Practice Guidelines for the Diagnosis of COVID-19-Associated Pulmonary Aspergillosis in an Intensive Care Setting.

Coronavirus disease-2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a new disease characterized by secondary Aspergillus mold infection in patients with COVID-19. It primarily affects patients with COVID-19 in critical state with acute respiratory distress syndrome, requiring intensive care and mechanical ventilation. CAPA has a higher mortality rate than COVID-19, posing a serious threat to affected individuals. COVID-19 is a potential risk factor for CAPA and has already claimed a massive death toll worldwide since its outbreak in December 2019. Its second wave is currently progressing towards a peak, while the third wave of this devastating pandemic is expected to follow. Therefore, an early and accurate diagnosis of CAPA is of utmost importance for effective clinical management of this highly fatal disease. However, there are no uniform criteria for diagnosing CAPA in an intensive care setting. Therefore, based on a review of existing information and our own experience, we have proposed new criteria in the form of practice guidelines for diagnosing CAPA, focusing on the points relevant for intensivists and pulmonary and critical care physicians. The main highlights of these guidelines include the role of CAPA-appropriate test specimens, clinical risk factors, computed tomography of the thorax, and non-culture-based indirect and direct mycological evidence for diagnosing CAPA in the intensive care unit. These guidelines classify the diagnosis of CAPA into suspected, possible, and probable categories to facilitate clinical decision-making. We hope that these practice guidelines will adequately address the diagnostic challenges of CAPA, providing an easy-to-use and practical algorithm to clinicians for rapid diagnosis and clinical management of the disease.

New insights into development and mortality of COVID-19-associated pulmonary aspergillosis in a homogenous cohort of 1161 intensive care patients.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has been widely reported but homogenous large cohort studies are needed to gain real-world insights about the disease. METHODS: We collected clinical and laboratory data of 1161 patients hospitalised at our Institute from March 2020 to August 2021, defined their CAPA pathology, and analysed the data of CAPA/non-CAPA and deceased/survived CAPA patients using univariable and multivariable models. RESULTS: The overall prevalence and mortality of CAPA in our homogenous cohort of 1161 patients were 6.4% and 47.3%, respectively. The mortality of CAPA was higher than that of non-CAPA patients (hazard ratio: 1.8 [95% confidence interval: 1.1-2.8]). Diabetes (odds ratio [OR] 1.92 [1.15-3.21]); persistent fever (2.54 [1.17-5.53]); hemoptysis (7.91 [4.45-14.06]); and lung lesions of cavitation (8.78 [2.27-34.03]), consolidation (9.06 [2.03-40.39]), and nodules (8.26 [2.39-28.58]) were associated with development of CAPA by multivariable analysis. Acute respiratory distress syndrome (ARDS) (2.68 [1.09-6.55]), a high computed tomography score index (OR 1.18 [1.08-1.29]; p < .001), and pulse glucocorticoid treatment (HR 4.0 [1.3-9.2]) were associated with mortality of the disease. Whereas neutrophilic leukocytosis (development: 1.09 [1.03-1.15] and mortality: 1.17 [1.08-1.28]) and lymphopenia (development: 0.68 [0.51-0.91] and mortality: 0.40 [0.20-0.83]) were associated with the development as well as mortality of CAPA. CONCLUSION: We observed a low but likely underestimated prevalence of CAPA in our study. CAPA is a disease with high mortality and diabetes is a significant factor for its development while ARDS and pulse glucocorticoid treatment are significant factors for its mortality. Cellular immune dysregulation may have a central role in CAPA from its development to mortality.

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.

Clinical outcomes and cortical reserve in adrenal histoplasmosis-A retrospective follow-up study of 40 patients.

OBJECTIVE: Detailed studies of Addison's disease resulting from disseminated adrenal histoplasmosis (AH) are not available. We describe the presentation and prognosis of AH and cortisol status before and after antifungal therapy. DESIGN: Single-centre retrospective hospital-based study of 40 consecutive adults with AH [39 males; age (mean ± SD) 53 ± 11 years] was conducted between 2006 and 2018. The median duration of follow-up was 2.5 years (range 0.2-12 years). PATIENTS AND METHODS: AH was diagnosed by bilateral adrenal enlargement on CT scan and presence of Histoplasma by histology and/or culture of biopsied adrenal tissue. All patients received oral itraconazole and, if required, amphotericin B as per guidelines. ACTH-stimulated serum cortisol (normal > 500 nmol/L) was measured in 38 patients at diagnosis and re-tested after one year of antifungal therapy in 21 patients. RESULTS: Seventy-three per cent of patients had primary adrenal insufficiency (PAI) and one-third had an adrenal crisis at presentation. HIV antibody was negative in all patients. Of the 29 patients who completed antifungal therapy, 25 (86%) were in remission at last follow-up. Overall, 8 (20%) patients died: three had a sudden death, four had severe histoplasmosis and one died due to adrenal crisis. No patient with PAI became eucortisolemic on re-testing after one year of antifungal therapy. Of the eight patients with normal cortisol at diagnosis, two developed adrenal insufficiency on follow-up. CONCLUSION: All patients with AH tested negative for HIV antibody. While patients achieved a high rate of clinical remission after antifungal therapy, overall mortality was significant. Cortisol insufficiency did not normalize despite treatment.

Microsporidial myositis in adult-onset immunodeficiency: case-based review.

Polymyositis is a diagnosis of exclusion. In patients with odd features, it can be of infective etiology. A high index of suspicion is required for diagnosis. A 55-year-old gentleman presented with gradual-onset proximal muscle weakness. Examination revealed mild distal weakness but no rash. Muscle enzymes were raised and tests for autoantibodies were negative. Biopsy revealed microsporidiosis. In view of this unusual infection, immunodeficiency was considered and he was found to have lymphopenia which antedated his illness. Later, he developed cranial nerve palsies due to multiple lesions in the pons. In addition, he had Cytomegalovirus viremia. Literature was reviewed to identify 20 cases of microsporidial myositis, its presentation, underlying immunodeficient state, and clinical course. Infective polymyositis should be considered in a patient with paucity of clinical and serological autoimmune features. Lymphopenia can point to underlying immunodeficiency. CMV infection could be the contributor to or bystander-effect of idiopathic lymphopenia.

Case 249: Intramuscular Mycetoma.

History A 21-year-old man presented with swelling of the medial aspect of the left thigh of 1-month duration. There was no history of fever or penetrating injury in the left thigh. The patient had undergone renal transplantation 7 years earlier and had been taking immunosuppressants since transplantation. He had undergone two surgeries at the same site in the medial aspect of the left thigh in the past 3 years for a similar problem. At physical examination, there was swelling in the medial aspect of the left thigh, with mild tenderness. A surgical scar was noted anterior to the swelling ( Fig 1 ). No redness or discharging sinus was present. Laboratory results were as follows: hemoglobin level, 11.3 g/dL (normal range, 13.8-17.2 g/dL); white blood cell count, 9.7 × 109/L (normal range, [4-11] × 109/L); neutrophil, 75% (normal range, 48%-77%); lymphocyte, 22% (normal range, 10%-24%); eosinophil, 1% (normal range, 0.3%- 7%); monocyte, 1% (normal range, 0.6%-10%); serum creatinine level, 1.3 mg/dL (114.9 µmol/L) (normal range, 0.5-1.6 mg/dL [44.2-141.4 µmol/L]); and serum glucose (random) level, 82 mg/dL (4.5 mmol/L) (normal range, 79-140 mg/dL [4.4-7.8 mmol/L]). Radiography of the left thigh showed soft-tissue swelling in the medial aspect of the left thigh, without underlying bone involvement (not shown). Ultrasonography (US) and magnetic resonance (MR) imaging of the left thigh were performed. [Figure: see text].

Candida auris candidaemia in Indian ICUs: analysis of risk factors.

Objectives: To identify the risk factors associated with Candida auris candidaemia, as this fungus now poses a global threat. Methods: We performed a subgroup analysis of a previously reported study of 27 Indian ICUs. The clinical data of candidaemia cases due to C. auris and other Candida species were compared to determine significant risk factors associated with C. auris infection. Results: Of the 1400 candidaemia cases reported earlier, 74 (5.3%) from 19 of 27 ICUs were due to C. auris . The duration of ICU stay prior to candidaemia diagnosis was significantly longer in patients with C. auris candidaemia (median 25, IQR 12-45 days) compared with the non- auris group (median 15, IQR 9-28, P < 0.001). Based on logistic regression modelling, admission to north Indian ICUs [OR 2.1 (1.2-3.8); P = 0.012], public-sector hospital [OR 2.2 (1.2-3.9); P = 0.006], underlying respiratory illness [OR 2.1 (1.3-3.6); P = 0.002], vascular surgery [OR 2.3 (1.00-5.36); P = 0.048], prior antifungal exposure [OR 2.8 (1.6-4.8); P < 0.001] and low APACHE II score [OR 0.8 (0.8-0.9); P = 0.007] were significantly associated with C. auris candidaemia. The majority (45/51, 88.2%) of the isolates were clonal. A considerable number of isolates were resistant to fluconazole ( n = 43, 58.1%), amphotericin B ( n = 10, 13.5%) and caspofungin ( n = 7, 9.5%). Conclusions: Although C. auris infection has been observed across India, the number of cases is higher in public-sector hospitals in the north of the country. Longer stay in ICU, underlying respiratory illness, vascular surgery, medical intervention and antifungal exposure are the major risk factors for acquiring C. auris infection even among patients showing lower levels of morbidity.

Invasive Candidiasis in Severe Acute Pancreatitis: Experience from a Tertiary Care Teaching Hospital.

BACKGROUND: Invasive candidiasis (IC) is associated with increased morbidity in severe acute pancreatitis (SAP). There is limited information regarding the predisposing factors, Candida species distribution and in vitro susceptibility. METHODOLOGY: Current data have been derived from a larger prospective nonintervention study conducted on 200 critically ill patients which was done to study the antifungal prescription practices, collect epidemiological data, and perform an external validation of risk prediction models for IC under senior research associateship program of Council of Scientific and Industrial Research New Delhi. Of these critically ill patients, thirty had SAP and were included for analysis. RESULTS: There were 23 males and 7 females. Out of eight patients (27%) who developed IC, three had isolated candidemia, two had isolated deep-seated candidiasis while three had both candidemia and deep-seated candidiasis. SAP patients with IC had a longer duration of Intensive Care Unit stay, hospital stay, days on mechanical ventilation and duration of shock. Mortality was not different between SAP patients with or without IC. CONCLUSION: There is a high rate of Candida infection in SAP. More studies are needed to generate epidemiological data and develop antifungal stewardship in this subset of high-risk population.

External Validation of Risk Prediction Scores for Invasive Candidiasis in a Medical/Surgical Intensive Care Unit: An Observational Study.

BACKGROUND: The aim of this study was to conduct external validation of risk prediction scores for invasive candidiasis. METHODS: We conducted a prospective observational study in a 12-bedded adult medical/surgical Intensive Care Unit (ICU) to evaluate Candida score >3, colonization index (CI) >0.5, corrected CI >0.4 (CCI), and Ostrosky's clinical prediction rule (CPR). Patients' characteristics and risk factors for invasive candidiasis were noted. Patients were divided into two groups; invasive candidiasis and no-invasive candidiasis. RESULTS: Of 198 patients, 17 developed invasive candidiasis. Discriminatory power (area under receiver operator curve [AUROC]) for Candida score, CI, CCI, and CPR were 0.66, 0.67, 0.63, and 0.62, respectively. A large number of patients in the no-invasive candidiasis group (114 out of 181) were exposed to antifungal agents during their stay in ICU. Subgroup analysis was carried out after excluding such patients from no-invasive candidiasis group. AUROC of Candida score, CI, CCI, and CPR were 0.7, 0.7, 0.65, and 0.72, respectively, and positive predictive values (PPVs) were in the range of 25%-47%, along with negative predictive values (NPVs) in the range of 84%-96% in the subgroup analysis. CONCLUSION: Currently available risk prediction scores have good NPV but poor PPV. They are useful for selecting patients who are not likely to benefit from antifungal therapy.

Role of Procalcitonin and C-Reactive Protein As Biomarkers of Infection in Children With Liver Disease.

OBJECTIVES: Early and accurate identification of infection in patients with liver disease is challenging. The present study evaluated the role of procalcitonin (PCT) and C-reactive protein (CRP) as biomarkers of bacterial infection in children with liver disease. METHODS: Demographic and clinical data of consecutive children admitted with acute liver failure (ALF) or decompensated chronic liver disease (DCLD) were collected. PCT and CRP were measured within 24 hours of admission. Blood and urine culture, chest x-ray, and ascitic fluid analysis were done. RESULTS: One hundred sixty-four children (113 boys, age 76 [0.5-204] months, ALF 69, DCLD 95) were enrolled. Seventy-seven (47%) had infection. Most common site was ascitic fluid (n = 35), followed by urinary tract (n = 26), pneumonia (n = 22), and blood stream infection (n = 16). Twenty-one children had multiple-site infections, 18 had severe sepsis, and 36 had systemic inflammatory response syndrome. PCT and CRP correlated with infection severity, higher in severe sepsis (8.3 [3.5-38] ng/mL and 4.1 [0.3-13.8] mg/dL) than only infection (0.89 [0.1-8] ng/mL and 1.7 [0.32-24] mg/dL) and no infection (0.3 [0.1-6.75] ng/mL and 0.3 [0.1-4.16 mg/dL]). Systemic inflammatory response syndrome was more common in patients with infection (31/77 vs 5/87, P = 0.00). PCT (>0.5 ng/mL) and CRP (>0.6 mg/dL) performed better in DCLD (AUC of 0.90 and 0.83) compared with patients with ALF (AUC of 0.73 and 0.69). CONCLUSIONS: PCT and CRP are reliable markers of infection and correlate with infection severity in children with liver disease. Their diagnostic accuracy is better in DCLD than ALF cases.

Invasive candidiasis in non neutropenic critically ill - need for region-specific management guidelines.

Use of antifungal agents has increased over past few decades. A number of risk factors such as immunosuppression, broad spectrum antibiotics, dialysis, pancreatitis, surgery, etc., have been linked with the increased risk of invasive candidiasis. Though there are various guidelines available for the use of antifungal therapy, local/regional epidemiology plays an important role in determining the appropriate choice of agent in situations where the offending organism is not known (i.e. empirical, prophylactic or preemptive therapy). Developing countries like India need to generate their own epidemiological data to facilitate appropriate use of antifungal therapy. In this article, the authors have highlighted the need for region-specific policies/guidelines for treatment of invasive candidiasis. Currently available Indian literature on candidemia epidemiology has also been summarized here.

Nocardiosis in kidney transplant recipients: A tertiary care center experience.

INTRODUCTION: Kidney transplant recipients are at increased risk of opportunistic infections, including Nocardia. The incidence of nocardiosis in kidney transplant recipients is 0.4-1.3%. The data regarding its epidemiology and outcomes is limited. METHODS: This was a 10-year retrospective observational study from January 2012 to December 2021 at a tertiary care center in northern India, in which all kidney transplant recipients with Nocardia infection were included and followed. RESULTS: 12 (1.1%) patients had a Nocardia infection among the 1108 kidney transplant recipients. All were living donor kidney transplant recipients, and the mean age at diagnosis was 48.67 ± 12.60 years. Nocardia infection occurred at a median of 26 months (range 4-235) post-transplantation, with 4 (33.1%) of the cases occurring within a year of transplant. Breakthrough infection occurred in 7 (58.3%) patients on cotrimoxazole prophylaxis. 41.7% (n = 5) cases had an episode of rejection in the preceding year of Nocardia diagnosis. Concurrent cytomegalovirus (CMV) infection was present in one (8.3%) case. The lung was the most frequently involved organ. Microscopy was positive in all the cases; while culture was positive in 10 cases, and antimicrobial susceptibility testing (AST) were performed for these isolates. The majority (60%) of isolates were resistant to cotrimoxazole. All tested isolates remained susceptible to Amikacin, Imipenem, and Linezolid. No patients experienced Nocardia recurrence after completion of antibiotic therapy. The mortality at 12 months was 66.7% (n = 4), and only one death was Nocardia-related. CONCLUSION: Nocardia may cause a late-manifesting infection beyond the traditional window. The cotrimoxazole prophylaxis may not be sufficient for Nocardia prevention.

Clinico-epidemiological characteristics of early- versus late-onset cytomegalovirus disease among renal transplant recipients: A two-decade experience.

BACKGROUND: Reactivation of cytomegalovirus (CMV) infection in transplant patients is high because of immunosuppression. We have evaluated the clinical and epidemiological characteristics of early versus late onset of CMV infection among renal transplant recipients. METHODS: A single center retrospective observational study was conducted among renal transplant recipients who underwent kidney transplant between January 2002 and December 2021. CMV disease was classified as early or late depending on its detection prior to or after 90 days post-transplantation. Herein, we reported the differences between early and late onset of CMV disease with respect to clinical symptoms, the use of immunosuppression and the impact on graft outcomes. RESULTS: Out of total 2164 renal transplant recipients, 156 patients (7.2%) were diagnosed with CMV disease. Among these 156 patients, 25 patients (16%) had early CMV while 131 patients (84%) had late CMV. Overall, the two groups did not differ with respect to the induction or maintenance of immunosuppressive agents. However, the proportion of CMV syndrome was greater among early (56.0%) than late (26.7%) CMV groups (p = 0.01). In contrast, tissue invasive disease was more frequent among late (73.3%) in comparison to early (44.0%) CMV groups (p = 0.01). Among clinical symptoms, diarrhea was more frequent in late (63.4%) vs. early (36%) CMV-affected patients (p = 0.01). Graft loss occurred in 4.0% of early CMV group vs. 25.2% of late CMV group (p = 0.03). Neither of the clinical groups differed with respect to occurrence of biopsy-proven allograft rejection post-infection. CONCLUSIONS: Early CMV disease presents more frequently as CMV syndrome while late CMV disease usually manifests itself as tissue invasive disease. Graft loss is more common in patients with late onset of CMV disease.

Etiology, clinical characteristics and mortality among Indian patients with Addison's disease.

The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n = 89) patients (ages 15-83 years) diagnosed with PAI between 2006 and 2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1-15.7) years. Eighty-six subjects underwent an abdominal computerized tomography scan or ultrasonography, and adrenal biopsy was performed in 60 patients. The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty-two percent of patients presented with an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly-splenomegaly and type 2 diabetes mellitus (63% vs 15%, P < 0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). Causes of death included adrenal crises, progressive AH and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

Spectrum of fungal infection in a neurology tertiary care center in India.

There is a paucity of studies on spectrum of fungal infections in neurology care. This study reports clinical, MRI and outcome of patients with central nervous system (CNS) fungal infections. 39 patients with CNS fungal infections treated in neurology service during the last 3 years were included and a detailed medical history and clinical examination were undertaken. Cranial MRI including paranasal sinuses were carried out and the location and nature of abnormalities were noted. Fungal infection was confirmed by CSF examination or histopathology. Death during hospital stay was noted. The median age was 37 (8-72) years and 8 were females. The clinical features included altered sensorium in 31, focal motor deficits in 13, visual loss in 12, seizures in 10, diplopia in 7, and papilledema in 9 patients. 28 patients had the following predisposing conditions: HIV in 15, diabetes in 8, corticosteroid in 2 and alcohol, immunosuppression, neutropenia and analgesic abuse in 1 patient each. On CT or MRI scan, 5 patients had meningeal enhancement, 7 sinusitis, 10 each granuloma and infarction, 4 hydrocephalous and 1 cerebral venous sinus thrombosis. 28 patients had cryptococcal meningitis, 7 zygomycosis, 2 aspergillosis and 1 each candida and phaeohyphomycosis. Death was related to the type of fungal infection; all patients with zygomycosis and candida infection died. Rhinocerebral form of fungal infection due to zygomycetes has poorer survival compared to meningitis group which was mainly due to cryptococcal infection.