Infectious complications in children with nephrotic syndrome: Can they be prevented?

Background: Sixty percent of children with nephrotic syndrome have frequently relapsing or steroid-dependent course. Serious infections like peritonitis, cellulitis, pneumonia etc. and anasarca with reduced urine output and complications there of including acute kidney injury and thromboembolism contribute significantly to morbidity and mortality in these children. Methods: Questionnaire-based module to study infectious complications in children with nephrotic syndrome was circulated through survey monkey portal to paediatric nephrologists in our country. Twenty-two responded. Forty percent said that they saw patients with severe infections once a month. Fish bone analysis conducted on such patients reporting to our centre over next 3 months revealed that only 22% regularly monitored urine protein by dipstick. We proposed that reduction in time to report relapse by regularly monitoring urine protein could reduce complications in these children. Six urine protein dipsticks were handed over to patients who presented >7 days since relapse or with severe infection or anasarca in the last 1 year. These children were followed up for the next 1 year and given six more urine dipsticks every 3 months. Results: Twenty-three patients were given urine protein dipsticks. Nine of them had 12 severe complications in the previous 6 months. None had any serious infections/anasarca on follow-up. Sixteen new patients had 14 serious complications in this time. Conclusions: Early detection of relapse by home monitoring of urine protein by dipsticks was effective in significantly reducing the number of patients with severe infections and anasarca with reduced urine output.

New-onset diabetic ketoacidosis with purpura fulminans in a child with COVID-19-related multisystem inflammatory syndrome.

BACKGROUND: Coronavirus disease 2019 (COVID 19) usually causes a mild illness among children. However, in a minority of children, it may be associated with the life-threatening multisystem inflammatory syndrome (MIS-C), or thrombotic microangiopathy, or sequelae like type-1 diabetes mellitus (T1DM). We describe a previously healthy, 12-year-old boy with new-onset T1DM with diabetic ketoacidosis (DKA) in the setting of MIS-C, with a course complicated by thrombotic microangiopathy. CASE PRESENTATION: The patient presented with four days history of fever, non-bilious vomiting, polyuria and polydipsia. On evaluation, he was noted to have diabetic ketoacidosis. Although Diabetic ketoacidosis with insulin and intravenous fluids, his hospital course was notable for shock requiring vasopressor, purpura fulminans with eschar formation, neurological manifestations (left hemiparesis due to right middle cerebral artery territory infarct, mononeuritis multiplex) and thrombotic microangiopathy. MIS-C-like illness secondary to COVID-19 was suspected due to diabetic ketoacidosis, thrombotic microangiopathy, elevated inflammatory markers, history of contact with COVID-19-infected individual and detectable COVID-19 IgG antibodies. He improved following management with methylprednisolone, intravenous immunoglobulin, low-molecular-weight heparin and aspirin, and was discharged on hospital day 48. CONCLUSION: MIS-C-like illness should be considered in children and adolescents presenting with complex multisystem involvement in this era of COVID 19. Management with immunomodulatory agents can be lifesaving.

Impact of Cerebral Oxygen Saturation Monitoring on Short-term Neurodevelopmental Outcomes in Neonates with Encephalopathy - A Prospective Cohort Study.

BACKGROUND: Near-infrared spectroscopy (NIRS) has been used for monitoring cerebral oxygen saturation (rSO2) in neonates. There is a lack of data from low-middle income countries (LMIC) setting of cerebral rSO2 in neonates with encephalopathy of diverse etiologies. This study aimed to monitor cerebral rSO2 using NIRS in encephalopathic neonates to maintain the rSO2 between 55 to 85 % in the first 72 hours of admission to improve short-term neurodevelopmental outcomes (NDO). MATERIALS AND METHODS: This prospective cohort study enrolled encephalopathic neonates with hypoxic- ischemic encephalopathy (HIE) and non-HIE etiologies into 8 clinical categories. The cerebral rSO2 was monitored and targeted to be between 55 to 85 %, with predefined actions and management alterations over 72 hours. The neurodevelopmental assessment was conducted at 3, 6, and 9-12 months corrected age. Moreover, the motor and mental developmental quotients (MoDQ) (MeDQ) were recorded and compared to historical control. RESULTS: A total of 120 neonates were enrolled and assessed for NDO. The MoDQ (mean ± SD) was 92.55 ± 14.85, 93.80 ± 13.20, 91.02 ± 12.69 and MeDQ (mean ± SD) was 91.80 ± 12.98, 91.80 ± 13.69, 88.41 ± 11.60 at 3, 6 and 9-12 months. The MoDQ and MeDQ scores of the historic cohort at 12 months were 86.35 ± 20.34 and 86.58 ± 18.27. The mean difference [MD (95 %CI)] for MoDQ was - 4.670 (- 8.48 to - 0.85) (p=0.0165) and for MeDQ was - 1.83 (- 5.26 to 1.6) (p=0.29). There was a negative correlation between the composite developmental quotient (CoDQ) with mean rSO2 and a positive correlation with cerebral fractional tissue oxygen extraction (CFTOE). Neonates with HIE and neonatal encephalopathy (NE) (n=37/120) had the lowest motor and mental DQ on neurodevelopmental assessment. Clinical categories, neonatal meningitis (NM), and intraventricular hemorrhage (IVH) improved in DQ scores over the study period. CONCLUSION: Monitoring and maintaining cerebral rSO2 between 55-85 % through appropriate management changes improved neurodevelopmental scores at the 12-month follow-up in neonates with encephalopathy caused by varied etiologies.

Clinical and molecular spectrum associated with Polymerase-γ related disorders.

BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

Upshaw-Schulman Syndrome with a Novel Deletion in Exon 17 of ADAMTS 13 Gene.

Upshaw-Schulman syndrome is a rare congenital form of thrombotic thrombocytopenic purpura (TTP) characterized by single or recurrent episodes of thrombocytopenia, microangiopathic hemolyticanemia (MAHA), and widespread microvascular thrombosis, leading to the ischemic damage of multiple organs (mainly kidney, heart and brain). A 6-mo-old female infant, second born of a third-degree consanguineous marriage, with a history of severe neonatal jaundice with thrombocytopenia secondary to hemolysis requiring exchange transfusion on day 2 of life, presented with high-grade fever without focus of 2-d duration. Initial workup revealed microangiopathic hemolyticanemia with thrombocytopenia. In view of microangiopathic hemolyticanemia with thrombocytopenia against a background of severe neonatal jaundice, a diagnosis of congenital TTP was considered and was managed with FFP transfusion. The diagnosis was confirmed with her exome sequencing showing autosomal recessive homozygous frameshift deletion c.2063delG (p.Trp688fs) at Exon 17 (NM_139025) of ADAMTS 13 gene.

Correction of hypernatremic dehydration in neonates with supervised breast-feeding: A cross-sectional observational study.

BACKGROUND: Hypernatremic dehydration is an uncommon but a serious cause of readmission in neonates especially in the ones on exclusive breast-feeding. The management of such neonates is challenging as serious complications can occur both because of hypernatremic dehydration and its rapid correction. The aim was to study the clinical profile of neonates with hypernatremic dehydration and determine the outcome of these neonates after appropriate management. METHODS: This is a prospective cross-sectional observational study of neonates readmitted with hypernatremic dehydration in a tertiary care hospital in a 12-month period from March 2017 to February 2018. The inclusion criterion was as follows: all neonates with serum sodium >145 mEq/l. The exclusion criteria were as follows: neonates with hypoglycemia, positive sepsis screen and any other congenital diseases. Neonates with serum sodium between 145 and 160 mEq/l were treated with supervised quantified oral feeds at 150 ml/kg/day, unless they had features of shock. Neonates who had serum sodium ≥160 mEq/l were given intravenous (IV) fluids initially. RESULTS: A total of 2412 deliveries took place during the study period. Hypernatremic dehydration was reported in 46 (1.9%) of them, which required admission. We found that all these neonates were exclusively breast-fed, with 81.3% neonates born to primigravidae. One neonate presented with seizures, and one, with metabolic acidosis. More than 50% neonates had acute kidney injury (AKI) on admission. No neonates in our study developed central nervous system (CNS) complications such as cerebral venous thrombosis, convulsions or intracranial haemorrhage, and complete recovery from AKI was documented in all neonates. CONCLUSION: Hypernatremic dehydration can be a serious problem even in term healthy neonates especially in exclusively breast-fed neonates born to primiparous women. Our study shows that quantified oral feeding is effective in successful management of hypernatremic dehydration and not associated with the dreaded CNS complications due to rapid correction.

Novel RNASEH2C mutation in multiple members of a large family: insights into phenotypic spectrum of Aicardi-Goutières Syndrome.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a genetic inflammatory disorder that presents with early infantile encephalopathy. We report the clinical and molecular details of multiple members of a family with AGS secondary to a novel RNASEH2C mutation, highlighting the evolution of phenotypic abnormalities in AGS. METHODS: Between February 2018 and June 2019, a pedigree tree was constructed for 141 members of a family. The clinical and radiological details of 14 symptomatic children were chronicled and compared with the asymptomatic family members. Genetic analysis was performed on 23 individuals (six symptomatic). This involved whole exome sequencing for one patient and confirmation of the identified indel variant in other family members. RESULTS: The symptomatic children were diagnosed as AGS secondary to a novel indel variation in exon 2 of the RNASEH2C gene (chr11:65487843_65487846delinsGCCA). Clinically, between the ages of 2 and 6 months, the symptomatic children developed irritability (14/14), unexplained fever (9/14), chill blains (12/14), sleep irregularities (14/14) and developmental delay (14/14), with deterioration to vegetative state at a median (IQR) age of 10.5 months (9.25-11). In addition, chill blains were observed in 5/17 (29.4%) carrier individuals. Neuroimaging demonstrated a gradual progression of calcification involving basal ganglia, periventricular white matter and dentate nucleus. Three patients also demonstrated presence of subependymal germinolytic cysts. CONCLUSION: This report highlights a novel founder RNASEH2C mutation and the phenotypic evolution of AGS. In addition, we report chill blains in one-third of RNASEH2C mutation carriers. Neuroradiologically, the report illustrates novel MRI findings and demonstrates a progression pattern of disease. These findings will aid in earlier suspicion and diagnosis of AGS.