Mixed Aspergillosis and Mucormycosis Infections in Patients with COVID-19: Case Series and Literature Review.

BACKGROUND: Mucormycosis and aspergillosis are angioinvasive infections mainly occurring in immunocompromised patients. However, mixed infection with mucormycosis and aspergillosis in post-COVID-19 patients is rare. In this report, we will report four cases and comprehensively review the published literature on COVID-19 associated mixed infection of aspergillosis and mucormycosis. METHOD: Besides four of our cases, we searched for published articles using PubMed/MEDLINE, Scopus, and Web of Science databases from the beginning of 2020 until October 2023. RESULT: During the COVID-19 pandemic, we analyzed 52 cases (4 from our research and 48 from other studies). The most common underlying disease (59.6%) was diabetes mellitus. However, 19.2% of COVID-19 patients had no underlying condition. Interestingly, rhino-orbital-cerebral mucormycosis featured prominently in India and Iran, while other countries primarily reported a higher prevalence of pulmonary cases. CONCLUSION: In conclusion, this study highlights the presence of mixed aspergillosis and mucormycosis in COVID-19 patients who previously had common underlying diseases or even a healthy immune system. Therefore, managing COVID-19 patients should involve screening serum and respiratory samples using biomarkers to detect superinfections.

The relationship between biofilm formation and mortality in patients with Candida tropicalis candidemia.

BACKGROUND: Biofilm formation by Candida species is an influential virulence factor in candidemia pathogenesis. We investigated the relationship between biofilm formation of Candida tropicalis isolates with the clinical characteristics and mortality outcomes in patients with candidemia. MATERIALS AND METHODS: Thirty-nine C. tropicalis isolates were recovered from patients with candidemia admitted to two university hospitals in Tehran, Iran. Biofilm mass and metabolic activity of C. tropicalis biofilms were assessed in vitro with two colorimetric methods. The sessile minimum inhibitory concentrations (SMICs) were evaluated in vitro by treating preformed biofilms with diluted concentrations of azoles according to CLSI-M27 A3/S4 protocol, followed by metabolic activity quantification. The expressions of ERG11, UPC2, MDR1, and CDR1 genes were also evaluated. RESULTS: All C. tropicalis isolates produced biofilm. Respectively, higher <7-day and ≥7-day mortality rates were found among cases with high metabolic activity (46.7% vs. 13%, P = 0.03) and high biofilm mass (31.8% vs. 0, P = 0.029). Sessile cells had high resistance to fluconazole, voriconazole, and itraconazole. The azole minimum inhibitory concentrations (MICs) of C. tropicalis sessile were significantly greater than the planktonic minimum inhibitory concentrations (PMICs). In fluconazole-treated biofilms, the expression of ERG11 and UPC2 genes was increased. CONCLUSION: Our findings highlight the importance of C. tropicalis biofilm formation as an important factor in candidemia pathogenesis and the clinical outcome of patients with candidemia.

Vulvovaginal candidiasis in Iran: A systematic review and meta-analysis on the epidemiology, clinical manifestations, demographic characteristics, risk factors, etiologic agents and laboratory diagnosis.

Vulvovaginal candidiasis is a global issue of concern due to its association with economic costs, sexually transmitted infections, and ascending genital tract diseases. This infection affects 75% of women on at least one occasion over a lifetime. The present systematic review and meta-analysis is the first to determine the prevalence of vulvovaginal candidiasis in Iranian women. We searched national (SID, IranDoc, Iranmedex, and Magiran) and international (PubMed, Scopus, Google Scholar, and web of science) databases for studies published between May 2000 until May 2020 reporting the epidemiologic features of vulvovaginal candidiasis in Iranian women. Inclusion and exclusion criteria were defined to select eligible studies. Data were extracted and presented according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The results of the meta-analysis were visualized as a forest plot representing the prevalence estimates of each study. Heterogeneity was also analyzed using the I2, and Chi2 statistics. The literature search revealed 1929 studies, of which 39 studies met the eligibility criteria, consisting of 10536 women with vulvovaginal symptoms from 24 different cities covering all parts of Iran. The city with the highest number of studies was Tehran (5/39). The overall prevalence of vulvovaginal candidiasis among Iranian women was 47% (95% CI, 0/38-0/55%) and Candida albicans was the most prevalent etiologic agent. The use of oral contraceptive pills (OCPs) was the predominant risk factor for developing vulvovaginal candidiasis and vaginal cheese-like discharges were the predominant clinical manifestation in Iranian women suffering from vulvovaginal candidiasis. The 25-34-year-old age group has the highest prevalence. A high level of I2 (I2 = 98.7%, P = 0.000) and Chi2 (Chi2 = 2993.57, P < 0.001) was obtained among studies, which provides evidence of notable heterogeneity between studies. The present meta-analysis revealed a high prevalence of vulvovaginal candidiasis in Iranian women. Given that this infection is associated with the enhanced susceptibility to sexually transmitted diseases (HIV, chlamydia, genital herpes, genital warts, gonorrhea, hepatitis, syphilis, and trichomoniasis) and also is related to the increased probability of preterm birth, congenital cutaneous candidiasis, preterm labor, and infertility, taking preventive measures such as awareness of patients as well as monitoring and controlling of the syndrome are essential.

Virulence Factors and Azole-Resistant Mechanism of Candida Tropicalis Isolated from Candidemia.

BACKGROUND: Limited knowledge exists on the virulence factors of Candida tropicalis and the mechanisms of azole resistance that lead to an intensified pathogenicity and treatment failure. We aimed to evaluate the virulence factors and molecular mechanisms of azole resistance among C. tropicalis isolated from patients with candidemia. MATERIALS AND METHODS: Several virulence factors, including extracellular enzymatic activities, cell surface hydrophobicity (CSH), and biofilm formation, were evaluated. Antifungal susceptibility pattern and expression level of ERG11, UPC2, MDR1, and CDR1 genes of eight (4 fluconazole resistance and 4 fluconazole susceptible) clinical C. tropicalis isolates were assessed. The correlation between the virulence factors and antifungal susceptibility patterns was analyzed. RESULTS: During a 4 year study, forty-five C. tropicalis isolates were recovered from candidemia patients. The isolates expressed different frequencies of virulence determinants as follows: coagulase 4 (8.9%), phospholipase 5 (11.1%), proteinase 31 (68.9%), esterase 43 (95.6%), hemolysin 44 (97.8%), biofilm formation 45 (100%) and CSH 45(100%). All the isolates were susceptible to amphotericin B and showed the highest resistance to voriconazole. There was a significant positive correlation between micafungin minimum inhibitory concentrations (MICs) and hemolysin production (rs = 0.316). However, we found a negative correlation between fluconazole MICs and esterase production (rs = -0.383). We observed the high expression of ERG11 and UPC2 genes in fluconazole-resistant C. tropicalis isolates. CONCLUSION: C. tropicalis isolated from candidemia patients extensively displayed capacities for biofilm formation, hemolysis, esterase activity, and hydrophobicity. In addition, the overexpression of ERG11 and UPC2 genes was considered one of the possible mechanisms of azole resistance.

Antifungal susceptibility, genotyping, resistance mechanism, and clinical profile of Candida tropicalis blood isolates.

Candida tropicalis is one of the major candidaemia agents, associated with the highest mortality rates among Candida species, and developing resistance to azoles. Little is known about the molecular mechanisms of azole resistance, genotypic diversity, and the clinical background of C. tropicalis infections. Consequently, this study was designed to address those questions. Sixty-four C. tropicalis bloodstream isolates from 62 patients from three cities in Iran (2014-2019) were analyzed. Strain identification, antifungal susceptibility testing, and genotypic diversity analysis were performed by MALDI-TOF MS, CLSI-M27 A3/S4 protocol, and amplified fragment length polymorphism (AFLP) fingerprinting, respectively. Genes related to drug resistance (ERG11, MRR1, TAC1, UPC2, and FKS1 hotspot9s) were sequenced. The overall mortality rate was 59.6% (37/62). Strains were resistant to micafungin [minimum inhibitory concentration (MIC) ≥1 µg/ml, 2/64], itraconazole (MIC > 0.5 µg/ml, 2/64), fluconazole (FLZ; MIC ≥ 8 µg/ml, 4/64), and voriconazole (MIC ≥ 1 µg/ml, 7/64). Pan-azole and FLZ + VRZ resistance were observed in one and two isolates, respectively, while none of the patients were exposed to azoles. MRR1 (T255P, 647S), TAC1 (N164I, R47Q), and UPC2 (T241A, Q340H, T381S) mutations were exclusively identified in FLZ-resistant isolates. AFLP fingerprinting revealed five major and seven minor genotypes; genotype G4 was predominant in all centers. The increasing number of FLZ-R C. tropicalis blood isolates and acquiring FLZ-R in FLZ-naive patients limit the efficiency of FLZ, especially in developing countries. The high mortality rate warrants reaching a consensus regarding the nosocomial mode of C. tropicalis transmission.

Concomitant tuberculosis and aspergillosis in patients with COVID-19: a case report.

Coexisting pulmonary aspergillosis and tuberculosis in a post-COVID-19 patient is rare. Here, we are going to report a case of combined pulmonary aspergillosis and tuberculosis in a 51-year-old female who was previously diagnosed with COVID-19 pneumonia. The patient was treated with voriconazole and anti-tuberculosis agents.

Assessment of species distribution and virulence factors of oral fungal carriage among hospitalized patients with COVID-19: a case-control study.

Background: The COVID-19 pandemic highlighted the need to study oral fungal carriage and its potential impact. In oral fungal environments, factors like changes in respiratory epithelium, increased pathogen attachment, local inflammation, and virulence factors could influence COVID-19 severity. The authors conducted a study to explore oral fungal carriage in COVID-19 patients and compare it to a healthy control group. Methods: The authors executed a case-control investigation including 144 COVID-19 patients and an equivalent number of 144 healthy controls. The matching criteria encompassed age, sex, body mass index, and the history of antibiotic and antiviral medication intake. This research was performed over a span of 12 months from May 2021 to May 2022. The mouth area was sampled with a cotton-tipped swab. Subsequently, all the samples underwent fungal culture and PCR-sequencing procedures. Results: In COVID-19 patients, oral fungal carriage was three times higher compared to healthy controls. Candida was the exclusive genus found in both groups, with Candida albicans being the most frequently isolated species (90.79%). Among COVID-19 patients, Candida species showed significantly higher esterase, proteinase, and hemolysin activity compared to healthy individuals. Both groups exhibited elevated levels of C. albicans virulence factors compared to non-albicans species. Conclusions: It is crucial to understand the way that virulence factors of oral fungal carriage act in COVID-19 patients in order to come up with novel antifungal medications, identify the contributing factors to drug resistance, and manage clinical outcomes.

Pneumocystis pneumonia in COVID-19 patients: A comprehensive review.

The admitted patients of intensive care units with coronavirus disease 2019 (COVID-19) meet the challenges of subsequent infections. Opportunistic fungal infections such as Pneumocystis pneumonia (PCP) are among the important factors in the context of COVID-19 patients affecting illness severity and mortality. We reviewed the literature on COVID-19 patients with PCP to identify features of this infection. Although studies confirmed at least the presence of one immunosuppressive condition in half of PCP patients, this disease can also occur in immunocompetent patients who developed the immunosuppressive condition during Covid-19 treatment. The major risk factors associated with COVID-19 patients with PCP can be considered low lymphocyte counts and corticosteroid therapy. Diagnostic and treatment options are complicated by the overlapping clinical and radiologic characteristics of PCP and COVID-19 pneumonia. Therefore, physicians should comprehensively evaluate high-risk patients for PCP prophylaxis.

Corrigendum to "Pneumocystis pneumonia in COVID-19 patients: A comprehensive review" [Heliyon 9(2) (February 2023) e13618].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e13618.].

The Prevalence, Etiological Agents, Clinical Features, Treatment, and Diagnosis of HIV-Associated Oral Candidiasis in Pediatrics Across the World: A Systematic Review and Meta-Analysis.

In HIV-infected pediatrics, oral candidiasis (OC) is a global issue of concern due to its association with dysphagia, malnutrition, and mortality. The present systematic review and meta-analysis are the first to determine the prevalence of OC in HIV-infected pediatrics worldwide. We searched international (PubMed, Web of Science, Scopus, and Embase) databases for studies published between January 2000 to May 2020 reporting the epidemiologic features of OC in HIV-infected pediatrics. Inclusion and exclusion criteria were defined to select eligible studies. Data were extracted and presented according to PRISMA guidelines. The results of the meta-analysis were visualized as a forest plot. Heterogeneity was also analyzed using the I 2, and τ2 statistics. The publication bias was evaluated using Egger test. The literature search revealed 1926 studies, of which 34 studies met the eligibility criteria, consisting of 4,474 HIV-infected pediatrics from 12 different countries. The overall prevalence of OC among HIV-infected pediatrics was 23.9% (95% CI 17.3-32.0%), and Candida albicans was the most prevalent etiologic agent. Pseudomembranous candidiasis was the predominant clinical manifestation in HIV-infected pediatrics suffering from OC. Thirty articles involving 4,051 individuals provided data on HIV treatment status. Among the 4,051 individuals, 468 (11.53%) did not receive HIV treatment. The data from 11 articles demonstrated that HIV treatment was significantly associated with a reduction in oral Candida colonization or infection. In contrast, others showed the opposite relationship or did not report any statistical data. A high level of I 2 (I 2 = 96%, P < 0.01) and τ2 (τ2 = 1.36, P < 0.01) was obtained among studies, which provides evidence of notable heterogeneity between studies. OC is approximately frequent in HIV-positive children. Therefore, efforts should be made to teach dental and non-dental clinicians who care for HIV-infected pediatrics to diagnose and treat this infection.

Correction to: Molecular identification of aflatoxigenic Aspergillus species in dried nuts and grains collected from Tehran, Iran.

[This corrects the article DOI: 10.1007/s40201-021-00734-6.].

Molecular identification of aflatoxigenic Aspergillus species in dried nuts and grains collected from Tehran, Iran.

Introduction: Agricultural commodities contaminated by molds and mycotoxins can be considered as public health problems in less developed countries, particularly in Iran. Hence the main purpose of this study was to identify mold fungi and molecular analysis of the most important species of aflatoxin-B1-producing Aspergillus species in some dried nuts and grains in local markets in Tehran. Materials and methods: Two hundred fifty samples of wheat, rice, corn, pistachios, and peanuts were collected from the five different locations of Tehran between January 2018 and January 2019. The samples were analyzed by using direct seed inoculation method and grain crushing method. Fungal strains were identified as Aspergillus spp. on the basis of morphological characters and further confirmed by using of ß-tubulin gene sequencing. To differentiate between aflatoxigenic and non-aflatoxigenic Aspergillus spp., the isolates were screened for the presence of aflatoxigenic genes (nor-1, ver-1, omtA, and aflR). Results: One-handed forty-eight aflatoxigenic Aspergillus isolates (144 A. flavus and 4 A. parasiticus) were identified and aflR gene was the most frequent gene in these species. Five isolates (4 A. flavus, 1 A. parasiticus) had quadruplet pattern, 64 isolates (63 A. flavus, 1 A. parasiticus) had more than 1 gene and 39 isolates (38 A. flavus,1 A. parasiticus) did not have any genes. Conclusion: According to the contamination of dried nuts and grains by some aflatoxigenic fungi, an extensive surveillance is necessary to provide a wider view on these products. Moreover, effective and efficient aflatoxin control program requires identifying and managing key elements that are effective in reducing mycotoxin production at farm level or in storage conditions.

The mycological and molecular study of Pneumocystis jiroveci pneumonia among HIV and non-HIV immunocompromised patients hospitalized in pulmonary units in Guilan, Northern Iran.

BACKGROUND AND OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is a serious infection that usually affects those with a weak immune system. Since the prevalence of this infection in Iran and in the world is not clearly defined, the present study aimed to evaluate the incidence, clinical spectrum, and demographic characteristics of PJP among HIV and non-HIV immunocompromised patients. MATERIALS AND METHODS: Bronchoalveolar Lavage (BAL) specimens were obtained from 3 groups of immunocompromised patients, including acquired immunodeficiency syndrome (AIDS) patients, diabetic patients, and patients receiving immunosuppressive therapies. All were hospitalized in pulmonary units. The specimens were examined using microscopic methods (Giemsa and calcofluor white staining) and the nested-PCR technique based on mtLSU-rRNA gene. RESULTS: A total of 120 BAL samples were collected. From 12.5% (5 from 40) of HIV-infected patients, 5% (2 from 40) of patients receiving immunosuppressive therapies, and 2.5% (1 from 40) of diabetic patients Pneumocystis jiroveci was isolated. There was not any association between the prevalence of PJP and the patient's gender (p= 0.557) and age (p= 0.681). Fever and dyspnea (n=7, 87.5%), nonproductive cough and abnormal auscultation sound (n=5, 62.5%), and also chills and weight loss (n=2, 25%) were the documented clinical symptoms of PJP. Also, the results showed that none of the samples had positive results for P. jiroveci with microscopic tests while using the nested-PCR method 8 samples had positive results. CONCLUSION: Since PJP often causes symptoms that are similar to other illnesses, such as the flu or tuberculosis, clinical and laboratory findings should be used simultaneously for making the final decision on drug administration.

Proven pulmonary aspergillosis in a COVID-19 patient: A case report.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) has become a significant clinical challenge in healthcare settings all over the world. Critically ill COVID-19 patients with acute respiratory distress syndrome may be at increased risk of co-infection with pulmonary aspergillosis. This study aimed to describe a clinical case of proven pulmonary aspergillosis caused by Aspergillus tubingensis in a 59-year-old man with a history of hospitalization due to COVID-19 infection. CASE REPORT: The Covid-19 infection was confirmed by positive nasopharyngeal polymerase chain reaction. He had a cavitary lesion measured 20 mm in diameter with intracavitary soft tissue density in the left lung in the first chest computerized tomography scan. After 25 days, he showed two cavitary lesions in both lungs which raised suspicion of fungal infection; hence, the patient underwent a trans-thoracic biopsy of the cavitary lesion. The direct examination and culture of the biopsy material revealed Aspergillus species. To confirm the Aspergillus species identification, the beta-tubulin region was sequenced. The patient was treated with oral voriconazole. CONCLUSION: This report underlined the importance of early diagnosis and management of invasive fungal infections in severe COVID-19 patients.