Steroid-responsive anemia with bony dysplasias: What lurks behind!

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by diaphyseal dysplasia of long bones, bone marrow fibrosis, and steroid-responsive anemia. Patients with this disease have a mutation in the thromboxane-AS1 (TBXAS1) gene located on chromosome 7q33.34. They present with short stature, varying grades of myelofibrosis, and, hence cytopenias. Patients with the above presentation were evaluated through clinical presentation, X-ray of long bones, bone marrow examinations, and confirmed by genetic testing. In this article, we present two cases: The first case is a 3-year-old boy who presented with progressive pallor and ecchymotic patches for a year. On investigation, he had bicytopenia and bone marrow fibrosis. His anemia was steroid responsive and was finally diagnosed as GHDD. The second case is a 20-month-old girl who presented with blood in stools, developmental delay, anemia, and increased intensity of long bones on X-ray. Since other investigations were normal, suspicion of GHDD was raised, and a genetic workup was conducted which suggested mutation in TBXAS1 gene, confirming the diagnosis of GHDD. Children with refractory anemia and cortical thickening on skeletogram should always be evaluated for dysplasias. Timely treatment with steroids reduces transfusion requirements and halts bone damage, thus leading to better growth and improved quality of life.

Common Salt versus Silver Nitrate for the Treatment of Umbilical Granuloma in Infants: An Open-label, Single-center, Pilot Randomized Controlled Trial.

Aim: This study aims to compare the efficacy and safety of topical application of common salt (CS) in comparison to silver nitrate (SN) for treating infants with umbilical granuloma (UG). Materials and Methods: We conducted an open-label, prospective, single-center, pilot randomized controlled trial. Thirty-seven infants with a clinical UG diagnosis were enrolled between October 2022 and July 2023, excluding those previously treated for UG. Patients were randomly assigned (using the Randomizer® app) to receive either topical CS (applied thrice daily by caregivers at home for 5 days) or SN (applied by pediatric surgeon in clinic and kept under occlusive dressing for 48 h). Patients with partial/no healing received an additional session of the same treatment. Nonresponders transitioned from CS to SN, and vice versa, for two more applications. Healing rates were compared with a significance level of α =0.05. Results: Out of 34 patients (18 CS and 16 SN), 32 successfully completed the trial (17 CS and 15 SN). No significant differences were observed in baseline characteristics. Efficacy rates of CS (19/22; 86.36%) and SN (11/17; 64.71%) did not significantly differ (P = 0.056; 95% confidence interval [CI] -0.4832-0.0502). No major adverse events were reported. CS showed superior healing outcomes in infants below 3 months of age (19/22; 86.36%) compared to SN (11/17; 64.71%) (P = 0.056; 95% CI - 0.4832-0.0502). The timing of umbilical cord detachment did not significantly affect healing rates. Conclusion: Widespread availability, ease of access, suitability for safe home application, and cost-effectiveness make CS a primary treatment option for UG. Larger patient cohorts are needed for conclusive results.

Clinical, immunological and molecular findings of patients with DOCK-8 deficiency from India.

DOCK8 deficiency affects various cell subsets belonging to both the innate and adaptive immune systems. Clinical diagnosis is challenging, as many cases present with severe atopic dermatitis as the only initial manifestation. Though flow cytometry helps in the presumptive diagnosis of DOCK8-deficient patients by evaluating their DOCK8 protein expression, it requires subsequent confirmation by molecular genetic analysis. Currently, haematopoietic stem cell transplantation (HSCT) is the only curative treatment option available for these patients. There is a paucity of data from India on the clinical diversity and molecular spectrum of DOCK8 deficiency. In the present study, we report the clinical, immunological and molecular findings of 17 DOCK8-deficient patients from India diagnosed over the last 5 years.

Narsoplimab for severe transplant-associated thrombotic microangiopathy.

BACKGROUND: Transplantation-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome linked to the overactivation of complement pathways. It manifests with microangiopathic hemolytic anemia, consumptive thrombocytopenia, and microvascular thrombosis leading to ischemic tissue injury. Mannose residues on fungi and viruses activate the mannose-binding lectin complement pathway, and hence activation of the lectin pathway could be one of the reasons for triggering TA-TMA. Narsoplimab, a human monoclonal antibody targeting MASP-2 is a potent inhibitor of the lectin pathway. We describe the transplant course of a pediatric patient who developed TA-TMA following Candida-triggered macrophage activation syndrome and was treated with Narsoplimab. The data collection was performed prospectively. CASE PRESENTATION: The six-year-old girl underwent a human leucocyte antigen (HLA) haploidentical hematopoietic stem cell transplant using post-transplant Cyclophosphamide for severe aplastic anemia. In the second week of the transplant, the patient developed macrophage activation syndrome necessitating treatment with steroids and intravenous immunoglobulin. Subsequently, USG abdomen and blood fungal PCR revealed the diagnosis of hepatosplenic candidiasis. Candida-triggered macrophage activation syndrome responded to antifungals, steroids, intravenous immunoglobulin, and alemtuzumab. However, the subsequent clinical course was complicated by thrombotic microangiopathy. The patient developed hypertension in the 2nd week, followed by high lactate dehydrogenase (1010 U/L), schistocytes (5 per hpf), low haptoglobin (< 5 mg/dl), thrombocytopenia, and anemia in the 3rd week. Ciclosporin was stopped, and the patient was treated with 10 days of defibrotide without response. The course was further complicated by the involvement of the gastrointestinal tract and kidneys. She had per rectal bleeding with frequent but low-volume stools, severe abdominal pain, and hypoalbuminemia with a rising urine protein:creatinine ratio. Narsoplimab was started in the 5th week of the transplant. A fall in lactate dehydrogenase was observed after starting Narsoplimab. This was followed by the resolution of gastrointestinal symptoms, proteinuria, and recovery of cytopenia. The second episode of TA-TMA occurred with parvoviraemia and was also successfully treated with Narsoplimab. CONCLUSION: Lectin pathway inhibition could be useful in treating the fatal complication of transplant-associated thrombotic microangiopathy.

Application of the Clamshell Thoracotomy in an Infant with a Large Mediastinal Tumor.

Historically it was recommended for emergency thoracotomy in thoracic trauma as the last resort when there was cardiopulmonary arrest. Nowadays, the only indications are lung transplantation and huge mediastinal masses. We report the use of a clamshell thoracotomy in a 7-month-old boy with a large anterior mediastinal mass extending into the bilateral thoracic cavities.

SLGT2 Inhibitor Rescues Myelopoiesis in G6PC3 Deficiency.

The energy metabolism of myeloid cells depends primarily on glycolysis. 1,5-Anhydroglucitol (1,5AG), a natural monosaccharide, is erroneously phosphorylated by glucose-phosphorylating enzymes to produce 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a powerful inhibitor of hexokinases. The endoplasmic reticulum transporter (SLC37A4/G6PT) and the phosphatase G6PC3 cooperate to dephosphorylate 1,5AG6P. Failure to eliminate 1,5AG6P is the mechanism of neutrophil dysfunction and death in G6PC3-deficient mice. Sodium glucose cotransporter 2 (SLGT2) inhibitor reduces 1,5AG level in the blood and restores the neutrophil count in G6PC3-deficient mice. In the investigator-initiated study, a 30-year-old G6PC3-deficient woman with recurrent infections, distressing gastrointestinal symptoms, and multi-lineage cytopenia was treated with an SLGT2-inhibitor. A significant increase in all the hematopoietic cell lineages and substantial improvement in the quality of life was observed.

Multisystem Inflammatory Syndrome in Children: Clinical Features and Management-Intensive Care Experience from a Pediatric Public Hospital in Western India.

BACKGROUND: Multisystem inflammatory syndrome (MIS) associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2) (MIS-C) in children is being increasingly reported across the world. MATERIALS AND METHODS: Children fulfilling the World Health Organization criteria of MIS-C needing pediatric intensive care unit between April 15 and July 26, 2020 were studied. RESULTS: There were 21 patients with median age of 7 years [interquartile range (IQR) 1.9-12.1], of which 11 were females. SARS-CoV-2 real-time polymerase chain reaction positive in 8/21 and/or antibody positive 16/21. Fever was present in all patients, and gastrointestinal symptoms being second most frequent (16/21). One child had aplastic anemia, while the rest had no comorbidities. Nearly all presented with shock (n = 20/21) and 90% needed vasoactive drugs with a median Vasoactive Inotropic Score of 40 (IQR 20-95). Thirteen children needed ventilatory support and one needed peritoneal dialysis. Nine children had left ventricular dysfunction and five had dilatation of coronaries on echocardiography. Inflammatory markers C-reactive protein [98 mg/dL (IQR 89-119)], serum ferritin [710 mg/dL (IQR 422-1,609)], and serum interleukin-6 levels [215 ng/L (IQR 43-527)] were uniformly elevated. Eighteen children received pulse methyl-prednisolone, eleven intravenous immunoglobulins, and four tocilizumab. Eighteen children (86%) were discharged home while three died. CONCLUSION: In our cohort, MIS-C was seen in previously healthy children with fever, gastrointestinal symptoms, and shock. Early and aggressive management of shock and immune modulation with methyl-prednisolone and intravenous immunoglobulin were used. HOW TO CITE THIS ARTICLE: Shobhavat L, Solomon R, Rao S, Bhagat I, Prabhu S, Prabhu S, et al. Multisystem Inflammatory Syndrome in Children: Clinical Features and Management-Intensive Care Experience from a Pediatric Public Hospital in Western India. Indian J Crit Care Med 2020;24(11):1089-1094.

Cleavage-resistant RIPK1-induced autoinflammatory syndrome-A report of three generations with periodic fever and clinical response to colchicine.

The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.

Pediatric Zinner syndrome variants: Case series with newer insights into pathogenesis in early childhood.

INTRODUCTION: Zinner Syndrome (ZS) is a rare congenital disorder characterized by seminal vesicle cysts (SVC) and ipsilateral upper urinary tract abnormalities, mainly due to developmental anomalies of the mesonephric duct. This series highlights our institutional experience with pediatric ZS, with a review of the current literature offering insights into its etiopathogenesis in early childhood. MATERIAL AND METHODS: A retrospective case review of pediatric ZS diagnosed at our institution from 2019 to 2023, alongside a comprehensive literature review. RESULTS: Four pediatric ZS cases were identified, a neonate, an infant and two older (pre-pubertal) children, presenting with recurrent epididymo-orchitis and/or UTIs. The two older children had duplex systems, both undergoing curative upper moiety heminephrectomy; the infant underwent nephroureterectomy and the neonate is under observation, asymptomatic for past 18 months. DISCUSSION: When Zinner identified the link between unilateral renal agenesis and ipsilateral SVC in 1914, the condition's embryological basis was attributed to incorrect ureteric bud migration from the mesonephric duct, failing to stimulate the metanephros, leading to renal agenesis/dysplasia and this disruption was hypothesized to obstruct seminal vesicle drainage, causing cyst formation. Another theory suggests anomalous development of the distal mesonephric duct leading to ejaculatory duct atresia/stenosis which results in cystic enlargement of the seminal vesicles which, in turn, leads to aberrant ureteral budding, resulting in renal malformations. It is our belief that the SVCs, that are typically problematic in adolescence/adulthood due to secretion accumulation, sometimes manifest in childhood due to urinary reflux into the seminal vesicles, leading to epididymo-orchitis or UTIs. This contrasts with adult pathogenesis, where ejaculatory duct obstruction predominates. Hence, treatment leans towards a conservative approach for asymptomatic cases, with surgery reserved for symptomatic children. The scope of this case series is limited by the rare nature of ZS in prepubertal children (41 published cases in English literature), preventing a comprehensive understanding of its untreated natural history and restricting the formulation of generalized recommendations. CONCLUSION: The variability in presentation of ZS in children necessitates a tailored approach. Unlike adults, where ejaculatory duct obstruction is the common cause, pediatric ZS symptoms mainly stem from urethra-cystic reflux, leading to recurrent infections.

The role of graft T-cell size in patients receiving alemtuzumab serotherapy for non-malignant disorders: results of an institutional protocol.

Although graft T cells assist in engraftment, mediate antiviral immune-reconstitution, and cause graft-versus-host disease, graft size is not determined by T-cell content of the graft. The conventional method of graft size determination based on CD34+ cells with alemtuzumab serotherapy is associated with delayed immune reconstitution, contributing to an increased risk of viral infections and graft failure. Alemtuzumab, a long half-life anti-CD52 monoclonal antibody is a robust T-cell depleting serotherapy, and relatively spares memory-effector T cells compared to naïve T cells. We therefore hypothesized that graft size based on T-cell content in patients receiving peripheral blood stem cell graft with alemtuzumab serotherapy would facilitate immune-reconstitution without increasing the risk of graft-versus-host disease. We retrospectively analysed twenty-six consecutive patients with non-malignant disorders grafted using alemtuzumab serotherapy and capping of graft T cells to a maximum of 600 million/kg. The graft T-cell capping protocol resulted in early immune-reconstitution without increasing the risk of severe graft-versus-host disease. Graft T-cell content correlated with CD4+ T-cell reconstitution and acute graft-versus-host disease. The course of CMV viraemia was predictable without recurrence and associated with early T-cell recovery. No patient developed chronic graft-versus-host disease. Overall survival at one year was 100% and disease-free survival was 96% at a median of 899 days (range: 243-1562). Graft size determined by peripheral blood stem cell graft T-cell content in patients receiving alemtuzumab serotherapy for non-malignant disorders is safe and leads to early T-cell immune-reconstitution with excellent survival outcomes.

Effect of delamanid on interim outcomes of bacteriological conversion amongst pediatric drug resistant tuberculosis cases in India.

AIM: To determine the bacteriological conversion rate after 6 months of Delamanid (DLM) based treatment in children with drug-resistant tuberculosis (DR-TB) and determine factors associated with bacteriological conversion. METHODS: This is a descriptive retrospective study done in children between the age of 6-17 years with DR-TB who received DLM-based therapy from October 2018 to May 2021. The drug resistance pattern of TB was detected using Xpert RIF/MTB and phenotypic drug sensitivity testing (DST) on TB-MGIT culture reports. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for 6 months. Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analyzed. RESULTS: Sixty patients received DLM of which two had extrapulmonary TB (EPTB) and sputum conversion could not be assessed. The mean age at presentation was 12.69 ± 3.03 years. Five patients (8.3%) died while on DLM treatment. On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which three patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation. CONCLUSION: Sputum bacteriological conversion rate was almost 80% at the end of 6 months of DLM-based treatment.

Treatment of Umbilical Granuloma in Infants With Topical Application of Common Salt: A Scoping Review.

BACKGROUND: Common salt is a safe, effective and cheap home-made remedy for umbilical granuloma. The aim of this scoping review is to identify and summarize the available evidence and examine the research conducted on salt treatment for umbilical granuloma. METHODS: A literature search was performed in the second week of September, 2022 using Google scholar, PubMed, MEDLINE and EMBASE databases using the keywords 'umbilical granuloma' and 'salt treatment' to identify all English articles pertaining to salt treatment for umbilical granuloma. Tables were made to summarize the methodological characteristics, results and the dosage regimens of salt used by different authors. The Cochrane Collaboration's tool was used for assessing risk of bias in RCTs. The indexing statuses of the journals publishing these studies were also noted. The overall efficacy with the use of common salt was calculated by adding the success rates mentioned in each study. RESULTS: Twenty-four articles (2 systematic reviews, 6 Randomized Controlled Trials, 11 prospective cohort studies, 1 case control study, 3 retrospective case series and 1 case report) were included. An overall 93.91% success rate (1033/1100) was seen with common salt application, without any reports of complications/recurrences. CONCLUSION: Topical application of common salt for umbilical granulomas is simple, effective and inexpensive. This scoping review provides a broader outlook at the existing level of evidence and may help in planning interventional comparative studies, so that recommendations can be formulated. It also highlights a lack of properly designed randomized controlled trials on this topic. LEVEL OF EVIDENCE: I.

Reduced toxicity conditioning and a high CD34+ cell dose can achieve full donor chimerism in DOCK8 deficiency.

Background: Biallelic mutations in the dedicator of cytokinesis 8 (DOCK8) gene were identified as the cause of combined immunodeficiency in 2009. Survival rates without hematopoietic stem cell transplant in patients with DOCK8 deficiency decline from 87% at 10 years to 33% at 30 years. Hematopoietic stem cell transplant is therefore the recommended treatment for cure of DOCK8 deficiency. However, patients with DOCK8 deficiency have multiple infectious comorbidities; hence, they cannot tolerate myeloablative conditioning. Reduced intensity conditioning reduces the risk of transplant-related mortality but increases the possibility of mixed chimerism. Mixed chimerism in children with immunodeficiency increases the risk of autoimmunity and the need for long-term immunoglobulin infusion. Objective: Here we have sought to devise a strategy for reducing the possibility of mixed chimerism without increasing the risk of transplant-related mortality. Methods: To balance the risk of transplant-related mortality and mixed chimerism, we used treosulfan-based reduced toxicity conditioning with a high CD34+ cell dose and differential T-cell capping for HLA-matched and haploidentical transplants. Results: We are able to report that by using the aforementioned novel strategy, we achieved excellent transplant outcomes in the first cohort of high-risk patients with DOCK8 deficiency from India. Conclusion: High CD34+ cell dose and reduced toxicity conditioning can achieve full donor chimerism in DOCK8 deficiency.