Mitsuhiko Nambu

Increased oxidative stress in childhood atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease of unknown etiology. To examine the involvement of impaired homeostasis of oxygen/nitrogen radicals in childhood AD, we compared the levels of urinary 8-hydroxy-2-deoxyguanosine (marker of oxidative stress), nitrite/nitrate (marker of nitric oxide synthesis) and selenium (marker of selenium store) in 27 children with AD to those of 25 healthy control children. Urinary 8-hydroxy-2-deoxyguanosine was significantly higher and nitrite/nitrate levels were significantly lower in patients with AD than in the control. Urinary selenium levels were similar in both groups. Our findings suggest that impaired homeostasis of oxygen/nitrogen radicals and increased oxidative stress are involved in the pathophysiology of childhood AD, and indicate that suppression of oxidative stress might be a potentially useful strategy for the treatment of AD.

Association between interleukin‐18 gene polymorphism 105A/C and asthma

Background IL‐18 has been shown to exert anti‐allergic or allergy‐promoting activities, but the existence of genetic polymorphisms in the coding regions of IL‐18 gene has not been demonstrated.

Recurrent hemophagocytic lymphohistiocytosis accompanied by Kikuchi's disease

Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK)-cell activity, increased levels of serum ferritin, and increased levels of soluble interleukin (IL)-2 receptor in the serum and the cerebrospinal fluid [1]. It is proposed that the diagnosis of HLH can be established if five of these eight criteria are met [1]. Other less-common features include lymphadenopathy and skin rash. HLH can be classified as primary or secondary HLH. Primary HLHs include several types of familial HLHs (FHLs) [2 – 4] and the HLHs associated with primary immune deficiencies, and shows continuous or recurrent hemophagocytosis. Secondary HLHs include HLHs associated with infections, malignancies, or autoimmune diseases, and are not usually recurrent. Both primary and secondary HLH can be fatal. Kikuchi’s disease (KD; also known as Kikuchi – Fujimoto disease or subacute histiocytic necrotizing lymphadenitis) is characterized by fever, fatigue, and lymphadenitis. Affected lymph nodes show patchy necrotic areas with karyorrhexis surrounded by activated histiocytes. The cause of KD is still unknown. Although an infectious etiology is suspected, bacteria, fungi, toxoplasma, and Epstein-Barr virus (EBV) have been shown not to be associated with the disease. KD is benign and shows a self-limited clinical course [5,6]. Only 11 cases of concurrent HLH and KD have been reported, none of which was recurrent [7 – 16]. To our knowledge, this is the first report of a case of recurrent HLH accompanied by KD. The patient was a 13-year-old Japanese boy with atopic dermatitis and bronchial asthma, but who was otherwise healthy. Left inguinal tender lymphadenopathy appeared 2 weeks before hospitalization and ameliorated without any medication within 1 week. Fever and tender lymphadenopathy of the left axillary and right inguinal lymph nodes appeared 2 days before hospitalization. Hepatosplenomegaly was noticed upon hospitalization. Laboratory examinations showed marked leukopenia (white blood cell count 1.7610/l; absolute neutrophil count 0.37610/l), mild thrombocytopenia (13.5610/l), hypertriglyceridemia (306 mg/dl), low NK-cell activity (15%, normal range 18 – 40%), and an increased level of soluble IL-2 receptor (982 U/ml). The bone marrow (BM) was hypocellular, which was confirmed by both aspiration and biopsy, and revealed increased number of histiocytes (9.5%), most of which showed hemophagocytosis [Figure 1(a)]. These results showed that five of the eight diagnostic criteria for HLH were met [1]. The karyotype of BM was 46, XY [12/12]. Clonal rearrangements of the TCRG and IgH genes were not detected. PCR assays for cytomegalovirus (CMV), parvovirus B19, and hepatitis C virus (HCV), and serological assays for rubella, hepatitis B virus (HBV), and EBV did not indicate that the HLH was associated with any of these viruses. Results of cerebrospinal fluid assays and cranial magnetic resonance imaging showed no abnormalities. The patient did not have albinism,

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 ≧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.

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

BACKGROUNDnOmalizumab 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 25xa0ng/ml (target level of suppression).nnnMETHODSnThirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200xa0μg/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.nnnRESULTSnThe geometric mean serum free IgE level at 24 weeks was 15.6xa0ng/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 (pxa0<xa00.001), versus baseline. Quality-of-life scores were also significantly improved (pxa0<xa00.001). 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.nnnCONCLUSIONSnIn Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25xa0ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

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.

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

BACKGROUNDnOmalizumab 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 havent 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.nnnMETHODSnThirty-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).nnnRESULTSnThirty-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 didnt 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), pxa0<xa00.001 for QOL, 1.33 vs 0.16, pxa0<xa00.001 for hospitalization, 0.68 vs 0.15, pxa0=xa00.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state.nnnCONCLUSIONSnLong-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified.

Cohen's Syndrome with Diabetes Mellitus

We report a case of 12‐year‐old girl with Cohens syndrome (CS) associated with diabetes mellitus (DM). She had the characteristic facies, with a short philtrum, an open‐mouth appearance, prominent maxillary central incisors, high palate, mild maxillary hypoplasia and micrognathia. Other features included truncal obesity, short stature, mental deficiency, small hands and feet, and accentuated thoracic kyphosis. She had been hypotonic during the neonatal and early infantile periods. Laboratory examinations showed hyperglycemia and glucosuria. HbAl and HbA1 c levels were raised. A 75‐g oral glucose tolerance test (OGTT) showed glucose intolerance consistent with DM, but there was a normal level of urinary C‐peptide. There were no islet cell antibodies (ICAs) and no history of ketoacidosis. This is the first reported case of CS with non‐insulin‐dependent diabetes mellitus (NIDDM).

Hospitalizations Associated with Pandemic Influenza A (H1N1) 2009 in Asthmatic Children in Japan

BACKGROUNDnThe 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.nnnMETHODSnAn 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.nnnRESULTSnA 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.nnnCONCLUSIONSnAsthma may not be a risk factor for severe pdm (H1N1) 2009 infection in children.

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

BackgroundThe 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 MethodsWe 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.ResultsCladosporium 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.ConclusionsThe 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.