Oxygen saturation thresholds in managing sickle cell disease at US children's hospitals.

BACKGROUND: Adequate oxygen saturation (SpO2 ) is crucial for managing sickle cell disease (SCD). Children with SCD are at increased risk for occult hypoxemia; therefore, understanding SpO2 threshold practices would help identify barriers to oxygen optimization in a population sensitive to oxyhemoglobin imbalances. We investigated SpO2 cutoff levels used in clinical algorithms for management of acute SCD events at children's hospitals across the United States, and determined their consistency with recommended national guidelines (SpO2  > 95%). METHODS: Clinical pathways and algorithms used for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in SCD were obtained and reviewed from large children's hospitals in the United States. RESULTS: Responses were obtained from 94% (140/149) of eligible children's hospitals. Of these, 63 (45%) had available clinical algorithms to manage VOC and ACS. SpO2 cutoff was provided in 71.4% (45/63) of clinical algorithms. Substantial variation in SpO2 cutoff levels was noted, ranging from ≥90% to more than 95%. Only seven hospitals (5% of total hospitals and 15.6% of hospitals with clinical algorithms available) specified oxygen cutoffs that were consistent with national guidelines. Hospitals geographically located in the South (46.8%; n = 29/62) and Midwest (54.8%; n = 17/31) were more likely to have VOC and ACS clinical algorithms, compared to the Northeast (26.5%; n = 9/34) and West (36.4%; n = 8/22). CONCLUSION: There is inconsistency in the use of clinical algorithms and oxygen thresholds for VOC and ACS across US children's hospitals. Children with SCD could be at risk for insufficient oxygen therapy during adverse acute events.

Pulmonary outcomes of congenital diaphragmatic hernia patients based on defect size (CDH Study Group Stage).

Background: Congenital diaphragmatic hernia (CDH) is associated with significant pulmonary morbidity. Previous investigation has shown that postnatal inpatient morbidity is linked to diaphragmatic defect size. The objective of this study was to evaluate long-term pulmonary outcomes by CDH study group defect size. Methods: A retrospective analysis was conducted for CDH patients (n=133) managed in a neonatal intensive care unit (NICU) at a single children's hospital within an adult hospital system and subsequently followed up at a comprehensive multidisciplinary CDH clinic (n=102) from January 2012 to April 2022. CDH patients were stratified according to Congenital Diaphragmatic Hernia Study Group (CDHSG) Stage, and then categorized as low-risk (LR), defect size A and B, or high-risk (HR), defect size C and D. Inpatient data, including the presence of pulmonary hypertension, extracorporeal life support (ECLS) utilization, and mechanical ventilation days, were collected. Post-discharge data including the prevalence of asthma, pulmonary hypertension, emergency department visits, the total number of hospitalizations, and average rehospitalization days were collected. Frequentist analysis was used. Results: The outcomes for 133 NICU patients were analyzed (HR: n=54, LR: n=79). During NICU stay, the prevalence of pulmonary hypertension [HR: 16/54 (30%) vs. LR: 9/79 (12%), P=0.009], ECLS utilization [HR: 19/54 (35%) vs. LR: 4/79 (5%), P<0.001], and the average number of mechanical ventilation days [HR: 17 days (IQR: 12-27) vs. LR: 5 days (IQR: 2-9), P<0.001] were significantly higher in the HR CDH group. Post NICU discharge, the prevalence of asthma [HR: 20/54 (37%), vs. LR: 17/79 (22%), P=0.050)] and the total days of rehospitalization [HR: 9 (IQR: 2-27) vs. LR: 4 (IQR: 1-8), P=0.035] were significantly higher in HR group. Of the patients seen in the comprehensive multidisciplinary CDH clinic, obstructive lung disease measured by impulse oscillometry was increased in the HR CDH population compared to the reference group [median R5Hz was 12.95 kPa/(L/s) in CDH vs. 9.8 kPa/(L/s) (P=0.010)]. Conclusions: HR CDHSG Stage is associated with worse inpatient and long-term pulmonary outcomes.

Screening for asthma in preschool children with sickle cell disease.

BACKGROUND: Asthma in preschool children is poorly defined, proving to be a challenge for early detection. The Breathmobile Case Identification Survey (BCIS) has been shown to be a feasible screening tool in older SCD children and could be effective in younger children. We attempted to validate the BCIS as an asthma screening tool in preschool children with SCD. METHODS: This is a prospective, single-center study of 50 children aged 2-5 years with SCD. BCIS was administered to all patients and a pulmonologist blinded to the results evaluated patients for asthma. Demographic, clinical, and laboratory data were obtained to assess risk factors for asthma and acute chest syndrome in this population. RESULTS: Asthma prevalence (n = 3/50; 6%) was lower than atopic dermatitis (20%) and allergic rhinitis (32%). Sensitivity (100%), specificity (85%), positive predictive value (30%), and negative predictive value (100%) of the BCIS were high. Clinical demographics, atopic dermatitis, allergic rhinitis, asthma, viral respiratory infection, hematology parameters, sickle hemoglobin subtype, tobacco smoke exposure, and hydroxyurea were not different between patients with or without history of ACS, although eosinophil was significantly lower in the ACS group (p = 0.0093). All those with asthma had ACS, known viral respiratory infection resulting in hospitalization (3 RSV and 1 influenza), and HbSS (homozygous Hemoglobin SS) subtype. CONCLUSION: The BCIS is an effective asthma screening tool in preschool children with SCD. Asthma prevalence in young children with SCD is low. Previously known ACS risk factors were not seen, possibly from the beneficial effects of early life initiation of hydroxyurea.

Prebirth effects of climate change on children's respiratory health.

PURPOSE OF REVIEW: To date, there is no evidence that humanity will implement appropriate mitigation measures to avoid the catastrophic impact of climate change on the planet and human health. Vulnerable populations such as pregnant women and children will be the most affected. This review highlights epidemiologic data on climate change-related prenatal environmental exposures affecting the fetus and children's respiratory health. RECENT FINDINGS: Research on outcomes of prenatal exposure to climate change-related environmental changes and pediatric pulmonary health is limited. In addition to adverse pregnancy outcomes known to affect lung development, changes in lung function, increased prevalence of wheezing, atopy, and respiratory infections have been associated with prenatal exposure to increased temperatures, air pollution, and maternal stress. The mechanisms behind these changes are ill-defined, although oxidative stress, impaired placental functioning, and epigenetic modifications have been observed. However, the long-term impact of these changes remains unknown. SUMMARY: The detrimental impact of the climate crisis on pediatric respiratory health begins before birth, highlighting the inherent vulnerability of pregnant women and children. Research and advocacy, along with mitigation and adaptation measures, must be implemented to protect pregnant women and children, the most affected but the least responsible for the climate crisis.

Pulmonary hypertension screening in children with sickle cell disease.

BACKGROUND: Screening for pulmonary hypertension (PHT) is recommended in children with sickle cell disease (SCD). However, best approaches are poorly described. We examined the utility of PHT symptoms, echocardiogram (ECHO), N-terminal-pro hormone brain natriuretic peptide (NT-proBNP), and BNP to screen for PHT in the SCD pediatric population. METHODS: Children (8-18 years old) with SCD-HbSS and HbSthal° were prospectively included and underwent PHT screening. The screening consisted of a comprehensive PHT symptoms evaluation, ECHO measurement, and NT-proBNP and BNP levels. RESULTS: A total of 73 patients were included (mean age 12 ± 5.7 years; >80% on hydroxyurea), of which 37% had a symptom consistent with PHT, including exertional dyspnea (26.5%), fatigue (17.6%), palpitation (14.7%), and chest pain (10.3%). ECHO was obtained in 53 (72.6%) patients, with only ECHO of 48 patients included in the final analysis. Elevated ECHO peak tricuspid regurgitant jet velocity (TRV) >2.5 m/s or indirect findings to suggest PHT were seen in only two of 48 (4.2%). No significant differences were seen between those with and without PHT symptoms when compared for NT-proBNP, BNP, hemoglobin, pulmonary function testing, fractional exhaled nitric oxide, asthma, oxygen saturation, and sleep apnea. CONCLUSION: PHT symptoms are not consistent with ECHO, NT-proBNP nor BNP findings in children with SCD. PHT prevalence based on TRV was low in children on hydroxyurea, therefore screening may not be warranted for this group.

Sleep Apnea Screening in Children With Sickle Cell Anemia.

BACKGROUND: Screening for obstructive sleep apnea (OSA) is recommended by current guidelines in children with sickle cell anemia (SCA), but no specific approach is described. The Pediatric Sleep Questionnaire (PSQ) is a validated detection tool for OSA in children. We assessed the utility of PSQ to screen for OSA in children with concomitant SCA and snoring. MATERIALS AND METHODS: A prospective study, in children 4 to 18 years old with SCA. Subjects were assessed for snoring and PSQ administered at the same visit. All children with snoring were then referred for polysomnography. RESULTS: A total of 106 subjects were screened. Habitual snoring prevalence was 51/106 (48.1%). In the snoring group, OSA was detected in 83.9% (apnea-hypopnea index [AHI] ≥1.0/h) and 22.6% (AHI ≥5.0/h), respectively. Sensitivity and specificity of PSQ in children with snoring was 46.2% and 20.0% (AHI ≥1.0/h), and 57.1% and 50.0% (AHI ≥5.0/h), respectively. Physician assessment for snoring had a high sensitivity of 70.3% but low specificity of 58.4% (AHI ≥1.0/h), and 87.5% and 41.5% (AHI ≥5.0/h), respectively. CONCLUSION: PSQ is a poor screening tool for detection of OSA in those children with SCA who snore. Physician assessment for snoring could however be an initial approach before polysomnography.

Telemedicine for Children With Medical Complexity: A Randomized Clinical Trial.

BACKGROUND: Telemedicine is widely used but has uncertain value. We assessed telemedicine to further improve outcomes and reduce costs of comprehensive care (CC) for medically complex children. METHODS: We conducted a single-center randomized clinical trial comparing telemedicine with CC relative to CC alone for medically complex children in reducing care days outside the home (clinic, emergency department, or hospital; primary outcome), rate of children developing serious illnesses (causing death, ICU admission, or hospital stay >7 days), and health system costs. We used intent-to-treat Bayesian analyses with neutral prior assuming no benefit. All participants received CC, which included 24/7 phone access to primary care providers (PCPs), low patient-to-PCP ratio, and hospital consultation from PCPs. The telemedicine group also received remote audiovisual communication with the PCPs. RESULTS: Between August 22, 2018, and March 23, 2020, we randomly assigned 422 medically complex children (209 to CC with telemedicine and 213 to CC alone) before meeting predefined stopping rules. The probability of a reduction with CC with telemedicine versus CC alone was 99% for care days outside the home (12.94 vs 16.94 per child-year; Bayesian rate ratio, 0.80 [95% credible interval, 0.66-0.98]), 95% for rate of children with a serious illness (0.29 vs 0.62 per child-year; rate ratio, 0.68 [0.43-1.07]) and 91% for mean total health system costs (US$33 718 vs US$41 281 per child-year; Bayesian cost ratio, 0.85 [0.67-1.08]). CONCLUSION: The addition of telemedicine to CC likely reduced care days outside the home, serious illnesses, other adverse outcomes, and health care costs for medically complex children.

Unexpected results of a randomized quality improvement program for children with severe asthma.

Objective: To assess whether an asthma intervention program reduces treatment days outside the home among children with severe asthma receiving comprehensive care (CC) in our center.Methods: Between October 21, 2014 and September 28, 2016, children with severe asthma were randomized to receive CC alone (n = 29) or CC plus the asthma intervention program (n = 34) which involved collaboration with pharmacists and school nurses, motivational interviewing, and tracking the one-second forced expiratory volume at home. All patients were followed through March 31, 2017. Frequentist and Bayesian intent-to-treat analyses were performed.Results: The asthma intervention program doubled the telephone calls between the staff and families (753 vs 356 per 100 child years for the intervention group vs. control group; Rate Ratio [RR], 2.11 [95% confidence interval, 1.29-3.45]). Yet, we found no evidence that it reduced the composite number of days of healthcare outside home which includes: clinic visits, ED visits, and hospital admissions (1179 vs 958 per 100 child-years in the intervention group vs. control group; [RR], 1.23 [95% CI, 0.82-1.84]) or secondary outcomes which are individual components (clinic visits, ED visits, hospitalizations, PICU admissions and school absences; RR 1.15 - 2.30; p > 0.05). Bayesian analysis indicated a 67% probability that the intervention program increases total treatment days outside the home and only a 14% probability of a true decrease of >20% as originally hypothesized.Conclusion: A multi-component intervention program provided to children with severe asthma failed to reduce and may have increased days of healthcare outside home and school absenteeism.

Validation of the breathmobile case identification survey for asthma screening in children with sickle cell disease.

Background: Asthma is a chronic airway disorder with variable/recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an inflammation. The expert panel report of the National Heart Lung and Blood Institute recommends asthma screening in sickle cell disease (SCD); however, specific approach is not mentioned. We hypothesize that the breathmobile case identification survey (BCIS) is a valid asthma screening tool in children with SCD.Methods: This prospective, single-center study enrolled 129 SCD patients aged 5 to 18 years from March 2016 to March 2018. All patients completed BCIS, spirometry, and fractional exhaled nitric oxide (FeNO). A single pulmonologist blinded to the BCIS results evaluated patients for asthma.Results: Asthma prevalence was 41%. Male gender (60.4%; p = 0.041), allergic rhinitis (86.8%; p < 0.01), hydroxyurea usage (73.6%; p < 0.01), and family history of asthma (34%; p < 0.01) were higher but not self-reported parental asthma history, eczema, and tobacco smoke exposure in the asthma group compared to the nonasthma group. FEV1 (p = 0.003), FVC (p = 0.02), FEV1/FVC (p = 0.053), and FEF25-75% (p = 0.02) were lower in asthma. FeNO levels were comparable in both groups. The sensitivity, specificity, positive predictive value, and negative predictive value of the abbreviated BCIS were 67.3%, 90.8%, 83.3%, and 80.2% for asthma; and 82.1%, 90.8%, 76.7%, and 93.2% for persistent asthma, respectively. Persistent asthma patients had a trend of higher hydroxyurea use (82.8% vs. 58.3%; p = 0.049) and tobacco smoke exposure (55.2% vs. 29.2%; p = 0.057) compared to intermittent asthma.Conclusion: We have validated the BCIS to screen for asthma in SCD. Spirometry but not FeNO may support an asthma diagnosis.

Hospital Consultation From Outpatient Clinicians for Medically Complex Children: A Randomized Clinical Trial.

Importance: Children with medical complexity (CMC) frequently experience fragmented care. We have demonstrated that outpatient comprehensive care (CC) reduces serious illnesses, hospitalizations, and costs for high-risk CMC. Yet continuity of care for CMC is often disrupted with emergency department (ED) visits and hospitalizations. Objective: To evaluate a hospital consultation (HC) service for CMC from their outpatient CC clinicians. Design, Setting, and Participants: Randomized quality improvement trial at the University of Texas Health Science Center at Houston with an outpatient CC clinic and tertiary pediatric hospital (Children's Memorial Hermann Hospital). Participants included high-risk CMC (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrolling in our clinic) receiving CC. Data were analyzed between January 11, 2018, and December 20, 2019. Interventions: The HC included serial discussions between CC clinicians, ED physicians, and hospitalists addressing need for admission, inpatient treatment, and transition back to outpatient care. Usual hospital care (UHC) involved routine pediatric hospitalist care. Main Outcomes and Measures: Total hospital days (primary outcome), PICU days, hospitalizations, and health system costs in skeptical bayesian analyses (using a prior probability assuming no benefit). Results: From October 3, 2016, through October 2, 2017, 342 CMC were randomized to either HC (n = 167) or UHC (n = 175) before meeting the predefined bayesian stopping guideline (>80% probability of reduced hospital days). In intention-to-treat analyses, the probability that HC reduced total hospital days was 91% (2.72 vs 6.01 per child-year; bayesian rate ratio [RR], 0.61; 95% credible interval [CrI], 0.30-1.26). The probability of a reduction with HC vs UHC was 98% for hospitalizations (0.60 vs 0.93 per child-year; RR, 0.68; 95% CrI, 0.48-0.97), 89% for PICU days (0.77 vs 1.89 per child-year; RR, 0.59; 95% CrI, 0.26-1.38), and 94% for mean total health system costs ($24 928 vs $42 276 per child-year; cost ratio, 0.67; 95% CrI, 0.41-1.10). In secondary analysis using a bayesian prior centered at RR of 0.78, reflecting the opinion of 7 experts knowledgeable about CMC, the probability that HC reduced hospital days was 96%. Conclusions and Relevance: Among CMC receiving comprehensive outpatient care, an HC service from outpatient clinicians likely reduced total hospital days, hospitalizations, PICU days, other outcomes, and health system costs. Additional trials of an HC service from outpatient CC clinicians are needed for CMC in other centers. Trial Registration: ClinicalTrials.gov Identifier: NCT02870387.

Cardiac arrhythmias associated with volume-assured pressure support mode in a patient with autonomic dysfunction and mitochondrial disease.

NONE: A 15-year-old boy with autonomic dysfunction and mitochondrial disease was diagnosed with sleep-related hypoventilation at 6 years of age and treated with bilevel positive airway pressure therapy. At 12 years of age, treatment was transitioned to volume-assured pressure support (VAPS) due to clinical evidence of respiratory muscle weakness. Subsequent titration polysomnogram revealed the emergence of cardiac arrhythmia (isolated premature ventricular contractions, bigeminy, and trigeminy) while on VAPS mode that improved after transition to bilevel positive airway pressure therapy. During the titration study, higher tidal volumes correlated with increased pressures and the presence of arrhythmia. Prior to initiation of VAPS therapy, the patient had normal electrocardiogram evaluations. This case highlights the potential relationship between VAPS therapy and cardiac arrhythmias, especially in patients with underlying conditions with associated cardiac abnormalities, such as autonomic dysfunction and mitochondrial disease. While using VAPS mode, patients should be closely monitored for cardiac rhythm abnormalities.

Neurocognitive functioning in individuals with congenital central hypoventilation syndrome.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by respiratory system abnormalities, including alveolar hypoventilation and autonomic nervous system dysregulation. CCHS is associated with compromised brain development and neurocognitive functioning. Studies that evaluate cognitive skills in CCHS are limited, and no study has considered cognitive abilities in conjunction with psychosocial and adaptive functioning. Moreover, the roles of pertinent medical variables such as genetic characteristics are also important to consider in the context of neurocognitive functioning. METHODS: Seven participants with CCHS ranging in age from 1 to 20 years underwent neuropsychological evaluations in a clinic setting. RESULTS: Neurocognitive testing indicated borderline impaired neurocognitive skills, on average, as well as relative weaknesses in working memory. Important strengths, including good coping skills and relatively strong social skills, may serve as protective factors in this population. CONCLUSION: CCHS was associated with poor neurocognitive outcomes, especially with some polyalanine repeat expansion mutations (PARMS) genotype. These findings have important implications for individuals with CCHS as well as medical providers for this population.

Screening Children with a Family History of Central Congenital Hypoventilation Syndrome.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of an autonomic nervous disorder that affects breathing. It is characterized by respiratory insufficiency secondary to insensitivity to hypoxemia and hypercarbia, particularly during sleep leading to persistent apnea. We report four individuals across two generations harboring heterozygous 25 polyalanine repeats mutations (PARMs) in PHOX2B with a varying degree of phenotypic clinical manifestations. Two family members who reported to be "asymptomatic" were subsequently diagnosed with CCHS, based on genetic testing, obtained because of their family history. Genetic studies in the family including a mother and three offsprings revealed in-frame five amino acid PARMs of PHOX2B consistent with CCHS in addition to full clinical assessment. All affected individuals had evidence of hypercapnia on blood gas analysis with PCO2 in the range of 32-70 (mean; 61). Nocturnal polysomnogram revealed evidence of hypoventilation in two individuals (1 offspring and mother) with the end-tidal CO2 median of 54. Magnetic resonance imaging of brain revealed no abnormalities in the brain stem. There was no evidence of cor pulmonale on echocardiograms in all individuals. Neuropsychological testing was conducted on all four patients; two patients (mother and 1 offspring) had normal results, while the other two offspring exhibited some impairments on neuropsychological testing. This case series emphasizes the importance of screening first-degree relatives of individuals with confirmed CCHS to minimize complications associated with long-term ventilatory impairment. It also suggests that some patients with CCHS should undergo neuropsychological evaluations to assess for cognitive weaknesses secondary to their CCHS.

The Effect of Comprehensive Medical Care on the Long-Term Outcomes of Children Discharged from the NICU with Tracheostomy.

BACKGROUND: Survival of infants with complex care has led to a growing population of technology-dependent children. Medical technology introduces additional complexity to patient care. Outcomes after NICU discharge comparing Usual Care (UC) with Comprehensive Care (CC) remain elusive. OBJECTIVE: To compare the outcomes of technology-dependent infants discharged from NICU with tracheostomy following UC versus CC. METHODS: A single site retrospective study evaluated forty-three (N=43) technology-dependent infants discharged from NICU with tracheostomy over 5½ years (2011-2017). CC provided 24-hour accessible healthcare-providers using an enhanced medical home. Mortality, total hospital admissions, 30-days readmission rate, time-to-mechanical ventilation liberation, and time-to-decannulation were compared between groups. RESULTS: CC group showed significantly lower mortality (3.4%) versus UC (35.7%), RR, 0.09 [95%CI, 0.12-0.75], P=0.025. CC reduced total hospital admissions to 78 per 100 child-years versus 162 for UC; RR, 0.48 [95% CI, 0.25-0.93], P=0.03. The 30-day readmission rate was 21% compared to 36% in UC; RR, 0.58 [95% CI, 0.21-1.58], P=0.29). In competing-risk regression analysis (treating death as a competing-risk), hazard of having mechanical ventilation removal in CC was two times higher than UC; SHR, 2.19 [95% CI, 0.70-6.84]. There was no difference in time-to-decannulation between groups; SHR, 1.09 [95% CI, 0.37-3.15]. CONCLUSION: CC significantly decreased mortality, total number of hospital admissions and length of time-to-mechanical ventilation liberation.

Characteristics and Outcomes of Children with Clinical History of Atopic Versus Non-atopic Asthma Admitted to a Tertiary Pediatric Intensive Care Unit.

BACKGROUND: Children admitted to the Pediatric Intensive Care Unit (PICU) with status asthmaticus have variable clinical courses, and predicting their outcomes is challenging. Identifying characteristics in these patients that may require more intense intervention is important for clinical decision-making. OBJECTIVE: This study sought to determine the characteristics and outcomes, specifically length of stay and mortality, of atopic versus non-atopic asthmatics admitted to a PICU with status asthmaticus. METHODS: A retrospective study was conducted at a children's hospital from November 1, 2008 to October 31, 2013. A total of 90 children admitted to the PICU were included in the analysis. Patients were divided into two groups based on the presence of specific historical data indicative of a clinical history of atopy. Children were considered to be atopic if they had a parental history of asthma, a personal history of eczema, or a combined history of wheezing (apart from colds) and allergic rhinitis (diagnosed by a medical provider). The median hospital Length Of Stay (LOS), PICU LOS, cardiopulmonary arrest, and mortality were compared between atopic and non-atopic asthma groups. Regression models were used to estimate the LOS stratified by atopic or non-atopic and by history of intubation in present hospitalization. RESULTS: Median hospital LOS for atopic children was 5.9 days (IQR of 3.8-8.7) and 3.5 days (IQR of 2.2-5.5) for non-atopic asthmatics (z = 2.9, p = 0.0042). The median PICU LOS was 2.5 days (IQR 1.4-6.1) for atopic asthmatics and 1.6 days (IQR 1.1-2.4) for non-atopic asthmatics (z = 2.5, p = 0.0141). The median LOS was significantly higher for atopic intubated patients compared to non-atopic intubated patients (p=0.021). Although there was an increased tendency towards intubation in the atopic group, the difference was not significant. There was no significant difference in cardiopulmonary arrest or mortality. CONCLUSION: A clinical history of atopic asthma in children admitted to the PICU with status asthmaticus was associated with longer length of stays The longest LOS was observed when atopic patients required intubation.

Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V.

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

Role of prophylactic azithromycin to reduce airway inflammation and mortality in a RSV mouse infection model.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of morbidity and mortality in vulnerable populations. Macrolides have received considerable attention for their anti-inflammatory actions beyond their antibacterial effect. We hypothesize that prophylactic azithromycin will be effective in reducing the severity of RSV infection in a mouse model. METHODS: Four groups of BALB/c mice were studied for 8 days: Control (C), RSV-infected (R), early prophylaxis with daily azithromycin from days 1 to 8, (E), and late prophylaxis with daily azithromycin from days 4 to 8 (L). Mice were infected with RSV on day 4, except for the control group. All groups were followed for a total of 8 days when bronchoalveolar lavage cell count and cytokines levels were measured. Mouse weight, histopathology, and mortality data were obtained. RESULTS: Prophylactic azithromycin significantly attenuated post-viral weight loss between group R and both groups E and L (P = 0.0236, 0.0179, respectively). IL-6, IL-5, and Interferon-Gamma were significantly lower in group L (P = 0.0294, 0.0131, and 0.0056, respectively) compared with group R. The total cell count was significantly lower for group L as compared with group R (P < 0.05). Mortality was only observed in group R (8%). Lung histology in the prophylactic groups showed diminished inflammatory infiltrates and cellularity when compared with group R. CONCLUSION: Prophylactic azithromycin effectively reduced weight loss, airway inflammation, cytokine levels and mortality in RSV-infected mice. These results support the rationale for future clinical trials to evaluate the effects of prophylactic azithromycin for RSV infection.

Use of Nasal Non-Invasive Ventilation with a RAM Cannula in the Outpatient Home Setting.

BACKGROUND: Nasal non-invasive-ventilation (Nasal NIV) is a mode of ventilatory support providing positive pressure to patients via a nasal interface. The RAM Cannula is an oxygen delivery device that can be used as an alternative approach to deliver positive pressure. Together they have been successfully used to provide respiratory support in neonatal in-patient settings. OBJECTIVE: To describe the outpatient use of Nasal NIV/RAM Cannula as a feasible alternative for home respiratory support in children with chronic respiratory failure. METHODS: We performed a retrospective case series of 18 children (4 months to 19 years old) using the Nasal NIV/RAM Cannula in the Pediatric Pulmonary Clinic at the McGovern Medical School, UTHealth (2014-16). Consideration for Nasal NIV/RAM Cannula utilization included: inability to wean-off in-patient respiratory support, comfort for dyspnea, intolerability of conventional mask interfaces and tracheostomy avoidance. RESULTS: Average age was 7 years. 50% were Caucasian, 38% African-American and 11% Hispanics. Pulmonary disorders included: chest wall weakness (38%), central control abnormalities (33%), obstructive lung disease (16%) and restrictive lung disease (11%). Indications for Nasal NIV/RAM Cannula initiation included: CPAP/BPAP masks intolerability (11%), dyspnea secondary to chest wall weakness (38%) and tracheostomy avoidance (50%). Average length of use of Nasal NIV/RAM Cannula was 8.4 months. Successful implementation of Nasal NIV/Ram Cannula was 94%. One patient required a tracheostomy following the use of Nasal NIV/RAM Cannula. Significant decrease in arterial PaCO2 pre and post Nasal NIV/RAM cannula initiation was notable (p=0.001). CONCLUSION: Outpatient use of Nasal NIV/RAM Cannula may prove to be a feasible and save treatment alternative for children with chronic respiratory failure, chest wall weakness, dyspnea and traditional nasal/face mask intolerance to avoid tracheostomy.

Mitochondrial Disorder Aggravated by Metoprolol.

Beta-adrenergic blocking agents or beta-blockers are a class of medications used to treat cardiac arrhythmias and systemic hypertension. In therapeutic dosages, they have known adverse outcomes that can include muscular fatigue and cramping, dizziness, and dyspnea. In patients with mitochondrial disease, these effects can be amplified. Previous case reports have been published in the adult population; however, their impact in pediatric patients has not been reported. We describe a pediatric patient with a mitochondrial disorder who developed respiratory distress after metoprolol was prescribed for hypertension. As the patient improved with discontinuation of medication and no alternative etiology was found for symptoms, we surmise that administration of metoprolol aggravated his mitochondrial dysfunction, thus worsening underlying chest wall weakness.

Anti-inflammatory effect of prophylactic macrolides on children with chronic lung disease: a protocol for a double-blinded randomised controlled trial.

INTRODUCTION: Recent studies suggest that the high mortality rate of respiratory viral infections is a result of an overactive neutrophilic inflammatory response. Macrolides have anti-inflammatory properties, including the ability to downregulate the inflammatory cascade, attenuate excessive cytokine production in viral infections, and may reduce virus-related exacerbations. In this study, we will test the hypothesis that prophylactic macrolides will reduce the severity of respiratory viral illness in children with chronic lung disease by preventing the full activation of the inflammatory cascade. METHODS AND ANALYSIS: A randomised double-blind placebo-controlled trial that will enrol 92 children to receive either azithromycin or placebo for a period of 3-6 months during two respiratory syncytial virus (RSV) seasons (2015-2016 and 2016-2017). We expect a reduction of at least 20% in the total number of days of unscheduled face-to-face encounters in the treatment group as compared with placebo group. Standard frequentist and Bayesian analyses will be performed using an intent-to-treat approach. DISCUSSION: We predict that the prophylactic use of azithromycin will reduce the morbidity associated with respiratory viral infections during the winter season in patients with chronic lung disease as evidenced by a reduction in the total number of days with unscheduled face-to-face provider encounters. ETHICS AND DISSEMINATION: This research study was approved by the Institutional Review Board of the University of Texas Health Science Center in Houston on 9 October 2014. On completion, the results will be published. TRIAL REGISTRATION NUMBER: NCT02544984.