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.

Mondini dysplasia with recurrent bacterial meningitis caused by three different pathogens.

Mondini dysplasia is rare, but has an important association with recurrent bacterial meningitis. We herein describe the case of a 3-year-old girl with unilateral sensorineural hearing loss who presented with three independent episodes of bacterial meningitis within 8 months. Temporal bone computed tomography indicated the characteristic features of Mondini dysplasia in the right inner ear. This was treated by surgical closure of the inner ear defect via oval window and additional vaccination was administered. Appropriate vaccination might prevent the recurrent bacterial meningitis associated with Mondini dysplasia.

Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan.

PURPOSE: To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. METHODS: Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1ß levels were measured by ELISA. RESULTS: The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3-6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C-reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 ± 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-α and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1ß, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1ß production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes. CONCLUSIONS: Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder-associated genes.

In vitro analysis of the functional effects of an NLRP3 G809S variant with the co-existence of MEFV haplotype variants in atypical autoinflammatory syndrome.

PURPOSE: Hereditary periodic fever syndromes have been considered monogenic diseases. However, some recent reports have described patients with co-existence of recurrent fever responsible genes. This study assessed whether a rare variant, found in Japanese children showing atypical autoinflammatory syndrome, located in the leucine-rich repeat domain of Nod-like receptor family, pyrin domain containing 3 (NLRP3) with co-existence of Mediterranean fever (MEFV) haplotype variants may contribute to a proinflammatory phenotype using a systematic approach. METHODS: Cytokine production in serum or from peripheral blood monocytes was measured by ELISA. DNA sequence analysis of genes including NLRP3, MEFV, mevalonate kinase (MVK), and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) were performed on patient samples. In vitro functional assays determined the effects of the NLRP3 variants and pyrin using NF-κB activation and speck formation assays. RESULTS: A heterozygous genetic variant of NLRP3, G809S, was found in samples from both patients. Additionally the previously reported heterozygous MEFV variants (P369S-R408Q or E148Q-P369S-R408Q) were also detected in both patients. Serum IL-1ra and sTNFR1 levels increased in the attack phase of the disease in both patients. The production levels of IL-1ß from monocytes isolated from both cases were elevated following LPS and IFN-γ stimulation. The NLRP3 G809S variant demonstrated no increase of NF-κB activity following monosodium urate stimulation, whereas it significantly increased speck formation by interacting with apoptosis-associated speck-like protein with caspase recruitment domain. CONCLUSIONS: The phenotype of atypical autoinflammatory disease in patients could be modified by a synergistic effect with two other variants of autoinflammatory-associated genes.

Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients.

The etiology of cryopyrin-associated periodic syndrome (CAPS) is caused by germline gene mutations in NOD-like receptor family, pryin domain containing 3 (NLRP3)/cold-induced autoinflammatory syndrome 1 (CIAS1). CAPS includes diseases with various severities. The aim of this study was to characterize patients according to the disease severity of CAPS. Five Japanese patients with four kinds of gene variations in NLRP3 were found and diagnosed as CAPS or juvenile idiopathic arthritis. Two mutations in NLRP3, Y563N and E688K, found in CAPS patients exhibit significant positive activities in the nuclear factor-κB reporter gene assay. Increased serum interleukin (IL)-18 levels were only observed in severe cases of CAPS. In mild cases of CAPS, the serum IL-18 levels were not increased, although lipopolysaccharide- or hypothermia-enhanced IL-1ß and IL-18 production levels by their peripheral blood mononuclear cells were detectable. This series of case reports suggests that a combination of in vitro assays could be a useful tool for the diagnosis and characterization of the disease severity of CAPS.

Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism.

PURPOSE: To describe a case of autosomal-dominant (AD)-chronic mucocutaneous candidiasis (CMC) with a signal transducer and activator of transcription (STAT) 1 gene mutation, and some of the important complications of this disease such as chronic hepatitis. METHODS: We present a 23-year-old woman with CMC, chronic active hepatitis, and hypothyroidism. Her father also had CMC. We performed several immunological analyses of blood and liver samples, and searched for gene mutations for CMC in the patient and her father. RESULTS: We identified the heterozygous substitution c.821 G > A (p.Arg274Gln) in the STAT1 gene of both the patient and her father. The level of ß-glucan induced interferon (IFN)-γ in her blood cells was significantly low. Immunoblot analysis detected serum anti-interleukin (IL)-17 F autoantibody. She was found to have increased (low-titer) antibodies related to her hypothyroidism and hepatitis. Her serum IL-18 levels fluctuated with her AST and ALT levels. Liver biopsy revealed CD68-positive cell infiltration and IL-18 expression in the sinusoidal regions. These results suggest that the chronic active hepatitis in this patient may be exacerbated by the excessive IL-18 accumulation caused by recurrent mucocutaneous fungal infection, and decreased IFN-γ production. CONCLUSIONS: AD-CMC is known to be caused by a gain-of-function mutation of the STAT1 gene. Chronic active hepatitis is a rare complication of AD-CMC, with currently unknown pathogenesis. It seems that the clinical phenotype in this patient is modified by autoimmune mechanisms and cytokine dysregulation. AD-CMC can be complicated by various immune disorders including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Computed tomographic findings of Kawasaki disease with cervical lymphadenopathy.

OBJECTIVE: The purpose of this study was to describe CT findings in patients with Kawasaki disease with cervical lymphadenopathy. MATERIALS AND METHODS: Twelve patients with cervical lymphadenopathy were difficult to diagnose at the initial visit and underwent CT for the assessment of lymphadenopathy. Computed tomographic images were assessed for numbers, sizes, locations of enlarged nodes, and other imaging findings. RESULTS: Seventy-two enlarged nodes were identified. The maximum diameter of enlarged nodes ranged from 1.0 to 2.5 cm (mean, 1.5 cm). Lymphadenopathy was unilateral in 8 patients (67%) and located at level IB in 2 patients, II in 50 patients, III in 10 patients, IV in 1 patient, and V in 9 patients. Perinodal infiltration was found in 10 patients (83%), and 3 patients (25%) had focal low attenuation within nodes. Retropharyngeal hypodense area was present in 4 patients (33%), peritonsilar hypodense area in 3 patients (25%), and enlarged tonsils in 4 patients (33%). CONCLUSIONS: Cervical lymphadenopathy in Kawasaki disease usually showed unilateral distribution predominantly at levels II, III, and V with perinodal infiltration occasionally accompanied by retropharyngeal hypodense area, peritonsilar hypodense area, and enlarged tonsils.

Repeated-dose pharmacokinetics of inhaled ciclesonide (CIC-HFA) in Japanese children with bronchial asthma: a phase I study.

BACKGROUND: Ciclesonide (CIC) is a highly safe, inhaled corticosteroid (ICS) that is converted into a pharmacologically active metabolite (des-isobutyryl-ciclesonide); this metabolite, in turn, exerts a local anti-inflammatory effect on lung tissue. The present study was undertaken to analyze the pharmacokinetics of des-isobutyryl-ciclesonide in the serum of Japanese children with bronchial asthma treated by repeated doses of CIC and to compare the data thus obtained with those obtained for Caucasian children with bronchial asthma. METHODS: Eight Japanese children with bronchial asthma were treated for 7 days with CIC-hydrofluoroalkalane (CIC-HFA) 200 µg/day administered by a metered-dose inhaler. The study was designed to assess the pharmacokinetics after 7-day repeated administration by which the steady state can be achieved, based on the results of an earlier study involving healthy Japanese adult males who received 7-day repeated administration of CIC-HFA. Blood was sampled at multiple time points on Day 7 of treatment for measurement of the serum des-isobutyryl-ciclesonide level. RESULTS: The pharmacokinetic parameters (AUC from time zero to last observed concentration [AUC(t)], AUC over the dosage interval τ at steady state [AUC(ss)], maximum concentration [C(max)], and terminal elimination half-life [T(1/2)]) and the temporal changes in the serum levels of des-isobutyryl-ciclesonide after repeated administration of CIC-HFA (200 µg/day) in Japanese children with bronchial asthma differed only slightly from those in Caucasian children with bronchial asthma. No serious adverse events were noted during the study period. Additionally, no abnormalities were detected in the serum cortisol level, other laboratory parameters, or vital signs. CONCLUSIONS: Our results suggest that there is little difference in the pharmacokinetics of des-isobutyryl-ciclesonide up on repeated administration of CIC-HFA between Japanese and Caucasian children with bronchial asthma. And our study suggests that CIC-HFA (200 µg/day, once daily) can be administered safely for 7 days, without raising any safety concerns.

Carnitine palmitoyltransferase 2 deficiency: the time-course of blood and urinary acylcarnitine levels during initial L-carnitine supplementation.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is one of the most common mitochondrial beta-oxidation defects. A female patient with an infantile form of CPT2 deficiency first presented as having a Reye-like syndrome with hypoglycemic convulsions. Oral L-carnitine supplementation was administered since serum free carnitine level was very low (less than 10 micromol/L), indicating secondary carnitine deficiency. Her serum and urinary acylcarnitine profiles were analyzed successively to evaluate time-course effects of L-carnitine supplementation. After the first two days of L-carnitine supplementation, the serum level of free carnitine was elevated; however, the serum levels of acylcarnitines and the urinary excretion of both free carnitine and acylcarnitines remained low. A peak of the serum free carnitine level was detected on day 5, followed by a peak of acetylcarnitine on day 7, and peaks of long-chain acylcarnitines, such as C16, C18, C18:1 and C18:2 carnitines, on day 9. Thereafter free carnitine became predominant again. These peaks of the serum levels corresponded to urinary excretion peaks of free carnitine, acetylcarnitine, and medium-chain dicarboxylic carnitines, respectively. It took several days for oral L-carnitine administration to increase the serum carnitine levels, probably because the intracellular stores were depleted. Thereafter, the administration increased the excretion of abnormal acylcarnitines, some of which had accumulated within the tissues. The excretion of medium-chain dicarboxylic carnitines dramatically decreased on day 13, suggesting improvement of tissue acylcarnitine accumulation. These time-course changes in blood and urinary acylcarnitine levels after L-carnitine supplementation support the effectiveness of L-carnitine supplementation to CPT2-deficient patients.

Escherichia coli O-157-induced hemolytic uremic syndrome: Usefulness of SCWP score for the prediction of neurological complication.

BACKGROUND: Hemolytic uremic syndrome (HUS) is commonly caused by hemorrhagic colitis with Shiga toxin-producing Escherichia coli O-157. Central nervous system (CNS) involvements, including seizures, encephalopathy and brain infarction, are serious complications, but there are no useful scores for the prediction of CNS complications. METHODS: Routine laboratory data at onset of HUS were re-evaluated in 14 patients to find useful parameters for the prediction of CNS complication. RESULTS: Serum sodium and total protein were significantly lower and C-reactive protein (CRP) and white blood cell counts were significantly higher in patients with CNS complications than in patients without. A cumulated score, SCWP score (sodium, CRP, white blood cell count, and total protein) discriminated better between patients with/without CNS complications than individual values. CONCLUSIONS: SCWP score would be useful for prediction of CNS complications.

The response of bovine beta-lactoglobulin-specific T-cell clones to single amino acid substitution of T-cell core epitope.

Cow's milk is one of the most common food allergens in the first year of life, with approximately 2.5% of infants experiencing an allergic reaction to it. Beta-lactoglobulin (BLG) is one of the major allergens in cow's milk. Previously, we reported that four of six T-cell clones (TCC) which were established from cow's milk allergy patients recognized BLGp97-117 as the core sequence and also recognized BLG in association with the human leucocyte antigen (HLA)-DRB1*0405 allele. Using two of these four TCCs, we evaluated the T-cell response to BLG peptides with single amino acid substitution or deletion and identified BLGp102-112 as the minimum essential region in BLGp97-117. In the alanine-scan assay, the proliferative responses of TCCs to pE108A disappeared, and the proliferative responses of TCCs to pC106A decreased. In the analog peptide proliferation assay, pY102S had retained some T-cell response to the two TCCs. Collecting these results, we propose a motif for the interaction between the HLA-DRB1*0405 allele and antigen peptide, and suggest that BLGp105-108 are important residues to retain the TCR/BLG-peptide/HLA complex. pY102A and pY102S are partial agonists for the T-cell receptor. These peptides might be considered as candidate peptides for the modification of the T-cell response to BLG in cow's milk allergy.

Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency.

In some patients with common variable immunodeficiency (CVID) and immunoglobulin (Ig) A deficiency (IgAD), tumor necrosis factor (TNF) family receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) gene mutations have been reported. B cells from individuals with TACI mutations do not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL) which probably suggests impaired isotype switching. To clarify the pathogenesis of CVID and IgAD of Japanese patients, we investigated the mutations of TNF family members TACI, APRIL, B-cell activating factor (BAFF), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) genes and the expression levels of BAFF and APRIL in patients with CVID, IgAD and X-linked agammaglobulinaemia (XLA). We also investigated the relationship between age and the blood plasma levels of BAFF and APRIL. The causative gene mutations of TNF family members in our patients were not detected. In healthy subjects, the BAFF and APRIL plasma levels correlated inversely with age. The BAFF and APRIL plasma levels of patients with CVID, IgAD and XLA were significantly higher than those of healthy children. Elevated BAFF and APRIL expression levels might partially reflect the common immunological feature of primary antibody deficiency.

[QOL questionnaire for pediatric patients with bronchial asthma and their parents or caregivers. Preparation and evaluation of the short form version 2008 (Gifu)].

BACKGROUND: The QOL questionnaire version 2001 for pediatric patients with bronchial asthma and their parents or caregivers includes 15 questions for patients under the age of 4 years and 20 questions for patients over the age of 4 years. We have already reported that the QOL questionnaire version 2001 reflects reliability (including reproducibility), factorial validity, and changes in paroxysmal attacks of asthma. In this study, we revised the questionnaire for use in routine medical practice. METHODS AND RESULTS: In this study, based on the data of a previous report, the number of questions was reduced further and it was revised to the questionnaire the short form by integrated data. The revised version 2008 (Gifu) consisted of emotional burden, asthma attack, instability of symptoms and proper acceptance of asthma as a common factor, moreover 4 or more years old added load of exercise factor which consisted of two questions in each factor. This QOL short form questionnaire version 2008 (Gifu) is a disease specific questionnaire in comparison with health control, bronchial asthma and non-asthmatic patients, such as atopic dermatitis and allergic rhinitis. CONCLUSION: Although Cronbach's alpha fell with reduction of the number of questions, we conclude that it was acceptable in the clinical practice.

Refractory osteomyelitis caused by bacille Calmette-Guérin vaccination: a case report.

A male infant, 1 and a half years old, was affected with bacille Calmette-Guérin osteomyelitis of the left tibia. The gyrB DNA direct sequencing, followed by restriction fragment length polymorphism of genomic DNA from a biopsy sample of the lesion, made diagnosis rapid.

Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2b therapy: case report and review of the literature.

Diffuse lymphangiomatosis is a very rare congenital disease, characterized by diffuse or multifocal lymphangioma in the skeletal tissue, spleen, liver, mediastinum, and/or lung. The prognosis is usually poor, especially for children with thoracic lesion, and treatments for the disease are controversial. The authors report a 9-year-old boy with diffuse lymphangiomatosis involving the thorax with pleural effusions, the spleen, and systemic bone. The patient was treated with pegylated interferon alfa-2b, and achieved good clinical and radiological improvement.

Lymphocyte Responses to Chymotrypsin- or Trypsin V-Digested beta-Lactoglobulin in Patients with Cow's Milk Allergy.

: Chymotrypsin- or trypsin V- (a mixture of trypsin and chymotrypsin) digested beta-lactoglobulin (BLG) peptides were prepared and were confirmed to have much less immunoglobulin (lg)G and lgE reactivity compared with intact BLG by IgG inhibition enzymelinked immunosorbent assay and IgE dot blotting. The lymphocyte responses to intact BLG and these peptides were examined using peripheral blood mononuclear cells (PBMCs) from 10 patients with cow's milk allergy. The PBMCs from most patients had lower lymphocyte responses to chymotrypsin- and trypsin V-digested BLG peptides than those to intact BLG. However, PBMCs from one and two patients retained significant proliferative responses to both peptides and to only the former peptide, respectively. Interferon-c production stimulated by chymotrypsin-digested peptides was still detectable in all five patients tested. Chymotrypsindigested BLG reduced lgE reactivity but still induced some lymphocyte responses.

Neuroradiologic findings in Sotos syndrome.

Sotos syndrome is a well-known anomaly syndrome characterized by overgrowth, characteristic facial gestalt, and developmental delay, and haploinsufficiency of the NSD1 gene has been revealed as one of the major genetic causes. However, there have been only a few reports on neuroradiologic findings by computed tomography (CT) or magnetic resonance imaging (MRI), and functional examination of the brain has not been reported. We examined three cases with typical Sotos syndrome, which also were confirmed by genetic analysis with a specific probe for the NSD1 gene. The results of MRI showed the characteristic features that have been reported previously. The findings obtained by using single-photon emission computed tomography and magnetic resonance spectroscopy suggested an association between mental delay and behavioral tendency in Sotos syndrome and immaturity in frontal brain function.