Suwat Benjaponpitak

The biodiversity hypothesis and allergic disease: world allergy organization position statement

Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.

Reduced prevalence of allergic disease in patients with multiple sclerosis is associated with enhanced IL-12 production

BACKGROUND We previously showed that the prevalence of allergic disease is decreased in patients with multiple sclerosis (MS); however, the mechanisms that explain this finding have not previously been defined. OBJECTIVES We have demonstrated that protection of patients with MS from allergic disease may be caused by the production in monocytes from these patients of elevated quantities of IL-12 compared with that observed in monocytes from individuals with allergies. METHODS Purified monocytes from peripheral blood of subjects with or without allergies and from individuals with MS were directly stimulated with Staphylococcus aureus Cowan strain I in the absence of T cells. IL-12 was quantitated by a sensitive reverse transcription, competitive PCR. RESULTS IL-12 production was 5-fold greater in monocytes from patients with MS (n = 11) than that from individuals with allergies (n = 10) (for subjects with MS, 1.90+/-0.18 vs 1.24+/-0.19 log10 fmol/microL for individuals with allergies) (P = .02). Although the production of IL-12 in monocytes from patients with MS was slightly higher than that from subjects without allergies, this difference was not statistically significant. CONCLUSIONS IL-12 production in individuals with MS is much greater than in individuals with allergies. Because IL-12 induces TH1 cytokine synthesis and reduces the production of TH2 cytokines, which amplify and prolong allergic inflammation, these studies suggest that enhanced IL-12 production may protect individuals with MS from the development of allergy but may predispose such individuals toward autoimmune inflammation in the central nervous system.

Immunogenicity and safety study of a new DTaP–IPV–Hep B–PRP-T combined vaccine compared to a licensed DTaP–IPV–Hep B//PRP-T comparator, both concomitantly administered with a 7-valent pneumococcal conjugate vaccine at 2, 4, and 6 months of age in Thai infants

OBJECTIVE To assess a new, fully-liquid, hexavalent DTaP-IPV-Hep B-PRP-T vaccine (diphtheria toxoid (D), tetanus toxoid (T), acellular pertussis (aP), inactivated poliovirus (IPV), hepatitis B (Hep B), and Haemophilus influenzae type b polysaccharide conjugated to tetanus protein (PRP-T) antigens) compared to a licensed DTaP-IPV-Hep B//PRP-T vaccine following primary series co-administration with a 7-valent pneumococcal conjugate vaccine (PCV7). METHODS This was a randomized, phase III, observer-blind study in Thai infants (N=412), who received DTaP-IPV-Hep B-PRP-T or DTaP-IPV-Hep B//PRP-T at 2, 4, and 6 months of age, co-administered with PCV7. All received Hep B at birth. Non-inferiority for Hep B ≥ 10 mIU/ml and PRP ≥0.15μg/ml was analyzed (DTaP-IPV-Hep B-PRP-T relative to DTaP-IPV-Hep B//PRP-T) at 1 month post-primary. Seroprotection/seroconversion and geometric mean titers (GMTs) were analyzed descriptively for all hexavalent components. Safety was evaluated from parental reports. RESULTS Anti-Hep B and anti-PRP antibody seroprotection rates were high for DTaP-IPV-Hep B-PRP-T (n=189) and DTaP-IPV-Hep B//PRP-T (n=190), and non-inferiority was demonstrated. Anti-D and anti-T ≥ 0.01 IU/ml, anti-polio types 1, 2, and 3 ≥ 8 (1/dil), and anti-PT and anti-FHA seroconversion were high and similar in each group. For DTaP-IPV-Hep B-PRP-T and DTaP-IPV-Hep B//PRP-T, anti-Hep B ≥ 100 mIU/ml was 98.4% and 99.5% (GMTs 2477 and 2442 mIU/ml), respectively; anti-PRP ≥ 1.0 μg/ml was 85.2% and 71.1% (GMTs 5.07 and 2.41 μg/ml), respectively. Safety profiles were comparable. There were no vaccine-related serious adverse events. CONCLUSIONS Following co-administration with PCV7 the investigational DTaP-IPV-Hep B-PRP-T vaccine was safe and immunogenic. Non-inferiority to DTaP-IPV-Hep B//PRP-T was shown for Hep B and PRP.

The use of rituximab as an adjuvant for immune tolerance therapy in a hemophilia B boy with inhibitor and anaphylaxis to factor IX concentrate.

We describe a 10-year-old severe hemophilia B boy with a stop codon mutation of exon 2 in the factor IX gene who developed high inhibitor of 70 Bethesda units (BU) from 12 months of age after exposure to prothrombin complex concentrate for 14 days. The inhibitor spontaneously disappeared within 3 months. The patient, however, exhibited anaphylactic reaction to the administration of prothrombin complex concentrate and factor IX concentrate at ages 15 and 23 months, respectively. Although recombinant activated factor VII was alternatively given, he suffered from progressive hemophilic arthropathy. At the age of 10 years, the boy underwent desensitization to factor IX concentrate and could tolerate factor IX concentrate of 40 U/kg administered on day 9 of desensitization. Unfortunately, the inhibitor of 16 BU was detected on day 6 and rapidly increased to 180 BU on day 9 of desensitization. Rituximab 375 mg/m2 per week was therefore immediately initiated on day 10 and a total of four doses were given. The inhibitor gradually decreased to 21.5 BU after the fourth dose of rituximab. The daily factor IX concentrate administration of 40 U/kg was continued for 1 month and decreased to three times per week for another month, and then to once to twice per week for the remaining 14 months of desensitization. The patient was able to attend regular school and the most recent inhibitor ranged from 4.4 to 10 BU. No proteinuria or alteration of renal function was found. In conclusion, rituximab is a helpful adjuvant to immune tolerance therapy in a hemophilia B boy with inhibitor and anaphylaxis to factor IX concentrate.

Phenobarbital‐induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children

Aromatic anticonvulsant–induced severe cutaneous adverse drug reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are fatal immune‐mediated adverse drug reactions. CYP2C19, a cytochrome P450 isoform, plays a role in metabolic rate of aromatic anticonvulsant. HLA‐B*1502 has also been demonstrated to be associated with carbamazepine‐induced SJS‐TEN.

Cow's milk protein allergy: immunological response in children with cow's milk protein tolerance.

OBJECTIVE To study changes in immunological responses in patients with CMPA during symptomatic and asymptomatic episodes of cows milk protein tolerance status. METHODS 27 CMPA patients were enrolled and underwent diagnostic evaluation, including CM challenge test, skin prick test and specific IgE to CM. Blood samples were collected in two periods from those who became tolerant (n = 13) and those with persistent CMA (n = 14), in order to measure in vitro PBMC responses to cows milk protein (IL-10, IFN-γ, IL-5), IgG4 to β-lactoglobulin, casein, BLG-IgG4/IgE ratio and the CAS-IgG4/IgE ratio. RESULTS Seventy percent of CMPA patients in our study were male with a mean age at diagnosis of 8 months and mean age of onset of 3 months. The reaction time to CM ranged from within 7 minutes to within 14 days. Positive IgE-sensitization was defined as either a specific IgE to CM of more than 0.35 kUA/L (N=11) or SPTs positive for CM and/or fresh cows milk (N=20). Forty-eight percent of the patients (n = 13) could tolerate CM by 13.38 months (8-19 months). Mean specific-IgE levels to CM were 4.1 kUA/L (range 0.35-14.3 kUA/L). Determination of the cytokine (IL-10, IFN-γ, IL-5) response to BLG revealed significantly higher IL-10 levels during the tolerance phase (212.93 vs 142.46 pg/ml, P = .011). There was a significant increase in BLG-IgG4 and the BLG-IgG4/IgE ratio in the tolerance phase when compared to the symptomatic phase. CONCLUSIONS IL-10, BLG-IgG4 and the BLG-IgG4/IgE ratio were higher in CMPA patients during the tolerance phase compared to the symptomatic phase.

International consensus (ICON) on: clinical consequences of mite hypersensitivity, a global problem

Since mite allergens are the most relevant inducers of allergic diseases worldwide, resulting in significant morbidity and increased burden on health services, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), the European Academy of Allergy and Clinical Immunology (EAACI), and the World Allergy Organization (WAO), has proposed to issue an International Consensus (ICON) on the clinical consequences of mite hypersensitivity. The objectives of this document are to highlight aspects of mite biology that are clinically relevant, to update the current knowledge on mite allergens, routes of sensitization, the genetics of IgE responses to mites, the epidemiologic aspects of mite hypersensitivity, the clinical pictures induced by mites, the diagnosis, specific immunotherapeutic approaches, and prevention.

Pediatric anaphylaxis: triggers, clinical features, and treatment in a tertiary-care hospital

BACKGROUND Anaphylaxis is a life-threatening condition. There are limited data about its etiology and clinical characteristics in Asian children with anaphylaxis. OBJECTIVE To investigate triggers, presenting symptoms, treatment and clinical course of anaphylaxis in Thai children. METHOD Medical record of children who were diagnosed with anaphylaxis between 2004 and 2013 at Ramathibodi Hospital, Bangkok, Thailand were reviewed. RESULTS One hundred-seventy two episodes of anaphylaxis occurred in 160 children (91 boys, 69 girls) aged 3 months to 18 years. Anaphylaxis increased from 2.7 cases/1000 pediatric admission to 4.51 cases/1000 pediatric admission between 2004-2008 and 2009-2013. The main causes were food (34.92%), drug (33.1%), blood components (23.8%), insect sting (9%), and unidentified causes (2.8%). Allergy to the triggers was known prior to anaphylaxis in 42 episodes (24.6%). Treatment consisted of epinephrine intramuscularly (93.8%), corticosteroids (92.5%), H₁antihistamines (96%), H₂antihistamines (50%), and β₂agonists nebulization (35.1%). Biphasic anaphylaxis occurred in 8.7% of the documented episodes and severe anaphylaxis in 34.3% of the documented episodes. Biphasic anaphylaxis and severe anaphylaxis were associated with fewer administrations of intramuscular epinephrine (OR 0.08 [95% CI 0.014-0.43]; p =0.01 and OR 9.36 [95% CI 2.5-34.7]; p <0.001 respectively). There were no fatality cases. There were associations between triggers of anaphylaxis and atopic histories, patients with severe anaphylaxis and cardiovascular involvement (p <0.01). CONCLUSIONS The incidence of anaphylaxis in Thai children is increasing. Anaphylaxis in children commonly occurred without the histories of prior reaction to the causative agent. Less frequent treatment with intramuscular epinephrine was associated with biphasic and severe anaphylaxis. A better knowledge of patterns and causes of anaphylaxis might contribute to a better management.

Comparison of conjunctival and nasal provocation tests in allergic rhinitis children with Dermatophagoides pteronyssinus sensitization

BACKGROUND Nasal provocation tests (NPTs) are indicated in confirming the diagnosis of allergic rhinitis if the clinical history, skin tests or sIgE are inconclusive. NPTs are time- consuming, technically difficult and expensive to perform. Consequently, conjunctival provocation tests (CPTs), which are easier, cheaper and safer should be considered as an alternative method. No recent study has compared CPTs with NPTs in allergic rhinitis children. OBJECTIVE To compare CPTs with NPTs in allergic rhinitis children with house dust mite sensitization METHODS Fifty-five children with allergic rhinitis were included. Thirty-six children had positive skin prick tests (SPTs) to Dermatophagoides pteronyssinus (Dp). NPTs were performed by spraying 0.1 ml of Dp extract with concentrations of 50, 200 and 500 AU/ml to each nostril at 15 minute interval. The clinical symptom scores, anterior rhinomanometry results and nasal peak flow testing were performed to assess the responses. For CPTs, 0.1 ml of the same concentration of allergen extract was droppedinto one eye and the control solution was dropped into the other. The responses were assessed by clinical symptom scores. The tests were stopped when the subject reported a positive response, or continued to the maximum concentration. RESULTS The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CPT compared with NPT are 97.1% (84.7-99.9), 90.5% (69.6-98.8), 94.3% (80.8-99.3), 95% (75.1-99.9) and 94.5 (84.9-98.9), respectively in all patients. Among individual allergic rhinitis subjects the sensitivity, specificity, PPV and NPV are 100%. CONCLUSIONS CPT can be an alternative test for NPT in allergic rhinitis children with house dust mite sensitization, even if they do not have conjunctival symptoms.

Association of HLA genotypes with phenobarbital hypersensitivity in children

Phenobarbital hypersensitivity is one of the common drug hypersensitivity syndromes in children. Clinical symptoms of phenobarbital hypersensitivity vary from maculopapular rashes (MPs) to severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens‐Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug hypersensitivity has been demonstrated to be associated with variations in the HLA genotypes. This study was to investigate the association between the variations of HLA genotypes and phenobarbital hypersensitivity in Thai children.