Trends of humoral immune responses to heterologous antigenic exposure due to vaccination & omicron SARS-CoV-2 infection: Implications for boosting

Background & objectives: Vaccination and natural infection can both augment the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how omicron infection has affected the vaccine-induced and hybrid immunity is not well studied in Indian population. The present study was aimed to assess the durability and change in responses of humoral immunity with age, prior natural infection, vaccine type and duration with a minimum gap of six months post-two doses with either ChAdOx1 nCov-19 or BBV152 prior- and post-emergence of the omicron variant. Methods: A total of 1300 participants were included in this observational study between November 2021 and May 2022. Participants had completed at least six months after vaccination (2 doses) with either ChAdOx1 nCoV-19 or an inactivated whole virus vaccine BBV152. They were grouped according to their age (? or ?60 yr) and prior exposure of SARS-CoV-2 infection. Five hundred and sixteen of these participants were followed up after emergence of the Omicron variant. The main outcome was durability and augmentation of the humoral immune response as determined by anti-receptor-binding domain (RBD) immunoglobulin G (IgG) concentrations, anti-nucleocapsid antibodies and anti-omicron RBD antibodies. Live virus neutralization assay was conducted for neutralizing antibodies against four variants – ancestral, delta and omicron and omicron sublineage BA.5. Results: Before the omicron surge, serum anti-RBD IgG antibodies were detected in 87 per cent participants after a median gap of eight months from the second vaccine dose, with a median titre of 114 [interquartile range (IQR) 32, 302] BAU/ml. The levels increased to 594 (252, 1230) BAU/ml post- omicron surge (P<0.001) with 97 per cent participants having detectable antibodies, although only 40 had symptomatic infection during the omicron surge irrespective of vaccine type and previous history of infection. Those with prior natural infection and vaccination had higher anti-RBD IgG titre at baseline, which increased further [352 (IQR 131, 869) to 816 (IQR 383, 2001) BAU/ml] (P<0.001). The antibody levels remained elevated after a mean time gap of 10 months, although there was a decline of 41 per cent. The geometric mean titre was 452.54, 172.80, 83.1 and 76.99 against the ancestral, delta, omicron and omicron BA.5 variants in the live virus neutralization assay. Interpretation & conclusions: Anti-RBD IgG antibodies were detected in 85 per cent of participants after a median gap of eight months following the second vaccine dose. Omicron infection probably resulted in a substantial proportion of asymptomatic infection in the first four months in our study population and boosted the vaccine-induced humoral immune response, which declined but still remained durable over 10 months

Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices. Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP. Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/ hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuroimaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Management of Infants with Congenital Adrenal Hyperplasia

Treatment of congenital adrenal hyperplasia (CAH) requires lifelong replacement of glucocorticoids with regular follow up to manageassociated morbidities. The current review focuses on follow-up and management of infants diagnosed with classical CAH pertinent toIndian context. Early initiation of oral hydrocortisone in divided doses is recommended after diagnosis in newborn period, infancy andchildhood. Fludrocortisone is recommended for all infants with classical CAH. All infants should be monitored as per protocol fordisease and treatment related complications. The role of prenatal steroids to pregnant women with previous history of CAH affectedinfant for prevention of virilization of female fetus is controversial.

Newborn Screening and Diagnosis of Infants with Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is an autosomal recessive endocrine disorder which can manifest after birth with ambiguousgenitalia and salt-wasting crisis. However, genital ambiguity is not seen in male babies and may be mild in female babies, leading to amissed diagnosis of classical CAH at birth. In this review, we provide a standard operating protocol for routine newborn screening forCAH in Indian settings. A standardization of first tier screening tests with a single consistent set of cut-off values stratified by gestationalage is also suggested. The protocol also recommends a two-tier protocol of initial immunoassay/time resolved fluoroimmunoassayfollowed by liquid chromatography tandem mass spectrometry for confirmation of screen positive babies, wherever feasible. Routinemolecular and genetic testing is not essential for establishing the diagnosis in all screen positive babies, but has significant utility inprenatal diagnosis and genetic counseling for future pregnancy.

Testing Modalities for Inborn Errors of Metabolism – What a Clinician Needs to Know?

The present century is being hailed as the century for genetic therapies, and inborn errors of metabolism is leading the way. As we gearourselves for treating children with genetic and metabolic disorders, the key is to recognize them early and accurately for best outcomes.In these changing times with advent of technology, clinicians are now more aware, exposed and well equipped with the armamentariumof diagnostic modalities. However, it is difficult to choose between the tests without a baseline knowledge about testing for genetic andmetabolic disorders. The key question for a clinician when dealing with a suspected metabolic disorder case is ‘what test to order’ and‘how to proceed.’ The current article provides a rational view on the various laboratory testing modalities available for diagnosis of inbornerrors of metabolism. The article provides details of the basic and advanced metabolic tests that can be ordered in appropriate settings

Association Between Neonatal Thyroid Stimulating Hormone Status and Maternal Urinary Iodine Status

Background: Maternal urinary iodine concentration (MUIC) andpercentage of neonates with Thyroid stimulating hormone (TSH)>5 mIU/L are amongst the parameters suggested for assessingadequate iodine status.Objective: To assess the correlation between MUIC andneonatal TSH levels.Study design: Cross-sectional.Settings: Tertiary care center in Delhi, India, between November2015 to November 2016.Participants: Postnatal mother-neonate dyads.Methods: TSH levels assessed among neonatal samples werestratified as below and above 5 mIU/L. MUIC was measured in544 mothers, 400 mother-neonate dyads with neonatal TSHlevels >5 mIU/L (cases) and 144 mother-neonate newbornmother dyads with neonatal TSH <5 mIU/L (controls).Results: The percentage of mothers with iodine insufficiency(9.8% vs 5.6%) as well as iodine excess (54.3% vs 41.7%) weresignificant higher in cases than controls. Mean TSH was alsohigher (P=0.0002) in both the iodine deficient and iodine excessgroup. There was no correlation between neonatal TSH valuesand MUIC.Conclusions: Lack of correlation between neonatal TSH andMUIC is due to iodine excess together with iodine deficiency.

Utility of Detecting sof Gene as Evidence of Streptococcus pyogenes Infection in Acute Rheumatic Fever

Objectives: To determine the diagnostic accuracy of polymerase chain reaction-baseddetection of sof gene compared to throat swab culture for S. pyogenes infection in patientswith acute rheumatic fever and those with recurrence of rheumatic activity. Methods: 40patients between 3 to 18 years of age, with clinical diagnosis of acute rheumatic fever or newactivity in established rheumatic heart disease were included. The amplicon of 228bp of sofgene was detected using a polymerase chain reaction-based technique and the results werecompared with throat swab culture for Streptococcus pyogenes. Results: 10 patients hada positive throat swab culture and 11 had sof gene detected. The sensitivity and specificityof the test was 100% and 96.7%, respectively compared to throat swab culture (P=0.001).The positive predictive value and the negative predictive value was 90.9% and 100%respectively. Conclusions: Polymerase chain reaction-based detection of sof geneprovides an alternative to throat swab culture in diagnosing activity in Acute RheumaticFever or established Rheumatic heart disease.

An Optimal Capillary Screen Cut-off of Thyroid Stimulating Hormone for Diagnosing Congenital Hypothyroidism: Data from a Pilot Newborn Screening Program in Delhi

Objective: To determine an appropriate cut-off of capillaryThyroid stimulating hormone (TSH) for congenitalhypothyroidism.Study design: Cross-sectional.Participants: 174,000 neonates born in different hospitals ofDelhi, India, from November 2014 to October 2016.Main outcome measures: Correlation between initial andrepeat capillary TSH level and subsequent venous free thyroxine(fT4) level.Results: 102 newborns with initial/ repeat capillary TSH level of≥20 mIU/L (n=174) were confirmed to have congenitalhypothyroidism at mean (SD) age of 5 (4) days. A goodcorrelation between capillary TSH level and confirmatory venousfT4 level and postnatal age of sampling was obtained (r -0.6,-0.4). The area under the ROC curve (AUC) was 0.81 (95%CI0.75 to 0.88), indicating referral capillary TSH level of 20 mIU/L tobe a good predictor of subsequent high venous TSH level.Conclusion: A cut off of ≥20 mIU/L for capillary TSH screeningbeyond 24 hours of life is optimal in the Indian setting for decidingfurther recall and workup, keeping a balance between sensitivityand recall rate.

Consensus Statement of the Indian Academy of Pediatrics on Diagnosis and Management of Fragile X Syndrome in India

Justification:Fragile X Syndrome (FXS) is the most common genetic cause of inherited intellectual disability and autism spectrumdisorder (ASD). Early identification results in appropriate management and improvement in functioning. Risk assessment in other familymembers can lead to prevention of the disorder. This necessitated the formulation of IAP recommendations for the diagnosis andmanagement of FXS in Indian children and adolescents.Process:The meeting on formulation of national consensus guidelines on Fragile X syndrome was organized by the Indian Academy ofPediatrics in New Delhi on 25th February, 2017. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists,Pediatric Neurologists, Gynecologists, Geneticists, Clinical Psychologists and Remedial Educators, and representatives of ParentOrganizations. Guidelines were framed after extensive discussions. A writing committee was formed that drafted the manuscript,which was circulated among members for critical appraisal, and finalized.Recommendations: The committee recommended that early diagnosis of FXS is crucial for early, timely and appropriatemanagement. The interventions including timely occupational therapy, speech therapy and behavioral modifications help to improve thedevelopmental potential and reduce the maladaptive behavior. Pharmacotherapy may be needed to control and improve behavioralsymptoms. In addition, the emergence of targeted treatments such as low dose sertraline, metformin and /or minocycline may also behelpful for behavior, and perhaps cognition. Genetic counselling is helpful to communicate the risk for future children with FXS orpermutation involvement.

Autism Spectrum Disorders and Celiac Disease: Is there an Association?

We included 150 children aged 2-12 years with Autism SpectrumDisorders and normal serum total IgA levels, and screened themfor celiac disease using anti-tissue transglutaminase IgA levels.All the children were screen negative, suggesting lack ofpositive association between Autism Spectrum Disorders andCeliac disease.

Diagnosis and Management of Gaucher Disease in India – Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics

Justification: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinicalmanifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD haspaucity of information and optimal management guidelines for Indian patients.Process: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invitedexperts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed andthe draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016at the annual meeting of the Indian Academy of Medical Genetics.Objectives: These guidelines are intended to serve as a standard framework for treating physicians and the health care systems foroptimal management of Gaucher disease in India and to define unique needs of this patient population.Recommendations: Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequentlyexperience diagnostic delays during which severe irreversible complications occur. Leucocyte acid ?-glucosidase activity ismandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathicdisease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved byearly initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such asseizures and or/ neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein arefor diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrenceof the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encounteredin our population

Newborn Screening for G6PD Deficiency: A 2-year Data from North India.

Glucose-6-phosphate dehydrogenase (G6PD) defi ciency is the most common erythrocyte enzymopathy, being present in more than 400 million people worldwide that may lead to neonatal jaundice or hemolytic crisis due to drugs or infections. In our study, we aimed to study the frequency of G6PD defi ciency in neonates and the proportion of defi cient neonates, who developed neonatal hyperbilirubinemia in the study population. The study was an observational one, conducted at the Division of Genetics of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, over a 2-year period from January 2011 to December 2012. A total of 6,000 newborns delivered during that period underwent newborn screening on 24-72 h of birth. Neonatal hyperbilirubinemia was presented in 13.3% of the study population. Of female neonates, 16% demonstrated G6PD defi ciency. This is worth noting for an X-linked recessive trait. Thus, in view of a high gene frequency for a disorder that is manageable with just elimination of few drugs and foodstuff, we stress the need for a newborn screening program for G6PD deficiency.

Ultra Rice Technology: Acceptable Micronutrient Losses and Limited Microbial Growth Enable Shelf Life Extension.

Objectives: The objective of this research was to determine if Ultra Rice (UR) fortified grains are shelf stable and suitable for consumption after 24 months (m) of storage and to document micronutrient losses to determine overages that must be included in the initial formulation. A longer shelf life will prevent the unnecessary disposal of fortified grains at 12m, enable fortified rice grains to be blended prior to transport, and increase the likelihood that it will reach vulnerable populations. Methods: UR premix kernels were sampled from a World Vision warehouse in Burundi every 6m over 24 m. The growth of microorganisms was tested in a certified laboratory and compared with the World Food Programme's (WFP) food safety standards for fortified rice: 10,000 /gram for Aerobic colony count, 50 /gram for Bacillus cereus, 0/gram for E. coli, 10 /gram for Coliforms, 100 /gram for Yeasts and moulds, and negative results for Salmonella. Micronutrient losses were calculated between 0 and 24 m, accounting for moisture. Results: Microorganism growth remained at or below the WFP acceptable limits after 24 m of storage. The micronutrient data indicated losses of 0.5% folic acid, 15.0% thiamine, 18.5% iron, and 18.1% zinc after 24 m of storage. Conclusions: The lack of bacterial growth within UR fortified rice suggests it can be safely consumed for at least 24 m following production and the shelf life can be extended to 24 m under similar storage conditions. Micronutrient losses were small and these amounts will be used to calculate overages with greater precision when formulating future micronutrient premix. *Funded by USDA/NIFA.

Prenatal Screening: Perspective for the Pediatrician.

Pediatricians are the first contact of a child with genetic disorders such as Down Syndrome. After diagnosis, parents often express and wish that if it was possible to detect it during pregnancy and could it be avoided in the future pregnancy. This makes it essential that pediatricians should have some idea about the basic screening methods and strategy used during pregnancy.

Delayed Presentation of Rickets in a Child with Labyrinthine Aplasia, Microtia and Microdontia (LAMM) Syndrome.

Background: Labyrinthine Aplasia, Microtia and Microdontia (LAMM) syndrome is characterized by the complete absence of inner ear structures (Michel aplasia), microtia and microdontia. Hypophosphatemic rickets results from defects in the renal tubular reabsorption of filtered phosphate. Case characteristics: 13-year-old Indian girl presented with deafness since infancy and progressive wrist widening and genu valgum for last one year. Observation: Homozygous novel missense mutation in fibroblast growth factor 3. Message: LAMM syndrome and hypophosphatemic rickets may be associated.

Establishing National Neonatal Perinatal Database and Birth Defects Registry Network – Need of the Hour.

Early detection and prevention of birth defects is necessary to further reduce neonatal morbidity and mortality. A birth defect registry or surveillance system is necessary to assess the exact magnitude, profile and modifiable risk factors for birth defects. We review the existing efforts and suggest possible options for addressing this important issue. Connecting birth defects registry with the pre-existing programs such as National Neonatal Perinatal Database could be one of the option.

Heparin Co-factor II Thrombin Complex as a Biomarker for Mucopolysaccharidosis: Indian Experience.

Background: Serum heparin cofactor II-thrombin complex (HCII-T) is an emerging biomarker for mucopolysaccharidosis disease (MPS I and MPS II). Methods: Seventeen cases (6 MPS I and 11 MPS II) and sixty healthy controls were enrolled in study, conducted from September 2008 to December 2012. The mean ± SD age of MPS1 (n=6, 5 males) and MPS II was 7.02 ± 3.25 and 5.2 ± 2.15 years, respectively. Disease status was confirmed by clinical features and enzyme assay. Urinary glycosaminoglycans were measured in spot urine samples and expressed in relation to creatinine content. HCIIT measurement was done using sandwich ELISA at enrolment and after 12 and 24 months of recruitment. Results: Urinary glycosaminoglycans and HCIIT were elevated in all patients compared to their healthy controls. Both markers could not discriminate between the type of mucopolysaccharidosis. Conclusion: Heparin Cofactor II Thrombin Complex is a good biomarker for mucopolysaccharidosis I and II.

Intellectual Disability in Indian Children: Experience with a Stratified Approach for Etiological Diagnosis.

Objective: To study the clinico-etiological profile of children with intellectual disability using an algorithmic approach. Design: Cross-sectional study. Setting: Tertiary care centre in Northern India. Participants: Consecutive children aged 3 months to 12 years, presenting with intellectual disability, confirmed by Developmental Assessment Scale for Indian Infants, Binet Kulshreshtha Test and Vineland Social Maturity Scale. Method: All children were assessed on an internally validated structured proforma. A targeted approach included thyroid function tests, Brainstem evoked response audiometry, electroencephalogram, neuroimaging and metabolic screen done as a pre-decided schema. Genetic tests included karyotyping, molecular studies for Fragile X, Multiplex Ligation Dependent Probe Amplification and Array Comparative Genomic Hybridisation. Results: Data of 101 children (median age 22 months) was analyzed. The etiological yield was 82.1% with genetic causes being the most common (61.4%) followed by perinatal acquired (20.4%), CNS malformations (12%), external prenatal (3.6%), and postnatal acquired (2.4%). Mild delay was seen in 11.7%, moderate in 21.7%, severe in 30.6% and profound in 35.6%. Conclusion: It is possible to ascertain the diagnosis in most of the cases of intellectual disability using a judicious and sequential battery of tests.