Safety, efficacy and pharmacokinetics of palivizumab in off-label neonates, infants, and young children at risk for serious respiratory syncytial virus infection: a multicenter phase II clinical trial.

Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.

Study protocol: a multicenter, uncontrolled, open-label study of palivizumab in neonates, infants, and preschool children at high risk of severe respiratory syncytial virus infection.

BACKGROUND: The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. METHODS/DESIGN: This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. DISCUSSION: This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. TRIAL REGISTRATION: This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946 , registration date: September 10, 2019).

Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12-24, 36-48, and 60-72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

Transcutaneous blood gas monitoring among neonatal intensive care units in Japan.

BACKGROUND: This study aimed to investigate the utility of transcutaneous (tc) measurements of partial pressure of oxygen (tcPO2 ) and carbon dioxide (tcPCO2 ) monitoring in neonatal intensive care units (NICUs) in Japan. METHODS: At the end of 2016,we sent a survey questionnaire on tc monitoring to all 106 NICUs registered with the Japanese Neonatologist Association. The questions included usage, subjects, methods, management, and the practical usefulness of tc monitoring. RESULTS: The questionnaire was returned by 69 NICUs (65.1% of response rate). Seventeen institutions (24.6%) measured both tcPCO2 and tcPO2 , and 42 (60.9%) measured tcPCO2 alone. Transcutaneous PCO2 or tcPO2 monitoring was applied for "pre-viable" infants born at 22-23 weeks' gestational age (18.6% vs 23.5%), and infants of <500 g birthweight (30.5% vs 17.6%). The tcPCO2 and tcPO2 monitoring was started at birth in 49.2% and 70.6% of the newborn infants, respectively. The temperature of the sensor was set at <38°C for tcPCO2 in 54.3% and >42°C for tcPO2 in 58.9% of NICUs. The accuracy for tcPO2 was rated as good in 35.3% or moderate in 64.7%, of institutions but or for tcPCO2 as 1.7% or 93.2%of institutions , respectively. CONCLUSION: Transcutaneous monitoring was widely, but limitedly, used for preterm infants. The lower temperature of the tcPCO2 sensor compared to that reported in other developed countries might compromise the accuracy but increase the feasibility of tc monitoring in Japan.

Standardization of nitric oxide inhalation in extremely preterm infants in Japan.

BACKGROUND: In perinatal medicine, inhaled nitric oxide (iNO) has been an important tool for the treatment of full-term and late-preterm infants with persistent pulmonary hypertension of the newborn (PPHN) and hypoxemic respiratory failure (HRF). Its use in more premature infants, however, is controversial. To evaluate the current clinical practices regarding use of acute iNO in extremely preterm infants, a nationwide survey was conducted in Japan. METHODS: A questionnaire survey was conducted from May to September, 2015. Questionnaires about PPHN and iNO treatment were sent to the doctor in charge of the neonatal care unit in 213 perinatal medical centers (PMC) that possessed iNO equipment in Japan. RESULTS: A total of 143 of the 213 PMC provided responses (67.1%). A diagnosis of PPHN was made exclusively on echocardiography in all PMC. On definitive PPHN diagnosis, iNO was selected in the majority of the PMC (72%) and started from ≤10 p.p.m. in most PMC (49.7%) for extremely preterm infants. During iNO therapy, cardiac function was checked on echocardiography by a neonatologist every ≤8 h. iNO weaning was started when differential peripheral oxygen saturation (SpO2 ) disappeared, or when SpO2 reached 100% and so on. After iNO concentration reached 5 p.p.m., it was decreased gradually and carefully in five steps, taking 12-24 h to go from 5 to 0 p.p.m. CONCLUSIONS: Inhaled nitric oxide was predominantly used in extremely preterm infants as early rescue therapy for PPHN based on echocardiography performed by a neonatologist.

Computer Graphics Animation for Objective Self-Evaluation.

The increased number of students enrolling in dance classes in Japan has resulted in a shortage of qualified instructors, leaving classes to be taught by instructors who are not trained in dance. The authors developed a system specifically designed to help nonqualified dance instructors teach dance using motion capture and animation. The goal is to allow dancers to easily self-evaluate their own performances by comparing it to a standard example.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann, Sotos, and Kabuki syndromes: A nationwide survey in Japan.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.

Effect of hemodiafiltration therapy in a low-birthweight infant with congenital sepsis.

The clinical course of congenital neonatal sepsis due to Streptococcus pneumoniae progresses rapidly and results in multiorgan failure with high mortality. The swift progression of the disease limits the timeframe for conventional treatment, which often requires waiting for antibiotics to show efficacy. Here, we describe the case of a very low-birthweight (VLBW) female infant with congenital sepsis due to S. pneumoniae who was treated with continuous hemodiafiltration (CHDF) and polymyxin B-immobilized fiber column-direct hemoperfusion (PMX-DHP). The infant was born at 30 weeks' gestation and diagnosed with hypotension, disseminated intravascular coagulation, and pulmonary hypertension. CHDF and PMX-DHP were initiated approximately 11 h after birth. Mean blood pressure, oxygenation, and blood interleukin-6 began to improve after dialysis commencement, and the patient survived with mild sequelae. Combined CHDF and PMX-DHP may be effective in treating VLBW infants with severe septic shock.

[Paroxysmal automatic movements mimicking neonatal seizures induced by midazolam].

We have observed paroxysmal automatic movements including drum-beating and pedaling motions in three full-term neonates following intravenous bolus injections (0.1-0.3 mg/kg/dose) or drip infusions (0.2 mg/kg/h) of midazolam used for sedation. In one patient, abnormal movements were also induced by a bolus injection of midazolam during the EEG recording, and no change was revealed in the EEG during the episode. In another patient, abnormal movements were further worsened by an injection of diazepam. Interictal EEGs of all patients were normal. The clinical manifestations of these paroxysmal automatic movements and the mode of their appearance were quite similar in all patients. It is quite likely that abnormal movements in the patient without ictal EEG change do not have epileptic origin but brainstem release phenomenon induced by midazolam. Because the abnormal movements in the other two cases had similar clinical manifestations and mode of appearance, we suspected that these movements were also non-epileptic though ictal EEGs were not recorded in theses cases. When we encounter paroxysmal automatic movements mimicking neonatal seizures following intravenous midazolam administration, ictal EEG recordings are recommended. If there are no ictal changes, we should avoid treatment with anticonvulsant drugs for these movements. Since midazolam is frequently used in neonates for sedation during various examinations, future investigations on the selection of appropriate drugs and dosage for sedation in neonates, including the usage of midazolam, are necessary.

Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation.

A Japanese girl with neonatal-onset chronic hepatitis and systemic inflammation was diagnosed with hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). However, she lacked the typical HIDS features until the age of 32 months. She had compound heterozygous MVK mutations, H380R and A262P, the latter of which was novel. These findings suggest that HIDS patients could lack typical episodes of recurrent fever at the onset and that HIDS should be considered as a possible cause of neonatal-onset chronic hepatitis.

Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.

BACKGROUND: Respiratory syncytial virus (RSV) infection is a major cause of hospitalization during the winter among infants and young children. In 2002 palivizumab was introduced to high-risk infants for RSV hospitalization in Japan. It is important to characterize the hospitalized children due to RSV infection after the introduction of palivizumab. METHODS: A survey was conducted to collect the data from the hospitalized children at 12 participating hospitals during the winter of 2007. RESULTS: From October 2007 through April 2008, 8163 children were admitted to participating hospitals, with RSV infection accounting for 811 of those hospitalizations. Mean age in children with RSV infection at hospitalization was 12.4 ± 12.7 months, and children under 24 months of age accounted for 86.4%. The mean gestational age of those at birth was 38.0 ± 2.6 weeks, with 82.4% of the children born at term. Palivizumab was administered in 24 cases of RSV infection, while there were 28 patients who were not treated with palivizumab, even though they met the indication for palivizumab. Death, in a total of five cases, occurred in children who were not treated with palivizumab. CONCLUSIONS: Palivizumab has been widely used in high-risk infants who were covered by health insurance, and most of the hospitalized children with RSV infection in the study hospitals were not treated with palivizumab.