Prevalence of co-existent COVID-19-associated pulmonary aspergillosis (CAPA) and its impact on early mortality in patients with COVID-19-associated pulmonary mucormycosis (CAPM).

BACKGROUND: Data on mixed mould infection with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated pulmonary mucormycosis (CAPM) are sparse. OBJECTIVES: To ascertain the prevalence of co-existent CAPA in CAPM (mixed mould infection) and whether mixed mould infection is associated with early mortality (≤7 days of diagnosis). METHODS: We retrospectively analysed the data collected from 25 centres across India on COVID-19-associated mucormycosis. We included only CAPM and excluded subjects with disseminated or rhino-orbital mucormycosis. We defined co-existent CAPA if a respiratory specimen showed septate hyphae on smear, histopathology or culture grew Aspergillus spp. We also compare the demography, predisposing factors, severity of COVID-19, and management of CAPM patients with and without CAPA. Using a case-control design, we assess whether mixed mould infection (primary exposure) were associated with early mortality in CAPM. RESULTS: We included 105 patients with CAPM. The prevalence of mixed mould infection was 20% (21/105). Patients with mixed mould infection experienced early mortality (9/21 [42.9%] vs. 15/84 [17.9%]; p = 0.02) and poorer survival at 6 weeks (7/21 [33.3] vs. 46/77 [59.7%]; p = 0.03) than CAPM alone. On imaging, consolidation was more commonly encountered with mixed mould infections than CAPM. Co-existent CAPA (odds ratio [95% confidence interval], 19.1 [2.62-139.1]) was independently associated with early mortality in CAPM after adjusting for hypoxemia during COVID-19 and other factors. CONCLUSION: Coinfection of CAPA and CAPM was not uncommon in our CAPM patients and portends a worse prognosis. Prospective studies from different countries are required to know the impact of mixed mould infection.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Pan-Indian Clinical Registry of Invasive Fungal Infections Among Patients in the Intensive Care Unit: Protocol for a Multicentric Prospective Study.

BACKGROUND: Fungal infections are now a great public health threat, especially in those with underlying risk factors such as neutropenia, diabetes, high-dose steroid treatment, cancer chemotherapy, prolonged intensive care unit stay, and so on, which can lead to mycoses with higher mortality rates. The rates of these infections have been steadily increasing over the past 2 decades due to the increasing population of patients who are immunocompromised. However, the data regarding the exact burden of such infection are still not available from India. Therefore, this registry was initiated to collate systematic data on invasive fungal infections (IFIs) across the country. OBJECTIVE: The primary aim of this study is to create a multicenter digital clinical registry and monitor trends of IFIs and emerging fungal diseases, as well as early signals of any potential fungal outbreak in any region. The registry will also capture information on the antifungal resistance patterns and the contribution of fungal infections on overall morbidity and inpatient mortality across various conditions. METHODS: This multicenter, prospective, noninterventional observational study will be conducted by the Indian Council of Medical Research through a web-based data collection method from 8 Advanced Mycology Diagnostic and Research Centers across the country. Data on age, gender, clinical signs and symptoms, date of admission, date of discharge or death, diagnostic tests performed, identified pathogen details, antifungal susceptibility testing, outcome, and so on will be obtained from hospital records. Descriptive and multivariate statistical methods will be applied to investigate clinical manifestations, risk variables, and treatment outcomes. RESULTS: These Advanced Mycology Diagnostic and Research Centers are expected to find the hidden cases of fungal infections in the intensive care unit setting. The study will facilitate the enhancement of the precision of fungal infection diagnosis and prompt treatment modalities in response to antifungal drug sensitivity tests. This registry will improve our understanding of IFIs, support evidence-based clinical decision-making ability, and encourage public health policies and actions. CONCLUSIONS: Fungal diseases are a neglected public health problem. Fewer diagnostic facilities, scanty published data, and increased vulnerable patient groups make the situation worse. This is the first systematic clinical registry of IFIs in India. Data generated from this registry will increase our understanding related to the diagnosis, treatment, and prevention of fungal diseases in India by addressing pertinent gaps in mycology. This initiative will ensure a visible impact on public health in the country. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54672.

The Development of a Clinical Registry Digital Database on Invasive Fungal Infections in India: Advancing Epidemiological Understanding and Patient Care.

A well-structured digital database is essential for any national priority project as it can provide real-time data analysis and facilitate quick decision making. In recent times, particularly after the COVID-19 pandemic, invasive fungal infections (IFIs) have emerged as a significant public health challenge in India, affecting vulnerable population, including immunocompromised individuals. The lack of comprehensive and well-structured data on IFIs has hindered efforts to understand their true burden and optimize patient care. To address this critical knowledge gap, the ICMR has undertaken a Pan-India pioneer initiative to develop a network of Advanced Mycology Diagnostic research centres in different geographical zones of the country (ICMR-MycoNet). Under the aegis of this project, a clinical registry on IFIs in the ICUs is initiated. This process paper presents a detailed account of the steps involved in the establishment of a web-based data entering and monitoring platform to capture data electronically, ensuring robust and secure data collection and management. This system not only allows participating ICMR-MycoNet centres to enter patient information directly into the database using standardized Case Report Form (CRF) but also includes data validation checks to ensure the accuracy and completeness of entered data. It is complemented by a real-time, web-based, and adaptable data visualization platform. This registry aims to provide crucial epidemiological insights, promote evidence-based hospital infection control programs, and ultimately improve patient outcomes in the face of this formidable healthcare challenge.

Risk factors, mortality, and predictors of survival in COVID-19-associated pulmonary mucormycosis: a multicentre retrospective study from India.

OBJECTIVES: To compare COVID-19-associated pulmonary mucormycosis (CAPM) with COVID-19-associated rhino-orbital mucormycosis (CAROM), ascertain factors associated with CAPM among patients with COVID-19, and identify factors associated with 12-week mortality in CAPM. METHODS: We performed a retrospective multicentre cohort study. All study participants had COVID-19. We enrolled CAPM, CAROM, and COVID-19 subjects without mucormycosis (controls; age-matched). We collected information on demography, predisposing factors, and details of COVID-19 illness. Univariable analysis was used to compare CAPM and CAROM. We used multivariable logistic regression to evaluate factors associated with CAPM (with hypoxemia during COVID-19 as the primary exposure) and at 12-week mortality. RESULTS: We included 1724 cases (CAPM [n = 122], CAROM [n = 1602]) and 3911 controls. Male sex, renal transplantation, multimorbidity, neutrophil-lymphocyte ratio, intensive care admission, and cumulative glucocorticoid dose for COVID-19 were significantly higher in CAPM than in CAROM. On multivariable analysis, COVID-19-related hypoxemia (aOR, 2.384; 95% CI, 1.209-4.700), male sex, rural residence, diabetes mellitus, serum C-reactive protein, glucocorticoid, and zinc use during COVID-19 were independently associated with CAPM. CAPM reported a higher 12-week mortality than CAROM (56 of the 107 [52.3%] vs. 413 of the 1356 [30.5%]; p = 0.0001). Hypoxemia during COVID-19 (aOR [95% CI], 3.70 [1.34-10.25]) and Aspergillus co-infection (aOR [95% CI], 5.40 [1.23-23.64]) were independently associated with mortality in CAPM, whereas surgery was associated with better survival. DISCUSSION: CAPM is a distinct entity with a higher mortality than CAROM. Hypoxemia during COVID-19 illness is associated with CAPM. COVID-19 hypoxemia and Aspergillus co-infection were associated with higher mortality in CAPM.

Basidiobolomycosis caused by a rare species - Basidiobolus meristosporus.

A five-year girl was referred to our centre with swelling over the right lower back. The child was evaluated to rule out chronic cutaneous tuberculosis, lymphoma and soft tissue tumor. Biopsy of the lesion on culture yielded Basidiobolus species. Whole genome sequencing of the isolate identified it as Basidiobolus meristosporus. Sequencing of fungi pathogenic to humans which cannot be differentiated by conventional methods of speciation becomes essential to assign pathogenicity, understand epidemiology and resolve the nuances in the ever-evolving taxonomical classification.

A simple high-volume culture technique-Good substitute for polymerase chain reaction for the detection of Aspergillus species in bronchoalveolar lavage samples.

BACKGROUND: Aspergillus species is the most common agent of invasive pulmonary fungal disease. Culture-based diagnosis considered as gold standard is limited by the fungal load in samples. Detection of Aspergillus by polymerase chain reaction (PCR) has been included as a diagnostic criterion by European Organisation for Research and Treatment of Cancer (EORTC). Most routine laboratories lack facilities for molecular diagnosis. Better yield using high-volume culture (HVC) technique has been reported. Studies have not compared HVC and PCR for detection of Aspergillus species in respiratory samples from patients with suspected invasive pulmonary Aspergillosis (IPA) not on antifungal therapy. OBJECTIVE: This pilot study compared HVC and PCR for the detection of Aspergillus species in respiratory samples from treatment naïve patients. METHODS: Bronchoalveolar lavage (BAL) samples from 30 patients with clinical suspicion of IPA were evaluated. Direct microscopy, culture both conventional (CC) and HVC and qualitative Pan Aspergillus PCR were performed. Latent class model was used for statistical analysis. RESULTS: Sensitivity of HVC (100%) was better compared with CC (60%) and comparable to that of PCR (100%). Specificities of CC, HVC and PCR were 100%, 100% and 25%, respectively. CONCLUSION: High-volume culture is a simple cost-effective technique with a high sensitivity and specificity. It can be easily introduced in routine microbiology laboratories. In centres with the availability of infrastructure for molecular analysis, Aspergillus PCR with other mycological techniques can be used for better diagnosis and management of patients with IPA.

Multicenter Epidemiologic Study of Coronavirus Disease-Associated Mucormycosis, India.

During September-December 2020, we conducted a multicenter retrospective study across India to evaluate epidemiology and outcomes among cases of coronavirus disease (COVID-19)-associated mucormycosis (CAM). Among 287 mucormycosis patients, 187 (65.2%) had CAM; CAM prevalence was 0.27% among hospitalized COVID-19 patients. We noted a 2.1-fold rise in mucormycosis during the study period compared with September-December 2019. Uncontrolled diabetes mellitus was the most common underlying disease among CAM and non-CAM patients. COVID-19 was the only underlying disease in 32.6% of CAM patients. COVID-19-related hypoxemia and improper glucocorticoid use independently were associated with CAM. The mucormycosis case-fatality rate at 12 weeks was 45.7% but was similar for CAM and non-CAM patients. Age, rhino-orbital-cerebral involvement, and intensive care unit admission were associated with increased mortality rates; sequential antifungal drug treatment improved mucormycosis survival. The COVID-19 pandemic has led to increases in mucormycosis in India, partly from inappropriate glucocorticoid use.

A simple x-ray scoring system for the diagnosis of chronic pulmonary aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is a severe form of post-tuberculosis lung disease (PTBLD). Considering the high burden of TB in India, it can be concluded that the prevalence of CPA is also high. Chest x-ray though most feasible, interpretation is subjective. Therefore, decision on evaluation for CPA cannot be based on x-ray alone. OBJECTIVE: Present study evaluated an x-ray score as a marker for extent of lung damage in patients with PTBLD presenting with haemoptysis and its utility to predict Aspergillus serum IgG levels. METHODS: We used a modified scoring system developed by Anna Ralph et al X-ray score cut-offs of >71 and 40, with or without history of massive haemoptysis, were compared with serum IgG levels. RESULTS: With a chest x-ray score cut-off of 71, specificity was 88%. With an x-ray score of >71 combined with history of massive haemoptysis, 86% cases were found to be IgG positive. The specificity of this combination was 96%. CONCLUSION: This study concluded that a simple chest x-ray scoring system in addition to the symptom of massive haemoptysis helped in the decision on further evaluation of the subject for CPA, especially in resource constrained settings.

Phenotypic and molecular characterisation of Sporothrix globosa of diverse origin from India.

Sporotrichosis is one of the neglected tropical diseases causing subcutaneous chronic granulomatous lesion by thermally dimorphic fungi belonging to Sporothrix species. Sporothrix brasiliensis, Sporothrix mexicana and Sporothrix globosa are the common pathogenic species. In Asian countries, S. globosa constitutes nearly 99.3% of all Sporothrix species. We studied 63 cases of sporotrichosis of geographically diverse origin from India and Sporothrix isolates were characterised for its growth in different media, temperatures, ability to assimilate sugars and antifungal susceptibility profile. Molecular characterization was performed by sequencing of the calmodulin (CAL), beta tubulin (BT) and translational elongation factor 1-alpha (TEF-1α) and typing by fluorescent amplified fragment length polymorphism (FAFLP). In patients who presented with fixed (49.2%), lymphocutaneous lesions (23.8%), in 26.9% the details were not known, none had systemic dissemination. All the isolates tested were Sporothrix globosa and that could grow up to 35 °C and unable to grow at and beyond 37 °C. The assimilation of sucrose, ribitol and raffinose helps in identifying S. globosa. Sequences of CAL or BT or TEF-1α can differentiate S. globosa from other species in the complex. FAFLP results exhibited low genetic diversity. No correlation was noted between genotypes and clinical presentation, or geographic distribution. Itraconazole, terbinafine and posaconazole showed good in vitro antifungal activity against S. globosa whereas fluconazole and micafungin had no activity. S. globosa of Indian origin is relatively less pathogenic than other pathogenic Sporothrix species as it does not cause systemic dissemination and in the diagnostic laboratory, incubation of the cultures below 37 °C is essential for effective isolation.

A filamentous trio.

Opportunistic infections caused by fungi and unusual bacteria are predominantly encountered in the setting of immunosuppressed host. Co-infections with multiple such organisms can pose multiple challenges even to the astute clinician from establishing the diagnosis to drug interactions during treatment of such infections. We hereby present one such case of a triple opportunistic infection in an immunocompetent host and the difficulties faced in the therapeutic decision making.

Chronic granulomatous 'Aspergillus lung mass'.

The diverse clinicopathological spectrum of pulmonary aspergillosis is a consequence of varying levels of invasiveness of this ubiquitous fungus, which largely depends on the host immune response and pre-existing lung disease. The clinical presentation of pulmonary aspergillosis spans a wide spectrum from hypersensitivity to life threatening angio-invasive and disseminated disease. We report the case of a young immunocompetent male with no underlying lung disease, who presented with an incidentally detected 'infective mass' lesion in the lung associated with minimal respiratory symptoms. The diagnostic challenges posed by the unusual clinical, radiological and histological picture as well as the therapeutic dilemmas faced are discussed in this report.

Characteristics, outcome and risk factors for mortality of paediatric patients with ICU-acquired candidemia in India: A multicentre prospective study.

BACKGROUND: The epidemiology, clinical profile and outcome of paediatric candidemia vary considerably by age, healthcare settings and prevalent Candida species. Despite these differences, few comprehensive studies are undertaken. This nationwide study addresses this knowledge gap. METHODS: 487 children who contracted ICU-acquired candidemia at 23 Indian tertiary care centres were assessed for 398 variables spanning demography, clinical characteristics, microbiology, treatment and outcome. RESULTS: Both neonates (5.0 days; range = 3.0-9.5) and non-neonatal children (7.0 days; range = 3.0-13.0) developed candidemia early after ICU admission. Majority of neonates were premature (63.7%) with low birthweight (57.1%). Perinatal asphyxia (7.3%), pneumonia (8.2%), congenital heart disease (8.4%) and invasive procedures were common comorbidities, and antibiotic use (94.1%) was widespread. C tropicalis (24.7%) and C albicans (20.7%) dominated both age groups. Antifungal treatment (66.5%) and removal of central catheters (44.8%) lagged behind. Overall resistance was low; however, emergence of resistant C krusei and C auris needs attention. The 30-day crude mortality was 27.8% (neonates) and 29.4% (non-neonates). Logistic regression identified admission to public sector ICUs (OR = 5.64), mechanical ventilation (OR = 2.82), corticosteroid therapy (OR = 8.89) and antifungal therapy (OR = 0.22) as independent predictors of 30-day crude mortality in neonates. Similarly, admission to public sector ICUs (OR = 3.62), mechanical ventilation (OR = 3.13), exposure to carbapenems (OR = 2.18) and azole antifungal therapy (OR = 0.48) were independent predictors for non-neonates. CONCLUSIONS: Our findings reveal a distinct epidemiology, including early infection with a different spectrum of Candida species, calling for appropriate intervention strategies to reduce candidemia morbidity and mortality. Independent factors identified in our regression models can help tackle these challenges.

MIC and Upper Limit of Wild-Type Distribution for 13 Antifungal Agents against a Trichophyton mentagrophytes-Trichophyton interdigitale Complex of Indian Origin.

Dermatophytosis due to the Trichophyton mentagrophytes-Trichophyton interdigitale complex is being increasingly reported across India. Reports of therapeutic failure have surfaced recently, but there are no clinical break points (CBP) or epidemiological cutoffs (ECVs) available to guide the treatment of dermatophytosis. In this study, a total of 498 isolates of the T. mentagrophytes-interdigitale complex were collected from six medical centers over a period of five years (2014 to 2018). Antifungal susceptibility testing of the isolates was carried out for itraconazole, fluconazole, ketoconazole, voriconazole, luliconazole, sertaconazole, miconazole, clotrimazole, terbinafine, amorolfine, naftifine, ciclopirox olamine, and griseofulvin. The MICs (in mg/liter) comprising >95% of the modeled populations were as follows: 0.06 for miconazole, luliconazole, and amorolfine; 0.25 for voriconazole; 0.5 for itraconazole, ketoconazole, and ciclopirox olamine; 1 for clotrimazole and sertaconazole; 8 for terbinafine; 16 for naftifine; 32 for fluconazole; and 64 for griseofulvin. A high percentage of isolates above the upper limit of the wild-type MIC (UL-WT) were observed for miconazole (29%), luliconazole (13.9%), terbinafine (11.4%), naftifine (5.2%), and voriconazole (4.8%), while they were low for itraconazole (0.2%). Since the MICs of itraconazole were low against the T. mentagrophytes-interdigitale complex, this could be considered the choice of first-line treatment. The F397L mutation in the squalene epoxidase (SE) gene was observed in 77.1% of isolates with a terbinafine MIC of ≥1 mg/liter, but no mutation was detected in isolates with a terbinafine MIC of <1 mg/liter. In the absence of CBPs, evaluation of the UL-WT may be beneficial for managing dermatophytosis and monitoring the emergence of isolates with reduced susceptibility.

Microbiologic profile and clinical practices in urinary tract infections in a tertiary care center in Southern India.

CONTEXT: Studies reported differences in clinical profiles of urinary tract infections (UTIs) in patients with and without type 2 diabetes mellitus (T2DM). Studies on the impact of the pattern of antibiotic resistance of organisms causing UTI on actual clinical practice are lacking. OBJECTIVES: 1. To study the clinical and microbiologic profiles of UTIs. 2. To compare treatment given with the prevailing antimicrobial sensitivity. SETTINGS AND DESIGN: This is a cross-sectional study conducted in a tertiary care hospital. METHODS AND MATERIALS: Retrospective chart review of inpatients with UTI (N = 200, 100 each of patients with and without T2DM), aged >18 years with a positive urine culture. STATISTICAL ANALYSIS: We used the statistical package SPSS version 17. The categorical variables were analyzed by the Chi-square test. Data were considered significant if P value was less than 0.05. RESULTS: Similar to previous Indian studies, T2DM patients with UTI had significantly more asymptomatic bacteriuria, asymptomatic bacteriuria (32% vs. 6%), previous history of UTI (25% vs. 2%), and prior catheterization (16% vs. 1%). Escherichia coli (E. coli) was the most common organism isolated and showed sensitivity pattern of meropenem > netilmicin > amikacin > nitrofurantoin. Ceftriaxone was the most common empirical therapy given in spite the prevailing low sensitivity of E. coli to it. All ASB cases were treated unlike recommendations. CONCLUSIONS: Ceftriaxone is the most common empirical therapy given in spite the prevailing low sensitivity of E. coli to it. Cases of ASB were treated unlike recommendations.

Parathyridaria percutanea and Subcutaneous Phaeohyphomycosis.

Parathyridaria percutanea is an emerging fungus causing subcutaneous phaeohyphomycoses in renal transplant recipients in India. We identified P. percutanea from a patient with subcutaneous phaeohyphomycosis. From our culture collection, we identified the same fungus from 4 similar patients. We found 5 cases previously described in literature.

Actinomyces naeslundii causing pulmonary endobronchial Actinomycosis - A case report.

Actinomyces naeslundii is a commensal flora of the oral cavity and is generally considered as an avirulent saprophytic bacterium in immunocompetent patients. It can become an opportunistic anaerobic pathogen in oral cavity in patients with poor oral hygiene or tooth extraction and can cause periodontal disease. Pulmonary Actinomycosis is a rare manifestation and may be suspected in middle-aged male patients with cough and hemoptysis showing radiological findings of a peripheral mass or chronic consolidation in whom repeated aerobic cultures have yielded negative results. Here, we report isolation of A. naeslundii from the bronchoalveolar lavage sample from an immunocompetent patient who presented with chronic nonresolving pneumonia of 6 months duration.

Epidemiology and clinical outcomes of invasive mould infections in Indian intensive care units (FISF study).

BACKGROUND AND AIM: Due to limited data on invasive mould infections (IMIs) in the intensive care units (ICUs) of developing countries, we ascertain epidemiology and management of IMIs at 11 ICUs across India. METHODS: Consecutive patients with proven or probable/putative IMIs were enrolled during the study period. Subjects were categorized into classical (neutropenia, malignancy, transplant recipients on immunosuppression) and non-classical (chronic obstructive pulmonary disease, diabetes, liver disease and glucocorticoids) risk groups. We analyzed the demographic, laboratory variables and outcomes of these patients. RESULTS: 398 patients with IMIs (96 proven, 302 probable) were identified, amounting to a prevalence of 9.5 cases/1000 ICU admissions. The mean ±â€¯SD age of the participants was 45.6 ±â€¯21.9 years. The mean ±â€¯SD APACHE II score was 14.3 ±â€¯11.4. The IMIs were diagnosed at a median of 4 days after ICU admission. There were 145 and 253 subjects with classical and non-classical risk groups, respectively. Although Aspergillus spp. were the commonest (82.1%) isolates, Mucorales were detected in 14.4% subjects. A high APACHE II score and IMI due to mucormycosis were significant predictors of mortality. CONCLUSIONS: The study highlights the distinct epidemiology of IMIs in India ICUs with high burden, new susceptible patient groups and considerable number of non-Aspergillus mould infections. [clinicaltrials.gov: NCT02683642].