Japanese Pediatric Population Research Articles

Growth patterns and ratios of posterior cranial fossa structures in the Japanese pediatric population: a study utilizing CT scans.

The changes in the proportion of posterior cranial fossa structures during pediatric development remain unclear. This retrospective study aimed to investigate the growth patterns and ratios of these structures using CT scans. Head CT scans of pediatric patients with minor head trauma from Osaka Women's and Children's Hospital between March 2006 and May 2023 were analyzed. The study segmented the intracranial volume (ICV), posterior cranial fossa volume (PCFV), cerebellum volume (CBMV), and brainstem volume (BSV). Correlation coefficients were calculated among the parameters. Patients aged 0 to 10 years were divided into 15 age-related clusters, and mean and standard deviation values were measured. Growth curves were created by plotting mean values sequentially. Ratios such as PCFV/ICV and (CBMV + BSV)/PCFV were examined. Statistical analyses, including unpaired t tests and logarithmic curve fitting, were performed. A total of 234 CT scans (97 from females, 115 from infants under 1 year of age) were analyzed. Positive correlations were observed among the parameters, with the strongest between PCFV and CBMV. The growth curves for ICV, PCFV, CBMV, and BSV exhibited a two-phase process, with rapid growth until approximately 4 years of age, followed by stabilization. The ratios PCFV/ICV and (CBMV + BSV)/PCFV showed increasing trends from birth onwards, stabilizing by 4 and 1 years of age, respectively. This study provides insights into the growth patterns and ratios of posterior cranial fossa structures in the pediatric population. The findings demonstrate a two-phase growth process and increasing trends in the examined ratios.

Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion.

Physiologically based pharmacokinetic (PBPK) models are useful in bridging drug exposure in different ethnic groups, and there is increasing regulatory application of this approach in adults. Reported pediatric PBPK models tend to focus on the North European population, with few examples in other ethnic groups. This study describes the development and verification of a Japanese pediatric PBPK population. The development of the model was based on the existing North European pediatric population. Japanese systems and clinical data were collated from public databases and the literature, and the underlying demographics and equations were optimized so that physiological outputs represented the Japanese pediatric population. The model was tested using 14 different small molecule drugs, eliminated by a variety of pathways, including cytochrome P450 3A4 (CYP3A4) metabolism and renal excretion. Given the limitations of the clinical data, the overall performance of the model was good, with 44/62 predictions for PK parameters (area under the plasma drug concentration-time curve, AUC; maximum serum concentration, Cmax ; clearance, CL) being within 0.8- to 1.25-fold, 56/62 within 0.67- to 1.5-fold, and 61/62 within 0.5- to 2.0-fold of the observed values. Specific results for the 5 CYP3A4 substrates showed 20/31 cases were predicted within 0.8- to 1.25-fold, 27/31 within 0.67- to 1.5-fold, and all were within 0.5- to 2.0-fold of the observed values. Given the increased regulatory use of pediatric PBPK in drug development, expanding these models to other ethnic groups are important. Considering qualifying these models based on the context of use, there is a need to expand on the current research to include a larger range of drugs with different elimination pathways. Collaboration among academic, industry, model providers, and regulators will facilitate further development.

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD. ClinicalTrials.gov identifierNCT03395353

Non-ossifying fibromas and fibrous cortical defects around the knee - an epidemiologic survey in a Japanese pediatric population

BackgroundThe aim of the present study was to evaluate the prevalence of non-ossifying fibroma (NOF) and fibrous cortical defect (FCD) in a Japanese pediatric population and the association between the lesion size and pain.MethodsThis retrospective study, conducted across 10 Japanese institutions, included patients aged 5–15 years who had undergone standard antero-posterior and lateral view radiography of the knee. Using these radiographs, we diagnosed the lesion as a NOF or FCD. Patient demographics, including age, sex, the size and location of the NOF, and chief complaint were recorded. The lesion size was determined using radiographs. Student’s t-test was used to compare the associations between the lesion size and spontaneous pain.ResultsA total of 6222 subjects (3567 boys and 2455 girls) were included in this study. The number of NOF and FCD cases was 143 and 437, respectively, and the prevalence of NOF and FCD was 2.3% and 7.0%, respectively. The average size of NOF and FCD was 22.1 mm (range: 4–102 mm) and 13.2 mm (range: 5–21 mm), respectively. Three patients (2.1%) had pathological fractures due to NOF. Of the 140 NOFs and 437 FCDs, we obtained complaints from the medical records of 126 and 393 patients, respectively. The number of patients with spontaneous pain or other problems with NOF was 68 (54%) and 58 (46%), respectively, that of patients with FCD was 195 (50%) and 198 (50%) patients, respectively. The lesion size was not associated with spontaneous pain in either lesion (p = 0.67 and p = 0.27, respectively).ConclusionThe prevalence of NOF and FCD around the knee was lower than that reported in previous studies. The prevalence of NOF increased and that of FCD decreased with advancing age. In both lesions, the lesion size may not be associated with pain.

Prevalence of Hallermann-Streiff syndrome in a Japanese pediatric population.

Prevalence of Hallermann-Streiff syndrome in a Japanese pediatric population.

Narrative Review: The Process of Expanding the Manual of Antimicrobial Stewardship by the Government of Japan.

The Ministry of Health, Labour and Welfare has published the Manual of Antimicrobial Stewardship (1st edition) in June 2017 to improve the prescribing practice of antimicrobials for immunocompetent adult and pediatric (both school-aged and older children) patients. Due to the increasing demand for further promoting outpatient antimicrobial stewardship, we conducted a literature and national guideline review to identify the area of need. The results of our review revealed a high antimicrobial prescription rate in the Japanese pediatric population. Furthermore, although the Japanese clinical guidelines/guidance covered the fields of almost all infectious diseases, no system exists to estimate the incidence and treatment patterns of important infectious diseases such as asymptomatic bacteriuria, skin and soft tissue infections, and dental practices in Japan. Therefore, addressing the issues of both establishing surveillance systems and the implementation of guidelines/guidance can be the next step to promote further outpatient antimicrobial stewardship.

Pharmacokinetic analysis for model-supported therapeutic drug monitoring of busulfan in Japanese pediatric hematopoietic stem cell transplantation recipients.

This prospective observational study analyzed the pharmacokinetics of busulfan in Japanese children and evaluated the predicting accuracy of previous pediatric PPK models of busulfan. This study enrolled five patients (aged 2-12years, BW 14-48kg) receiving a busulfan-based conditioning regimen for hematopoietic stem cell transplantation at our hospital between January 2017 and December 2018. All patients received a 2-hour intravenous busulfan infusion four times daily for a total of 16 doses. After the infusions, 51 plasma samples were collected with the plasma busulfan concentration measured by liquid chromatography-tandem mass spectrometry. PPK model fitting was analyzed using the (%MPE) and the (%MAPE). Limited sampling strategies for estimating busulfan AUC were also evaluated. High interpatient variability was observed in the PK parameters. The most suitable PPK model that reflected our data was McCune's two-compartment model (%MPE -8.7, %MAPE 19.3). A combination sampling method using the busulfan concentration at 2 and 6hours after the start of the first busulfan dose was found to be able to estimate AUC4day . These results provide useful information on busulfan therapeutic drug monitoring in the Japanese pediatric population.

A retrospective study: Acute rheumatic fever and post-streptococcal reactive arthritis in Japan

BackgroundAcute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA) are immune-mediated consequences of group A streptococcal pharyngitis. ARF has declined in developed nations. No prevalence survey of PSRA has been conducted. This study evaluated the incidence and characteristics of ARF and PSRA in Japanese children. MethodsFrom 2010 to 2015, ARF and PSRA were evaluated using clinical data retrospectively collected by chart review from 528 hospitals. ResultsFrom 323 hospitals (61% response rate), 44 cases of ARF and 21 cases of PSRA were reported. Patients with ARF and/or PSRA were mainly from large cities in Japan. The mean age of ARF occurrence was 8.5 years, and the ratio of female/male patients was 16:28. Major manifestations in the acute phase included carditis, 27 cases (61.4%); polyarthritis, 22 cases (50%); erythema marginatum, 7 cases (15.9%); Sydenham chorea, 3 cases (6.8%); and subcutaneous nodules, 1 case (2.3%). Twenty-one (58.3%) patients had migratory arthritis. During the follow-up period, 6 patients (13.6%) showed mild carditis. For PRSA, the mean age was 8.2 years, and the ratio of female/male patients was 12:9. Six (28.6%) patients had monoarthritis, and 4 (19%) patients had migratory arthritis. No patient had carditis. ConclusionsAlthough ARF and PSRA are rare in the Japanese pediatric population, substantial numbers of patients with both conditions were identified in this study. We observed a high incidence of arthritis and carditis in ARF patients. No PSRA case was complicated with carditis. General pediatricians need to have updated information about ARF and PSRA, even in industrialized countries.

Incidence of diabetes mellitus and neoplasia in Japanese short-statured children treated with growth hormone in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS).

.The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope®, a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.

Four-year study of viruses that cause diarrhea in Japanese pediatric outpatients

Acute gastroenteritis continues to be a major public health problem worldwide. A wide variety of viruses associated with diarrhea disease is being reported continually. This study investigated the epidemiological situation of viruses that cause diarrhea in Japanese pediatric patients. This study enrolled a total of 2,381 fecal specimens collected between 2009 and 2013 from Japanese children with acute gastroenteritis. There is currently a 70.4% prevalence of viruses causing diarrhea among these Japanese pediatric outpatients. Norovirus was detected in 39.3% of the patients, whereas the prevalence of rotavirus, human parechovirus, enterovirus, adenovirus, sapovirus, astrovirus, and Aichi virus was 20.1, 6.6, 6.1, 5.6, 4.8, 2.3, and 0.1%, respectively. Co-infections were observed at the prevalence rates of 13.4 and 0.5% for double infections and triple infections, respectively. Mixed viral infections were found commonly in Japanese outpatients, and the norovirus seemed to play a major role in co-infections. Viral diarrhea cases were detected mostly in children younger than 3 years of age. The norovirus and rotavirus can be detected throughout the year, with a peak during the cold and dry seasons, whereas other common viruses are found during no specific season. Surveillance data revealed that a wide variety of viruses has caused diarrhea to circulate currently in Japanese pediatric outpatients, with very high detection rates; and norovirus and rotavirus are the most important pathogens. The data obtained from this study are valuable for compiling the overall picture of several viruses that causes diarrhea and associates with acute gastroenteritis in the Japanese pediatric population.

Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy

Objectives. In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. Methods and subjects. A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. Results. The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (<104 copies/ml) was observed in 43 and 29 patients, respectively. The sustained effects of IFN therapy were evaluated by comparison between 43 hepatitis B e-antigen (HBeAg)-positive patients treated with IFN and 67 patients with chronic hepatitis B observed without IFN therapy. A Cox’s proportional hazard analysis showed a higher seroconversion rate in the IFN group than in the untreated group (p = 0.003). Similarly, there were higher rates of ALT normalization and lower viral levels in the IFN group than in the untreated group (p = 0.001 for both). Conclusion. IFN therapy showed sustained effects for achieving ALT normalization and HBeAg seroconversion and for reducing the viral load in children with chronic hepatitis B.

Transmission route and genotype of chronic hepatitis B virus infection in children in Japan between 1976 and 2010: A retrospective, multicenter study.

The aim of this study was to clarify the trends of the infectious source of chronic hepatitis B virus (HBV) infection and the HBV genotype in the Japanese pediatric population over the last three decades. The present study was a retrospective, nationwide, multicenter study. Patients who were under 20 years of age when diagnosed with chronic HBV infection were eligible for enrollment in this study. A total of 430 patients (male/female, 256/174; age at the time of writing, 1-37 years; median age, 14 years; birth year, 1976-2010) from 11 hospitals were evaluated. The incidence of chronic HBV infection from 1976 to 1980, 1981-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2005 and 2006-2010 was 56, 52, 34, 37, 81, 92 and 78, respectively. Of the 430 patients, 304 (71%), 61 (14%), 11 (3%) and 54 (13%) were infected via mother-to-child transmission, close contact, blood transfusion and unknown source, respectively. After the introduction of perinatal immunoprophylaxis, the rate of mother-to-child transmission increased from 62% during the 1991-1995 period to 86% during the 2006-2010 period. The distributions of genotypes A, B, C, D and F were 3%, 9%, 86%, 2% and 1%, respectively. No obvious change was observed in the distribution of genotypes. Genotype C was significantly associated with mother-to-child transmission. Mother-to-child transmission remains the primary source of chronic HBV infection after the introduction of immunoprophylaxis. Taking measures to prevent immunoprophylaxis failure is essential to reduce pediatric chronic HBV infection in Japan.

Efficacy and Safety of Pulse Steroid Therapy in Japanese Pediatric Patients with Ulcerative Colitis: A Survey of the Japanese Society for Pediatric Inflammatory Bowel Disease

Aims: We have evaluated the therapeutic efficacy and safety of pulse steroid therapy for ulcerative colitis (UC) in a Japanese pediatric population by means of a survey. Methods: A questionnaire on UC patients treated with therapy between 2002 and 2006 was sent to 37 members of the Japanese Society for Pediatric Inflammatory Bowel Disease. Results: 21 of 62 cases in 6 of 19 centers registered in this study had been treated with pulse steroid therapy. The success rate of remission induction with this treatment was 55%, and improvement was observed in all cases in which remission was not achieved. There were no reports of any obvious side effects. The most common reason for using pulse steroid therapy was for remission induction in relapsed cases. Over the course of 12 (or fewer) months, the number of cases in which remission was maintained was only 1 in 4. However, the amount of concomitant steroid use had significantly decreased after 1 year. Conclusions: This survey shows that in Japan, pulse steroid therapy is used for a relatively large number of children with UC and is as an effective method of remission induction that has few side effects.

Genetic polymorphism of the salivary mucin gene MUC7 in severe caries in Japanese pediatric patients

Caries is a major oral disease whose onset and advance in a broad age group is lifestyle-related, but the genetic background of individuals is also a very important factor. Nevertheless, the relationship between caries frequency and genetic background remains unclear, especially for genetic polymorphisms of salivary proteins. The salivary mucin MG2 plays a role in facilitating the clearance of bacteria, interacts with Streptococcus mutans , which may be a caries pathogen, and can function as an antimicrobial agent. Here, we evaluated the statistical relationship of genetic polymorphisms of tandem repeats in the gene encoding MG2 ( MUC7 ) with the frequency of pediatric severe caries in the Japanese population. Genomic DNA from lingual mucosal cells of 70 healthy and 92 caries patients was purified, and the frequency of genetic polymorphisms in MUC7 was evaluated by PCR. The results indicated that alleles of 6 (the most common allele) and 5 tandem repeats were observed in control and caries groups. Differences in the frequencies of polymorphisms were analyzed by Fisher's exact test. P -values for the frequencies of polymorphisms in MUC7 were as follows: 5-5 versus 5-6 repeats, 0.743; 5-5 versus both 5-6 and 6-6 repeats, 1.00; 5-6 versus 6-6 repeats, 0.254; 5-6 versus both 5-5 and 6-6 repeats, 0.266; 6-6 versus 5-5 repeats, 1.00; 6-6 versus both 5-5 and 5-6 repeats, 0.341. Our data suggest no significant association between genetic polymorphisms in the MUC7 gene and caries susceptibility in the Japanese pediatric population.

Analysis of mutations in the amelogenin and the enamelin genes in severe caries in Japanese pediatric patients

Caries and periodontitis are major oral diseases, both widespread and serious. Caries is thought to be caused by multifactorial, lifestyle-related factors as well as the genetic background of the patient. However, little is known about relevant genetic factors. Since the quality and quantity of enamel plays a direct role in the susceptibility to caries, we set out our quest for genetic factors from the two proteins crucial to the formation of dental enamel: amelogenin and enamelin. We isolated genomic DNAs from lingual mucosal cells derived from healthy and caries subjects, and examined the frequency of single nucleotide polymorphisms (SNPs) by the polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method. We focused on the SNPs of the amelogenin gene (AMELX) at positions +287 and +522 (in both cases, a C to T substitution), and on position +2452 position of the enamelin gene (ENAM; here, too, a C to T substitution). The subjects were all of Japanese extraction, of which 67 individuals served as healthy controls and 80 patients with severe caries served as test subjects. The occurrence of the substitutions at AMELX(+287), (+522) and ENAM(+2452) were 12.2, 0.0 and 11.9% in the control group, and 2.5, 0.0 and 5.0% in the caries group, respectively. The P-values for the statistical frequency of SNPs for AMELX(+287) and ENAM(+2452) were 0.142 and 0.143, respectively. Our data suggest that there was no significant association between the SNPs of those genes and caries susceptibility in the Japanese pediatric population.

Detection and Genetic Characterization of Group A Rotavirus Strains Circulating among Children with Acute Gastroenteritis in Japan

A total of 603 fecal specimens collected from July 2005 to June 2006 from children with acute gastroenteritis, encompassing five different localities in Japan, were screened for group A rotavirus by reverse transcription-PCR. It was found that 117 fecal specimens (19.4%) were positive for group A rotavirus. Rotavirus infection was detected continuously from November to June, with the highest prevalence in April. The G (VP7 genotypes) and P (VP4 genotypes) types were further investigated. The predominant genotype was G1P[8] (70.1%), followed by G3P[8] (17.9%), G9P[8] (6.8%), and G2P[4] (2.6%). A number of unusual G1P[4] combinations were also detected during this study period. A novel nomenclature for G1 is proposed, in which worldwide rotavirus G1 strains are classified into 11 lineages with 17 sublineages. A wide range of amino acid substitutions (up to 34) in VP7 that are specific for G1 lineages and sublineages were identified. Interestingly, only short amino acid motifs located at positions 29 to 75 and 211 to 213 of VP7 defined correctly the phylogenetic G1 lineages and sublineages. Examination of the deduced sequences of antigenic regions of VP7 also revealed multiple particular amino acid substitutions that correlated with the phylogenetic G1 lineages and sublineages. Of note, at least three distinct clusters of rotavirus G1 isolates were cocirculating in the Japanese pediatric population studied.

Genetic characterization of group A rotavirus strains circulating among children with acute gastroenteritis in Japan in 2004–2005

A total of 752 fecal specimens collected from July 2004 to June 2005 from children with acute gastroenteritis in four localities in Japan (Maizuru, Tokyo, Sapporo, and Osaka) were screened for group A rotavirus by RT-PCR. It was found that 82 (10.9%) specimens were positive for group A rotavirus. The G-(VP7 genotypes) and P-(VP4 genotypes) types were further investigated. The P-types of 18 rotavirus strains, which could not be typed by RT-PCR, were determined by sequencing analysis. Of these, 94% (17/18) were P[8] with multiple point mutations at the VP4 primer-binding site. Another sample turned out to be a rare genotype P[9], which was closely related to feline rotavirus. The predominant genotype was G1P[8] (46.4%), followed by G3P[8] (32.9%) and G2P[4] (12.2%). A number of unusual combinations including, G1P[4] (1.2%), G2P[8] (1.2%), G3P[9] (1.2%), G1G3P[8] (1.2%), and G2G3P[8] (3.7%), were also detected. A new nomenclature of P[8] was proposed, in which worldwide rotavirus P[8] strains were classified into four sub-lineages, namely IA, IB, IIA, and IIB. A wide range of amino acid substitutions (up to 22) specific for P[8] lineages and sub-lineages were also identified. Interestingly, only short amino acid motifs located at positions 32–35, 121–135, and 195–236 of VP4 correctly defined the phylogenetic P[8] lineages and sub-lineages. Of note, at least two distinct clusters of rotavirus P[8] were co-circulating in the Japanese pediatric population studied.

Existence of multiple genotypes associated with acute gastroenteritis during 6‐year survey of norovirus infection in Japan

Norovirus (NoV) is recognized as one of the most common causative agent of diarrheal disease in young children worldwide. The current study was undertaken to determine the distribution of NoV genotypes in Japan. A total of 3,864 fecal specimens from children with acute gastroenteritis in five regions (Tokyo, Maizuru, Saga, Sapporo, and Osaka) of Japan from July 1995 to June 2001 were collected and then tested for the presence of NoV by RT-PCR. Three hundred sixty four were found to be positive for NoV, accounting for 11%. The highest prevalence of NoV infection was in November, December, and January as the early winter months in Japan. NoV was subjected to be further characterized to sequencing analysis. All NoVs belonged to two different genogroups I and II and these represented 3% and 97%, respectively. This finding indicated that NoV genogroup II was the dominant group causing acute gastroenteritis in Japan. Interestingly, NoV strains were classified into 16 distinct genotypes including genogroup II genotype 9 that was firstly identified in Japan. Of these, NoV genogroup II genotypes 3 and 4 dominated over other genotypes and became the leading strains in Japanese pediatric population. In conclusion, diarrhea due to NoV infection is still a health burden in Japan. This report also stresses the great genetic diversity as well as the importance of NoV causing the diarrhea in Japan.

Occurrence of Convulsions after Administration of Theophylline in a Large Japanese Pediatric Population with Asthma

The main objective of this study was to evaluate the incidence of convulsions in a large Japanese pediatric population (60,634 patients from 79 centers) treated with theophylline (T). Moreover, further details were obtained from the affected patients. Two sequential questionnaires were sent to centers in order to obtain data. The incidence rate of convulsions was 0.24% (127/54,066) in asthmatic patients treated with T vs. 0.36% (27/7,568) in asthmatic patients not treated with T (p = NS). Eight patients showed convulsions related to T treatment: this group included three infants≤1 year, high mean serum T concentration at the time of convulsion attack (16.7 ± 1.6 μg/mL), and high concomitant medication rate. The rate of recurrent convulsions after readministration of theophylline was higher for patients with epilepsy than for patients with febrile convulsions. In conclusion, the incidence of convulsions in pediatric patients was not affected by the use of theophylline as treatment for asthma. The low frequ...