Omalizumab in allergic diseases, a recent review.

Omalizumab is a biological engineered molecule, targeting the Cε3 domain of the IgE molecule. It binds with free IgE and prevents free IgE from attaching to high-affinity IgE receptor (FcεRI) on effector cells such as mast cells, basophils and also on dendritic cells. The result is a blocking of mediator release from these cells and the inhibition of antigen presentation by dendritic cells. In addition, omalizumab downregulates FcεRI expression on these effector cells. Omalizumab prevents early and late phase allergic reactions of skin and lungs. Omalizumab has been investigated extensively in moderate-to-severe asthma in adults and children. It effectively reduces rates of asthma exacerbation, emergency visits for asthma and hospital admissions among these patients. Currently, omalizumab is primarily indicated for patients, age 6 years and over, with moderate to severe asthma (GINA step 4). Omalizumab was investigated in patients with seasonal allergic rhinitis (to ragweed, birch and grass pollens) and has been found to improve rhinitis symptoms and to reduce medication use among these patients. Administered together with allergen immunotherapy, omalizumab reduced incidence of side effects and rates of anaphylaxis from allergen immunotherapy. Omalizumab has been investigated in the treatment of food allergy, atopic dermatitis and urticaria. Despite benefits observed from these initial trials, it further deserves investigations to clarify optimal conditions for use in these conditions. Side effects from omalizumab were few, however, it requires careful considerations in administration of this agent. An observational period (up to 2 hours after the first three doses) and the availability of auto-injectable epinephrine are recommended. Pharmacoeconomics of omalizumab is briefly reviewed. Omalizumab represents a major breakthrough of translational medicine in allergy.

The effect of montelukast on bronchial hyperreactivity and lung function in asthmatic children aged 6-13 years.

Background: Cysteinyl leukotrienes have been shown to play an important role in the pathogenesis of asthma. The effect of the leukotriene receptor antagonist, montelukast, on bronchial hyperreactivity (BHR) as measured by the methacholine challenge test in school children has not been reported. Objective: To determine the effect of montelukast (Singulairâ) on BHR measured by methacholine challenge and lung function tests in Thai asthmatic children aged 6-13 years. Materials and methods: This was a randomized, double-blind, placebo-controlled, crossover study performed in 29 mild to moderate persistent asthmatic children aged 6-13 years. Each child received crossover treatment with 6 weeks of montelukast (5 mg/day) and 6 weeks of placebo separated by a two-week washout period. Results: The improvement of FEV1 and FEV1/FVC after 6 weeks of treatment was significantly higher in montelukast group compared to those of placebo group (p<0.05). After 6 weeks of treatment, mean (+ SEM) PC was 20 in the placebo group (5.7 + 1.41 mg/ml) which was lower than in montelukast group (6.8 + 1.74 mg/ml) but there was no significant difference (p=0.79). Conclusion: Montelukast significantly improved FEV1 and FEV1/FVC but not BHR in mild to moderate persistent asthmatic children aged 6-13 years after the 6 weeks of treatment.

In-vivo allergenic potency of Siriraj Mite Allergen Vaccine (SMAV) comparing with standardized vaccine in mite-sensitive patients.

Background: The prevalence of allergic diseases, particularly asthma and allergic rhinitis, has increased tremendously in Thailand and worldwide. House dust mite (HDM) is the major IgE sensitizer among allergic children and adults. We have developed local standardized mite allergen extracts, Siriraj Mite Allergen Vaccine (SMAV) from Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) from our source materials which were highly purified (99%). Objective: To compare in-vivo allergenic potency of both SMAV Dp and Df with commercial standardized mite allergen vaccine by using skin prick testing in mite-sensitive individuals. Methods: This was a double-blind, randomized, self controlled study comparing SMAV and commercial standardized mite allergen vaccine (Dp and Df) by using skin prick testing in mite-sensitive adult volunteers, 18 – 60 years of age. Results: The study was performed in 54 adult volunteers (19 males, mean age 26.6 + 5.5 years old) who had positive skin test to commercial Dp and Df. Seventeen of them had no allergic disease. The most common allergic disease among the volunteers was allergic rhinitis (21/37). Mean wheal diameter of SMAV Dp and commercial Dp at the concentration of 10,000 and 5, 000 AU/ml were equivalent but at the concentration of 2,500 AU/ml was inequivalent. Mean wheal diameter of SMAV Dp was significantly larger than commercial Dp at concentration of 2,500 AU/ml (p < 0.05). Mean wheal diameter of SMAV Df and commercial Df at all 3 concentrations were equivalent. There was no systemic side effect in all subjects. Conclusion: The study demonstrated that in mite-sensitive adults, SPT using SMAV Dp (10,000 AU) and Df (10,000 AU) had equivalent allergenic potency to the commercial comparator without any systemic side effect.

Clinical characteristics of children with non-allergic rhinitis vs with allergic rhinitis.

Background: Allergic rhinitis (AR) and nonallergic rhinitis (NAR) are major causes of chronic rhinitis. Knowledge about children with non-allergic rhinitis is limited. Objective: To study clinical characteristics differentiating NAR and AR among children with chronic rhinitis. Methods: This is a retrospective, descriptive study of 302 children (with ages of 14 years or less) with chronic rhinitis evaluated at the pediatric allergy clinic, Siriraj Hospital between January and December 2006. Based on the results of skin prick test (SPT), they were classified into 2 groups, i.e., AR and NAR. Their medical records were reviewed with respect to clinical data on rhinitis and related symptoms. Results: There were 222 patients with AR and 80 with NAR (73.5% and 26.5%). Median age of onset of the disease among patients with NAR was younger than AR (p = 0.04) while the duration of disease among AR cases was longer than in NAR (p < 0.01). Severity of rhinitis, based on Allergic Rhinitis and its Impact on Asthma (ARIA), was not different between the two groups. Nasal pruritus, sneezing and eye symptoms were more commonly observed in AR than in NAR (p <0.01), whereas snoring and sinusitis were more common in NAR than in AR (p < 0.01). The presence of nasal pruritus, sneezing and eye symptoms strongly suggested AR (adjusted OR 2.73, 2.96, 1.49) while snoring was a risk factor for NAR

Nasal provocation test: how to maximize its clinical use.

In order to diagnose allergic rhinitis (AR), skin prick tests and serum specific IgE level are the most common used methods. But there are some conditions which the results of both methods do not correlate with the clinical presentation of AR. Nasal provocation test is the method of detecting local IgE at the shock organ. There are some variations of NPT in terms of dosage, allergen administration, evaluation and scoring system. This article summarized the usefulness of NPT, its indication and contraindication, dosage and instillation techniques for allergens and evaluation of outcome in the hope that if we can standardize the procedure and make it easier to perform, NPT will be applied more in clinical practice. In addition normal values among Asian ethnics are presented for appropriate interpretation of the test

A combination of intravenous immunoglobulin and pulse methylprednisolone extended survival in pulmonary alveolar proteinosis with chronic interstitial pneumonitis: a case report.

Pulmonary alveolar proteinosis (PAP) is characterized by intra-alveolar accumulation of lipoproteinaceous material. The severe chronic pulmonary disease and susceptibility to pulmonary infection is a prominent feature of the disease. We reported a case of postnatal-onset PAP and chronic interstitial pneumonitis in a girl with chronic respiratory distress since she was 5 months of age. A lung biopsy confirmed the diagnosis. The therapeutic bronchoalveolar lavages, a short trial of granulocyte colony-stimulation factor (G-CSF) and a combination of low dose methylprednisolone and hydroxychloroquine were used at different times without noting satisfactory improvement. Intravenous immunoglobulin (IVIG) and pulse methylprednisolone were given monthly with gradual recovery. She did not require oxygen supplement after 21 months of this combination. Our report suggested that IVIG and pulse methylprednisolone might have a potential role in the treatment of PAP with chronic interstitial pneumonitis.

The accumulation of dust mite allergens on mattresses made of different kinds of materials.

Background: Different mattress materials may affect the accumulation of allergens. Objective: To compare the amount of group 1 dust mite allergens (Der p1 + Der f1) on mattresses made of different kinds of materials before and after use. Methods: Sixty new mattresses made of kapok, synthetic fiber, coconut fiber and sponge-like polyurethane, were placed in the house officers’ dormitory at Siriraj hospital, Thailand. The dust samples were collected before (0), 1, 2, 3, 6, 9 and 12 months after the mattresses were used. Group 1 dust mite allergens were analyzed using two-site monoclonal antibody ELISA. Results: Der f1 made up 86.7 % of group 1 allergens found in the matress dust. After the 2nd month, only the mean level in sponge-like polyurethane mattress was under 2 µg/g dust (sensitized level). At the 6th month, the mean levels were 13.1 in coconut, 21.7 in kapok and 17.3 µg/g dust in synthetic fiber, all of which were more than 10 µg/g dust (symptomatic level). At the 9th month, the level in sponge-like polyurethane mattress was increased to 11.2 µg/g. At 12th month the level in coconut fiber, sponge-like polyurethane synthetic fiber and kapok mattresses were 20.2, 22.4, 28.9 and 32.2 µg/g dust respectively. Conclusions: The accumulation rate in kapok and synthetic mattresses was significantly higher than coconut and sponge-like polyurethane mattresses. The mean level of group 1 mite allergens exceeded 10 µg/g dust after the 6th month of use in coconut fiber, kapok and synthetic fiber and at the 9th month in sponge-like polyurethane mattress.

Allergic rhinitis and its impact on asthma update (ARIA 2008) - western and asian-pacific perspective.

The prevalence of allergic diseases such as allergic rhinitis (AR) and asthma is markedly increasing worldwide as societies adopt western life styles. Allergic sensitization is an important risk factor for asthma and AR, and asthma often co-exists with AR. An estimated 300 million people worldwide have asthma, about 50% of whom live in developing countries and about 400 million people suffer from AR. Yet, AR is often under-diagnosed and under-treated due to a lack of appreciation of the disease burden and its impact on quality of life, as well as its social impact at school and at the workplace. However, AR with or without asthma is a huge economic burden. Thus, there was clearly a need for a global evidence-based document which would highlight the interactions between the upper and lower airways including diagnosis, epidemiology, common risk factors, management and prevention. The Allergic Rhinitis and its Impact on Asthma (ARIA) document was first published in 2001 as a state-of-the-art guide-line for the specialist, the general practitioner and other health care professionals. Subsequent new evidence re-garding the pathomechanisms, new drugs and increased knowledge have resulted in the publication of the ARIA 2008 update. The present review summarizes the ARIA update with particular emphasis on the current status of AR and asthma in the Asia-Pacific region and discusses the Western and Asian perspective

Immediate type hypersensitivity to chemotherapeutic agents in pediatric patients.

Nine patients (3 boys and 6 girls) with a median age of 9.5 years, with immediate type hypersensitivi-ty reactions to chemotherapeutic agents were reviewed. The presenting symptoms were urticaria (4/9) and ana-phylaxis (5/9). The causative agents were vincristine (2/9), L-asparaginase (2/9), mesna (1/9), cyclosporine (1/9), carboplatin (2/9) and cyclophosphamide (1/9). Three of the five patients with anaphylaxis were changed to alterna-tive chemotherapeutic agents. In two cases alternative drugs were not available and the patients underwent safe and successful desensitization. Three of the 4 patients with urticaria were successfully exposed to graded chal-lenges with cyclosporine, carboplatin and cyclophosphamide, respectively. In the other case with generalized urti-caria, mesna was withdrawn due to a positive intradermal test. In patients with immediate type hypersensitivity reactions to chemotherapeutic drugs, if effective alternative chemotherapeutic agents are not available and/or the skin test is negative, a careful drug challenge and/or desensitization should be performed.

A novel mutation of the IL12RB1 gene in a child with nocardiosis, recurrent salmonellosis and neurofibromatosis type I: First case report from Thailand.

Genetic defects of interleukin (IL)-12/23-and interferon (IFN)-γ-mediated immunity can cause in-creased susceptibility to intracellular microbes. Among these defects, a mutation of the gene encoding the IL-12 receptor β1 (IL-12Rβ1) is the most common worldwide. A 12-year old Thai boy with pre-existing neurofibromatosis type 1 (NF1) was evaluated for primary immunodeficiency after a history of tuberculous lymphadenitis, recurrent Salmonella infections and nocardiosis. Flow cytometry of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) revealed a defect in the IL-12Rβ1 surface expression. A genetic study showed a novel nonsense homozygous mutation of the IL12RB1 gene in exon 4 (402C>A), confirming the diagnosis of IL-12Rβ1 deficiency. This is the first case report of a primary IL-12Rβ1 deficiency in Thailand with the interesting finding of a coexisting NF1.

Wheat-dependent, exercise-induced anaphylaxis in Thai children: A report of 5 cases.

Wheat is not an uncommon cause of food-dependent, exercise-induced anaphylaxis. This study aims to describe common clinical characteristics and laboratory manifestations of the disease. Five children, aged 8-14 years were evaluated. An atopic history was found in 20% of the patients. All patients had symptoms which involved the skin and three had hypotension. Serum specific IgE for wheat was measured and showed a positive result in 2 patients. A three-day challenge protocol with an open challenge for wheat on day 1, an exercise chal-lenge test on day 2 and another exercise challenge test on day 3 after a meal containing wheat was performed. Four patients completed the three-day challenge protocol. Anaphylaxis occurred in 2 out of 4 patients who con-sumed more than 100 grams of wheat prior to the exercise. The three-day challenge protocol is a definitive diag-nostic tool to confirm the diagnosis of WDEIA. However, the amount of wheat used for challenging should be at least 100 grams. Abbreviations: WDEIA, wheat-dependent, exercise-induced anaphylaxis; FDEIA, food-dependent, exercise-induced anaphylaxis; SPT, skin prick test.

Is silent sinusitis a cause of chronic urticaria in children.

The etiologies of chronic urticaria (CU) comprise a wide variety of disorders including chronic infec-tions. The association of sinusitis and CU is controversial due to the lack of a control group. The objective of this study was to investigate the role of silent sinusitis as a cause of CU in children. A sinus X-ray (SXR) was performed in 107 children with CU. SXR abnormalities were found in 52.3% of the patients. Nine patients (8.4%) had symp-toms of sinusitis and were treated with amoxicillin/clavulanate. Five of these patients (55.6%) had CU remission. Forty-seven patients (43.9%) who had an abnormal SXR without sinusitis symptoms were randomized into treated (23 patients) and control (24 patients) groups. Eighteen patients (78.3%) in the treated group and 15 patients (62.5%) in the control group had CU remission (p = 0.24). These data did not support a causal relationship of si-nusitis and CU in children.

The utility of the World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) system for the assessment of adverse drug reactions in hospitalized children.

Although the World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) system has been suggested as a practical tool for classifying adverse drug reactions (ADRs), verification of such system has not been examined. The objective of this study was to evaluate the usefulness of the WHO-UMC classification for the diagnosis of ADRs. The gold standard was the results of drug challenges and serum tryptase in cases of anaphylaxis. Twenty-seven children had ADRs classified by the WHO-UMC system. The causality terms were 'certain' in 4/27, 'probable' in 6/27, 'possible' in 10/27 and 'unlikely' in 7/27 of the patients. Skin prick tests and intradermal tests were positive in 1/20 and 1/5 of the patients, respectively. Drug challenges and serum tryptase were positive in 8/26 and 1/3 of the patients, respectively. After complete evaluation, the positive and negative ADRs were documented in 9/27 patients (33.33%) and 18/27 patients (66.67%), respectively. The multi-level likelihood ratios for ADRs using the WHO-UMC system were infinity in causality term 'certain', 2 in 'probable', 0.5 in 'possible', and 0 in 'unlikely'. In conclusion, causality term 'certain' and 'unlikely' of the WHO-UMC system had large impact on the likelihood of ADRs. In contrast, the causality term 'probable' and 'possible' had small impact on the likelihood of ADRs. Drug challenges and serum tryptase were helpful to confirm ADRs categorized by WHO-UMC system.

Efficacy of montelukast and loratadine as treatment for allergic rhinitis in children.

The objective of this study was to compare the effectiveness of montelukast combined with loratadine once daily to loratadine alone for a 2-week treatment course of allergic rhinitis in a randomized, double-blind placebo controlled trial which enrolled 115 children, 6- 15-years-old. The patients were randomly assigned to receive montelukast and loratadine (treatment group) or placebo and loratadine (control group). The primary outcome was the mean percent change of the total daytime nasal symptom scores (PDTS) and secondary outcomes were the mean percent changes of the nighttime nasal, daytime eye and composite symptom scores (PNTS, PES, PCS), as well as the nasal secretion, turbinate swelling and nasal congestion scores (PNSS, PTSS, PNCS). There were no significant differences in the PDTS of the 2 groups. The change in the night time nasal congestion score (PNTS-congestion) was higher in the treatment group, but not statistically significant (p = 0.077). Only the mean percent change in decreased turbinate swelling was significantly greater in the montelukast and loratadine group than the loratadine alone group (-22 +/- 7 vs. -1 +/- 5, p < 0.05).

Successful treatment of disseminated BCG infection in a SCID patient with granulocyte colony stimulating factor.

Severe combined immunodeficiencies (SCID) are disorders with impairment of humoral and cellular immune functions. The prognosis of disseminated bacillus Calmette-Guérin (BCG) infection in immunocompromised host is unfavorable since response to standard therapy is poor. We report a successful treatment of disseminated BCG infection with granulocyte colony stimulating factor (G-CSF) in a patient with severe combined immunodeficiency. The patient failed to response to intensive anti-tuberculous (anti-TB) therapy. After 2 months of G-CSF, in addition to anti-TB treatment, the clinical signs of disseminated BCG infection were improved. Since serious BCG infections in SCID are not uncommon in developing countries, where BCG vaccination is mandatory to all newborns, the combination of G-CSF and anti-TB drugs should be considered in immunocompromised patients with protracted mycobacterial infection.

A novel mutation of the CYBB gene resulting in severe form of X-linked chronic granulomatous disease.

We evaluated a boy who had multiple Salmonella septicemia, Aspergillus pneumonia and brain abscesses. His nitroblue tetrazolium (NBT) test was reportedly abnormal. The dihydrorhodamine (DHR) flow cytometry assay was compatible with typical X-linked chronic granulomatous disease (X-CGD). CYBB analysis revealed a novel complex mutation atggacg --> ttca in exon 12 (base pairs 1532-1538). As a result, 3 amino acids Tyr 511, Gly 512 and Arg 513 were deleted and replaced by 2 amino acids, Phe and Gln. The DHR and mutation analysis of his mother showed normal DHR pattern and no mutations in exon 12 of CYBB gene. In conclusion, any children with multiple Salmonella and Aspergillus infection should be suspected of CGD. NBT test, DHR assay and gene analysis are helpful toolsto confirm the diagnosis e v en i n the case of de novo mutation.

Recurrent Campylobacter lari bacteremia in X-linked agammaglobulinemia: a case report and review.

X-linked agammaglobulinemia (XLA) is a primary immune deficiency disease with a B-cell defect. We present the first XLA patient who had recurrent Campylobacter lari bacteremia. High dose intravenous immunoglobulin combined with azithromycin once per week, and a complete avoidance of bacterial reservoirs may be helpful for the prevention of C. lari bacteremia.

Chronic rhinosinusitis and recurrent nasal polyps in two children with IgG subclass deficiency and review of the literature.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disorder of mucosa of the nose and the paranasal sinuses. Two major forms of CRS can be differentiated; CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The pathophysiology and etiology of nasal polyps (NPs) are partly understood. IgG subclass deficiency was shown to be associated with an increased susceptibility to infections. However the association between NPs and IgG subclass deficiency has never been reported. OBJECTIVES: To report two cases of recalcitrant CRS and recurrent NPs with IgG subclass deficiency. CASE REPORT: Two children (6 and 8 year-old boys) were referred to the Pediatric Allergy/Immunology Clinic, Siriraj Hospital due to a prolonged history of CRS and recurrent NPs. Both of them were treated with aggressive medical (topical and systemic corticosteroids, antibiotics, leukotriene antagonist, nasal irrigation) as well as surgical therapy, without significant improvement. Immunologic investigation in both patients showed that IgG, IgA, and IgM level were normal. IgG subclasses level in patient No. 1 were IgG1 1,235 (280-1120) mg/dl (79%), IgG2 235 (30-630) mg/dl (23.5%), IgG3 27.3 (40-250) mg/dl (1.74%), and IgG4 92.4 (11-620) mg/dl (5.9%). IgG subclasses level in patient No. 2 were IgG1 1,139 (280-1120) mg/dl (82.5%), IgG2 170 (30-630) mg/dl (12.3%), IgG3 5.6 (40-250) mg/dl (0.4%), IgG4 65.7 (11-620) mg/dl (4.8%). The diagnosis of CRS and recurrent NPs with IgG3 subclass deficiency in the first patient and IgG2/IgG3 subclass deficiency in the second patient were made. Patient No. 1 was given monthly IVIG therapy for the total of 7 courses and medications were gradually tapered. Currently, the patient is doing well after the cessation of IVIG therapy for 3 months. Patient No. 2 denied the IVIG treatment and was lost to follow up. CONCLUSION: We reported two cases of recalcitrant CRS and recurrent NPs in children. Immunologic work up revealed IgG subclass deficiency. The treatment with monthly IVIG improved CRS and NPs in treated patient which brought up the possibility of association between NPs and IgG subclass deficiency. Further study on the direct role of IVIG in NPs will be needed in the future.