Gene-environment interaction in autoimmune disease.

Autoimmune disease manifests in numerous forms, but as a disease group is relatively common in the population. It is complex in aetiology, with genetic and environmental determinants. The involvement of gene variants in autoimmune disease is well established, and evidence for significant involvement of the environment in various disease forms is growing. These factors may act independently, or they may interact, with the effect of one factor influenced by the presence of another. Identifying combinations of genetic and environmental factors that interact in autoimmune disease has the capacity to more fully explain disease risk profile, and to uncover underlying molecular mechanisms contributing to disease pathogenesis. In turn, such knowledge is likely to contribute significantly to the development of personalised medicine, and targeted preventative approaches. In this review, we consider the current evidence for gene-environment (G-E) interaction in autoimmune disease. Large-scale G-E interaction research efforts, while well-justified, face significant practical and methodological challenges. However, it is clear from the evidence that has already been generated that knowledge on how genes and environment interact at a biological level will be crucial in fully understanding the processes that manifest as autoimmunity.

Intolerance to food additives - does it exist?

'Food intolerance' is often confused with a range of adverse symptoms which may be coincidental to ingestion of food. 'Food intolerance' is defined as a reaction in which symptoms must be objectively reproducible and not known to involve an immunological mechanism. A more precise term is non-allergic food hypersensitivity, which contrasts with food allergies which are due to an immunological mechanism. Some children will experience food reactions to food additives. Reported symptoms range from urticaria/angioedema to hyperactive behaviours. While parents/carers report that over one fifth of children experience of food reaction, only 1 in 20 of these are confirmed to have a non-allergic food hypersensitivity on testing.

Allergic rhinitis in children.

Allergic rhinitis affects up to 40% of children but is commonly undiagnosed. Careful assessment of nasal symptoms allows for the most appropriate therapeutic options to be chosen. Allergen avoidance is often difficult in practice. Antihistamines are of limited benefit in allergic rhinitis caused by house dust mite and other perennial allergens, where symptoms, predominantly nasal obstruction, are not histamine mediated. In contrast, symptoms triggered by pollen, such as nasal itch, rhinorrhoea and sneezing, are relieved by antihistamines. Intranasal steroids are the treatment of choice for persistent moderate-severe allergic rhinitis and are more effective than antihistamines for relief of nasal obstruction. Failure to respond to intranasal medications is often caused by poor compliance or inefficient use of nasal sprays. Immunotherapy may be a useful, if expensive, option, particularly where symptoms are because of a specific pollen. The benefits of immunotherapy in house dust mite-induced rhinitis and asthma remain controversial.

Refractory symptoms successfully treated with leukotriene inhibition in a child with systemic mastocytosis.

Montelukast was effective in treating refractory abdominal and urinary symptoms in a child with systemic mastocytosis.

Parental perceptions and dietary adherence in children with seafood allergy.

BACKGROUND: Allergy to seafood (fish, mollusc and crustacean) is increasing and is now a leading cause of food anaphylaxis, but there is only limited data on the impact of seafood allergy on affected children and their families. METHODS: We assessed dietary adherence and perceptions of seafood allergy amongst the parents of 94 children presenting to a specialist allergy clinic with proven seafood allergy, by means of a postal questionnaire and cross-referencing the data obtained to clinical records. RESULTS: One-quarter of parents were unable to correctly recall the dietary advice provided. Nonetheless 89% of parents implemented a safe diet, but over half followed a more stringent elimination than that recommended. One-fifth of the children had subsequent allergic reactions to seafood after diagnosis, and these were generally a result of accidental rather than intentional exposure or cross-contamination. Provision of an adrenaline auto-injector device was associated with increased adherence to dietary advice. Oral food challenges had a beneficial effect on parental perceptions and were helpful to parents in managing their child's allergy. CONCLUSIONS: Seafood allergy has a significant adverse effect on anxiety and stress in the families of affected children. Parental recall of dietary advice is variable and many tend to impose more stringent dietary avoidance than that recommended. Despite this, subsequent accidental reactions are common. Thus, the avoidance of seafood in children may be more difficult than often presumed.

Effects of early cat or dog ownership on sensitisation and asthma in a high-risk cohort without disease-related modification of exposure.

Variation in the observed association between pet ownership and allergic disease may be attributable to selection bias and confounding. The aim of this study was to suggest a method to assess disease-related modification of exposure and second to examine how cat acquisition or dog ownership in early life affects atopy and asthma at 5 years. Information on sociodemographic factors and cat and dog ownership was collected longitudinally in an initially cat-free Australian birth cohort based on children with a family history of asthma. At age 5 years, 516 children were assessed for wheezing, and 488 for sensitisation. Data showed that by age 5 years, 82 children had acquired a cat. Early manifestations of allergic disease did not foreshadow a reduced rate of subsequent acquisition of a cat. Independent risk factors for acquiring a cat were exposure to tobacco smoke at home odds ratio (OR) 1.92 [95% confidence interval (CI) 1.13, 3.26], maternal education < or =12 years OR 1.95 [1.08, 3.51] and dog ownership OR 2.23 [1.23, 4.05]. Cat or dog exposure in the first 5 years was associated with a decreased risk of any allergen sensitisation, OR 0.50 [0.28, 0.88] but no association with wheeze OR 0.96 [0.57, 1.61]. This risk was not affected by age at which the cat was acquired or whether the pet was kept in- or outdoors. In conclusion, cat or dog ownership reduced the risk of subsequent atopy in this high-risk birth cohort. This cannot be explained by disease-related modification of exposure. Public health recommendations on the effect of cat and dog ownership should be based on birth cohort studies where possible selection bias has been taken into account.

Allergic rhinitis.

Childhood rhinitis may be classified into non-allergic and allergic. Allergic rhinitis is further divided into seasonal and perennial. Seasonal rhinitis is a disease particularly of teenagers and young adults and appears to be less common in primary and pre school age children. In seasonal rhinitis, with relevant grass pollen sensitization, the link between the allergen exposure and rhinitis is clear cut. However, in other situations such as perennial rhinitis and house dust mite allergen sensitization, the link between symptoms and allergen exposure is less certain. Avoidance of allergens often proves to be difficult in practice. Intranasal steroids are the treatment of choice for persistent moderate-severe allergic rhinitis and are more effective than antihistamines for relief of nasal obstruction. Antihistamines are effective for control of histamine related symptoms such as itching, rhinorrhoea and sneezing. The use and benefits of sublingual or injectable immunotherapy in children are controversial.

Management of cow's milk protein allergy in infants and young children: an expert panel perspective.

Cow's milk protein allergy is a condition commonly managed by general practitioners and paediatricians. The diagnosis is usually made in the first 12 months of life. Management of immediate allergic reactions and anaphylaxis includes the prevention of accidental food ingestion and provision of an adrenaline autoinjector, if appropriate. By contrast, the clinical course of delayed food-allergic manifestations is characterised by chronicity, and is often associated with nutritional or behavioural sequelae. Correct diagnosis of these non-IgE-mediated conditions may be delayed due to a lack of reliable diagnostic markers. This review aims to guide clinicians in the: (i) diagnostic evaluation (skin prick testing or measurement of food-specific serum IgE levels; indications for diagnostic challenges for suspected IgE- and non-IgE-mediated food allergy), (ii) dietary treatment, (iii) assessment of response to treatment, (iv) differential diagnosis and further diagnostic work-up in non-responders, (v) follow-up assessment of tolerance development and (vi) recommendations for further referral.

New action plans for the management of anaphylaxis.

The Australasian Society for Clinical Immunology and Allergy has developed new anaphylaxis action plans intended for use across Australasia. These educational tools aim to give patients and carers easily accessible information about key steps in the emergency treatment of acute allergic reactions and anaphylaxis. This article outlines the rationale for these plans, introduces two new action plans and key practice points to consider when providing these plans. Action plans are primarily an educational tool for patients considered to be at risk of anaphylaxis. They also function in a similar fashion to a doctor's letter, providing written information that patients and parents can give to child care centres, schools and employers to assist in the provision of appropriate care.

Anaphylaxis following quadrivalent human papillomavirus vaccination.

BACKGROUND: In 2007, Australia implemented the National human papillomavirus (HPV) Vaccination Program, which provides quadrivalent HPV vaccine free to all women aged 12-26 years. Following notification of 7 presumptive cases of anaphylaxis in the state of New South Wales, Australia, we verified cases and compared the incidence of anaphylaxis following HPV vaccination to other vaccines in comparable settings. METHODS: We contacted all patients with suspected anaphylaxis and obtained detailed histories from telephone interviews and a review of medical records. A multidisciplinary team determined whether each suspected case met the standardized Brighton definition. Some participants also received skin-prick allergy testing for common antigens and components of the HPV vaccine. RESULTS: Of 12 suspected cases, 8 were classified as anaphylaxis. Of these, 4 participants had negative skin-prick test results for intradermal Gardasil. From the 269 680 HPV vaccine doses administered in schools, 7 cases of anaphylaxis were identified, which represents an incidence rate of 2.6 per 100 000 doses (95% CI 1.0-5.3 per 100 000). In comparison, the rate of identified anaphylaxis was 0.1 per 100 000 doses (95% CI 0.003-0.7) for conjugated meningococcal C vaccination in a 2003 school-based program. INTERPRETATION: Based on the number of confirmed cases, the estimated rate of anaphylaxis following quadrivalent HPV vaccine was significantly higher than identified in comparable school-based delivery of other vaccines. However, overall rates were very low and managed appropriately with no serious sequelae.

Allergic rhinitis - practical management strategies.

BACKGROUND: Allergic rhinitis is a common condition associated with significant effects on quality of life. Readily available treatments can improve outcomes in rhinitis as well as associated allergic diseases such as asthma. Yet allergic rhinitis remains underdiagnosed and undertreated. OBJECTIVE: This article outlines practical strategies and evidence based management of allergic rhinitis. DISCUSSION: Allergic and nonallergic rhinitis often co-exist. Thorough history of allergen exposure and its relationship to symptoms is vital for the ordering and interpretation of investigations and for management decisions. Some allergen avoidance measures may be ineffective and may cause an unnecessary burden. Demonstrated effective strategies are patient education, intranasal steroids and immunotherapy ('desensitisation'). General practitioners play a vital role in all three strategies, and in supporting patients and families to self manage what is often a chronic condition.

Higher parental occupational social contact is associated with a reduced risk of incident pediatric type 1 diabetes: Mediation through molecular enteroviral indices.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.

Persistent linear bands in infancy acquired after local pressure: a consequence of mast cell activation?

A 10-month-old girl with marked symptomatic dermographism presented with linear bands at the sock line noted to have developed following an episode of localized urticaria and angioedema at the sock line. We speculate that release of mast cell mediators associated with the dermographism may have triggered the development of the linear bands.

Determinants of Neonatal Vitamin D Levels as Measured on Neonatal Dried Blood Spot Samples.

BACKGROUND: Vitamin D deficiency is linked to adverse childhood health outcomes, yet data on the distribution and quantifiable determinants of neonatal 25-hydroxyvitamin D3 (25OHD) concentration, a vitamin D biomarker, are limited. OBJECTIVE: Our aim was to identify determinants of neonatal 25OHD concentration, measured using neonatal dried blood spots (DBS). METHODS: A total of 259 ethnically diverse children aged 0-16 years born in Victoria, Australia, were recruited. Data included maternal sun exposure, skin type, 25OHD concentration on stored neonatal DBS, and genotypes at the target genes. Associations were investigated using multiple linear regression models. RESULTS: The median 25OHD concentration was 29.2 nmol/l (IQR 18.0-47.4). Measured 25OHD was <50 nmol/l in almost half of the neonatal sample. Ambient ultraviolet radiation (UVR) 6 weeks before birth was the strongest predictor of neonatal 25OHD, accounting for 23% of its variation. A further 10% was explained by infant genetic variants at GC (rs2282679), the gene encoding the vitamin D binding protein, and DHCR7 (rs12785878), a gene required for synthesis of 7-dehydrocholesterol, a precursor to 25OHD. DBS age explained 7%, and patterns of maternal sun exposure and clothing choices accounted for 4%. A child's skin colour was strongly associated with GC gene variants and not independent of these variants in predicting 25OHD. The final model explained 43% of the total variance in neonatal 25OHD concentration. CONCLUSION: Maternal lifestyle factors and infant genetic variants predict neonatal 25OHD levels; the importance of maternal UVR exposure in late pregnancy is highlighted.

Acquired T-helper 1 lymphocyte anergy following infection with Mycobacterium ulcerans.

We describe a patient with acquired T-helper lymphocyte anergy to mycobacteria following infection with Mycobacterium ulcerans. Before infection, the patient's peripheral blood mononuclear cells responded to in vitro stimulation with M. ulcerans by producing Th1 cytokines, but, after she developed an ulcer, the response was shifted toward production of Th2 cytokines. Immunomodulatory therapy may be an effective intervention for Buruli ulcer.

Cost of illness of atopic dermatitis in children: a societal perspective.

Childhood atopic dermatitis is a disorder with considerable social and financial costs. Consideration of these costs is increasingly important in view of the growing prevalence of atopic dermatitis, particularly in developed countries over recent decades. The family stress related to the care of children with moderate or severe atopic dermatitis is significantly greater than that of the care of children with type 1 diabetes mellitus. The factors contributing to family stress include sleep deprivation, loss of employment, time taken for care of atopic dermatitis and financial costs. The financial costs for the family and community include medical and hospital direct costs of treatments and indirect costs from loss of employment. There are many interventions utilised in the treatment of childhood atopic dermatitis which involve not only medical practitioners but nurses, pharmacists, dieticians, psychologists and purveyors of so-called alternative therapies such as naturopathy, aromatherapy and bioresonance, all of which contribute to the financial burdens on the parents and the community. It is possible that appropriate interventions directed to reducing trigger factors might produce worthwhile savings, although the cost benefit of these measures has not been demonstrated. In conclusion, atopic dermatitis should not be regarded as a minor skin disorder but as a condition which has the potential to be a major handicap with considerable personal, social and financial consequences both to the family and the community.

Comparison of anti-pneumococcal antibodies in cord blood from Australian indigenous and Gambian neonates and the implications for otitis media.

BACKGROUND: Australian indigenous infants experience the highest incidence of chronic suppurative and acute otitis media in the world with many babies developing disease in the early postnatal period. Streptococcus pneumoniae is the major cause of otitis media in this population. Infants are protected against bacterial disease in the first months of life by passive transfer of maternal antibody across the placenta during the late stages of gestation. We hypothesized that reduced passive immunity may contribute to increased disease risk in this population. We compared the concentrations and function of serotype-specific IgG in cord serum from Australian indigenous neonates and Gambian neonates, the latter experiences a similar socioeconomic status to Australian indigenous neonates. METHODS: Serotype-specific IgG, IgG1 and IgG2 were measured using a modified 3rd generation enzyme linked immunosorbent assay based on World Health Organization recommendations. Antibody avidity was measured using a modified sodium thiocyanate elution method. RESULTS: Australian indigenous neonates had significantly increased levels of serotype-specific IgG compared with Gambian populations for 6 of 12 serotypes (P < 0.02). There was no significant difference in antibody function, as measured by antibody avidity, between the 2 groups. CONCLUSIONS: An increased risk for otitis media in Australian indigenous neonates is not primarily determined by specific antibody titers against pneumococcal bacteria. Further investigation into the possible roles of the innate immune response and Eustachian tube dysfunction in the development of chronic otitis media amongst Australian indigenous infants is warranted.