Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by loss-of-function mutations. SMA is an autosomal recessive disorder affecting motor neurons that is typically caused by homozygous whole-gene deletions of SMN1. DMD is an X-linked recessive muscle disease most often due to exon deletions, but also duplications and smaller sized variants within the DMD gene. Gene replacement therapy offers the opportunity to correct the underlying genetic defect by the introduction of a functional gene. We review the transformative work from clinical trials to United States Food and Drug Administration approval of onasemnogene abeparvovec-xioi in SMA and its application in clinical practice and the early results of microdystrophin delivery in DMD. We also review the introduction of antisense oligonucleotides to alter pre-mRNA splicing to promote exon inclusion (as in nusinersen in SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular therapeutics. There are multiple promising novel genetically mediated therapies on the horizon, which in aggregate point towards a hopeful future for individuals with SMA and DMD.
Objectives: To evaluate the risk factors of recurrent pulmonary exacerbation and poor prognosis in children with idiopathic pulmonary hemosiderosis (IPH). Methods: In this multicenter study, 54 patinets with diagnosis of IPH included. Medical records were retrospectively reviewed from three tertiary care hospitals between 1979 and 2019. Also, current information and the long-term progress of patients was determined by contacting the families by telephone. Results: A total of 54 children were included. The median age of onset of symptoms was 4.5 ± 3.8 years. The median time from onset to diagnosis was 0.9 years ± 2.2. The mean number of recurrent episodes per child in the recurrence-positive group was 3.55 (1-15). Univariate analysis demonstrated that patients presenting with hypoxia or requiring transfusion at the time of presentation had significantly more recurrence episodes (P=0.002). Multivariate analysis showed that the presence of hypoxia at the time of initial presentation was a significant independent predictor of recurrent episodes (P=0.027). The median follow-up was 3.3 ± 4.8 years (0.75 months-27 years). There was a significant relationship between the presence of hypoxia, transfusion history, ANA positivity, and elevated transaminases at the time of initial evaluation and treatment response. Conclusions: The present study provides important information on the clinical course and outcome of pediatric IPH, and substantial information regarding factors that affect recurrent exacerbations and prognosis. Demonstrating of hypoxia as an independent risk factor in recurrence episodes could be guide physicians in the planning of treatment strategies.
The difference in morbidity and mortality between adult and pediatric COVID-19 infections is dramatic. Understanding pediatric-specific acute and delayed immune responses to SARS-CoV-2 is critical for the development of vaccination strategies, immune-targeted therapies, and treatment and prevention of MIS-C. The goal of this review is to highlight research developments in understanding of the immune responses to SARS-CoV-2 infections, with a specific focus on age-related immune responses.
Children less than 18 years of age account for an estimated 500,000 to 1.5 million global SARS-CoV-2 cases. Lower prevalence of COVID-19 among children, in addition to higher numbers of mild and asymptomatic cases, continues to provide challenges in determining appropriate prevention and treatment courses. Here, we summarize the current evidence on the transmission, clinical presentation, complications and risk factors in regards to SARS-CoV-2 in children and highlight crucial gaps in knowledge going forward. Based on current evidence, children are rarely the primary source of secondary transmission in the household or in child care and school settings and are more likely to contract the virus from an adult household member. Higher transmission rates are observed in older children (10-19 years old) compared to younger children (<10 years old). While increasing incidence of COVID-19 in neonates raises the suspicion of vertical transmission, it is unlikely that breast milk is a vehicle for transmission from mother to infant. The vast majority of clinical cases of COVID-19 in children are mild, but there are rare cases that have developed complications such as multisystem inflammatory syndrome in children (MIS-C), which often presents with severe cardiac symptoms requiring intensive care. Childhood obesity is associated with a higher risk of infection and a more severe clinical presentation. Although immediate mortality rates among children are low, long-term respiratory and developmental implications of the disease remain unknown in this young and vulnerable population.
Seasonal epidemics of influenza and the respiratory syncytial virus are the cause of substantial morbidity and mortality among children. During the global COVID-19 pandemic, the epidemiology of these viruses seems to have changed dramatically. In Australia and New Zealand, a significant decrease in both influenza and bronchiolities have been noticed during usual peak seasons. Data from early months of winter seasons in Europe are showing similar trends. This current scenario imposes a reconsideration of the paradigm that toddlers and young schoolchildren are the main drivers of seasonal RSV outbreaks and respiratory epidemics in general. In this paper, we summarize current literature, address current knowledge or role of adults in the respiratory syncitial virus epidemiology, describe the lessons learned from pertussis epidemics and call the international community to better understand the community transmission dynamics of respiratory infections in all age-groups. This can allow the establishment of better and more affordable preventive measures in the whole population level, which can ultimately save millions of child lives.
Background: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting. Methods: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 97 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland. Results: Before implementation of real-time QC in Bern, only 68% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After implementation of real-time QC, MBW test acceptability improved to 84% in Bern. In Zurich, after implementation of real-time QC, test acceptability improved from 50% to 90%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 97% in Bern and 100% in Zurich. Conclusion: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability.
Background: The COVID-19 pandemic has caused a global havoc with our limited understanding of the SARS-CoV-2, disease manifestations and management. Inadequacy of available data in pediatric patients coupled with evolving disease course makes it imperative to conduct a meta-analysis assessing the results of pediatric COVID-19 studies over the course of the pandemic. Methods: A random-effect meta-analysis was conducted using PRISMA guidelines. Two databases were screened for pediatric COVID-19 studies and selected articles reviewed for demographic, co-morbidities, clinical manifestations, laboratory and radiological evaluation, treatment and outcomes. Prevalence with mean and 95% confidence interval was calculated. Results: Out of 1703 articles, 37 articles comprising of 993 patients for a period of over six months and 72 variables were selected. This meta-analysis revealed that one-fourth of patients were asymptomatic (23.8%, 95% CI 17.6-31.2%) Fever (52.5%, 95% CI 45.7–59.1%) and cough (47.6%, 95% CI 41.2–54.0%) were the most common symptoms. The most frequently encountered white blood count abnormalities were neutropenia (16.6%, 95% CI 10.2-25.8%), lymphocytosis (15.3%, 95% CI 9.9–23.0%) and leukopenia (13.9%, 95% CI 10.1–18.8%). Ground glass opacities were the most common radiological finding of children with COVID-19 (35.9%, 95% CI 29.4-43%). The hospitalization rate was 95.9% (95% CI 91.9-98.0%) of which 11.2% (95% CI 4.7-24.2) were ICU admissions, and 4.2% (95% CI 2.6-6.9%) died. Conclusion: Majority of pediatric patients are asymptomatic or have mild manifestations similar to other upper respiratory viruses. Serious disease and death occurred in 15.4%. More studies are needed from a wider geographic area as the pandemic continues.
Rationale: Whether asthma constitutes a risk factor for COVID-19 is unclear. Here we aimed to assess whether asthma, the most common chronic disease in children, is a risk factor for COVID-19 in pediatric populations. Methods: We performed a systematic literature search in three stages: First, we reviewed PubMed, EMBASE and CINAHL for systematic reviews of SARS-CoC-2 and COVID-19 in pediatric populations, and reviewed their primary articles; second, we searched PubMed for studies on COVID-19 or SARS-CoV-2 and asthma/wheeze, and evaluated whether the resulting studies included pediatric populations; third, we repeated the second search in BioRxiv.org and MedRxiv.org to find pre-prints that may have information on pediatric asthma. Results: In the first search, eight systematic reviews were found, of which five were done in pediatric population; after reviewing 67 primary studies we found no data on pediatric asthma as a comorbidity for COVID-19. In the second search, we found 34 results in PubMed, of which five reported asthma in adults, but none included data on children. In the third search, 23 pre-prints in MedRxiv were identified with data on asthma, but again none with pediatric data. We found only one report by the U.S. CDC stating that 40/345 (~11.5%) children with data on chronic conditions had “chronic lung diseases including asthma”. Conclusion: There is scarcely any data on whether childhood asthma (or other pediatric respiratory diseases) constitute risk factors for SARS-CoV-2 infection or COVID-19 severity. Studies are needed that go beyond counting the number of cases in the pediatric age range.
We used the lung ultrasound score (LUSS) to analyze the ultrasound images and assess the lesions and aeration loss in 12 lung regions of 11 COVID-19 neonates born to mother with COVID-19 and 11 age- and gender-matched controls. In the COVID-19 group, 132 regions were reviewed and 83 regions (62.8%) detected abnormalities. Compared with controls, COVID-19 neonates showed more increased B-lines (83 regions), abnormal A-lines (83 regions), abnormal pleural line (29 regions) and subpleural consolidation (5 regions). among which 49 regions (37%) were normal, 73 regions (55%) scored 1, and 10 regions (8%) scored 2. The LUSS was significantly higher in COVID-19 group. All the lesions were bilateral, multiple regions involved, and mainly located in bilateral lower lobes and right middle lobe. The intra-observer and inter-observer reproducibility of LUSS were excellent. Lung ultrasound is a noninvasive and convenient method for the assessment of neonatal COVID-19 pneumonia and presents typical signs. LUSS provides valuable semi-quantitative information about the lesion distribution and severity.
Background: A crucial balance exists between oxidant and antioxidant mechanisms in the functional immune system. We aimed to evaluate the contributions of balance between these systems to coronavirus disease 2019 (COVID-19), a devastating pandemic caused by viral infection. Method: We analyzed serum oxidant and antioxidant stress parameters according to the clinical and demographic characteristics of children and adults with COVID-19 and compared them against the values of healthy controls. Serum native thiol (NT), total thiol (TT), disulfide, total antioxidant status, total oxidant status, and ischemia-modified albumin levels were evaluated and compared between groups. Results: A total of 79 children and 74 adults were evaluated in the present study, including 46 children and 40 adults with COVID-19, 33 healthy children, and 34 healthy adults. TT, NT, and disulfide levels were significantly lower in the adult COVID-19 group than in all other groups (p = 0.001, p = 0.001, and p = 0.005, respectively). Additionally, TT and NT levels were significantly lower in both pediatric and adult COVID-19 cases with severe disease course than mild/moderate course. TT and NT levels were identified as predictors for the diagnosis of the adult COVID-19 cases and as independent predictors for disease severity in both children and adults with COVID-19. Conclusion: Parameters that reveal the oxidant and antioxidant capacity, including TT and NT, appear to be good candidates for the accurate prediction of the clinical course among patients with COVID-19.
Background: The Coronavirus Disease 2019 (COVID-19) is causing of the new global pandemic and is responsible for millions of infections and thousands of deaths in the world. The lung ultrasound is a non-invasive and easily repeatable tool and can be carried out by the pediatrician at the bedside of children with a consequent reduction in the risk of transmission of the virus. Objective: To determine whether the lung ultrasound is a useful tool in identifying the signs of lung involvement in children with COVID-19 and whether can monitor the course of the disease. Methods: The study was made in the emergency department in a tertiary level pediatric hospital. All patients with swab-confirmed COVID-19 infection were subjected a lung ultrasound within 6 hours from admission and after 96 hours. Results: Among a total of 30 children, 18 (60%) were males, 4 reported exertional dyspnea and only 1 chest pain. The mean oxygen saturation was 98.8 ± 1.0 % in ambient air in emergency department and no patient needed oxygen therapy during hospitalization. After 96 hours we had observed ultrasound abnormality al the lung ultrasound only in 20% of the children. We found a statistically significant reduction in pleural irregularities (30% vs 16.7; p: .001) and in B lines (50% vs 20%; p: .008). Conclusions: lung ultrasound is safe and useful tool in detecting lung involvement in children with COVID-19 and in monitoring these patients during the course of disease.
Background: Acute asthma exacerbations are a common cause for emergency department (ED) visits and hospitalizations in children. Since the outbreak of COVID-19 and the education system closure/ total lockdown in Israel on March 2020, we have noticed a decrease in pediatric ED visits and an increase in hospitalizations of asthma exacerbations. Objective: to examine the patterns of ED visits for asthma exacerbations during COVID-19 outbreak, in comparison to the previous year. Methods: a retrospective study comparing asthma related ED visits and hospitalizations among children aged 2-18 years at a tertiary center in southern Israel. Three time periods were selected: 2020A (pre- lockdown, 1/2/20-14/3/20), 2020B (lockdown, 15/3/20-15/5/20) and 2020 C (post- lockdown, 16/5/20-30/6/20) and compared to the three parallel time periods in 2019. Data regarding demographics, number of ED visits and clinical severity parameters were collected and analyzed. Results: 512 children visited the ED for asthma exacerbation: 273 children during 2019 and 239 children during 2020, with significantly fewer ED visits per day during the lockdown period (1.8 vs 1.43, p<0.001), compared to the parallel period in 2019. Significantly higher hospitalization rate (47.1% vs 33.7%, p=0.05) and longer length of stay (LOS) (3.15 vs 1.9 days, p= 0.03) were observed during the lockdown. Conclusion: lockdown is associated with fewer ED visits for asthma exacerbation, probably due to; reduced exposure to viral infections and environmental allergens, decreased availability of primary physicians and families’ reluctance to arrive to the ED. ED visits during lockdown were characterized by higher hospitalization rate and longer LOS.
Background and Objectives: Extubation failure in preterm infants is associated with increased risk of mortality and morbidities. There is limited evidence to suggest if the increased morbidities are due to inherent differences among infants who fail or succeed; or whether these are due to a true respiratory setback among those who fail extubation. The aim of this study was to evaluate the respiratory status of infants who fail extubation and to assess the time taken for these infants to achieve pre-extubation respiratory status. Methods: This was a retrospective study of infants with birth weight ≤1,250 g who were born between January 2009 and December 2016. Infants were eligible if they failed first elective extubation. Extubation failure was defined as need for re-intubation within 5 days of extubation. Ventilator settings, blood gas parameters, respiratory severity score and ventilation index were used to assess respiratory status of infants. Results: Of 384 infants, 76% were successful and 24% failed extubation. Among those who failed extubation 91%, 77% and 56% infants remained intubated at 24 hours, 72 hours and 7 days, respectively. Respiratory status was worse at 24 hours and 72 hours after re-intubation when compared to pre-extubation levels. The median times for respiratory severity score and ventilation index to reach pre-extubation levels were 4 days and 7 days respectively. Conclusion: Among preterm infants, failed elective extubation is associated with a significant setback in the respiratory status. Infants who fail an extubation attempt may not achieve pre-extubation respiratory status for many days after reintubation.
Objectives: To characterize the clinical and genotypic features of Cystic fibrosis-associated pseudo-Bartter syndrome (CF-PBS) in Chinese children. Methods: We recruited and characterized the clinical manifestations of 11 Chinese children with CF-PBS. Sweat test, blood and urinary analysis, sputum culture, chest and sinus computed tomography, abdominal ultrasonography were obtained. Whole-exome sequencing, bioinformatics analysis, and sanger sequencing validation was performed to define the genotypes. Results: CF-PBS was accompanied by recurrent and/or persistent pneumonia (100%), pancreatitis (81.8%), vomit and/or diarrhea (63.6%), failure to thrive (FTT) (63.6%) and liver disease (54.5%) among our patients. The predominant organisms found in the airways was Pseudomonas aeruginosa (90.9%) and Staphylococcus aureus (81.8%). The mean concentration of blood gas and electrolytes were: PH 7.58, bicarbonate 40.8 mmol/L, sodium 126.7 mmol/L, chloride 80.0 mmol/L, and potassium 2.7 mmol/L, respectively. A high recurrence rate (54.5%) of PBS was observed despite continued electrolyte supplementation during follow up. 17 different mutations of CFTR gene were identified, and 9 of them turned out to be novel observations (c.262_266delTTATA, c.579+2insACAT, c.1210-3C>G, c.1733T>C, c.2236_2246delGAGGCGATACTinsAAAAATC, c.3635delT, c.3859delG, c.3964-7A>G and ΔE23 [c.3718-?_3873+?del]). The c.2909G>A/p.G970D was the most common mutation, with an allele frequency of 18.2%. c.1521_1523delCTT/p.F508del was the first time found with homozygous genotype in patients of Chinese origin. Conclusions: In China, CF-PBS always occurs early and repeatedly in infancy, accompanied by the high frequency of multi-system co-morbidities. Recurring in school-age patients is rare but does exist. The c.2909G>A/p.G970D is the most frequent mutation in Chinese patients with CF-PBS, showing a significant ethnic tendency of Chinese origin.
Background: Elevated Pre-discharge capillary blood gas partial pressure of carbon dioxide (pCO2) has been associated with increased adverse events including readmission. This study aimed to determine if pre-discharge pCO2 or 36-week pCO2 was associated with increased respiratory readmissions or other pulmonary healthcare utilization in the year after NICU discharge for infants with BPD discharged with home oxygen, using a standardized outpatient oxygen weaning protocol. Methods: This was a secondary cohort analysis of infants born <32 weeks gestational age with BPD, referred to our Pulmonary clinic for home oxygen therapy either from our level IV NICU or local level III NICUs between 2015-17. Infants with major non-respiratory comorbidities were excluded. Subject information was obtained from electronic health records. Results: Of 125 infants, 120 had complete 1-year follow-up. Twenty three percent of infants experienced a respiratory readmission after NICU discharge. There was no significant association between pre-discharge or 36-week pCO2 and respiratory readmissions, emergency room visits, new or increased bronchodilators or diuretics. Higher 36-week pCO2 was associated with a later corrected age when oxygen was discontinued (<6 months, median 54 mm Hg, Interquartile range (IQR) 51-61; 6-11 months, median 62 mm Hg IQR 57-65; ≥12 months, median 66 mm Hg, IQR 58-73; p=0.006). Conclusions: Neither pre-discharge pCO2 nor 36-week pCO2 was associated with one-year respiratory readmissions. Higher pCO2 at 36 weeks was associated with longer duration of home oxygen. Neonatal illness measures like 36-week pCO2 may be useful in communicating expectations for home oxygen therapy to families.
Background: Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA), a subset of ANCA, are associated with a multisystem vasculitis affecting small blood vessels in the body. A handful of adult patients who developed vasculitis post-COVID-19 infection have been reported. Although COVID-19 infection has been shown to drive an exaggerated immune response in the pediatric population, such as MIS-C (multisystem inflammatory syndrome in children), only one case of vasculitis following COVID-19 infection has been reported previously in children. Case presentation: Seventeen-year-old male with a past medical history of COVID-19 pneumonia two months prior presented with acute kidney injury/failure and diffuse alveolar hemorrhage (DAH). Rheumatologic workup revealed P-ANCA and Myeloperoxidase (MPO) positivity. Kidney biopsy showed necrotizing glomerulonephritis with limited immune complex deposition. Subsequently, he was treated with pulse steroids, plasmapheresis, and ultimately started on cyclophosphamide. Conclusions: To our knowledge, this report presents the second reported pediatric case of P-ANCA / MPO vasculitis following COVID-19 infection.
Introduction: The Lung Clearance Index (LCI) derived from the multiple-breath washout test (MBW), is both feasible and sensitive to early lung disease detection in young children with cystic fibrosis and asthma. The utility of LCI has not been studied in children with sickle cell disease (SCD). We hypothesized that children with SCD, with or without asthma or airway hyper reactivity (AHR), would have an elevated LCI compared to healthy controls. Methods: Children with SCD from a single center between the ages of 6-18 years were studied at baseline health and completed MBW, spirometry, plethysmography and blood draws for serum markers. Results were compared to healthy controls of similar race, age and gender. Results: Control subjects (n=35) had a significantly higher daytime oxygen saturation level, weight and body mass index (BMI) but not height compared to subjects with SCD (n=34). Total Lung Capacity(TLC) z-scores were significantly higher in the healthy controls compared to those with SCD (0.87 (1.13), 0.02 (1.27), p=0.005) while differences in Forced Expiratory Volume in 1 second (FEV1) z-scores approached significance (0.26 (0.97), -0.22 (1.09), p=0.055). There was no significant difference in LCI among the comparison groups (7.29 (0.72), 7.40 (0.69), p=0.514). Conclusion: LCI did not differentiate SCD from healthy controls in children between the ages of 6 and 18 years at baseline health. TLC may be an important pulmonary function measure to follow longitudinally in the pediatric SCD population.
Aims: In infants with chronic neonatal lung disease (CNLD), we aimed to identify predictors of home oxygen duration, predictors of discharge oxygen flow rates and the association of oxygen flow rates with respiratory outcomes.Methods: Retrospective review of infants with CNLD requiring home oxygen in 2016 and 2017. Hazard ratios (HR) were estimated from Cox proportional hazards regression models in the cohort. A multinomial logistic regression model examined the effects of maternal and infant variables on discharge oxygen flow rates. Kruskal-Wallis test with univariate linear regression and Fisher’s exact test with binomial univariate logistic regression were used to examine associations between oxygen flow groups and post-discharge clinical variables.Results: 149 infants were included. Median corrected gestational age (CGA) at oxygen cessation was 6.8 months (IQR 4.4) with 87.2% of infants weaned by 12 months CGA. Shorter initial neonatal intensive care unit (NICU) stay predicted faster oxygen weaning at 9 months (HR 0.99, 95%CI 0.98-1.00, p=0.02) and 12 months (HR 0.99, 95%CI 0.98-1.00, p=0.02). Infants with hypercarbia at discharge or discharged from NICU at higher CGA had higher odds of requiring ≥200mL/min relative to ≤125 mL/min oxygen. Infants discharged with >250mL/min oxygen were more likely to have a respiratory related admission before two years chronologic age. Conclusion: Shorter initial NICU stay was the best predictor of earlier home oxygen cessation. At NICU discharge, infants with hypercarbia or a higher CGA may require more home oxygen and experience more respiratory related hospital admission in the first two years of chronological age.