Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been sweeping across the globe. Based on a retrospective analysis of SARS and influenza data from China and worldwide, we surmise that the fungal co-infections associated with global COVID-19 might be missed or misdiagnosed. Although there are few publications, COVID-19 patients, especially severely ill or immunocompromised, have a higher probability of suffering from invasive mycoses. Aspergillus and Candida infections in COVID-19 patients will require early detection by a comprehensive diagnostic intervention (histopathology, direct microscopic examination, culture, (1,3)-ß-D-glucan, galactomannan, and PCR-based assays) to ensure effective treatments. We suggest it is prudent to assess the risk factors, the types of invasive mycosis, the strengths and limitations of diagnostic methods, clinical settings, and the need for standard or individualized treatment in COVID-19 patients. We provide a clinical flow diagram to assist the clinicians and laboratory experts in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as co-morbidities in COVID-19 patients.

Invasive Fungal Disease, Isavuconazole Treatment Failure, and Death in Acute Myeloid Leukemia Patients.

We present 2 fatal cases of invasive fungal disease with isavuconazole treatment failure in immunocompromised patients: one with a TR34-L98H azole-resistant Aspergillus fumigatus isolate and the other a Rhizomucor-A. fumigatus co-infection. Such patients probably require surveillance by galactomannan antigen detection and quantitative PCRs for A. fumigatus and Mucorales fungi.

Effects of fluconazole on the clinical outcome and immune response in fungal co-infected tuberculosis patients.

With overuse of the broad-spectrum antibiotics, the pulmonary fungal infection increasingly becomes the most common complication associated with senile pulmonary tuberculosis (TB) and attracts intensive attentions from clinicians. Here we presented the retrospective analysis of impact of fluconazole treatment on the clinical outcome and immune response in fungal co-infected tuberculosis patients. A randomized, double-blind, placebo-controlled trial of fluconazole (100 mg per day for consecutive weeks) in fungal-positive senile tuberculosis patients was conducted in our hospital. Peripheral eosinophil counts were computed by the automatic hematology analyzer. The secretory inflammatory cytokines interferon (IFN)-γ, tumor necrosis factor (TNF)-α and chemokines chemokine C-X-C motif ligand (CXCL)9, CXCL10, CXCL11 were determined with enzyme-linked immunosorbent assay kits. The peripheral T helper 1 cells (Th1) and regulatory T cells (Treg) population were analyzed by flow cytometry. None of significant difference in respect to baseline TB score was observed between placebo and fluconazole groups. Administration of fluconazole significantly stimulated eosinophils population and secretion of inflammatory cytokines IFN-γ and TNF-α. Simultaneously, the peripheral Th1% and chemokines including CXCL9, CSCL10, CXCL11 were markedly induced in response to fluconazole treatment. Fungal infection significantly affected host immunity during tuberculosis which was effectively reversed by fluconazole treatment.

Chaetomium globosum: Spotting a scarce saprophyte in bacterial-fungal co-infection of the sinuses in a post-COVID-19 patient.

Atypical fungal co-infections in post-COVID-19 patients may have been underreported due to limited diagnostic methods. We present a case of Chaetomium globosum sinusitis in a 55-year-old post-COVID-19 patient with pain in the left side of the face, mimicking rhino-cerebral mucormycosis. CT-paranasal sinuses showed mucosal thickening of left paranasal sinuses, biopsy of which grew a velvety, white colony. It was confirmed as Chaetomium globosum. The patient responded to oral Posaconazole therapy for three months. Prompt identification of atypical fungal agents is critical for appropriate treatment.

Clinical Challenges of Emerging and Re-Emerging Yeast Infections in the Context of the COVID-19 Pandemic.

During the geological eras, some fungi, through adaptation and/or environmental/ecological pressure, interacted directly and indirectly with humans, through occasionally harmful interaction interdependent on the individual's immunological condition. Infections caused by yeasts are underreported, subjugated, and underdiagnosed, and treatment is restricted to a few drugs, even after the significant progress of medicine and pharmacology. In the last centuries, antagonistically, there has been an exponential increase of immunocompromised individuals due to the use of immunosuppressive drugs such as corticosteroids, increased cases of transplants, chemotherapeutics, autoimmune diseases, neoplasms, and, more recently, coronavirus disease 2019 (COVID-19). This review aims to survey emerging and re-emerging yeast infections in the current clinical context. Currently, there is an immense clinical challenge for the rapid and correct diagnosis and treatment of systemic mycoses caused by yeasts due to the terrible increase in cases in the current context of COVID-19.

Bacterial and fungal co-infection is a major barrier in COVID-19 patients: A specific management and therapeutic strategy is required.

Microbial co-infections are another primary concern in patients with coronavirus disease 2019 (COVID-19), yet it is an untouched area among researchers. Preliminary data and systematic reviews only show the type of pathogens responsible for that, but its pathophysiology is still unknown. Studies show that these microbial co-infections are hospital-acquired/nosocomial infections, and patients admitted to intensive care units with invasive mechanical ventilation are highly susceptible to it. Patients with COVID-19 had elevated inflammatory cytokines and a weakened cell-mediated immune response, with lower CD4+ T and CD8+ T cell counts, indicating vulnerability to various co-infections. Despite this, there are only a few studies that recommend the management of co-infections.

Fungal co-infection in COVID-19 patients: evidence from a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19) has infected tens of millions of people worldwide within the last year. However, the incidence of fungal co-infection in COVID-19 patients remains unclear. To investigate the association between fungal co-infection and mortality due to COVID-19, we systematically searched Medline, Embase, MedRxiv and Cochrane Library for eligible studies published in the period from 1 January to 1 December 2020. We performed a meta-analysis of nine studies that met the inclusion criteria. In total, data from 2780 patients and 426 patients were included who were admitted to the ICU. In eight of the articles, 211 participants died due to COVID-19 infection, which means an overall mortality rate of 10.9%. The overall pooled proportion of fungal co-infection in COVID-19 patients was 0.12 (95% CI = 0.07-0.16, n = 2780, I2 = 96.8%). In terms of mortality in COVID-19 patients with fungal infection, the overall pooled proportion of mortality was 0.17 (95% CI = 0.10-0.24, n = 1944, I2 = 95.6%). These findings provide evidence suggesting a favorable use for empirical antibiotics in the majority of patients when COVID-19 infection is diagnosed. Our analysis is investigating the use of antifungal therapy to treat COVID-19 can serve as a comprehensive reference for COVID-19 treatment.

Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review.

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

Co-infection with influenza-associated acute respiratory distress syndrome requiring extracorporeal membrane oxygenation.

The co-infection frequency and impact among influenza-associated acute respiratory distress syndrome (ARDS) patients requiring extracorporeal membrane oxygenation (ECMO) are not known. This retrospective observational analysis concerned data prospectively collected from patients admitted to our medical intensive care unit (ICU) who received ECMO support for influenza-associated ARDS between 2009-2016. Co-infection was defined as occurring within 48 h following ICU admission. Among the 77 ARDS patients requiring ECMO support, 39 (51%) developed co-infections, with Staphylococcus aureus [18 (46%) of the co-infected patients] being the most prevalent pathogen. Panton-Valentin leukocidin (PVL)-producing S. aureus was isolated from 10 patients (56% of S. aureus co-infections and 26% of all co-infections). Co-infected patients were comparable with those without co-infection, except for BMI, initial disease severity and antibiotic treatment prior to admission. Co-infection was associated with higher in-ICU mortality (62% vs. 29%; P = 0.006) and with fewer ECMO-free days [median (IQR) 0 (0-19) vs. 23 (0-46); P = 0.004] and fewer mechanical ventilation-free days [0 (0-0) vs. 6 (0-35); P = 0.003] on Day 60. Multivariable analysis retained age >49 years, pre-ECMO Simplified Acute Physiology Score (SAPS) II score >70 and co-infection as independent predictors of hospital mortality. In conclusion, co-infection is frequent in ECMO-treated patients with influenza-associated ARDS, affecting ca. 50%, and is independently associated with poor outcome. Staphylococcus aureus was the most frequently identified pathogen, with a high rate of PVL-positive S. aureus. Whether specific therapy targeting PVL-producing S. aureus should be given remains to be determined.