Primary Ciliary Dyskinesia with Identical Genotype but Distinct Phenotypes in Two Siblings.

In this study, we report two cases of siblings diagnosed with primary ciliary dyskinesia (PCD) sharing an identical genotype yet exhibiting distinct phenotypes. A 13-year-old girl with acute pneumonia was admitted to our hospital. Chest and sinus radiography revealed situs inversus and bilateral maxillary sinusitis. Chest computed tomography revealed bronchiectasis. Her 6-year-old brother with acute bronchitis was admitted and was diagnosed with bronchial asthma due to recurrent wheezing. Unlike his sister, he did not have situs inversus. Both patients had a chronic wet cough and were diagnosed with bronchial asthma by their family doctor. The mean PCD rule (PICADAR) scores were 9 and 7, respectively. Genetic analysis confirmed the presence of the same homozygous mutation (c.546C > A,pTyr182Ter) in DNAI2. To date, there have been four reports of the same pathogenic variants but different PCD phenotypes. Pathological variants of DNAI2 cause the loss of the outer dynein arm, the absence of which results in a lack of primary ciliary movement involved in the left-right axis formation during the embryonic period. A lack of functional cilia results in randomized visceral asymmetry; hence, the same pathogenic variant may exhibit different phenotypes. PCD is often overlooked and is sometimes managed as bronchial asthma, as in these siblings. In our case, the PICADAR score was useful in predicting the clinical diagnosis of PCD.

Pediatric IgA-Dominant Infection-Related Glomerulonephritis.

The concept of infection-related glomerulonephritis (IRGN) has been introduced as adults diagnosed with glomerulonephritis often have coexisting active infections. Furthermore, IgA-dominant IRGN is associated with staphylococcal infections in adults with comorbidities, which often progress to end-stage renal disease. Little is known about IgA-dominant IRGN in children, and no consensus for a management strategy of this condition has been reached. We describe the case of a 9-year-old boy with IgA-dominant IRGN that was diagnosed using specific staining for nephritis-associated plasmin receptor (NAPlr)/plasmin activity and galactose-deficient IgA1 (Gd-IgA1), a marker of IgA nephropathy. The patient was successfully treated using a combination of prednisolone, mizoribine (an immunosuppressive drug), and lisinopril (an angiotensin-converting enzyme inhibitor) and three courses of methylprednisolone pulse therapy. The patient was admitted to our hospital with generalized edema, gross hematuria, proteinuria, hypertension, and renal dysfunction. Hypocomplementemia contributed to a diagnosis of IRGN, although the causative organism was unknown. A renal biopsy performed when the patient presented with nephrotic syndrome showed IgA deposition, positive staining for NAPlr, and negative staining for Gd-IgA1, in addition to findings consistent with IRGN, leading to a pathologic diagnosis of IgA-dominant IRGN. The histological staining for NAPlr/plasmin activity and Gd-IgA1, together with clinical symptoms, could be helpful for diagnosing IgA-dominant IRGN. Our findings indicate that otherwise healthy children can also develop IgA-dominant IRGN. Therefore, early diagnosis and aggressive treatment should be considered when IgA-dominant IRGN is suspected to avoid the possibility of incomplete recovery of renal function.

Maternal heated tobacco product use during pregnancy and allergy in offspring.

BACKGROUND: Little is known about the association between maternal use of heated tobacco products (HTPs) during pregnancy and the onset of allergy among offspring. This study aimed to determine whether maternal HTP smoking is associated with allergy in their offspring and to evaluate the potential dose-response association. METHODS: In this web-based, cross-sectional survey conducted in July and August 2021 in Japan, we investigated 5688 pairs of postpartum women and infants (<3 years). Clinical diagnoses of infant asthma, rhinitis, conjunctivitis, or atopic dermatitis were reported. Using multilevel Poisson regression, we estimated the prevalence ratios (PRs) and 95% confidence intervals (CIs) of allergy in infants with HTP smoking categories cross-classified by pregnancy periods, and adjusted for potential covariates including maternal cigarette smoking and partner's smoking status. Non-smokers served as the reference group. RESULTS: In total, 2.4% women smoked HTPs during pregnancy. Allergy occurred in 7.8% of the infants. The prevalence of allergy increased among the offspring of current HTP smokers during pregnancy at 15.2% (PR = 1.98, 95% CI 1.28-3.05); this association was the most pronounced during the first trimester but attenuated before pregnancy and postpartum. Dose-response associations were observed, for example a one-unit increase in daily maternal HTP use during pregnancy was associated with a 5% increase in allergy onset. Sub-group analyses excluding cigarette smokers during pregnancy and sensitivity analyses using the International Study of Asthma and Allergies in Childhood questionnaire showed a similar pattern. CONCLUSIONS: Maternal HTP smoking during pregnancy is associated with allergy in the offspring.

Association between residents' scholarly activities and publication requirement policy.

BACKGROUND: Scholarship is recognized as important in residency training worldwide. The Japan Pediatric Society (JPS) enacted a reform in 2017 to require publication of an article as a prerequisite for taking the board certification test, with the goal of increasing scholarly activity. METHODS: The purpose of this study was to provide a detailed description of the trends in residents' scholarly activities related to the JPS reform. A secondary analysis was performed on the cross-sectional database of pediatrics residents who took the certification test in 2015-2018. RESULTS: The enrolled participants were 2399 residents of which 79.7% passed the test. Publication of any type of article increased significantly (21%-22% to 100%; 0.1 to 0.3/person-year) after the implementation of the JPS reform, whereas academic presentations did not (89% to 91%; 1.2 to 1.3/person-year), both in terms of the percentage of the number of those who created them and the average rate of research production. Not only Japanese articles (11%-13% to 49%-53%; 0.04 to 0.15-0.17/person-year) or case reports (10%-14% to 51%-52%; 0.03-0.05 to 0.16-0.17/person-year), but also English articles (4%-5% to 15%-16%; 0.01-0.02 to 0.05/person-year) and original articles (5% to 11%-17%; 0.01 to 0.03-0.05/person-year) increased significantly. The number of each type of article publication was correlated with success in the board certification test (odds ratio 1.5-1.8). CONCLUSIONS: Scholarly activities of pediatrics residents were enhanced by the JPS implementation of the article requirement policy, which is crucial to fostering a scholarly culture. The most efficient measures to promote scholarship need to be persistently investigated.

Food protein-induced enterocolitis syndrome due to buckwheat: A case report.

Buckwheat is a rare causative food for food protein-induced enterocolitis syndrome (FPIES). To date, it is unknown what laboratory data patients with FPIES caused by buckwheat show. We report a 4-year-old female with FPIES caused by buckwheat and the laboratory results. Skin prick, specific IgE antibody, and basophil activation tests were negative; however, the lymphocyte stimulation test (LST) revealed a 10.2-fold increase in activation compared with the negative control. In an open-label oral food challenge (OFC) of 80 g boiled buckwheat noodles, 3 hours after ingestion, vomiting occurred four times in a 2-hour duration. Therefore, we diagnosed the patient with FPIES caused by buckwheat. Her neutrophil count, C-reactive protein, and thymus and activation-regulated chemokine were elevated after the OFC. Moreover, the patient had a positive reaction to the LST, which may theoretically be useful in diagnosing non-immunoglobulin E-mediated gastrointestinal food allergies. FPIES caused by buckwheat is rare; however, we found that the same laboratory results were observed in a comparison of FPIES cases caused by other foods.

Proton Pump Inhibitor to Treat an Eosinophilic Duodenal Ulcer with Esophageal Involvement: A Pediatric Case.

Eosinophilic gastrointestinal disorders are diseases that cause inflammation and dysfunction due to infiltration of eosinophils into various regions of the gastrointestinal tract. Symptoms and treatment vary depending on lesion severity. We describe the first pediatric case of an eosinophilic duodenal ulcer with esophageal involvement that was effectively treated using proton pump inhibitor monotherapy. A 12-year-old boy with no relevant family or medical history presented with a one-month history of epigastric pain. Laboratory test results were as follows: white blood cell count, 4,700/µL; eosinophil count, 150/µL (3.2%); and total IgE, 151.6 IU/L; and IgG antibodies for Helicobacter pylori were absent. Esophagogastroduodenoscopy revealed longitudinal linear furrows in the esophagus, indicating eosinophilic esophagitis with an A1 ulcer from the duodenal bulb to the descending duodenum. The patient was diagnosed with an eosinophilic duodenal ulcer with esophageal involvement based on pathological findings. Esomeprazole, a common proton pump inhibitor, was orally administered, after which the symptoms promptly improved. After two months, the esophagogastroduodenoscopy and pathological examination results showed improvement in both the esophagus and duodenum. There have been no previous reports of an eosinophilic duodenal ulcer with esophageal involvement without post-duodenal involvement at the time of diagnosis. The possibility of eosinophilic gastrointestinal disorders should be investigated in patients with duodenal ulcers by means of active biopsy, and patients should be investigated for other types of gastrointestinal lesions. Proton pump inhibitor monotherapy may be considered a first-line treatment for eosinophilic duodenal ulcers with esophageal involvement, depending on lesion severity.

Eosinophilic Duodenal Ulcer Exacerbation after Helicobacter pylori Eradication in a 14-Year-Old Boy.

Eosinophilic gastrointestinal disorders (EGIDs) cause various gastrointestinal symptoms due to infiltration of eosinophils into the gastrointestinal tract. Helicobacter pylori (H. pylori) is a microorganism that is associated with various diseases such as autoimmune diseases. In recent years, H. pylori is considered protective in inflammatory bowel diseases and gastrointestinal autoimmune disorders but is not known to be protective in EGIDs. A 14-year-old boy presented with epigastric pain and nausea, without diarrhea. His symptoms were not associated with meals. Blood examination showed an eosinophil count of 1,666 cells/µL (17.0%) and an interleukin-5 (IL-5) level of less than 3.9 pg/mL. Esophagogastroduodenoscopy showed chronic gastritis and duodenal ulcers. Capsule endoscopy and colonoscopy showed no abnormal findings. The patient was diagnosed with chronic gastritis due to H. pylori infection and eosinophilic duodenal ulcers. H. pylori eradication was performed. However, the abdominal pain worsened with elevated peripheral eosinophil count [2,314/µL (26%)] and serum IL-5 level (8.0 pg/mL). Montelukast administration improved the symptoms and laboratory findings [peripheral eosinophil count, 330/µL (5.9%); IL-5, < 3.9 pg/mL]. EGIDs should be considered as a cause of duodenal ulcers. H. pylori may be protective in EGIDs. Montelukast monotherapy may be considered as a first line treatment for eosinophilic duodenal lesions.

Extensive Subcutaneous Abscess due to Panton-Valentine Leucocidin-Positive Community-Associated Methicillin-Resistant Staphylococcus aureus in an Infant.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have increased worldwide in people without underlying diseases. CA-MRSA can often cause serious bacterial infections, especially skin and soft tissue infections (SSTI). Here, we describe a case of severe subcutaneous abscess due to Panton-Valentine leucocidin (PVL)-positive CA-MRSA in an infant without underlying diseases. A 4-month-old girl presented with a 4-day history of fever, with extensive redness and swelling of the lumbar region and buttocks. She was diagnosed with extensive subcutaneous abscess of the lumbar region and buttocks. Surgical drainage was performed, and a substantial volume of pus was drained. MRSA was detected in the pus on culture. Antibiotic therapy that covered MRSA was also administered for 3 weeks, and the abscess healed. As it was a severe SSTI due to MRSA, analysis of MRSA revealed PVL-positive MRSA. This patient had no underlying disease or history of antibiotic administration, and as MRSA was present in the nasopharyngeal cavity, it was considered a case of CA-MRSA. Furthermore, the prevalence of PVL-positive CA-MRSA in MRSA isolated from patients with SSTI has also increased in Japan. The Infectious Diseases Society of America recommends surgical intervention and empirical antibiotic therapy for MRSA-complicated SSTI cases in an era of CA-MRSA. Pediatricians must strongly consider the possibility of MRSA in children with severe SSTIs.

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder.

The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

Executive summary: Japanese pediatric guideline for the treatment and management of asthma (JPGL) 2020.

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. "Infant and preschool asthma" is diagnosed when young children (<6 years of age) have three or more episodes of clear expiratory wheezing, which continue for more than 24 h, and symptom improvement can be observed after beta-2 agonist inhalation. In children without clear improvement, diagnostic therapeutic trial for the duration of 1 month with controller treatment can be used. Since long-term management is initiated, the treatment level is adjusted based on the current control status and the management of risk factors, with the provision for holistic care. This underscores the smooth transition of pediatric patients into adult services. There are several differences between the JPGL and the guidelines of other countries. Further evidence is obtained as the utility of the newly proposed management plans should be evaluated in the Japanese population.

Incidence rate of vitamin D deficiency and FGF23 levels in 12- to 13-year-old adolescents in Japan.

INTRODUCTION: The incidence rate of vitamin D deficiency is increasing throughout the world. We measured the incidence rate of vitamin D deficiency and fibroblast growth factor 23 (FGF23) levels in 12- to 13-year-old adolescents in Japan. MATERIALS AND METHODS: A total of 492 adolescents (247 boys and 245 girls) from Japanese community enrolled in this study. 25 hydroxyvitamin D (25(OH)D) was measured with radioimmunoassay. In the subjects with low 25(OH)D levels (≦ 20 ng/ml), intact parathyroid hormone (iPTH), calcium (Ca), phosphorus (P), albumin (Alb), alkaline phosphatase (ALP) and FGF23 were measured. RESULTS: 25(OH)D levels were significantly lower in girls (20.9 ± 3.1 ng/ml) than in boys (22.2 ± 3.3 ng/ml) (p < 0.0001). Fifty-five boys (22.3%) and 83 (33.9%) girls showed vitamin D deficiency (< 20 ng/ml). One-hundred eighty-six (75.3%) boys and 162 (66.1%) girls showed vitamin D insufficiency (≧ 20 ng/ml, < 30 ng/ml). In the subjects whose 25(OH)D levels were ≦ 20 ng/ml, the levels of iPTH, Ca, P, Alb, ALP and FGF23 were 22.3 ± 9.0 pg/ml, 9.5 ± 0.4 mg/dl, 4.7 ± 0.6 mg/dl, 4.6 ± 0.3 g/dl, 920.8 ± 339.3 U/l and 42.6 ± 26.0 pg/ml, respectively. There was a significant negative association between serum 25(OH)D levels and iPTH [r = - 0.290 (p < 0.0001)]. There was no significant association between serum 25(OH)D levels and FGF23. CONCLUSION: We show that 28% of Japanese 12- to 13-year-old early adolescents suffer from vitamin D deficiency. Findings from this study indicate that vitamin D deficiency requires close oversight in public health during adolescence to ensure proper bone health.

Ulcerative colitis relapse after Helicobacter pylori eradication in a 12-year-old boy with duodenal ulcer.

BACKGROUND: Helicobacter pylori (H. pylori) prevalence is lower in patients with inflammatory bowel disease (IBD) than in those without IBD, suggesting that H. pylori plays a protective role in IBD. It has been reported that IBD may occur due to H. pylori eradication; however, it is unclear whether H. pylori eradication increases the incidence of IBD. Moreover, the effect of H. pylori eradication on IBD activity is unclear. CASE PRESENTATION: An 11-year-old boy diagnosed with ulcerative colitis (UC) was in clinical remission, with treatment involving 5-aminosalicylic acid. Fecal calprotectin (FC) level had decreased to 33.2 mg/kg, indicating mucosal healing. At age 12, he experienced epigastric pain on an empty stomach, which was relieved with dietary intake. His FC level was elevated without UC symptoms, such as diarrhea and bloody stools. He was diagnosed with H. pylori duodenal ulcer. H. pylori eradication (clarithromycin and amoxicillin for 7 days and a proton-pump inhibitor) led to symptom improvement the day after treatment initiation. However, he developed diarrhea and his FC level remained high despite improvement in duodenal ulcer symptoms and endoscopic findings of H. pylori eradication. Colonoscopy results indicated UC relapse. CONCLUSIONS: H. pylori eradication may worsen UC activity. However, further studies are required as this case report involved only one pediatric patient with increased UC activity after H. pylori eradication.

Postinfectious Bronchiolitis Obliterans Misdiagnosed as Bronchial Asthma in a Pediatric Patient.

Bronchiolitis obliterans is a chronic obstructive respiratory disease involving stenosis or occlusion of the bronchioles and smaller airways. The prognosis of bronchiolitis obliterans is poor, and the patient might require home oxygen therapy and/or lung transplantation. Bronchiolitis obliterans has various etiologies; in children, the most common causes are infections by respiratory pathogens like adenoviruses. In such cases, the condition is termed as postinfectious bronchiolitis obliterans. A 7-year-old girl was diagnosed with bronchial asthma at the age of 1 year and was on a regimen of a leukotriene receptor antagonist and an inhaled corticosteroid. At 1 year of age, she was admitted to our hospital with a respiratory syncytial virus infection, and despite continued treatment with the above drugs, she required frequent readmissions. At the age of 7 years, she was diagnosed with postinfectious bronchiolitis obliterans based on the following findings: mosaic perfusion on high-resolution chest computed tomography and ventilation-perfusion mismatch on ventilation-perfusion scintigraphy. A lung biopsy was not performed due to its invasiveness. It has been suggested that appropriate treatment during the early stage improves the prognosis of bronchiolitis obliterans. This disease might be misdiagnosed as bronchial asthma because of the clinical similarities. In patients who do not respond to the treatment for bronchial asthma, pediatricians should consider other diseases with similar signs and symptoms, such as bronchiolitis obliterans, in the differential diagnosis.

Effectiveness of Ursodeoxycholic Acid in the Treatment of Primary Sclerosing Cholangitis with Ulcerative Colitis: A Pediatric Case.

Primary sclerosing cholangitis is a rare disease with poor prognosis that potentially leads to liver cirrhosis and is often complicated by inflammatory bowel disease. Although ursodeoxycholic acid is the most commonly used drug to treat primary sclerosing cholangitis, its effectiveness in treating primary sclerosing cholangitis has not yet been established. An 11-year-old girl had a fever, upper and lower abdominal pain, and bloody stools. Colonoscopy revealed ulcerative colitis. She also had elevated hepatobiliary enzyme levels and C-reactive protein levels, indicating cholangitis after starting food intake, and primary sclerosing cholangitis was diagnosed with endoscopic retrograde cholangiography. Her hepatobiliary enzyme levels gradually improved after ursodeoxycholic acid was started, and symptoms did not recur after food intake. Primary sclerosing cholangitis should be considered if patients, even children, with inflammatory bowel disease, have upper abdominal pain with elevated biliary enzyme levels. The clinical guidelines for primary sclerosing cholangitis treatment have recommended that ursodeoxycholic acid should not be actively used. However, there are some recent reports stating its effectiveness for primary sclerosing cholangitis. In this patient, ursodeoxycholic acid may have been effective for the normalization of the hepatobiliary enzymes. However, it is unknown whether ursodeoxycholic acid improves long-term prognosis. Hence, further evidence regarding the effectiveness of ursodeoxycholic acid in the treatment of primary sclerosing cholangitis needs to be established.

Ustekinumab as the First Biological Agent for Crohn's Disease in a 10-Year-Old Girl.

Pediatric inflammatory bowel disease is associated with growth failure due to chronic inflammation, nutrient disorder, and the side effects of drugs, such as corticosteroids. Biological agents are therapeutic drugs that significantly improve the prognosis of patients with inflammatory bowel disease. The effectiveness of ustekinumab has been reported in the management of adult patients with inflammatory bowel disease. There are very few reports regarding the effectiveness and safety of ustekinumab in pediatric patients with inflammatory bowel disease, especially those who are biologically naive. A 10-year-old girl presented with chronic abdominal pain, diarrhea, and weight loss. Colonoscopy showed a longitudinal ulcer and cobblestone appearance in the ileum and discontinuous inflammation of the colon; therefore, she was diagnosed with Crohn's disease. She was prescribed a fat-restricted diet, elemental diet, 5-aminosalicylic acid, transient prednisolone, and ustekinumab. She achieved clinical and endoscopic remission based on the weighted Pediatric Crohn's Disease Activity Index, fecal calprotectin, and colonoscopy findings at week 75. This patient developed no adverse events, such as infusion reaction or susceptibility to infection over the 75 weeks. The use of ustekinumab as the first biological agent may be an effective and safe treatment for pediatric Crohn's disease.

Pru p 7 Predicts Severe Reactions after Ingestion of Peach in Japanese Children and Adolescents.

INTRODUCTION: Component-resolved diagnostics is used to diagnose food allergies. However, few reports have evaluated the severity of peach fruit allergy using peach allergen components, including Pru p 7. OBJECTIVE: This study aimed to predict peach fruit allergy severity based on the presence of specific IgE (sIgE) antibodies (Abs) to peach allergenic components. METHODS: Twenty-seven patients with peach fruit allergy were enrolled and classified into two groups: the local reaction (LR) group, including 12 patients with only oral or throat mucosal symptoms, and the systemic reaction (SR) group, including 15 patients, 10 of whom experienced anaphylaxis. Serum sIgE Abs against crude peach extract - Pru p 1, 2, 3, 4, and 7 - and tree pollen were measured. RESULTS: sIgE Ab titers of Pru p 1 and 4 and alder pollen in the LR group were significantly higher than those in the SR group. sIgE against Pru p 7 was significantly higher in the SR group than in the LR group. The frequencies of sIgE Abs against Pru p 1, 4, and 7 in the LR group were 91.7, 66.7, and 16.7%, respectively, while in the SR group these were 80, 20, and 60%. Sensitization to Pru p 2 and 3 was detected but limited in all patients. CONCLUSIONS: These findings suggest that sensitization to Pru p 1 and Pru p 4 is associated with local symptoms, and sensitization to Pru p 7 is associated with SR and anaphylaxis. To predict the severity of peach fruit allergy, it is useful to assess sIgE Ab reactions combining Pru p 1, 4, and 7.

Increased MUC1 plus a larger quantity and complex size for MUC5AC in the peripheral airway lumen of long-term tobacco smokers.

There is little information on mucins versus potential regulatory factors in the peripheral airway lumen of long-term smokers with (LTS+) and without (LTS-) chronic obstructive pulmonary disease (COPD). We explored these matters in bronchoalveolar lavage (BAL) samples from two study materials, both including LTS+ and LTS- with a very similar historic exposure to tobacco smoke, and healthy non-smokers (HNSs; n=4-20/group). Utilizing slot blot and immunodetection of processed (filtered and centrifuged), as well as unprocessed BAL samples from one of the materials, we compared the quantity and fraction of large complexes of mucins. All LTS displayed an enhanced (median) level of MUC5AC compared with HNS. LTS- displayed a higher level of large MUC5AC complexes than HNS while LTS+ displayed a similar trend. In all LTS, total MUC5AC correlated with blood leukocytes, BAL neutrophil elastase and net gelatinase activity. Large mucin complexes accounted for most MUC5B, without clear group differences. In all LTS, total MUC5B correlated with total MUC5AC and local bacteria. In the same groups, large MUC5B complexes correlated with serum cotinine. MUC1 was increased and correlated with BAL leukocytes in all LTS whereas MUC2 was very low and without clear group differences. Thus, the main part of MUC5AC and MUC5B is present as large complexes in the peripheral airway lumen and historic as well as current exposure to tobacco smoke emerge as potential regulatory factors, regardless of COPD per se. Bacteria, leukocytes and proteinases also constitute potential regulatory factors, of interest for future therapeutic strategies.

The efficacy and safety of fluticasone/salmeterol compared to fluticasone in children younger than four years of age.

BACKGROUND: Fluticasone propionate 50 µg/salmeterol xinafoate 25 µg (FP/SAL) is widely used in adults and children with asthma, but there is sparse information on its use in very young children. METHODS: This was a randomized, double-blind, multicentre, controlled trial conducted in children aged 8 months to 4 years. During a 2-week run-in period, they all received FP twice daily. At randomization, they commenced FP/SAL or FP twice daily for 8 weeks. All were then given FP/SAL only, in a 16-week open-label study continuation. Medications were inhaled through an AeroChamber Plus with attached face mask. The primary end-point was mean change in total asthma symptom scores from baseline to the last 7 days of the double-blind period. Analyses were undertaken in all children randomized to treatment and who received at least one dose of study medication. RESULTS: Three hundred children were randomized 1:1 to receive FP/SAL or FP. Mean change from baseline in total asthma symptom scores was -3.97 for FP/SAL and -3.01 with FP. The between-group difference was not statistically significant (P = 0.21; 95% confidence interval: -2.47, 0.54). No new safety signals were seen with FP/SAL. CONCLUSION: This is the first randomized, double-blind study of this size to evaluate FP/SAL in very young children with asthma. FP/SAL did not show superior efficacy to FP; no clear add-on effect of SAL was demonstrated. No clinically significant differences in safety were noted with FP/SAL usage.

Objective evaluation of wheezing in normal infants.

BACKGROUND: To evaluate the frequency of wheezing in infants, the presence of wheezing was examined in normal infants using a breath sound analyzer, METHODS: A total of 443 infants (age range, 3-24 months) were included in the present study. The existence of audible wheezing and faint wheezing/inaudible wheezing-like noises (FW) was confirmed on chest auscultation and a sound spectrogram. The breath sound parameters of the sound spectrum, frequency limiting 99% of power spectrum (F99 ), roll-off from 600 to 1,200 Hz (slope) and spectrum curve indices, total area under the curve of dB data (A3 /AT and B4 /AT ), and ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF50 and RPF75 ) were calculated. Using an original Japanese questionnaire, we examined the characteristics of the airway condition of all infants. RESULTS: Finally, a total of 398 infants were analyzed in the present study, and 283 were in good health while 115 had acute respiratory infection (ARI) in the last 7 days. No infants had audible wheezing on auscultation. Three infants without ARI (1.1%) and 10 infants with ARI (8.7%) had FW. In the evaluation of breath sound parameters, there were no marked differences between the infants with and without FW. CONCLUSIONS: Using a breath sound analyzer, wheezing and FW were recognized in only a few infants in good health. Infants recognized to have audible wheezing in daily practice may be at risk of developing recurrent wheezing/asthma.