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To evaluate the prognostic ability of serum ferritin when estimated within 5 days of onset of illness in children with severe sepsis admitted to a pediatric intensive care unit.This observational study enrolled children aged 1 month to 12 years with severe sepsis. Hemoglobin, serum ferritin and C-reactive protein levels were measured within five days of illness. Final outcomes were recorded in all enrolled children.70 children with median (IQR) age of 27 (8,108) months were enrolled during the study period (July, 2019 to August, 2021). 28 (40%) of these had poor outcome (non-survival). The median (IQR) level of serum ferritin was 1369 (558-5607) ng/mL in non-survivors and 282 (129-680) ng/mL in survivors (P0.05). A significant correlation was seen between serum ferritin and Pediatric Risk of Mortality III (PRISM III) score (r=0.364 P=0.002) and pediatric Sequential Organ Failure Assessment (pSOFA) score (r=0.246 P=0.04) at 48 hours of admission. 54 (77.1%) children were anemic. Serum ferritin levels in children with anemia also had a good predictive ability for poor outcome [AUC: 0.764, 95% CI: 0.634, 0.894].Serum ferritin levels, within five days of onset of illness, predicted poor outcome in critically ill children with severe sepsis and in children with microcytic anemia.

Corynebacterium (C.) diphtheriae is the agent for a contagious infection, diphtheria. It may manifest as pharyngitis with pseudomembrane formation and cervical lymphadenopathy, cutaneous infection, or as an asymptomatic carrier. Corynebacterium (C.) diphtheriae is not an invasive organism and it remains in the superficial layers of skin lesions and respiratory mucosa. Systemic complications, such as bacteremia, are rare. We report a case of toxigenic C. diphtheriae detected from blood culture of a 1-year-old male patient with burns, who succumbed to the infection after 8 days of stay in the hospital. Patient did not have specific clinical features suggestive of diphtheria. Initial identification of C. diphtheriae was done based on culture, Albert stain findings, biochemical tests and subsequently toxigenicity testing was done by polymerase chain reaction. Although diphtheria vaccination in infancy is universally recommended since the creation of the Expanded Program on Immunization in the 1970s, there have been reports of toxigenic strains of C. diphtheriae in a considerable number of cases. Rapid and accurate identification of C. diphtheriae infection is crucial to prevent mortality. Continued surveillance for diphtheria is needed to reduce transmission and mortality rates.

Our objective was to evaluate the role of optic nerve sheath diameter measurement by orbital ultrasound in monitoring children with nontraumatic coma and increased intracranial pressure (ICP). A single-center prospective observational study was conducted in the pediatric intensive care unit (PICU) of a tertiary care teaching hospital in Puducherry, India. Children admitted to the PICU with features of raised ICP were enrolled. Baseline characteristics and raised ICP characteristics were recorded. Optic nerve sheath diameter (ONSD) measurements were taken in all children in the supine position using bedside ultrasound with a 12 MHz linear probe. The probe was initially placed in the axial plane, and measurements were taken at a distance of 3 mm posterior to the site at which the optic nerve enters the globe. Measurements were recorded sequentially 8th hourly till ICP features got resolved or the patient died. Along with each measurement, clinical parameters were recorded. The ONSD measurements were compared with clinical features. We also recruited children admitted to the PICU for other conditions without features of raised ICP as controls. We compared ONSD measurements of cases with controls. In total, 185 children were recruited, of which 81 had features of raised ICP and 104 were without increased ICP. The ONSD measurements in children with raised ICP were significantly higher as compared with those without ICP. Among children with raised ICP, there was a negative correlation between ONSD and Glasgow Coma Scale scores (r = −0.739, p ≤ 0.0001). In children with raised ICP, there was a significant difference in ONSD at different intervals, demonstrating a falling trend from admission to 32nd-hour readings. ONSD measurements were higher in children with clinical signs of increased ICP compared with controls, thereby suggesting that this noninvasive measure may be helpful in the neuromonitoring of children with neurologic insults.

Objective Inflammation, a vital innate immune response against infection and injury, is mediated by macrophages. Spleen tyrosine kinase (Syk) regulates inflammatory responses in macrophages; however, its role and underlying mechanisms are uncertain. Materials and Methods In this study, overexpression and knockout (KO) cell preparations, phagocytosis analysis, confocal microscopy, reactive oxygen species (ROS) determination, mRNA analysis, and immunoprecipitation/western blotting analyses were used to investigate the role of Syk in phagocytosis and its underlying mechanisms in macrophages during inflammatory responses. Results Syk inhibition by Syk KO, Syk-specific small interfering RNA (siSyk), and a selective Syk inhibitor (piceatannol) significantly reduced the phagocytic activity of RAW264.7 cells. Syk inhibition also decreased cytochrome c generation by inhibiting ROS-generating enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and ROS scavenging suppressed the phagocytic activity of RAW264.7 cells. LPS induced the tyrosine nitration (N-Tyr) of suppressor of cytokine signaling 1 (SOCS1) through Syk-induced ROS generation in RAW264.7 cells. On the other hand, ROS scavenging suppressed the N-Tyr of SOCS1 and phagocytosis. Moreover, SOCS1 overexpression decreased phagocytic activity, and SOCS1 inhibition increased the phagocytic activity of RAW264.7 cells. Conclusion These results suggest that Syk plays a critical role in the phagocytic activity of macrophages by inducing ROS generation and suppressing SOCS1 through SOCS1 nitration during inflammatory responses.

SUMMARY Scrub typhus is being reported as the most common cause of childhood meningoencephalitis (ME) in India. Hence, we planned to estimate the proportion of scrub typhus infection among children aged 1 month to 12 years with the clinical diagnosis of ME and to evaluate their demographic, clinical and laboratory characteristics. This cohort study was conducted in the Department of Pediatrics of a tertiary care teaching hospital in south India. One hundred and twenty-seven consecutive children aged 1 month to 12 years with the clinical diagnosis of ME were the participants. Their socio-demographic factors, clinical details, laboratory reports and outcomes were analyzed. The etiological agent was identified in 71 (56%) children. Orientia tsutsugamushi (Scrub typhus) was the most common infection (24.4%), of all children with ME. Children aged ≥5 years were frequently affected by scrub typhus ME. Eschar, capillary leak, hepatomegaly and splenomegaly were the predominant clinical features of scrub typhus ME. Thrombocytopenia and deranged liver function tests were common in scrub typhus ME. To conclude, Orientia tsutsugamushi was the most common organism identified in our study. Prompt recognition of some tell-tale clinical signs of scrub typhus (such as eschar, thrombocytopenia and hepatosplenomegaly), and timely initiation of antibiotics would lead to better outcomes as evident from the study.

Context Clostridioides difficile infection (CDI) is one of the most common infectious causes of hospital-acquired diarrhea. The actual burden of the disease is underestimated in India due to inadequate diagnostic methods and limited studies conducted. Aims The aim of this study was to determine the burden and risk factors of CDI among patients with hospital-acquired diarrhea. Methods and Materials Stool specimen of patients (age > 1 year) with hospital-acquired diarrhea were screened for glutamate dehydrogenase antigen and toxin using an enzyme immunoassay. If both antigen and toxin were present, it was reported as positive for toxigenic CDI. Samples positive for antigen and negative for toxin were further tested with Cepheid GeneXpert assay for detecting the toxin producing gene. Results Of 75 patients (mean age 36.07 ± 20.79, 64% males), 14 (18.67%) patients were positive for toxigenic Clostridioides difficile (C. difficile) and 3 (4%) patients were nontoxigenic C. difficile. Addition of GeneXpert to the testing algorithm increased the yield of toxin detection in 5/14 patients who were negative by toxin assay. On analysis of risk factors, prolonged hospital stay was found to have significant association (p-value = 0.022). Patients with factors like intensive care unit stay, presence of diabetes mellitus as a comorbidity, and exposure to antibiotics like carbapenems and glycopeptides have been found to have a higher prevalence of CDI. Conclusions The prevalence of CDI in our population was 18.67% and the major risk factor associated was prolonged hospital stay. The addition of GeneXpert for the detection of toxin gene increased the yield from 12 to 18.68%.

Concerns have been raised in the media that 'the third wave' will severely affect children. Here, an experience of SARS-CoV-2 infection in children is reported. Of the 8,626 SARS-CoV-2 RT-PCR tests performed in children (0-17 y) from March 2020 to July 2021 at the authors' institute, 1470 (17%) were positive, [711/4821 (14.7%) during the first wave (July 2020 to January 2021), and 759/3583 (21.2%) during the second wave (February 2021 to July 2021)]. The children in both waves were similar in presentation (74.1% mildly symptomatic versus 80.2% mildly symptomatic; rest asymptomatic). None of them had COVID pneumonia. Five children died (0.3%), all of a serious primary non-COVID disease. Seventy-three cases of MIS-C during August 2020 to July 2021, with low mortality (2.7%) were also identified. The similarity in COVID-19 infection in children between the first and the second waves seems to suggest that the likelihood of the 'third wave' hitting children hard is low.

Background Deaths due to snakebites and serious adverse reactions to anti-snake venom (ASV) are both underreported in India. Serious adverse reactions to ASV are common, contributing significantly to mortality and morbidity. We conducted a study to determine the frequency of occurrence of severe adverse reactions to ASV in children and study the various risk factors and their outcomes. Patients and methods We carried out a retrospective record review of all children of snake envenomation admitted in our tertiary care teaching hospital, from January 2013 to December 2016. Children aged 0 to 12 years admitted for snake envenomation and who received ASV as part of their treatment were included. Details about their management, including ASV usage and any adverse effects noted, were collected on a standard data collection form. Results Sixty-eight children were enrolled. Hemotoxic (52.9%) envenomation was more common than neurotoxic (35.2%). Severe adverse reactions were present in 42.6%, hypotension in 38.2%, and bronchospasm in 4.4% of the children. The overall mortality rate was 16.1%, anaphylaxis to ASV contributing to 36.3% of them. Mortality was significantly higher in cases with severe adverse reactions (p = 0.005). ASV reactions were also significantly different with different manufacturers. Conclusions There is a high frequency of occurrence of severe adverse reactions to ASV resulting in significant morbidity and mortality. How to cite this article Hooda R, Parameswaran N, Subramanian M. Serious Adverse Reactions to Anti-snake Venom in Children with Snake Envenomation: An Underappreciated Contributor to Snakebite Mortality? Indian J Crit Care Med 2021;25(6):720–723.

To study the clinical profile and outcomes in children with multisystem inflammatory syndrome in children (MIS-C).Children aged 1 month to 15 years presenting with MIS-C (May 2020 to November 2021) were enrolled. Clinical, laboratory, echocardiography parameters and outcomes were analysed.Eighty-one children (median age 60 months (24-100)) were enrolled. Median duration of fever was 5 days (3-7). Twenty-nine (35.8%) had shock (severe MIS-C) including 23 (28.3%) requiring inotropes (median duration = 25 h (7.5-33)). Ten required mechanical ventilation, 12 had acute kidney injury and 1 child died. Left ventricular (LV) dysfunction was seen in 38 (46.9%), 16 (19.7%) had coronary artery abnormalities (CAA) and 13 (20%) had macrophage activation syndrome. Sixty-one (75.3%) were SARS CoV-2 positive (10 by RT-PCR and 51 by serology). Sixty-eight (83.9%) received immunomodulators. Younger age was significantly associated with CAA (P value = 0.05). Older age, LV dysfunction, SARS CoV-2 positivity, low platelet count and elevated serum ferritin were significantly associated with severe MIS-C (univariate analysis). Younger age was an independent predictor of CAA (P = 0.05); older age (P = 0.043) and low platelet count (P = 0.032) were independent predictors of severe MIS-C (multivariate logistic regression analysis).Our patients had diverse clinical manifestations with a good outcome. Younger age was significantly associated with CAA. Older age, LV dysfunction, low platelet count and elevated serum ferritin were significantly associated with severe MIS-C. Younger age is an independent predictor of CAA. Older age and low platelet count are independent predictors of severe MIS-C.

To evaluate the incidence of aminoglycoside-related nephrotoxicity and ascertain drug causality and its risk factors.This prospective study was conducted from January, 2019 to January, 2021, and recruited 110 consecutively admitted children aged 1 month to 12 years, receiving aminoglycosides for ≥4 days. Drug causality was assessed using Liverpool adverse drug reaction causality assessment tool.42 (38.2%) children developed acute kidney injury (AKI), with 71 (64.5%) having composite nephrotoxicity (AKI and/or tubular-dysfunction). Only 17 (15.5%) had AKI definitively attributable to aminoglycosides. Hypotension [OR 0.016 (95% CI 0.01-0.71), P=0.03], PRISM-III score 20-29% [OR 55.48 (95% CI 3.66-840.53), P=0.004] and post-surgery patients [OR 3.2 (95% CI 1.01-10.1), P=0.047] were independent predictors of AKI.Only a small proportion of children receiving aminoglycosides had AKI definitively attributable to the drug.

Antigen receptor–dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein–coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell–type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.

Oral treatment with probiotic bacteria has been shown to prevent bone loss in multiple models of osteoporosis. In previous studies we demonstrated that oral administration of Lactobacillus reuteri in healthy male mice increases bone density. The host and bacterial mechanisms of these effects however are not well understood. The objective of this study was to understand the role of lymphocytes in mediating the beneficial effects of L. reuteri on bone health in male mice. We administered L. reuteri in drinking water for 4 weeks to wild type or Rag knockout (lack mature T and B lymphocytes) male mice. While L. reuteri treatment increased bone density in wild type, no significant increases were seen in Rag knockout mice, suggesting that lymphocytes are critical for mediating the beneficial effects of L. reuteri on bone density. To understand the effect of L. reuteri on lymphocytes in the intestinal tissues, we isolated mesenteric lymph node (MLN) from naïve wild type mice. In ex vivo studies using whole mesenteric lymph node (MLN) as well as CD3+ T-cells, we demonstrate that live L. reuteri and its secreted factors have concentration-dependent effects on the expression of cytokines, including anti-inflammatory cytokine IL-10. Fractionation studies identified that the active component of L. reuteri is likely water soluble and small in size (L. reuteri supernatants, secrete factors that enhance osterix (transcription factor involved in osteoblast differentiation) expression in MC3T3-E1 osteoblasts. Together, these data suggest that L. reuteri secreted factors regulate T-lymphocytes which play an important role in mediating the beneficial effects of L. reuteri on bone density.

Type-1 diabetes (T1D) increases systemic inflammation, bone loss, and risk for bone fractures. Levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are decreased in T1D, however their role in T1D-induced osteoporosis is unknown. To address this, diabetes was induced in male IL-10 knockout (KO) and wild-type (WT) mice. Analyses of femur and vertebral trabecular bone volume fraction identified bone loss in T1D-WT mice at 4 and 12 weeks, which in T1D-IL-10-KO mice was further reduced at 4 weeks but not 12 weeks. IL-10 deficiency also increased the negative effects of T1D on cortical bone. Osteoblast marker osterix was decreased, while osteoclast markers were unchanged, suggesting that IL-10 promotes anabolic processes. MC3T3-E1 osteoblasts cultured under high glucose conditions displayed a decrease in osterix which was prevented by addition of IL-10. Taken together, our results suggest that IL-10 is important for promoting osteoblast maturation and reducing bone loss during early stages of T1D.

OBJECTIVE To compare the efficacy of insulin infusion of 0.05 Unit/kg/hour vs 0.1 Unit/kg/hour in the management of pediatric diabetic ketoacidosis (DKA). DESIGN Randomized, double-blind controlled clinical trial. SUBJECT Pediatric critical care division of a tertiary care hospital from October, 2014 to July, 2018. PARTICIPANTS Children aged 12 years or younger with a diagnosis of DKA. Children with septic shock and those who had received insulin before enrollment were excluded. INTERVENTION Low-dose (0.05 Unit/kg/hour) vs. Standard-dose (0.1 Unit/kg/hour) insulin infusion. OUTCOME MEASURES The primary endpoint was time for resolution of DKA (pH ≥7.3, bicarbonate ≥15 mEq/L, beta-hydroxybutyrate

How to cite this article: Lalgudi Ganesan S, Parameswaran N. Composite Outcomes for Clinical Trials in Critical Care: The Devil is in the Detail. Indian J Crit Care Med 2020;24(10):903-904.

Human metapneumovirus (hMPV) is a common cause of acute respiratory tract infections in children. In immunocompetent individuals, the course of hMPV infection is usually benign and self-limiting. A developmentally normal, previously healthy 4-year-old girl presented with pneumonia and later developed rhabdomyolysis and multi-organ dysfunction syndrome (MODS) which was fatal. Extensive microbiological investigation for a possible viral aetiology was positive only for hMPV, thus making it the first reported case of hMPV infection-related rhabdomyolysis.

Introduction The study aims to evaluate the association between a deficiency of Vitamin D level with the duration of hospital stay, pediatric intensive care unit (PICU) stay, and ventilation; the pediatric risk of mortality (PRISM) score, and the rate of readmission. Materials and methods This prospective observational study was conducted from November 2014 to October 2015, and the study population consisted of children admitted to the pediatric intensive care unit (PICU) in a tertiary care hospital of Puducherry. After measuring vitamin D levels, children were allotted into three categories depending on their serum 25(OH)D levels as the sufficient group (25[OH]D level ≥ 30 ng/mL), insufficient group (25[OH]D level = 20 - 29.9 ng/mL), and deficient group (25[OH]D level < 20 ng/mL). Among these three groups, the duration of hospital stay, PICU stay, and ventilation; the PRISM score, and the rate of readmission were compared. Results A total of 522 patients were included in the study. Based on their 25(OH)D level, 222 patients (42.5%) were in the sufficient category, 153 patients (29.3%) were in the deficient category, and 147 patients (28.2%) were in the insufficient category. Vitamin D deficiency state is not statistically significantly associated with the duration of hospital stay (P = .84), duration of PICU stay (P = .69), duration of ventilation (P = .48), PRISM score (P = .63), and rate of readmission (P = .91). Conclusions Longer hospital stay, prolonged PICU stay, longer duration of ventilation, and higher PRISM III score were independent risk factors for higher mortality in the PICU. However, lower vitamin D levels are not statistically significant to predict mortality among the study population.