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

Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction - MI3 Trial.

Background & objectives: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 108 autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy. Methods: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI). Results: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 108 (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study. Interpretation & conclusions: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.

Vitamin D levels in Indian children with intrathoracic tuberculosis.

Background & objectives: Deficiency of vitamin D, an immunomodulator agent, is associated with increased susceptibility to tuberculosis in adults, but only limited studies are available in the paediatric age group, especially regarding association of vitamin D with type and outcome of tuberculosis. We conducted this study to determine the baseline 25-hydroxy vitamin D levels in children suffering from intrathoracic tuberculosis and its association with type and outcome of tuberculosis. Methods: Children with intrathoracic tuberculosis, diagnosed on the basis of clinico-radiological criteria, were enrolled as part of a randomized controlled trial on micronutrient supplementation in paediatric tuberculosis patients. Levels of 25-hydroxy vitamin D were measured in serum samples collected prior to starting antitubercular therapy by chemiluminescent immunoassay technology. Results: Two hundred sixty six children (mean age of 106.9 ± 43.7 months; 57.1% girls) were enrolled. Chest X-ray was suggestive of primary pulmonary complex, progressive disease and pleural effusion in 81 (30.5%), 149 (56%) and 36 (13.5%) subjects, respectively. Median serum 25-hydroxy vitamin D level was 8 ng/ml (IQR 5, 12). One hundred and eighty six (69.9%) children were vitamin D deficient (serum 25-hydroxy vitamin D <12 ng/ml), 55 (20.7%) were insufficient (12 to <20 ng/ml) and 25 (9.4%) were vitamin D sufficient (≥ 20 ng/ml). lLevels of 25-hydroxy vitamin D were similar in all three types of intrathoracic tuberculosis, and in microbiologically confirmed and probable cases. Levels of 25-hydroxy vitamin D did not significantly affect outcome of the disease. Children who were deficient or insufficient were less likely to convert (become smear/culture negative) at two months as compared to those who were 25-hydroxy vitamin D sufficient (p<0.05). Interpretation & conclusions: Majority of Indian children with newly diagnosed intrathoracic tuberculosis were deficient in vitamin D. Type of disease or outcome was not affected by 25-hydroxy vitamin D levels in these children. However, children who did not demonstrate sputum conversion after intensive phase of antitubercular therapy had lower baseline 25-hydroxy vitamin D levels as compared to those who did.

Prospective multi-centre sentinel surveillance for Haemophilus influenzae type b & other bacterial meningitis in Indian children.

Background & objectives: Haemophilus influenzae type b (Hib) is one of the leading bacterial causes of invasive disease in populations without access to Hib conjugate vaccines (Hib-CV). India has recently decided to introduce Hib-CV into the routine immunization programme in selected States. Longitudinal data quantifying the burden of bacterial meningitis and the proportion of disease caused by various bacteria are needed to track the impact of Hib-CV once introduced. A hospital-based sentinel surveillance network was established at four places in the country and this study reports the results of this ongoing surveillance. Methods: Children aged 1 to 23 months with suspected bacterial meningitis were enrolled in Chennai, Lucknow, New Delhi, and Vellore between July 2008 and June 2010. All cerebrospinal fluid (CSF) samples were tested using cytological, biochemical, and culture methods. Samples with abnormal CSF (≥10 WBC per μl) were tested by latex agglutination test for common paediatric bacterial meningitis pathogens. Results: A total of 708 patients with abnormal CSF were identified, 89 of whom had a bacterial pathogen confirmed. Hib accounted for the majority of bacteriologically confirmed cases, 62 (70%), while Streptococcus pneumoniae and group B Streptococcus were identified in 12 (13%) and seven (8%) cases, respectively. The other eight cases were a mix of other bacteria. The proportion of abnormal CSF and probable bacterial meningitis that was caused by Hib was 74 and 58 per cent lower at Christian Medical College (CMC), Vellore, which had a 41 per cent coverage of Hib-CV among all suspected meningitis cases, compared to the combined average proportion at the other three centres where a coverage between 1 and 8 per cent was seen (P<0.001 and P= 0.05, respectively). Interpretation & conclusions: Hib was found to be the predominant cause of bacterial meningitis in young children in diverse geographic locations in India. Possible indications of herd immunity was seen at CMC compared to sites with low immunization coverage with Hib-CV. As Hib is the most common pathogen in bacterial meningitis, Hib-CV would have a large impact on bacterial meningitis in Indian children.

Neonatal Zinc Supplementation for Prevention of Mortality and Morbidity in Breastfed Low Birth Weight Infants: Systematic Review of Randomized Controlled Trials.

Objectives: To evaluate whether zinc supplements prevent mortality and morbidity in breastfed low birth weight infants. Methods: All randomized or qausi–randomized trials with individual or cluster allocation and using concurrent controls were included. Study population included LBW infants irrespective of gestational status who were exclusively or predominantly breastfed at the initiation of intervention. Intervention comprised zinc salts given as tablets or syrups orally to provide at least 1 RDA of elemental zinc for at least a period of 14 days, introduced within one month of birth. Electronic databases were searched irrespective of language and publication status. Findings: Three trials from developing countries met the inclusion criteria. Limited data did not indicate a reduced risk of mortality (1 trial, RR=1.11; 95% CI 0.57 to 2.18 at one year), hospitalization rate (1 trial, odds ratio 1.10; 95% CI 0.87 to 1.39), acute respiratory infection (1 trial), or diarrhea (2 trials). However, the trial reporting on mortality was not adequately powered for evaluating this outcome. There was no evidence of an increase in weight (3 trials) or height (2 trials) at either 6 months or one year of age, or of an increased risk of vomiting following zinc supplementation. Serum zinc levels at the end of intervention were significantly higher in the supplemented group (2 trials). Conclusions: In view of no convincing evidence of benefits from the limited data available, currently there is no justification for recommending routine zinc supplementation for breastfed LBW newborns in developing countries.

Current spectrum of malabsorption syndrome in adults in India.

Aim Tropical sprue was considered to be the most important cause of malabsorption in adults in India. However, several reports indicate that celiac disease is now recognized more frequently. Methods We analyzed the clinical presentation, endoscopic and histological features of 94 consecutive patients (age >12 years) with chronic diarrhea and malabsorption syndrome. The spectrum of disease in these patients and features differentiating celiac disease and tropical sprue are reported here. Results Celiac disease (n=61, 65%) was the most common cause of malabsorption followed by tropical sprue (21, 22%). Other conditions including cyclosporiasis (3), Crohn’s disease (2), common variable immunodeficiency (2), lymphangiectasia (1), William’s syndrome (1), and idiopathic malabsorption (3) accounted for the remainder. A greater number (21, 34%) of patients with celiac disease than those with tropical sprue (4, 19%) presented with atypical manifestations. Patients with celiac disease were younger (p=0.001), more often had anemia, (p=0.001), scalloping of folds (p=0.001), moderate (p=0.02) or severe (p=0.001) villous atrophy, higher grade of intraepithelial lymphocytic infiltration (p=0.001), crypt hyperplasia (p=0.001), cuboidal (p=0.001) and pseudostratified (p=0.009) surface epithelial cells, and diffuse (p=0.001) epithelial damage. In comparison, patients with tropical sprue were older and more often had normal duodenal folds, normal villi, tall columnar epithelial cells and focal epithelial damage. Conclusions Celiac disease was the most frequent cause of malabsorption syndrome in this series of patients. There are significant clinical and histological differences between celiac disease and tropical sprue.

Directing Diarrhoeal Disease Research towards Disease-burden Reduction.

Despite gains in controlling mortality relating to diarrhoeal disease, the burden of disease remains unacceptably high. To refocus health research to target disease-burden reduction as the goal of research in child health, the Child Health and Nutrition Research Initiative developed a systematic strategy to rank health research options. This priority-setting exercise included listing of 46 competitive research options in diarrhoeal disease and their critical and quantitative appraisal by 10 experts based on five criteria for research that reflect the ability of the research to be translated into interventions and achieved disease-burden reduction. These criteria included the answerability of the research questions; the efficacy and effectiveness of the intervention resulting from the research; the maximal potential for disease-burden reduction of the interventions derived from the research; the affordability, deliverability, and sustainability of the intervention supported by the research; and the overall effect of the research-derived intervention on equity. Experts scored each research option independently to delineate the best investments for diarrhoeal disease control in the developing world to reduce the burden of disease by 2015. Priority scores obtained for health policy and systems research obtained eight of the top 10 rankings in overall scores, indicating that current investments in health research are significantly different from those estimated to be the most effective in reducing the global burden of diarrhoeal disease by 2015.

Diagnosis of celiac disease.

Celiac disease is an immune mediated enteropathy initiated by ingestion of gluten, in genetically susceptible individuals. With changing epidemiology, celiac disease initially thought to affect only Europeans, has been increasingly reported from other parts of the world including India. However, its true prevalence in India is still not known, as the diagnosis is being missed. The gold standards for diagnosis have been characteristic small intestinal mucosal changes on gluten and a full clinical remission on its removal from the diet. Presence of serological antibodies, which disappear on gluten free diet further confirms the diagnosis. The understanding of the histopathology of celiac disease has changed over the years. The small bowel mucosal lesion of celiac disease is an evolutionary process with normal mucosal architecture and an increase in intraepithelial lymphocytes at one end of the spectrum and classical flat mucosa at the other. In the Indian subcontinent celiac disease has a heterogeneous histological presentation and the diagnosis may be missed if it is based only on severe mucosal changes or the serology is not considered when moderate or mild mucosal changes are present. The last two decades have shown that antiendomysical (Anti EMA) and anti tissue transglutaminase antibodies (anti-tTGA) have a sensitivity and specificity of more than 95% to diagnose celiac disease. Anti EMA tests being operator dependent are more liable to errors and anti- tTGA may be preferred for large scale screening. However, the different source of tTGA antigen, varied techniques of production and the use of arbitrary units by different commercial kits can influence the diagnostic accuracy of the anti-tTGA assay. There is a strong genetic association of celiac disease with HLA-DQ2 or DQ8. The presence of HLA-DQ2 hetrodimer in more than 97% of a group of North Indian patients with celiac disease indicates that this population has a similar genetic risk for the disease. HLA DQ2 typing can be used for ruling out celiac disease where the diagnosis is equivocal as it has a negative predictive value of greater than 95%. Given the protean clinical manifestation and the heterogeneous histology a standard algorithm for diagnosis of celiac disease is important.

Zinc in child health and disease.

Zinc deficiency is common in children from developing countries due to lack of intake of animal foods, high dietary phytate content, inadequate food intake and increased fecal losses during diarrhea. Zinc has a fundamental role in cellular metabolism, with profound effects on the immune system and the intestinal mucosa. Zinc supplementation has shown significant benefits in prevention and treatment of diarrhea and pneumonia. Routine zinc supplementation given to low birth weight babies for a year has resulted in substantial reduction in mortality. Zinc deficiency may have adverse effects on physical growth and neurodevelopment. WHO Task Force, 2001, and the National task Force of IAP has recommended use of zinc in the treatment of diarrhea. It is also recommended as part of standard case management in persistent diarrhea and in those with severe malnutrition. Further evidence is required for qualifying its use in treatment of other infective diseases like pneumonia and malaria. Improved dietary quality & intake, food fortification and cultivation of zinc dense plants are some ways of mitigating zinc deficiency.