Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.

BACKGROUND: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. METHODS: Thirty-eight Japanese children (aged 7-16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). RESULTS: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state. CONCLUSIONS: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified.

Incidence of febrile seizure in patients with Down syndrome.

BACKGROUND: It is unclear whether the incidence of febrile seizure (FS) in children with Down syndrome (DS) is higher or lower than in the general population. In this study, we investigated the incidence of FS in DS patients using mailed questionnaires. METHODS: The questionnaires were distributed to parents or caregivers of DS patients attending Osaka Medical College Hospital and six other facilities. The questionnaires were returned by mail from February 2012 to September 2013 from 323 families of DS patients (176 male, 147 female; age range, 3 months-47 years; median age, 5.0 years). To assess the incidence of FS in DS, we performed the following two analyses: (i) we calculated the incidence of FS among DS patients between the ages of 4 and 20 years (n = 199; 113 male, 86 female), and (ii) we extracted families with both DS and healthy siblings between the ages of 4 and 20 years (n = 150; 77 male, 73 female) and compared the incidence of FS in these sibling groups. RESULTS: Five DS patients had a past history of FS. The incidence of FS in DS was 2.5%. The incidence of FS was significantly lower in DS patients compared with healthy siblings (P < 0.003; OR, 0.14). CONCLUSION: The incidence of FS is lower in DS patients than in the general population.

Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy.

BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 µg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study. CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

Japanese pediatric guideline for the treatment and management of bronchial asthma 2012.

A new version of the Japanese pediatric guideline for the treatment and management of bronchial asthma was published in Japanese at the end of 2011. The guideline sets the pragmatic goal for clinicians treating childhood asthma as maintaining a "well-controlled level" for an extended period in which the child patient can lead a trouble-free daily life, not forgetting the ultimate goal of obtaining remission and/or cure. Important factors in the attainment of the pragmatic goal are: (i) appropriate use of anti-inflammatory drugs; (ii) elimination of environmental risk factors; and (iii) educational and enlightening activities for the patient and caregivers regarding adequate asthma management in daily life. The well-controlled level refers to a symptom-free state in which no transient coughs, wheezing, dyspnea or other symptoms associated with bronchial asthma are present, even for a short period of time. As was the case in the previous versions of the guideline, asthmatic children younger than 2 years of age are defined as infantile asthma patients. Special attention is paid to these patients in the new guideline: they often have rapid exacerbation and easily present chronic asthmatic conditions after the disease is established.

Hospitalizations associated with pandemic influenza A (H1N1) 2009 in asthmatic children in Japan.

BACKGROUND: The pandemic influenza A (H1N1) 2009 [pdm (H1N1) 2009] spread through the world in 2009, producing a serious epidemic in Japan. Since it was suggested early that asthma is a risk factor for an increased severity of the infection, the Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI) organized a working group for countermeasures, and investigated asthmatic children admitted to the hospitals for pdm (H1N1) 2009 infection. METHODS: An appeal was made on the home page of the JSPACI to medical practitioners to input clinical information about asthmatic and non-asthmatic children (0-19 years) admitted to the hospital with pdm (H1N1) 2009 infection. RESULTS: A total of 862 children (390 with asthma, and 472 without asthma) from 61 medical centers were registered, and the data of 333 asthmatic children and 388 non-asthmatic children in all were entered in the analyses. The mean age was 7.4 ± 2.9 years in the asthma group and 6.9 ± 3.8 years in the non-asthma group. The percentage of children admitted for respiratory symptoms was significantly higher in the asthma group than in the non-asthma group (p < 0.001). There was no significant difference in the frequency of admission to the ICU or need for mechanical ventilation support between the two groups. No definite trend was detected in the relationship between the severity of asthma and the intensity of asthma attack. Antiviral drugs were administered within 24 hours in about 85% of the patients in both groups. CONCLUSIONS: Asthma may not be a risk factor for severe pdm (H1N1) 2009 infection in children.

Japanese pediatric guidelines for the treatment and management of bronchial asthma 2008.

Abstract The fourth version of the Japanese Pediatric Guidelines for the Treatment and Management of Bronchial Asthma 2008 (JPGL 2008) was published by the Japanese Society of Pediatric Allergy and Clinical Immunology in December 2008. In JPGL 2008, the recommendations were revised on the basis of the JPGL 2005. The JPGL 2008 is different to the Global Initiative for Asthma guideline in that it contains the following items: a classification system of asthma severity; recommendations for long-term management organized by age; a special mention of infantile asthma; and an emphasis on prevention and early intervention. Here we show a summary of the JPGL 2008 revising our previous report concerning JPGL 2005.

[Prevalence of sensitization of Japanese cedar pollen in children from infancy to adolescence].

BACKGROUND: In Japan, morbidity of Japanese cedar pollinosis has dramatically increased, especially in children. However, little is known about the prevalence of pollinosis and sensitization to Japanese cedar pollen (JCP) in young children. OBJECTIVE: The aim of this study is to investigate the prevalence of sensitization to JCP in allergic and non-allergic children from infancy to adolescence. METHODS: Two hundred forty three children with allergic diseases (age 8 months-16 years, mean 5 years) and 137 children without allergic diseases (age 1 month-15 years, mean 4 years) were recruited. Their specific IgE to JCP, house dust mite, orchard grass pollen, egg white, and milk were measured with the CAP-RAST system. A questionnaire was filled out by their parents. RESULTS: The percentage of positive (> or = 2) CAP-RAST to JCP was 47.1% in children with allergic diseases and 19.9% in children without allergic diseases. In children with allergic diseases, the ratio had risen rapidly from 3 to 5 years old. In children without allergic diseases, the ratio of JCP sensitization has gradually increased from the infancy to adolescence. The youngest child who had been sensitized to JCP was 23-month-old boy with atopic dermatitis. The proportion of children who were born from January to march was significantly higher in JCP sensitized group than JCP non-sensitized group. The ratio of house dust mite and orchard grass pollen sensitization was higher in JCP sensitized group than those in JCP non-sensitized group. CONCLUSION: Large number of children acquire sensitization to JCP in their preschool age. We need to develop the way how to protect JCP sensitization in the early stage of life.

[A questionnaire survey of asthma in children with co-morbid allergic rhinitis].

BACKGROUND: Bronchial asthma is often complicated with allergic rhinitis (AR). OBJECTIVE: To investigate the relationship between the upper and lower airway diseases in children with asthma, we performed a questionnaire survey at 6 centers in Kinki area in Japan. METHODS: A questionnaire was filled out by parents of 333 asthmatic children (0-16 years, median age 7). It included questions concerning nasal symptoms, onset ages of rhinitis and asthma, correlation between nasal symptoms and asthma symptoms, and family history of allergic diseases. RESULTS: One hundred and fifty five (46.5%) subjects answered to have any nasal diseases; 20 with sinusitis, 46 with seasonal AR, and 119 (35.7%) with perennial AR. To further clarify the relationship of asthma and concomitant AR, we focused on patients with perennial AR and compared the clinical characteristics with patients with no nasal diseases. Percentage of non-atopic asthma was significantly lower in patients with comorbid AR than those without. Severity of asthma tended to be milder and family history of perennial AR was more often in the former than the latter group. Interestingly, asthmatic children with comorbid AR were more likely to have cold air-induced asthma exacerbations. In the subjects with comorbid AR, concomitant exacerbation of the upper and lower airways occurred in 38.7%. The median age of onset of asthma and nasal symptoms was 2 and 4 years, respectively. In 43.9% of them, upper airway symptoms started either before or simultaneously with asthma. CONCLUSION: The attention should be paid to the nasal symptoms in children with asthma, especially they have atopic asthma and positive family history of perennial allergic rhinitis. It is important that an appropriate diagnosis and treatment of nasal symptoms to better control asthma in children.

Comparison of the prevalence and characteristics of food hypersensitivity among adolescent and older women.

BACKGROUND AND OBJECTIVES: Although food hypersensitivity is a public health concern, its documentation among the elderly is limited. The current study aims to compare the prevalence and characteristics of food hypersensitivity among adolescent women between aged 18-24 with among older women >50 years of age. METHODS AND STUDY DESIGN: 660 female university students between the ages of 18 and 24 who volunteered were enrolled as adolescent subjects. 470 women >50 years old who visited the Health Care Centre of Kyoto Katsura Hospital for health check-ups were enrolled as the older subjects. A questionnaire created by ourselves asking the presence of food hypersensitivity, symptoms, causative food, personal or family history of other allergic disorders was distributed. RESULTS: The prevalence of food hypersensitivity was statistically similar between adolescent (8.2%) and older women (8.9%). Among them, only 24.1% of the adolescent women and 26.2% of the older women had been diagnosed by physicians as having food allergy. The main causative foods (fruits, shellfish and fish) and the manifestations relating to food hypersensitivity were almost identical between adolescent and older women. In both adolescent and older women, food hypersensitivity positive group showed significantly higher prevalence of personal or family history of allergic disorders than that in food hypersensitivity negative group. CONCLUSIONS: These data indicate that food hypersensitivity in older women should be given more attention because the prevalence of this condition was as common as that in adolescent women.

A case of hypertensive encephalopathy with extensive spinal lesions on MRI.

A 14-year-old female had repeated vomiting, headache, abdominal pain, visual field deficit and lethargy at the onset of hypertensive encephalopathy. Cerebrospinal fluid (CSF) test revealed a high level of IgG and protein. MRI demonstrated no supratentorial cerebral lesions but hyperintense lesions were observed from the lower pons to the Th8 level of spinal cord and cerebellar cortex on T2 weighted and FLAIR images without contrast enhancement. The two antihypertensive drugs stabilized to control her blood pressure and improved her clinical symptoms. Reexamination of MRI and cerebrospinal fluid test also revealed clear improvement of the above abnormalities. The abnormal findings on abdominal CT and renography led us to suspect renal infarction. Abdominal angiography demonstrated multifocal stenoses of renal interlobar arteries, which were supposed to supply the renal infarcted regions. These suggested that the renal infarctions due to fibromuscular dysplasia caused systemic hypertension. There have been only two reports that demonstrated spinal cord lesions in reversible posterior leukoencephalopathy syndrome (RPLES). We report extensive spinal lesions on MRI and a high level of IgG in CSF at the subacute phase in a young female with RPLES associated with hypertensive (brainstem) encephalopathy.

Differences in the asthma treatment of children between europe and Japan: a questionnaire-based survey using model cases.

BACKGROUND: : The aim of this study is to compare asthma controller therapy in children between Europe and Japan. MATERIALS AND METHODS: : A questionnaire-based survey was conducted at the 2007 annual meeting of the European Respiratory Society held in Stockholm. In total, 120 answers were collected from European doctors. We divided Europe into 5 areas: South, West, North, East, and Central. The same survey was conducted at the 40th annual meeting of the Japanese Society of Pediatric Pulmonology. Forty-three answers were collected from Japanese doctors. RESULTS: : Inhaled corticosteroids were used more frequently in Europe and antileukotrienes were used more frequently in Japan. There were also some differences in treatment in different areas of Europe. CONCLUSION: : This survey shows differences in the treatment of children with asthma in Europe and in Japan. European doctors prefer using inhaled corticosteroids, and Japanese doctors prefer using oral antileukotrienes. Because the number of the respondents is small and there may be some bias, further study on a large-scale for general clinicians providing medical care to asthma children is desirable.

Detection of Fungi in Indoor Environments and Fungus-Specific IgE Sensitization in Allergic Children.

BACKGROUND: : The aim of this study is to investigate relationships between fungal colonization in the house and IgE sensitization to fungi, and to clarify the effects of house care in relation to fungi. MATERIALS AND METHODS: : We measured levels of fungi in the houses of 52 allergic children. Of these, 32 children displayed detectable levels of IgE (≥0.35 UA/ml) to a combination of fungi (positive group). The remaining 20 children were not sensitized to fungi (negative group). Each fungus-specific IgE level was also measured in sera of the positive group, and a questionnaire-based survey was conducted for daily lifestyles. RESULTS: : Cladosporium was the most prevalent in the houses. From the 32 sera of the positive group, specific IgE levels ≥0.70 UA/ml were most frequently detected in 21 sera for Alternaria. Children in whose houses Alternaria was found displayed higher levels of Alternaria-IgE than those in whose houses where Alternaria was not found. In addition, Alternaria-IgE level was lower for children using an air purifier than for children who were not. Windows were more frequently opened for ventilation in negative-group houses than in positive-group houses. CONCLUSIONS: : The existence of Alternaria might strongly induce IgE sensitization for Alternaria. Using an air purifier and frequently opening windows may minimize fungal sensitization of allergic children.

Relationship between cord blood level of IgE specific for Dermatophagoides pteronyssinus and allergic manifestations in infancy.

The relationship between the cord blood level of IgE specific for Dermatophagoides pteronyssinus (Dp-IgE) and the development of allergic disorders in infants was investigated. None of the 10 infants who had no family history of allergic disorders and a cord blood Dp-IgE level of <0.07 IU/ml developed atopic dermatitis by 10 months of age. Among the infants whose mothers had atopy, those with a cord blood Dp-IgE level of > or =0.07 IU/ml showed a higher prevalence of allergic disorders at 3 years of age than those with a cord blood Dp-IgE level of <0.07 IU/ml. These observations suggest that the cord blood Dp-IgE level may be related to allergic manifestations in infancy.