IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. However, the complex interplay between protective antifungal immunity and immunopathology remains incompletely understood. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that Epha2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 limits IL-23 secretion in dendritic cells, while IL-23 signaling prevents ferroptotic myeloid cell death during infection. Further, ferroptosis aggravates inflammation during infection, while at the same time reducing the fungal killing capacity of macrophages. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

Prevalence of Candida infection in Covid-19 pandemic: A study from a tertiary care center in Central India

Background: Corona virus disease 2019 (COVID-19) infections may be associated with a wide range of bacterial and fungal co-infections. Candida and mucor are the common fungus encountered during this pandemic. Candida is one of the commonly encountered opportunistic fungi that cause superficial mucosal infections usually, but can invade tissue and produce life threatening infections. Candida species recognized as one of the major agent of hospital Acquired (nosocomial) fungal infections. Keeping this in background the current study was conducted. Aims and Objective: To estimate the prevalence of candida infection in tertiary care hospital of Indore. Materials and Methods: The present study was done in the period of one and half year. During this period all received clinical specimens like urine, sputum; high vaginal swab and pus suspected for fungal infection from Covid as well as non-Covid patients were processed according to standard protocol. The specimen was subjected to preliminary tests like wet mount, Gram’s stain, culture on sabourads dextrose agar (SDA) and Hichrome agar, germ tube test, sugar assimilation test and culture on Cornmeal agar (dalmau technique) for candida species were done. For statistical analysis Chi-square test was performed and p ≤ 0.05 was considered statistically significant. Results: The prevalence of Candidiasis was 0.86%. Non-albicans candida (65.9%) isolates was more than Candida albicans (34.07%). Among non-albicans species, C. tropicalis was 27.4% followed by C. glabrata 16.29%, C. krusei 15.55%,C. parapsilosis 5.92% and C. lusitenia 0.74% were the major isolates. Males were affected more than the females. In both the genders maximum patients were from the age group of >60 years. Maximum number of Candida isolates was from blood followed by urine, pus, sputum, vaginal swab and aural swab. Most common risk factors for candidiasis noted in this study was diabetes mellitus in both Covid as well as non-Covid patients. Conclusion: Non albicans candida are gradually increasing in India. Speciation of candida play an important role in preliminary treatment because different species is intrinsically resistant to different antifungal drugs and have different antifungal susceptibility pattern.

Uncovering Silent Fungal Infections complicating Obstructive Uropathy due to Renal Papillary Necrosis in Diabetic patients – A step towards preventing Recurrent Obstructive Uropathy.

Introduction and Objectives: Renal papillary necrosis is one of the common causes of obstructive uropa-thy in diabetic patients. During removal of necrosed renal papilla, many patients were observed to have fluffy necrotic material in the ureter, and renal pelvis, and a few among them present again with recurrent episodes of obstructive uropathy and sepsis following DJ stent removal. Our study aimed to identify thesignificance of this fluffy necrotic material and its evaluation by histopathological examination (HPE). Materials and Methods: This is a prospective observational study done in our institute by compiling data of 56 patients admitted with obstructive uropathy secondary to renal papillary necrosis who underwent a protocol-based treatment from 2016 to 2019. All these patients underwent initial DJ stenting followed by check flexible ureteroscopy or nephroscopy after 6 weeks. The white, necrotic fluffy material collected during initial DJ stenting or with subsequent flexible ureteronephroscopy was sent for HPE. All these patients were followed up for 1-3 years. Results: Out of 56 patients, 15 patients had fluffy necrotic material in the bladder on initial cystoscopy, of which 1 patient was diagnosed with aspergillosis and 1 patient with candida infection on HPE. During check flexible ureteroscopy (FU), 19 patients had minimal burden of fluffy necrotic material in renal pelvis, of which one patient was diagnosed with aspergillosis, one with candida (same patient diagnosed on cystoscopy), and one patient with both aspergillus and candida colonies on HPE. 5 patients had the significant burden of fluffy necrotic material in the renal pelvis, requiring removal via percutaneous nephroscopic access. Among these 5 patients, 2 were diagnosed with aspergillosis and 1 with candida infection on HPE. A total of 32 patients had single papilla, and 24 had multiple papillae in the pelvicalyceal system. 5 out of 7 patients with positive fungal pathology had negative fungal cultures. Compared to our historical data of 4% mortality and 22% recurrent obstructive uropathy in the 3 years preceding the adoption of this protocol, with the present protocol, no patient developed recurrent pyelonephritis during follow-up of 1–3 years after DJ stent removal following complete evacuation of necrotic material and appropriate antifungal treatment. Conclusion: This study highlights the need for check ureterorenoscopy and removal of all necrotic papillae and debris to establish a microbiological and histopathological diagnosis along with proper antifungal treatment to prevent episodes of recurrent pyelonephritis and obstructive uropathy.

Monocyte human leukocyte antigen-DR but not β-d-glucan may help early diagnosing invasive Candida infection in critically ill patients

Background Precision medicine risk stratification is desperately needed to both avoid systemic antifungals treatment delay and over prescription in the critically ill with risk factors. The aim of the present study was to explore the combination of host immunoparalysis biomarker (monocyte human leukocyte antigen-DR expression (mHLA-DR)) and Candida sp wall biomarker β-d-glucan in risk stratifying patients for secondary invasive Candida infection (IC). Methods Prospective observational study. Two intensive care units (ICU). All consecutive non-immunocompromised septic shock patients. Serial blood samples (n = 286) were collected at day 0, 2 and 7 and mHLA-DR and β-d-glucan were then retrospectively assayed after discharge. Secondary invasive Candida sp infection occurrence was then followed at clinicians’ discretion. Results Fifty patients were included, 42 (84%) had a Candida score equal or greater than 3 and 10 patients developed a secondary invasive Candida sp infection. ICU admission mHLA-DR expression and β-d-glucan (BDG) failed to predict secondary invasive Candida sp infection. Time-dependent cause-specific hazard ratio of IC was 6.56 [1.24–34.61] for mHLA-DR < 5000 Ab/c and 5.25 [0.47–58.9] for BDG > 350 pg/mL. Predictive negative value of mHLA-DR > 5000 Ab/c and BDG > 350 pg/mL combination at day 7 was 81% [95% CI 70–92]. Conclusions This study suggests that mHLA-DR may help predicting IC in high-risk patients with septic shock. The added value of BDG and other fungal tests should be regarded according to the host immune function markers.