Coronavirus disease 2019 (COVID-19)-associated invasive fungal infections are an important complication in a substantial number of critically ill, hospitalized patients with COVID-19. Three groups of fungal pathogens cause co-infections in COVID-19: Aspergillus, Mucorales and Candida species, including Candida auris. Here we review the incidence of COVID-19-associated invasive fungal infections caused by these fungi in low-, middle- and high-income countries. By evaluating the epidemiology, clinical risk factors, predisposing features of the host environment and immunological mechanisms that underlie the pathogenesis of these co-infections, we set the scene for future research and development of clinical guidance. 

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COVID-19-associated fungal infections

Candida auris, a recently recognized, often multidrug-resistant yeast, has become a significant fungal pathogen due to its ability to cause invasive infections and outbreaks in healthcare facilities which have been difficult to control and treat. The extraordinary abilities of C. auris to easily contaminate the environment around colonized patients and persist for long periods have recently resulted in major outbreaks in many countries. C. auris resists elimination by robust cleaning and other decontamination procedures, likely due to the formation of ‘dry’ biofilms. Susceptible hospitalized patients, particularly those with multiple comorbidities in intensive care settings, acquire C. auris rather easily from close contact with C. auris-infected patients, their environment, or the equipment used on colonized patients, often with fatal consequences. This review highlights the lessons learned from recent studies on the epidemiology, diagnosis, pathogenesis, susceptibility, and molecular basis of resistance to antifungal drugs and infection control measures to combat the spread of C. auris infections in healthcare facilities. Particular emphasis is given to interventions aiming to prevent new infections in healthcare facilities, including the screening of susceptible patients for colonization; the cleaning and decontamination of the environment, equipment, and colonized patients; and successful approaches to identify and treat infected patients, particularly during outbreaks.

Candida auris: Epidemiology, Diagnosis, Pathogenesis, Antifungal Susceptibility, and Infection Control Measures to Combat the Spread of Infections in Healthcare Facilities

Patients with severe COVID-19, such as individuals in intensive care units (ICU), are exceptionally susceptible to bacterial and fungal infections. The most prevalent fungal infections are aspergillosis and candidemia. Nonetheless, other fungal species (for instance, Histoplasma spp., Rhizopus spp., Mucor spp., Cryptococcus spp.) have recently been increasingly linked to opportunistic fungal diseases in COVID-19 patients. These fungal co-infections are described with rising incidence, severe illness, and death that is associated with host immune response. Awareness of the high risks of the occurrence of fungal co-infections is crucial to downgrade any arrear in diagnosis and treatment to support the prevention of severe illness and death directly related to these infections. This review analyses the fungal infections, treatments, outcome, and immune response, considering the possible role of the microbiome in these patients. The search was performed in Medline (PubMed), using the words “fungal infections COVID-19”, between 2020–2021.

Overview on the Prevalence of Fungal Infections, Immune Response, and Microbiome Role in COVID-19 Patients.

Individuals suffering from severe viral respiratory tract infections have recently emerged as "at risk" groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide. Fungal infections complicating influenza pneumonia are associated with increased disease severity and mortality, with invasive pulmonary aspergillosis being the most common manifestation. Strikingly, similar observations have been made during the current coronavirus disease 2019 (COVID-19) pandemic. The copathogenesis of respiratory viral and fungal coinfections is complex and involves a dynamic interplay between the host immune defenses and the virulence of the microbes involved that often results in failure to return to homeostasis. In this review, we discuss the main mechanisms underlying susceptibility to invasive fungal disease following respiratory viral infections. A comprehensive understanding of these interactions will aid the development of therapeutic modalities against newly identified targets to prevent and treat these emerging coinfections. 

Pathogenesis of Respiratory Viral and Fungal Coinfections

The emerging, often multidrug-resistant Candida auris is increasingly being associated with outbreaks in healthcare facilities. Here we describe the molecular epidemiology of a C. auris outbreak during 18 months, which started in 2018 in the high dependency unit (HDU) of a secondary-care hospital in Kuwait. Demographic and clinical data for candidemia and colonized patients were prospectively recorded. Clinical and environmental isolates were subjected to phenotypic and molecular identification; antifungal susceptibility testing by broth microdilution method; PCR-sequencing of ERG11 and FKS1 for resistance mechanisms to triazoles and echinocandins, respectively; and molecular fingerprinting by short tandem repeat (STR) analyses. Seventy-one (17 candidemic and 54 colonized) patients including 26 with candiduria and seven environmental samples yielded C. auris. All isolates were identified as C. auris by Vitek2, MALDI-TOF MS, PCR amplification and/or PCR-sequencing of rDNA. Twelve candidemia and 26 colonized patients were admitted or exposed to HDU. Following outbreak recognition, an intensive screening program was instituted for new patients. Despite treatment of all candidemia and 36 colonized patients, 9 of 17 candidemia and 27 of 54 colonized patients died with an overall crude mortality rate of ~50%. Nearly all isolates were resistant to fluconazole and contained the Y132F mutation in ERG11 except one patient's isolates, which were also distinct by STR typing. Only urine isolates from two patients developed echinocandin resistance with concomitant FKS1 mutations. The transmission of C. auris in this outbreak was linked to infected/colonized patients and the hospital environment. However, despite continuous surveillance and enforcement of infection control measures, sporadic new cases continued to occur, challenging the containment efforts.

Molecular Epidemiology of Candida Auris Outbreak in a Major Secondary-Care Hospital in Kuwait.

In addition to the increase in fungal infections that has been observed in the last few decades, it has been reported that severe clinical COVID-19 can increase the risk of invasive fungal infections. The main objective of this study was to evaluate if there had been an increase in candidaemia and invasive pulmonary aspergillosis (IPA) cases since the onset of the SARS-CoV-2 pandemic. Data were retrospectively collected from April 2019 to March 2021, from patients admitted to Consorcio Hospital General Universitario de Valencia (Spain). A total of 152 candidaemia cases (56 of which were due to Candida auris) and 108 possible IPA cases were detected. A great increase in candidaemia cases was produced during the first and the third epidemic waves of the SARS-CoV-2 pandemic (June 2020, and January 2021, respectively), while an increase in IPA cases was produced during the third wave. The 28-day mortality rates in patients affected by candidaemia and IPA increased in 2020 and 2021. C. auris has displaced the other Candida species, becoming the most isolated Candida species in blood cultures since the onset of the SARS-CoV-2 pandemic. Antifungal consumption increased in 2020 when compared to 2019, especially echinocandins, voriconazole and isavuconazole.

Impact of the SARS-CoV-2 Pandemic in Candidaemia, Invasive Aspergillosis and Antifungal Consumption in a Tertiary Hospital

The multi-resistant yeast Candida auris has become a global public health threat because of its ease to persist and spread in clinical environments, especially in intensive care units. One of the most severe manifestations of invasive candidiasis is candidaemia, whose epidemiology has evolved to more resistant non-albicansCandida species, such as C. auris. It is crucial to establish infection control policies in order to control an outbreak due to nosocomial pathogens, including the implementation of screening colonisation studies. We describe here our experience in managing a C. auris outbreak lasting more than two and a half years which, despite our efforts in establishing control measures and surveillance, is still ongoing. A total of 287 colonised patients and 47 blood stream infections (candidaemia) have been detected to date. The epidemiology of those patients with candidaemia and the susceptibility of C. auris isolates are also reported. Thirty-five patients with candidaemia (74.5%) were also previously colonised. Forty-three patients (91.5%) were hospitalised (61.7%) or had been hospitalised (29.8%) in the ICU before developing candidaemia. Antifungal therapy for candidaemia consisted of echinocandins in monotherapy or in combination with amphotericin B or isavuconazole. The most common underlying disease was abdominal surgery (29.8%). The thirty-day mortality rate was 23.4% and two cases of endophtalmitis due to C. auris were found. All isolates were resistant to fluconazole and susceptible to echinocandins and amphotericin B. One isolate became resistant to echinocandins two months after the first isolate. Although there are no established clinical breakpoints, minimum inhibitory concentrations for isavuconazole were low (≤ 1 μg/mL).

https://www.mdpi.com/2079-6382/9/9/558/pdf

Characteristics and Management of Candidaemia Episodes in an Established Candida auris Outbreak

Evaluation of a novel chromogenic medium for Candida spp. identification and comparison with CHROMagar™ Candida for the detection of Candida auris in surveillance samples

Resumen Candida auris es una levadura multirresistente emergente que causa infecciones invasivas graves y brotes con una alta mortalidad. El control de C . auris es un reto. Laboratorios, clinicos e instituciones sanitarias deben trabajar conjuntamente para mejorar la identificacion y el tratamiento de la infeccion, asi como el control de la transmision. Esta revision describe los aspectos generales de la biologia, diagnostico y tratamiento de C. auris, al igual que las recomendaciones publicadas recientemente por un grupo de expertos. Tambien se presenta la experiencia de un brote de C. auris en el Consorcio Hospital General Universitario de Valencia desde septiembre de 2017 hasta agosto de 2019. Se detectaron un total de 203 pacientes infectados y/o colonizados por C. auris. Se diagnosticaron 30 infecciones invasivas (29 candidemias y 1 meningitis). El 32% de las candidemias del ano 2018 fueron por C. auris. Todas las cepas fueron resistentes a fluconazol.

Candida auris: descripción de un brote

Background Rapid and reliable laboratory methods are required for detecting the nosocomial yeast Candida auris AurisID® (Olm Diagnostics, England) is a real-time PCR assay approved for detecting C auris in fungal cultures as well as directly from blood samples, involving a nucleic acid extraction as a prior step Objectives The purpose of this study is to validate the AurisID® kit for direct detection of C auris from surveillance samples without prior DNA extraction and to analyze the results of implementing this methodology to our daily laboratory routine protocol for C auris surveillance studies Methods Our PCR method using the AurisID® kit was compared with our routine protocol, consisting of culture in CHROMagar® Candida and identification by mass spectrometry A total of 113 swabs were used for validation and 136 pair of surveillance samples were tested Limit of detection (LOD) was determined by using swabs in Amies transport medium which were spiked in a series of dilutions of a C auris standardized suspension (05 McFarland) Results The PCR method showed high sensitivity, specificity, predictive positive value and predictive negative value (966%, 100%, 100% and 982%, respectively) when compared to the routine protocol LOD was 500 CFU/mL, which corresponds to approximately 1 CFU/PCR Conclusions Our PCR method using the AurisID® kit allows a reduction in the turnaround time for surveillance of C auris compared to other methods These results are expected to contribute to control C auris outbreaks, allowing isolation of patients and cleaning of environmental surfaces in advance

Juan V Mulet Bayona

Papers

Impact of the SARS-CoV-2 Pandemic in Candidaemia, Invasive Aspergillosis and Antifungal Consumption in a Tertiary Hospital

Characteristics and Management of Candidaemia Episodes in an Established Candida auris Outbreak

Evaluation of a novel chromogenic medium for Candida spp. identification and comparison with CHROMagar™ Candida for the detection of Candida auris in surveillance samples

Candida auris: descripción de un brote

Validation and implementation of a commercial real-time PCR assay for direct detection of Candida auris from surveillance samples.