Transmission patterns of C1-INH deficiency hereditary angioedema favors a wild-type male offspring: Our experience at Chandigarh, India.

BACKGROUND: Deficiency of C1-inhibitor (C1-INH) protein, caused by pathogenic variants in the Serpin family G member 1 (SERPING1) gene, is the commonest pathophysiological abnormality (in ∼95 % cases) in patients with hereditary angioedema (HAE). C1-INH protein provides negative control over kallikrein-kinin system (KKS). Although the inheritance of the HAE-C1-INH is autosomal dominant, female predominance has often been observed in patients with HAE. OBJECTIVE: To analyze the risk of transmission of SERPING1 gene variant from father or mother to their offspring. METHODS: Pedigree charts of 42 families with a confirmed diagnosis of HAE-C1-INH and a pathogenic variant in the SERPING1 gene were analysed. Patients with HAE who had had at least one child were included for analyses to assess the risk of transmission from the father or mother to their offspring. RESULTS: Overall, 49 % (189/385) of all offspring inherited the genetic defect. In the subgroup analyses, 54.8 % (90/164) female offspring and 44.8 % (99/221; p < 0.02) male offspring inherited the genetic defect. Inheritance of the genetic defect was significantly lower in male offspring. Fathers with SERPING1 gene variant had a statistically significant skewed transmission of the wild type to the male offspring as compared to the variant (57.8 % wild type vs. 42.1 % variant; p < 0.02), whereas no statistically significant difference was found when a father transmitted the variant to a female offspring. Mothers with SERPING1 gene variant had no statistically significant difference in variant transmission to male or female offsprings. CONCLUSION: Results of the study suggest that the transmission pattern of SERPING1 gene variant favours the transmission of wild-type alleles in males, especially when the father is the carrier; hence, overall, fewer males and more female offspring inherited the variant. This could be because of a selection of wild-type male sperms during spermatogenesis, as the KLK system has been reported to play a crucial role in the regulation of spermatogenesis. Although, a similar pattern was observed in the maternal transmission of the SERPING1 gene variant; the difference was not statistically significant, likely because of a small sample size.

Delay in diagnosis is the most important proximate reason for mortality in hereditary angio-oedema: our experience at Chandigarh, India.

BACKGROUND: Hereditary angio-oedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of nonpruritic subcutaneous and/or submucosal oedema. Laryngeal oedema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for the management of HAE, mortality was as high as 30%. Mortality has significantly declined in countries where first-line treatment options are available and patients can access these therapies. There is a paucity of literature on the outcomes of patients with HAE in developing countries where availability of and access to first-line treatment options are still a challenge. OBJECTIVES: To report our experience on mortality in patients with HAE and to report factors associated with the death of these patients. METHODS: We carried out a record review of all patients diagnosed with HAE between January 1996 and August 2022. Families with HAE who had reported the death of at least one family member/relative from laryngeal oedema were studied in detail. RESULTS: Of the 65 families (170 patients) registered in the clinic, 16 families reported the death of at least one family member/relative from laryngeal oedema (total of 36 deaths). Of these 16 families, 14 reported that 1 or more family members had experienced at least 1 attack of laryngeal oedema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid, while the remaining 35 patients were not diagnosed with HAE at the time of their death. At the time of death of all 36 patients, at least 1 other family member had symptoms suggestive of HAE, but the diagnosis was not established for the family. CONCLUSIONS: To our knowledge, this is the largest single-centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. The delay in diagnosis is the most important reason for mortality.

Modulation of autophagy and mTOR signaling pathway genes in respiratory epithelium by respiratory syncytial virus (RSV) in children suffering from acute lower respiratory tract infections.

The study was planned to carry out the molecular characterization of the respiratory syncytial virus (RSV) circulating strains and to elucidate the gene expression of autophagy and mammalian target of rapamycin (mTOR) signaling pathways in children with acute lower respiratory tract infection (ALRTI). Nasopharyngeal aspirate (NPA) samples (n = 145) from children suffering from ALRTI were subjected to the detection of RSV. Of them, 31 RSV positive strains were subjected for sequencing. Semi-quantitative gene expression analysis for mTOR signaling and autophagy pathway genes was performed in respiratory tract epithelial cells using 25 RSV positive cases, and 10 age and sex matched healthy control subjects. Five representative genes were selected for each pathway and subjected to SYBR green real-time polymerase chain reaction. RSV was positive in 69 (47.6%) samples and the representative (n = 31) RSV strains belonged to RSV-A. Thirty-one strains of RSV-A on phylogenetic analysis clustered with the novel ON1 genotype having 72 bp nucleotide duplicationby targeting the ecto-domain portion of the G gene. Further, the stains belonged to lineage 1 (51.6%), followed by lineage 3 (29%) and lineage 2 (19.4%). Autophagy gene expression analysis revealed significant upregulation in NPC1 and ATG3 autophagy genes. mTOR, AKT1, and TSC1 genes of the mTOR pathway were significantly downregulated in RSV positive patients. Thus, RSV infection inducing autophagy pathway genes (NPC1 and ATG3) and suppressing mTOR signaling pathway genes (AKT1, mTOR, and TSC1) to possibly evade the host immune system through dysregulating these pathways for its way of survival within the host.

Clinico-virological Profile, Intensive Care Needs, and Outcome of Infants with Acute Viral Bronchiolitis: A Prospective Observational Study.

OBJECTIVES: The objective of the study was to describe the clinico-virological profile, treatment details, intensive care needs, and outcome of infants with acute viral bronchiolitis (AVB). METHODOLOGY: In this prospective observational study, 173 infants with AVB admitted to the pediatric emergency room and pediatric intensive care unit (PICU) of a tertiary care teaching hospital in North India during November 2019 to February 2020 were enrolled. The data collection included clinical features, viruses detected [respiratory syncytial virus (RSV), rhinovirus, influenza A virus, parainfluenza virus (PIV) 2 and 3, and human metapneumovirus (hMPV)], complications, intensive care needs, treatment, and outcomes. Multivariate analysis was performed to determine independent predictors for PICU admission. RESULTS: Most common symptoms were rapid breathing (98.8%), cough (98.3%), and fever (74%). On examination, tachypnea (98.8%), chest retractions (93.6%), respiratory failure (84.4%), wheezing (49.7%), and crepitations (23.1%) were observed. RSV and rhinovirus were the predominant isolates. Complications were noted in 25% of cases as encephalopathy (17.3%), transaminitis (14.3%), shock (13.9%), acute kidney injury (AKI) (7.5%), myocarditis (6.4%), multiple organ dysfunction syndrome (MODS) (5.8%), and acute respiratory distress syndrome (ARDS) (4.6%). More than one-third of cases required PICU admission. The treatment details included nasal cannula oxygen (11%), continuous positive airway pressure (51.4%), high-flow nasal cannula (14.5%), mechanical ventilation (23.1%), nebulization (74%), antibiotics (35.9%), and vasoactive drugs (13.9%). The mortality was 8.1%. Underlying comorbidity, chest retractions, respiratory failure at admission, presence of shock, and need for mechanical ventilation were independent predictors of PICU admission. Isolation of virus or coinfection was not associated with disease severity, intensive care needs, and outcomes. CONCLUSION: Among infants with AVB, RSV and rhinovirus were predominant. One-third infants with AVB needed PICU admission. The presence of comorbidity, chest retractions, respiratory failure, shock, and need for mechanical ventilation independently predicted PICU admission. HOW TO CITE THIS ARTICLE: Angurana SK, Takia L, Sarkar S, Jangra I, Bora I, Ratho RK, et al. Clinico-virological Profile, Intensive Care Needs, and Outcome of Infants with Acute Viral Bronchiolitis: A Prospective Observational Study. Indian J Crit Care Med 2021;25(11):1301-1307.