Wasu Kamchaisatian

Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in children with human immunodeficiency virus undergoing highly active antiretroviral therapy

BACKGROUND The 23-valent pneumococcal polysaccharide vaccine (23PSV) has been recommended for children infected with human immunodeficiency virus (HIV); however, the efficacy of this vaccination in HIV-infected children undergoing highly active antiretroviral therapy (HAART) has not been studied. OBJECTIVE To study the immunogenicity and immunologic protection of 23PSV in HIV-infected children after stable HAART. METHODS Serotype-specific IgG antibodies to 12 pneumococcal capsular polysaccharides were analyzed before and after 23PSV vaccination in 41 HIV-infected children undergoing HAART and compared with 95 HIV-negative control children. Seropositivity, clinical protection, and additional clinical protection from 23PSV were calculated based on serotype specific IgG antibody levels and on the known incidence of these serotypes for causing invasive disease. RESULTS Children with HIV infection undergoing HAART developed a significant increase in specific IgG levels to Streptococcus pneumoniae after 23PSV vaccination (0.95 vs 1.84 micro/gmL, P < .001). The HIV-infected children with CD4+ cell counts of 25% or higher at the time of vaccination developed a higher additional clinical protection gain from 23PSV vaccination than did children with a lower percentage of CD4+ cells. CONCLUSIONS HIV-infected children undergoing stable HAART develop a significant immunologic response to 23PSV, especially those with higher T-cell counts and lower viral loads at the time of vaccination.

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.

Association analysis of CYP2C9*3 and phenytoin-induced severe cutaneous adverse reactions (SCARs) in Thai epilepsy children

CYP2C9 is the key enzyme in aromatic antiepileptic drugs (AEDs) metabolism. CYP2C9*3 is a loss of function polymorphism. This study was designed to investigate genetic association between CYP2C9*3 and aromatic AED-induced severe cutaneous adverse reactions (SCARs) in Thai children. The 37 aromatic AED-induced SCARs patients (20 phenobarbital and 17 phenytoin) and 35 tolerances (19 phenobarbital and 16 phenytoin) were enrolled. CYP2C9*3 was genotyped by allele-specific PCRs. The association between CYP2C9*3 with phenytoin-induced SCARs and phenobarbital-induced SCARs were analyzed in comparison with tolerances and healthy samples. Significant association between phenytoin-induced SCARs and CYP2C9*3 was discovered (odds ratio=14.52; 95% confidence interval (CI)=1.18–∞, P-value=0.044). CYP2C9*3 was not associated with phenobarbital-induced SCARs. This study is the first report of CYP2C9*3 association to phenytoin-induced SCARs in Thai epileptic children. The CYP2C9*3 is a reasonable predictive genetic marker to anticipate SCARs from phenytoin.

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.

Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations

AbstractX-linked agammaglobulinemia is caused by mutations in the human BTK gene, leading to recurrent pyogenic infections. We describe four novel and three known BTK-mutations in seven patients from seven (six Thai and one Burmese) families. All but one were sporadic cases. Patients 1 and 2 had recurrent mutations in exon 10 (R288W) and exon 17 (R562W), respectively. Patient 3, a previously healthy individual who presented with pseudomonas sepsis with ecthyma gangrenosum had a known mutation in exon 17 (1749delT), leading to frameshift effect (F583fsX586). Patient 4 manifested with sepsis and concurrent acute appendicitis and pneumonia. He had a mutation, IVS8 + 1G > A, which led to an insertion of intron 8 into the transcripts. In Patient 5, a novel change in exon 7, c.588G > C, initially presumed Q196H, was found to cause a leaky splicing mutation, resulting in three distinct transcripts containing 17, 108, and 190 bp of the 5′-terminal of intron 7, which led to truncated peptides consisting of 203 and 211 amino acid residues (or Q196fsX204 and Q196fsX212, respectively). Patient 6 had a mutation in exon 14 (W421X), while patient 7 had a newly defined large deletion of exons 6-9. All of the mothers tested were mutation carriers. Transcript analysis in three mothers who were heterozygous for frameshift mutations revealed a minimal amount of aberrant transcripts, while their affected children had full expression of the mutant alleles, suggesting rapid degradation due to nonsense-mediated mRNA decay in the mothers. This is the first report of mutations of BTK from Thailand.

Donor Lymphocyte Infusion Can Eliminate Mixed Chimerism in Nonmyeloablative Stem Cell Transplantation for Correction of Hyper-IgM Syndrome

bone marrow transplantation has been reported to be a potential cure for HIM [4] . However, the nonmyeloablative stem cell transplantation (NST) approach in this condition has been cited in only 4 cases [5–7] . The male patient in this report fi rst presented at the age of 3 years with a history of recurrent sinusitis and pneumonia, oral ulcers and neutropenia. Refl ecting a signifi cant family history, his only male sibling died at the age of 1 year and 6 months with a history of severe sepsis and neutropenia. During the ensuing 2-year period following his initial presentation, the patient continued to experience numerous medical problems. Despite cholangiopathy and hepatitis related to opportunistic infection being common in HIM patients, our patient did not develop compromised liver function before NST, as in previous reports [6, 8] . Laboratory studies demonstrated persistently low absolute neutrophil counts ( ! 0.5 ! 10 9 /l), hypogammaglobulinemia with very low levels of IgA ( ! 7 mg/dl) and IgG (201 mg/dl), but an elevated level of IgM (463 mg/dl). Lymphocyte subpopulations were as follows: CD4 1.49 ! 10 9 /l (52%), CD8 0.77 ! 10 9 /l (27%), CD4/CD8 ratio 1.9 and CD19 0.43 ! 10 9 /l (15%). Delayed-type hypersensitivity tests with purifi ed protein derivatives, diphtheria, tetanus and candida antigens Hyper-IgM syndrome (HIM) is a rare immunodefi ciency disease in which the ability of B cells to switch immunoglobulin production from IgM to IgG, IgA and IgE is impaired. A variety of mutations of the gene encoding the CD40 ligand (CD40L) are responsible for this immunodefi ciency. The functional effect of such a mutation signifi es that the CD40L on T cells can no longer interact with the CD40 glycoprotein on the surface of B cells. This defect of the CD40-CD40L interaction of B and T cells demonstrates the inability to switch from IgM-secreting to IgGand IgA-secreting B cells [1] . Recently, a rare condition with the mutation in the CD40 gene has been identifi ed [2] . Quantitative defi ciency of IgG and IgA leads to recurrent infections of the respiratory tract. Patients with HIM are at higher risk of developing autoimmune disorders and lymphomas, as well as becoming neutropenic. In addition, they are more susceptible to opportunistic microorganisms [3] . The recommended treatment for HIM includes regular intravenous immunoglobulin (IVIG) infusions and antimicrobial prophylaxis against Pneumocystis carinii infections. Neutropenia in HIM has been treated successfully with an increased dose of IVIG and/or granulocyte colony-stimulating factor [1, 3] . Moreover, allogeneic Received: December 27, 2004 Accepted after revision: March 15, 2005

Immunoglobulin values in healthy Thai children aged ≤ 24 months determined by nephelometry.

BACKGROUND Variation of normal immunoglobulin (Ig) levels between different genetic and environment factors has been studied. Although antibody deficiency diseases can start from infancy, data of Ig reference levels in children aged ≤24 months are still limited, especially in Asian children. PURPOSE The aim of this study was to determine serum IgG, IgA, IgM, and IgG subclasses in healthy Thai children from the newborn period to age 24 months. METHODS Serum samples were collected from healthy Thai children age <1-24 months to measured serum IgG, IgA, IgM, and IgG subclasses by nephelometry. RESULTS Of the 100 infants, 44% were female with a median (range) age of 13 (0.3-24) months. The geometric mean IgG was 803 mg/dL, IgA 36 mg/dL, and IgM 102 mg/dL. The mean IgG1 was 646 mg/dL, IgG2 127 mg/dL, IgG3 45 mg/dL, and IgG4 17 mg/dL. The average ratios of IgG subclass 1:2:3:4 were 77:15:6:2%. No significant differences in each immunoglobulin isotype between genders were found. Our mean IgG level was slightly lower than that in healthy Thai children, measured by radial diffusion method but not significant except 1-3 months (p = 0.016). However, the mean IgG level in our study was higher than that reported by radial diffusion in healthy US children (p <0.001). CONCLUSIONS This study illustrated the importance of having normal Ig values from age- and ethnically-matched controls by high precision nephelometric assay in order to appropriately diagnose immunologic disorders in Asian infants.