Formula milk companies and allergy healthcare professionals in India.

India is a low-middle income country with a population of 1.4 billion and home to one quarter of the world's children. Exclusive breastfeeding until 6 months and continued breastfeeding until at least 2 years as per global recommendations are common practice. The Indian government and associated organisations have strived to protect breastfeeding, which is important in a country with high under-5 mortality, malnutrition and stunting. Allergic disease is under-recognised in India, but despite the absence of a dedicated allergy medical specialty, awareness of allergy is increasing among healthcare practitioners and in the general population. In high-income countries, overdiagnosis of allergy has become recognised as an issue in recent years. Allergy healthcare professionals have also attracted criticism for close relationships with the formula industry, which appear to have contributed to excessive use of specialised formula products and undermining of breastfeeding. Specialised formula has been used unnecessarily for preventing allergy, based on fraudulent and selectively reported science; and for managing normal infant symptoms which are mislabelled as milk allergy. This forms part of a broader formula industry corporate strategy to widen the boundaries of illness in order to expand sales and markets. In India, allergic disease management is hindered by limited understanding of the disease entity among practitioners, low access to diagnostics, limited healthcare resources, high exposure to air pollution and a large, diverse population. Data specific to India on allergic disease prevalence and interpreting allergy diagnostics are incomplete. The knowledge gaps mean allergy management in India is often extrapolated from guidance developed in high-income countries with low breastfeeding rates. As the allergy specialty develops in India, local guidance and practice will need to recognise the threat that current allergy practice poses to India's normative infant feeding culture, and ensure that breastfeeding continues to be supported at all levels.

Practical management of suspected hypersensitivity reactions to anti-tuberculosis drugs.

Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is highest in Low-Middle Income countries (LMICs). Prompt institution of, and compliance with, therapy are cornerstones for a favourable outcome in TB and to mitigate the risk of multiple drug resistant (MDR)-TB, which is challenging to treat. There is some evidence that adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs) to anti-TB drugs occur in over 60% and 3%-4% of patients respectively. Both ADRs and HSRs represent significant barriers to treatment adherence and are recognised risk factors for MDR-TB. HSRs to anti-TB drugs are usually cutaneous and benign, occur within few weeks after commencement of therapy and are likely to be T-cell mediated. Severe and systemic T-cell mediated HSRs and IgE mediated anaphylaxis to anti-TB drugs are relatively rare, but important to recognise and treat promptly. T-cell-mediated HSRs are more frequent amongst patients with co-existing HIV infection. Some patients develop multiple sensitisation to anti-TB drugs. Whilst skin tests, patch tests and in vitro diagnostics have been used in the investigation of HSRs to anti-TB drugs, their predictive value is not established, they are onerous, require specialist input of an allergist and are resource-dependent. This is compounded by the global, unmet demand for allergy specialists, particularly in low-income countries (LICs)/LMICs and now the challenging circumstances of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This narrative review provides a critical analysis of the limited published evidence on this topic and proposes a cautious and pragmatic approach to optimise and standardise the management of HSRs to anti-TB drugs. This includes clinical risk stratification and a dual strategy involving sequential re-challenge and rapid drug desensitisation. Furthermore, a concerted international effort is needed to generate real-time data on ADRs, HSRs, safety and clinical outcomes of these interventions.

Impact of Air Pollution on Allergic Rhinitis and Asthma: Consensus Statement by Indian Academy of Pediatrics.

JUSTIFICATION: Rising air pollution is an ever-growing threat to many human diseases. Poor air quality has been directly correlated with respiratory allergies with a disproportionate affection among the pediatric age group. A clear understanding of common air pollutants and their potential contribution in allergic rhinitis and asthma is lacking. OBJECTIVE: To formulate a consensus statement for appropriate understanding among pediatricians and general practitioners about the effects of air pollution on respiratory allergies and their prevention. PROCESS: A group of experts (Pediatric pulmonologists and allergy specialists) from across India were appointed by the Indian Academy of Pediatrics (IAP) to formulate a consensus statement on 'Allergy and Air pollution'. A virtual meeting was conducted on 6th April 2020 to discuss in detail regarding various issues related to the subject and a writing committee was formed with broad consensus. After extensive literature review and multiple virtual sessions, the current document was prepared and circulated via email to the representatives from central IAP and IAP environment chapter. All the experts approved the consensus with minor modifications after a detailed discussion on 29th September 2020 on a virtual platform. RECOMMENDATIONS: Air pollution is the emerging contributor to respiratory allergies due to various mechanisms including oxidative stress and compromised mucociliary clearance. Children are more vulnerable to both outdoor and indoor pollution, due to their unique physiological characteristics. Knowledge about pollutant particle size and air quality index will help in demarcating level and extent of airway involvement. Relevant environmental history in difficult allergic rhinitis and asthma cases, along with conventional pharmacological measures, is warranted. Multipronged approach, targeted at community, physician and individual levels, needs to be emphasized to improve air quality and reduce economic and psychological burden of respiratory allergies.

Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of Keratoconus.

Keratoconus (KC) is an ectatic disease of the cornea characterized by localized thinning and protrusion causing irregular astigmatism, which can lead to significant visual impairment. KC has often been associated with allergy and/or atopy, which are immune-mediated inflammatory reactions primarily driven by IgE. A higher proportion of KC patients were reported to have history or suffer from systemic and/or ocular allergy with elevated allergen-specific IgE and/or total serum IgE. Eye rubbing, one of the risk factors for worsening of the disease and developing related complications in KC, is associated with IgE driven conditions. The current review enumerates and contextualizes the evidence related to IgE in mediating KC pathogenesis, including aberrant extra-cellular matrix remodeling. This review also discusses clinical strategies directed at modulating IgE-mediated responses in the management of KC, and the emerging academic and plausible clinical relevance of assessing serum and tear IgE (allergen-specific and total) status in improving the understanding of disease pathobiology, treatment planning, and prognosis.

Management of adverse reactions to first-line tuberculosis antibiotics.

PURPOSE OF REVIEW: Tuberculosis (TB) is the commonest infectious cause of death globally. Adverse reactions to first-line tuberculosis antibiotics are common and have a major impact on the outcomes of patients as second-line antibiotics are less effective and more toxic. The present review addresses the most recent literature regarding epidemiology, investigating reactions, and reintroducing treatment in patients who have had their treatment interrupted. RECENT FINDINGS: Studies have demonstrated that up to 60% of patients experience adverse reactions to TB treatment; around a third of these are idiosyncratic and may relate to immune sensitization. There is an increased risk in patients with HIV. For patients with severe cutaneous reactions patch testing has an important role; however, systemic reactions to patch testing are common in patients with HIV. In-vitro testing remains limited to specialist centers but studies have identified drug-specific lymphocyte responses in patients with cutaneous and liver reactions. Desensitization of patients with severe cutaneous reactions have been demonstrated to be possible, albeit at high risk. SUMMARY: Management of these patients remains suboptimal. Better identification of predisposing factors, such as HLA alleles, are needed to identify patients at risk. Improved in-vitro diagnostics will reduce the need to re-expose the patient to the drug and optimized desensitization regimens will improve patient safety when drugs have to be re-introduced.

OPINION: Primary prevention of allergy - Will it soon become a reality?

It is generally accepted that allergic diseases are not curable and not preventable, but mainly controllable using pharmacotherapy (i.e. symptomatic medication). Recent research, however, demonstrated that a number of specific interventions can lead to (partial) primary prevention of allergy, especially of atopic dermatitis (AD) and food allergy (FA). Three types of primary prevention strategies have been successfully studied: early administration of bacterial products (most studies are on probiotics), early moisturizing in infants at risk for AD and early exposure to allergenic foods (peanut and egg). Results of these studies indicate that the stage might have been set. Surely, much more research needs to be carried out before advice can be given in clinical practice. This opinion article discusses the three types of beneficial interventions and gives ideas for future research, which might show the way for better strategies in primary prevention of allergic diseases.

Essential role of the plasmid hik31 operon in regulating central metabolism in the dark in Synechocystis sp. PCC 6803.

The plasmid hik31 operon (P3, slr6039-slr6041) is located on the pSYSX plasmid in Synechocystis sp. PCC 6803. A P3 mutant (ΔP3) had a growth defect in the dark and a pigment defect that was worsened by the addition of glucose. The glucose defect was from incomplete metabolism of the substrate, was pH dependent, and completely overcome by the addition of bicarbonate. Addition of organic carbon and nitrogen sources partly alleviated the defects of the mutant in the dark. Electron micrographs of the mutant revealed larger cells with division defects, glycogen limitation, lack of carboxysomes, deteriorated thylakoids and accumulation of polyhydroxybutyrate and cyanophycin. A microarray experiment over two days of growth in light-dark plus glucose revealed downregulation of several photosynthesis, amino acid biosynthesis, energy metabolism genes; and an upregulation of cell envelope and transport and binding genes in the mutant. ΔP3 had an imbalance in carbon and nitrogen levels and many sugar catabolic and cell division genes were negatively affected after the first dark period. The mutant suffered from oxidative and osmotic stress, macronutrient limitation, and an energy deficit. Therefore, the P3 operon is an important regulator of central metabolism and cell division in the dark.

Functions of the duplicated hik31 operons in central metabolism and responses to light, dark, and carbon sources in Synechocystis sp. strain PCC 6803.

There are two closely related hik31 operons involved in signal transduction on the chromosome and the pSYSX plasmid in the cyanobacterium Synechocystis sp. strain PCC 6803. We studied the growth, cell morphology, and gene expression in operon and hik mutants for both copies, under different growth conditions, to examine whether the duplicated copies have the same or different functions and gene targets and whether they are similarly regulated. Phenotype analysis suggested that both operons regulated common and separate targets in the light and the dark. The chromosomal operon was involved in the negative control of autotrophic events, whereas the plasmid operon was involved in the positive control of heterotrophic events. Both the plasmid and double operon mutant cells were larger and had division defects. The growth data also showed a regulatory role for the chromosomal hik gene under high-CO(2) conditions and the plasmid operon under low-O(2) conditions. Metal stress experiments indicated a role for the chromosomal hik gene and operon in mediating Zn and Cd tolerance, the plasmid operon in Co tolerance, and the chromosomal operon and plasmid hik gene in Ni tolerance. We conclude that both operons are differentially and temporally regulated. We suggest that the chromosomal operon is the primarily expressed copy and the plasmid operon acts as a backup to maintain appropriate gene dosages. Both operons share an integrated regulatory relationship and are induced in high light, in glucose, and in active cell growth. Additionally, the plasmid operon is induced in the dark with or without glucose.

Gene expression under low-oxygen conditions in the cyanobacterium Synechocystis sp. PCC 6803 demonstrates Hik31-dependent and -independent responses.

We have investigated the response of the cyanobacterium Synechocystis sp. PCC 6803 during growth at very low O2 concentration (bubbled with 99.9 % N(2)/0.1 % CO2). Significant transcriptional changes upon low-O2 incubation included upregulation of a cluster of genes that contained psbA1 and an operon that includes a gene encoding the two-component regulatory histidine kinase, Hik31. This regulatory cluster is of particular interest, since there are virtually identical copies on both the chromosome and plasmid pSYSX. We used a knockout mutant lacking the chromosomal copy of hik31 and studied differential transcription during the aerobic-low-O2 transition in this ΔHik31 strain and the wild-type. We observed two distinct responses to this transition, one Hik31 dependent, the other Hik31 independent. The Hik31-independent responses included the psbA1 induction and genes involved in chlorophyll biosynthesis. In addition, there were changes in a number of genes that may be involved in assembling or stabilizing photosystem (PS)II, and the hox operon and the LexA-like protein (Sll1626) were upregulated during low-O2 growth. This family of responses mostly focused on PSII and overall redox control. There was also a large set of genes that responded differently in the absence of the chromosomal Hik31. In the vast majority of these cases, Hik31 functioned as a repressor and transcription was enhanced when Hik31 was deleted. Genes in this category encoded both core and peripheral proteins for PSI and PSII, the main phycobilisome proteins, chaperones, the ATP synthase cluster and virtually all of the ribosomal proteins. These findings, coupled with the fact that ΔHik31 grew better than the wild-type under low-O2 conditions, suggested that Hik31 helps to regulate growth and overall cellular homeostasis. We detected changes in the transcription of other regulatory genes that may compensate for the loss of Hik31. We conclude that Hik31 regulates an important series of genes that relate to energy production and growth and that help to determine how Synechocystis responds to changes in O2 conditions.