Melting temperature mapping method in children: Rapid identification of pathogenic microbes.

INTRODUCTION: The melting temperature (Tm) mapping method (TM) identifies bacterial species by intrinsic patterns of Tm values in the 16S ribosomal RNA gene (16S rDNA) extracted directly from whole blood. We examined potential clinical application of TM in children with bloodstream infection (BSI). METHODS: This was a prospective observational study at a children's hospital in Japan from 2018 to 2021. In patients with diagnosed or suspected BSI, we investigated the match rates of pathogenic bacteria identified by TM and blood culture (BC), the inspection time to identification of TM, and the amount of bacterial DNA in blood samples. RESULTS: The median age of 81 patients (93 samples) was 3.6 years. Of 23 samples identified by TM, 11 samples matched the bacterial species with BC (positive-match rate, 48 %). Of 64 TM-negative samples, 62 samples were negative for BC (negative-match rate, 97 %). Six samples, including one containing two pathogenic bacterial species, were not suitable for TM identification. In total, the matched samples were 73 of 93 samples (match rate, 78 %). There were seven samples identified by TM in BC-negative samples from blood collected after antibiotic therapy. Interestingly, the bacteria were matched with BC before antibiotic administration. These TM samples contained as many 16S rDNA copies as the BC-positive samples. The median inspection time to identification using TM was 4.7 h. CONCLUSIONS: In children with BSI, TM had high negative-match rates with BC, the potential to identify the pathogenic bacteria even in patients on antibiotic therapy, and more rapid identification compared to BC. REGISTERING CLINICAL TRIALS: UMIN000041359https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000047220.

Advanced airway management for pediatric out-of-hospital cardiac arrest: A systematic review and network meta-analysis.

OBJECTIVES: Although airway management is important in pediatric resuscitation, the effectiveness of bag-mask ventilation (BMV) and advanced airway management (AAM), such as endotracheal intubation (ETI) and supraglottic airway (SGA) devices, for prehospital resuscitation of pediatric out-of-hospital cardiac arrest (OHCA) remains unclear. We aimed to determine the efficacy of AAM during prehospital resuscitation of pediatric OHCA cases. METHODS: We searched four databases from their inception to November 2022 and included randomized controlled trials and observational studies with appropriate adjustments for confounders that evaluated prehospital AAM for OHCA in children aged <18 years in quantitative synthesis. We compared three interventions (BMV, ETI, and SGA) via network meta-analysis using the GRADE Working Group approach. The outcome measures were survival and favorable neurological outcomes at hospital discharge or 1 month after cardiac arrest. RESULTS: Five studies (including one clinical trial and four cohort studies with rigorous confounding adjustment) involving 4852 patients were analyzed in our quantitative synthesis. Compared with ETI, BMV was associated with survival (relative risk [RR] 0.44 [95% confidence intervals (CI) 0.25-0.77]) (very low certainty). There were no significant association with survival in the other comparisons (SGA vs. BMV: RR 0.62 [95% CI 0.33-1.15] [low certainty], ETI vs. SGA: RR 0.71 [95% CI 0.39-1.32] [very low certainty]). There was no significant association with favorable neurological outcomes in any comparison (ETI vs. BMV: RR 0.33 [95% CI 0.11-1.02]; SGA vs. BMV: RR 0.50 [95% CI 0.14-1.80]; ETI vs. SGA: RR 0.66 [95% CI 0.18-2.46]) (all very low certainty). In the ranking analysis, the hierarches for efficacy for survival and favorable neurological outcome were BMV > SGA > ETI. CONCLUSION: Although the available evidence is from observational studies and its certainty is low to very low, prehospital AAM for pediatric OHCA did not improve outcomes.

Clinical Utility and Patient Distribution of Brief Resolved Unexplained Event Classification for Apparent Life-Threatening Events.

OBJECTIVES: In 2016, brief resolved unexplained events (BRUEs) were proposed as alternative concepts to apparent life-threatening event (ALTE). The clinical utility of managing ALTE cases according to the BRUE classification is controversial. To verify the clinical utility of the BRUE criteria, we evaluated the proportion of ALTE patients who met and those who did not meet the BRUE criteria and assessed the diagnoses and outcomes of each group. METHODS: We retrospectively investigated patients with ALTE younger than 12 months who visited the emergency department of the National Center for Child Health and Development from April 2008 to March 2020. The patients were classified into the higher-risk and lower-risk BRUE groups; however, those who did not meet the BRUE criteria were classified into the ALTE-not-BRUE group. We evaluated the diagnoses and outcomes of each group. Adverse outcomes included death, recurrence, aspiration, choking, trauma, infection, convulsions, heart disease, metabolic disease, allergies, and others. RESULTS: Over the period of 12 years, a total of 192 patients were included, among which 140 patients (71%) were classified into the ALTE-not-BRUE group, 43 (22%) into the higher-risk BRUE group, and 9 (5%) into the lower-risk BRUE group. Adverse outcomes occurred in 27 patients in the ALTE-not-BRUE group and 10 patients in the higher-risk BRUE group. No adverse outcome occurred in the lower-risk BRUE group. CONCLUSIONS: Many of the patients with ALTE were classified into the ALTE-not-BRUE group, suggesting that replacing ALTE with BRUE is difficult. Although patients classified as lower-risk BRUE showed no adverse outcomes, there were only a few of them. In the pediatric emergency medicine setting, the BRUE risk classification may be beneficial for certain patients.

A simple screening method for heterozygous female patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD), caused by X-linked OTC mutations, is characterized by life-threatening hyperammonemia. Heterozygous female patients are often asymptomatic and usually have milder disease than affected male patients, but can have higher morbidity and mortality rates if the disease progresses prior to diagnosis. Our purpose was to establish a screening method for female heterozygotes with OTCD. We retrospectively identified female patients who underwent plasma amino acid analysis at the National Center for Child Health and Development, using data from electronic medical records from March 2002 to September 2021. We extracted patient age, medical history, and biochemical data, including plasma amino acid levels. Patients were categorized into several groups according to their underlying diseases; those with underlying diseases that could potentially affect plasma amino acid levels, such as mitochondrial disease or short bowel syndrome, were excluded, except for untreated OTCD. Biochemical values were compared between OTCD patients and others using the Mann-Whitney U test. The receiver operator characteristic analysis was performed to assess the diagnostic capability for detecting OTCD in each subject. For patients with multiple test data, the most recent of the measurement dates was used in the analysis. The data sets of 976 patients were included. There were significant differences in values of glutamine, citrulline, arginine, and ammonia, but the diagnostic capacity of each alone was inadequate. By contrast, the (glutamine + glycine)/(citrulline + arginine) ratio was appropriate for discriminating heterozygous female patients with OTCD, with a sensitivity of 100% and specificity of 98.6% when the cutoff level was 15.8; the AUC for this discrimination was 0.996 (95% confidence interval, 0.992 to 1.000). These findings could help identify heterozygous female patients with OTCD before the onset of clinical disease.

Food-Induced Anaphylaxis among Children Weighing <15 kg: A Single-Center Case Series of the Pediatric Emergency Department.

INTRODUCTION: Food-induced anaphylaxis among infants shows an increasing prevalence; however, the prescription of epinephrine auto-injectors (EAIs) for children weighing <15 kg is associated with issues of the needle length and the epinephrine dose. Several studies have shown age-related differences in food-induced anaphylaxis, although little is known about the weight-related differences in food-induced anaphylaxis. This study aimed to reveal the incidence, clinical characteristics, and management of food-induced anaphylaxis in children weighing <15 kg. METHODS: This chart review included children who visited the pediatric emergency department (ED) of the National Center for Child Health and Development (Tokyo, Japan) from January 2014 to December 2016 and were diagnosed with food-induced anaphylaxis. The severity of anaphylaxis was evaluated using the Sampson Grading Scale. RESULTS: Of 89,232 ED visits, 444 visits included patients with food-induced anaphylaxis, after excluding cases of food-induced anaphylaxis related to oral desensitization therapy. The incidence was 4.98 per 1,000 visits. More than half of the children (n = 247/444, 55.6%) weighed <15 kg. The proportion of grade 3 and higher severity anaphylactic symptoms was 74.5% (184/247) in children weighing <15 kg and 79.2% (156/197) in children weighing 15 kg or more. The recurrence rate of food-induced anaphylaxis was 22.3% (55/247) in children weighing <15 kg and 48.7% (96/197) in children weighing 15 kg or more. Among the children weighing <15 kg, the proportion of those with recurrent food-induced anaphylaxis was 4 times higher in children weighing 10-15 kg than in those weighing <10 kg (32.2% [47/146] vs. 7.9% [8/101]). The proportion of patients who were prescribed EAIs before each visit was 25.5% (14/55) in children weighing <15 kg with a history of food-induced anaphylaxis. CONCLUSION: Food-induced anaphylaxis among children weighing <15 kg occurred as frequently and was as severe as that among children weighing 15 kg or more. However, the proportion of patients prescribed EAIs was very low in children weighing <15 kg with food-induced anaphylaxis. The potential need for EAIs is suggested among children weighing <15 kg, especially among children weighing 10 kg or more but <15 kg.

Clinical features and outcomes of coronavirus disease 2019 in early infants in Japan: A case series and literature review.

The clinical picture in early infants with COVID-19 has been described in a limited number of reports, mainly from European countries, United States, and China, but not Japan. Although several reports suggested that early infants can develop more severe COVID-19 disease than older children, risk factors for severe illness and differences according to nationality or ethnicity remain unclear. We report a case series of 13 infants ≤90 days old with COVID-19 in Japan. All patients had mild outcomes and did not require respiratory support or intensive care.

Clinical characteristics of pediatric patients with COVID-19 between Omicron era vs. pre-Omicron era.

INTRODUCTION: Detailed data on clinical characteristics in children with the omicron strain of SARS-COV-2 are limited. METHODS: We conducted a retrospective observational study of children with COVID-19 at the National Center for Child Health and Development to evaluate the clinical manifestations during and before the emergence of the omicron variant. Only symptomatic patients without underlying diseases were included. Participants were divided into two temporal groups: the "omicron era" (1/2022-2/2022) and the "pre-omicron era," where the delta variant predominated (7/2021-11/2021). The patients were subclassified into an older vaccine-eligible group (aged 12-17 years), a younger vaccine-eligible group (aged 5-11 years), and a vaccine-ineligible group (aged 0-4 years). RESULTS: We compared 113 patients in the omicron era with 106 in the pre-omicron era. Most patients in both eras had non-severe disease, and no patients required mechanical ventilation or died. Among patients aged 0-4 years, sore throat and hoarseness were more common during the omicron era than the pre-omicron era (11.1% vs. 0.0% and 11.1% vs. 1.5%, respectively). Croup syndrome was diagnosed in all patients with hoarseness. Among patients aged 5-11 years, vomiting was more frequent during the omicron era (47.2%) than during the pre-omicron era (21.7%). Cough and rhinorrhea were less common during the omicron era in patients aged 0-4 and 5-11 years, respectively, than during the pre-omicron era. CONCLUSIONS: In children with COVID-19, clinical manifestations differed between the omicron and pre-omicron eras. In the Omicron era, croup syndrome was more frequent in vaccine-ineligible children.

Type B adverse drug reactions to antibiotics and antibiotic allergy in infants and children.

BACKGROUND: Distinguishing allergic reactions from non-allergic type B adverse drug reactions (ADRs) to antibiotics is challenging, particularly in children, because we lack epidemiological information that can be used in primary care situations. This study aimed to investigate the characteristics of type B ADRs to antibiotics and antibiotic allergy (AA) in previously healthy children. METHODS: This was a retrospective cohort study of previously healthy children admitted for treating urinary tract infections over a 10 year period. The primary outcome was the frequency of type B ADRs and AAs that were assessed by pediatricians. Secondary outcomes include demographic data about patients' backgrounds, infections, treatments, ADRs, and action against ADRs. All the data were collected via patients' medical records. RESULTS: Out of 791 participants, type B ADRs were reported in 77 children (9.7%), and AA labeling was performed in six children (0.8%). Physicians assessed 30.4% of type B ADRs as severe or life-threatening symptoms. All patients were discharged without long-term complications. Physicians detected the primary cause (individual patient host factors or environmental risks) in 39 cases of type B ADRs. CONCLUSION: Type B ADRs to antibiotics were frequently reported even in previously healthy children. Physicians should use appropriate techniques (e.g., specialist consulting and skin testing) when they suspect that a type B ADR might be an AA. Labeling and de-labeling programs and tools for type B ADRs related to antibiotics should be implemented to prevent the mislabeling of AA.

Plasma exchange and infliximab as a third-line therapy for refractory infantile Kawasaki disease.

BACKGROUND: The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown. METHODS: A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated. RESULTS: Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group. CONCLUSIONS: Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited.

Benzodiazepine Use for Pediatric Patients With Suspected Nonconvulsive Status Epilepticus With or Without Simplified Electroencephalogram: A Retrospective Cohort Study.

OBJECTIVES: In the present study, we aimed to determine the changes in the administration rate of benzodiazepines for pediatric patients with suspected nonconvulsive status epilepticus (NCSE) before and after the introduction of simplified electroencephalography (sEEG) in the emergency department. METHODS: This retrospective cohort study included patients who were younger than 18 years and were admitted to the emergency department from August 1, 2009, to July 31, 2017, with altered level of consciousness and nonpurposeful movement of eyes or extremities after the cessation of convulsive status epilepticus. Patients with apparent persistent convulsions, those who were fully conscious on arrival, and those who were transferred from another hospital were excluded. The patients were categorized into pre and post groups based on the introduction of sEEG, and benzodiazepine administration was compared between the 2 groups. RESULTS: During the study period, 464 patients with status epilepticus visited our emergency department and 69 and 93 patients fulfilling the study criteria were categorized into the pre and post groups, respectively. There were no significant differences in patient background characteristics between the 2 groups. Simplified electroencephalography was recorded in 52 patients in the post group. Benzodiazepines were administered in 44 of 69 patients (63.8%) in the pre group and 44 of 93 (47.3%) in the post group, and the benzodiazepine administration rate was significantly decreased after the introduction of sEEG ( P = 0.04). The hospitalization rate was significantly lower in the post group, but there were no significant differences in the rates of intensive care unit admission, reconvulsion after discharge, and final diagnoses between the 2 groups. CONCLUSIONS: Simplified electroencephalography might aid in determining the need for anticonvulsant treatment for suspected NCSE in pediatric patients. Albeit not a definitive diagnostic tool, sEEG might be a reliable choice in the evaluation of pediatric patients with suspected NCSE.

Transitional care for inflammatory bowel disease: A survey of Japanese pediatric gastroenterologists.

BACKGROUND: In 2019 we reported the results of a Japanese national survey designed to explore the views of adult gastroenterologists regarding transitional care for patients with childhood-onset inflammatory bowel disease (IBD). For the present study, we conducted a similar survey of pediatric gastroenterologists to compare the views of the two sets of specialists. METHODS: The survey conducted in 2019 involved 48 representative members of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition. They were contacted by conventional mail and their answers were not anonymized. Respondents who had already referred patients with IBD to adult gastroenterologists were asked in a questionnaire to rank the importance of specific statements on a Likert scale. RESULTS: The response rate was 79% and 29 (60%) of the respondents had experienced transitional care for patients with IBD. Transfer to adult care was considered by 90% of the respondents to be the ideal form of medical care for adolescents/young adults with IBD. However, 59% of the respondents had experienced some degree of difficulty when making referrals for such care. The majority of pediatric gastroenterologists considered that the ideal age for transfer was 18-22 years. Among the respondents, physicians at municipal hospitals considered that the presence of diseases other than IBD and a shortage of manpower were significantly more important issues than other practice settings. CONCLUSIONS: The present survey revealed that the general views regarding transitional care for IBD between pediatric and adult gastroenterologists were similar, except for the appropriate time for transfer. The results underline the importance of preparing a transition program appropriate to practice settings.

Allele frequencies of Bordetella pertussis virulence-associated genes identified from pediatric patients with severe respiratory infections.

Bordetella pertussis (B. pertussis) infection occasionally causes severe respiratory infections in children. Potential association between virulence-associated gene alleles and severe clinical outcomes has been suggested; however, frequencies of these alleles in pediatric patients with severe pertussis have not been clarified. We retrospectively tested stored respiratory samples collected from B. pertussis-positive patients by polymerase chain reaction targeting for major virulence-associated genes; fimbrae (fim) serotype 3 (fim3), pertactin (prn), pertussis toxin A (ptxA), and pertussis toxin promotor (ptxP). Based on the identified sequences, multilocus sequence typing (MLST) was conducted. Association of gene allele frequency and clinical outcomes such as management in pediatric intensive care unit, intubation, and mortality was analyzed. Out of 25 patients with available samples, the most prevalent allele for each virulence-associated gene was fim3A (17/21, 83%), ptxA1 (20/23, 87%), prn2 (13/16, 81%), and ptxP3 (14/17, 82%). In the study, total of 3 MLST types were identified; MLST-1 from 3 patients (19%), MLST-2 from 10 patients (63%), and MLST-4 from 3 patients (19%). Detection rate of the major MLST type; MLST-2 was significantly higher for patients who required intubation compared to those who did not (6/6, 100% vs 4/10, 40%; p = 0.034). In conclusion, MLST-2 was the most common MLST type in B. pertussis isolated from Japanese children with severe pertussis. Further studies investigating its causal association with disease severity is warranted.

Urinary tract infection due to anaerobic bacteria in a two-month-old infant.

The significance of anaerobic bacteria as a pathogen in urinary tract infection (UTI) in children is unclear. A two-month-old infant presenting with poor feeding received a diagnosis of polymicrobial anaerobic UTI by next-generation sequencing and was found to have obstructive uropathy. Anaerobic bacteria may be a cause of UTI in children with urinary tract obstruction.

Adult gastroenterologists' views on transitional care: Results from a survey.

BACKGROUND: In 2018, Japanese guidelines for autonomy support of patients with inflammatory bowel disease (IBD) in the transitional period were published. These guidelines, however, were prepared mainly by pediatric gastroenterologists. In order to improve such supportive guidelines, it is necessary for pediatric gastroenterologists to be aware of the attitudes and expectations of adult gastroenterologists. Accordingly, the first Japanese national survey designed to explore the views of adult gastroenterologists regarding successful transitional care was conducted. METHODS: The survey involved institutions at which adult gastroenterologists in the Ministry of Health, Labor and Welfare of Japan's Inflammatory Bowel Diseases Study Group, were working. Physicians were contacted by conventional mail, and their answers were not anonymized. A total of 100 eligible adult institutions were identified. Further specific subgroup analysis was conducted. RESULTS: A response rate of 34% was achieved. Seventy-six percent of the respondents had experienced some degree of difficulty when accepting patients with childhood-onset IBD referred from pediatric gastroenterologists. With regard to the ideal form of medical care for adolescent patients with IBD, transfer to adult care was supported by 94% of the respondents. Only 27% of respondents, however, stated they would have no hesitation in accepting patients referred from pediatric care centers. Two crucial areas requiring improvement were identified: inadequate clinical summaries and lack of patient independence from their parents/caregivers. CONCLUSIONS: The present survey results reinforce the importance of a transitional program of education for childhood-onset IBD patients and the need to improve communication between adult and pediatric gastroenterologists.

Risk factors of long hospital stay for immunoglobulin A vasculitis: Single-center study.

BACKGROUND: Immunoglobulin A (IgA) vasculitis is a common, systemic childhood disease that occasionally interferes with oral intake of food and necessitates hospitalization. In Japan, there are no reports on the length of hospitalization or factors related to long-term hospitalization in children with IgA vasculitis. In this study, we investigated the factors related to long-term hospitalization. METHODS: We reviewed the medical records of children aged ≤15 years with IgA vasculitis who were admitted to the National Center for Child Health and Development (Tokyo, Japan) between March 2008 and April 2017. We reviewed their gender, age, previous episodes, digestive symptoms, fever, laboratory data, urine analysis, ultrasound, and use of glucocorticoid on admission day. We compared the long-stay (≥10 days) group (L) and the short-stay (≤9 days) group (S) on logistic regression analysis. RESULTS: Of the 68 children included in the analysis, 34 were male, and the average age was 71.9 ± 26.4 months. The median period of hospitalization was 10.5 days (range, 0.5-75 days), and 36 children were allocated to group L. In the logistic regression model including age, gender, gastrointestinal (GI) bleeding, and use of glucocorticoid, male sex (OR: 4.2; 95%CI: 1.3-13.5) and GI bleeding (OR: 7.6; 95%CI: 1.4-41.5) were significantly associated with hospitalization ≥10 days. CONCLUSIONS: In children with IgA vasculitis, male patients and those with GI bleeding were more likely to have a hospital stay ≥10 days.

Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis.

Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008-2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013-2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.

Pertussis without apparent cough in a disabled girl with a tracheostomy.

Pertussis is characterized by intense, prolonged coughing in children often followed by a distinctive whooping sound on inspiration. However, the clinical manifestations and natural course of pertussis in disabled children are largely unknown. We experienced a case of pertussis in a disabled girl who had previously undergone a tracheostomy and laryngotracheal separation. She presented with increased tracheal secretions and required hospitalization but did not develop a cough. Pertussis was suspected from the sputum Gram stain, which revealed numerous, short gram-negative rods that did not grow on chocolate agar. A nucleic acid amplification test was positive for Bordetella pertussis and the patient improved on azithromycin. Pertussis may present without its cardinal symptoms in disabled children.