very high lipolytic enzyme activity, which were considered as virulence factors since they might be related to the colonization, proliferation, invasion and persistence in host tissues (Petrokilidou et al., 2019). However, Malassezia yeasts lacked fatty acid synthase and δ-9 desaturase, making them unable to synthesize lipids thus suggesting that they might need to inhabit lipid-rich skin or use exogenous lipids (Vijaya Chandra et al., 2021). Colonization of M. furfur on the surfaces of skin and catheter might increase the chance of invasive infections, and parenteral lipid emulsions could play an important role in their growth. Contamination during catheter placement, injection of contaminated lipids, hematogenous seeding of the catheter from a distant source, migration of M. furfur from the exit site on skin along the outer wall of the catheter and from the catheter hub through the lumen have been suggested as possible infection pathways (Marcon and Powell, 1987).

This study showed that invasive infections caused by M. furfur were special in that most of them occurred in prematurity, immunocompromised hosts, and patients requiring TPN via CVADs due to severe gastrointestinal disease and/or bowel resection. Given that these risk factors were largely unmodifiable, M. furfur invasive infections were likely to continue in the future. Studies have found that there were no differences in clinical features or laboratory markers between candida and Malassezia fungemia (Iatta et al., 2014). However, M. furfur fungemia appeared earlier and lasted longer than candidemia, which undoubtedly increased its mortality (Rhimi et al., 2020). In addition, infections caused by M. furfur seemed to be more complicated and more likely to lead to disseminated infections of the lungs, heart, kidneys, liver, spleen, and brain than M. pachyderm as another Malassezia causing fungemia (Huang et al., 2020). Hence, early diagnosis and timely and effective treatment were the key to reduce the mortality of invasive infections caused by M. furfur.

Isolation and accurate identification of M. furfur from the site of infection is currently the gold standard for the diagnosis of related infections. Unlike other studies, M. furfur grew on SDA plates in our case, which might differ in nutrient composition from plates from different manufacturers, or the small amount of lipids remaining in the specimen might have contributed to its growth. However, the dust-like colonies were easily overlooked, and its morphological characteristics were not typical due to poor growth. M. furfur did not grow well on SDA plate, but colony morphology could be clearly observed after cultured on SDA covered with sterile olive oil. Olive oil was composed of oleic acid and triglyceride esters of palmitic acid, which were good for promoting the growth of M. furfur (Devlin, 2006). It grew at temperatures between 25°C and 37°C, with optimal growth at 35°C-37°C (Dankner et al., 1987). If M. furfur infection was suspected, the clinician should alert the microbiology personnel at the time of culture submission. In our case, pink colonies of M. furfur were clearly visible on our modified chromogenic Candida medium (covered with sterile olive oil). MALDI-TOF MS was increasingly used and provided faster and more reliable identification at the Malassezia species level (Rhimi et al., 2021). In recent years, the development of molecular methods such as next-generation sequencing (NGS) had made it possible to identify yeasts directly from clinical specimens without the need to cultivate. Moreover, DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) could differentiate the vast majority of Malassezia species (Didehdar et al., 2014; Lian et al., 2014).

Thus far, the antifungal susceptibility testing recommended by the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) was not suitable for Malassezia species due to their lipid-dependent nature, slow growth and a tendency to form cell clusters (Rhimi et al., 2021). A variety of alternative procedures for the broth micro-dilution have been proposed in recent years, such as modified LN broth FastFung broth and modified Dixon broth (Far et al., 2018; Abdillah et al., 2021). However, there is neither standard parameters including incubation time, culture media and inoculation amount established for the determination of MIC values of Malassezia spp. nor susceptibility/resistance breakpoints of antifungal drugs. Thereby, standard procedures for antimicrobial susceptibility profiles of Malassezia species needed to be further established.

Azoles, polyenes and echinocandins were the main antifungal agents used to manage various types of fungal infections. The first two antifungal drugs were frequently employed to treat Malassezia-related infections in humans and animals. Topical antifungal agents (mainly azoles) were adequate for the treatment of localized skin lesions, while systemic fluconazole (FLZ) or itraconazole (ITZ) for severe skin diseases. Intravenous AmB or its formulations was recommended for the treatment of systemic infections caused by M. furfur (Chen et al., 2020; Chen et al., 2021). The antifungal activity of l-AmB was higher than deoxycholate AmB, which might be contributed to the lipophilic nature of this yeast (Iatta et al., 2015). Usually, approximately 24 days of AmB treatment might be useful for a positive outcome of M. furfur fungemia (Rhimi et al., 2020). Furthermore, the observed in vitro susceptibility values suggested that Malassezia might be intrinsically resistant to echinocandins such as caspofungin and micafungin (Rhimi et al., 2021). If echinocandins were used to prevent fungal infection in hospitalized patients, they might be selective for Malassezia, potentially leading to Malassezia-related infections.

The formation of fungal biofilms not only played an important role in the pathogenesis, but also increased the resistance to immune defense and antifungal therapy (Le Mauff, 2020; Pathakumari et al., 2020). Successful eradication of biofilm-associated fungi was difficult, mainly because it required higher concentrations of antifungal agents than those needed to kill planktonic cells, which were generally toxic to the host. Removal or exchange of medical devices containing biofilms was the most important treatment for biofilm infections (Muakkassa and Ghannoum, 2016). In patients with catheter-related M. furfur infections, catheter removal, discontinuation of parenteral lipid nutrition and the institution of systemic antifungal treatment were recommended (Pedrosa et al., 2018).

All-cause mortality rate in this study was 27.9% (24/86). All deaths had CVADs, and 20 patients received TPN infusion. As risk factors for M. furfur infection, whether indwelling catheter and TPN infusion were associated with the mortality needed further investigation. Although 17 patients received the recommended AmB or l-AmB treatment, the cause of death was likely related to delayed diagnosis, delayed administration of medication, and failure to combine the removal of the indwelling catheter. However, this was a retrospective study, and the data about the time from hospitalization to diagnosis and the time from diagnosis to medication were missing, so the cause of death could not be further discussed, which was also the limitation of this study.

In summary, we provide a case report and literature review on invasive infections caused by M. furfur, demonstrating the epidemiology, risk factors, pathogenesis, diagnosis and treatment. M. furfur invasive infections generally present with nonspecific symptoms and occur in preterm infants or patients with immunocompromised or underlying gastrointestinal diseases. Indwelling catheter and TPN infusion are the main risk factors and involved in the pathogenesis of infection. Pathogenic diagnosis requires special attention to the lipophilic characteristics of M. furfur. Standard procedures for in vitro antimicrobial susceptibility testing of M. furfur needed to be further established. Currently, the most commonly used anti-M. furfur drugs in clinical practice are azoles and polyenes, especially AmB or l-AMB. Removal of the catheter and termination of TPN infusion are effective in the treatment of M. furfur invasive infections.

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