Dysphagia and Lung Disease in Children With Spinal Muscular Atrophy Treated With Disease-Modifying Agents.

OBJECTIVES: Disease-modifying agents (DMAs) for the treatment of spinal muscular atrophy (SMA) have evolved the SMA phenotype with improved survival. Ongoing oropharyngeal dysphagia and respiratory complications are reported. The extent of dysphagia and respiratory morbidity in this population, since DMAs' introduction, has not been well described. METHODS: A whole-population study involved all children with treated SMA types 1-3 in our facility. Videofluoroscopic swallow studies (type 1 alone), chest CT scans, and clinical data were collected. RESULTS: Thirty-six children were included (n = 9 type 1, n = 14 type 2, and n = 13 type 3; age range 0.3-15.4 years). Abnormal swallowing characteristics were demonstrated in all children with type 1 (n = 8; 100%). Bronchiectasis was found on chest CT: 3 of 9 (33.3%), 2 of 14 (14.3%), and 2 of 13 (15.4%) of type 1, 2, and 3, respectively. Atelectasis, mucus plugging, bronchial wall thickening, and parenchymal changes were common. DISCUSSION: Swallow impairments were universal in children with type 1. Bronchiectasis was common in all pediatric SMA types, with a prevalence of 1 in 5. Routine monitoring and management of dysphagia/recurrent respiratory infection should be implemented for improvement in lung health.

Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.

INTRODUCTION: Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown. AIM: To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment. METHODS: A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test. RESULTS: Twenty-eight patients (15 male, aged 0.08-18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was -0.58 (95% CI -0.75 to -0.41), and post initiation was -0.25 (95% CI -0.46 to -0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea-Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1-10.1) at initiation to 2.7 events/hour (IQR 0.7-5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen. CONCLUSION: The first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

Persistent Pseudomonas aeruginosa infection associated with non-invasive ventilation in a child with spinal muscular atrophy type 1.

NONE: Current standards of care suggest the use of non-invasive positive pressure ventilation (NIV) in children with spinal muscular atrophy and symptomatic respiratory failure. Theoretical concerns exist regarding NIV equipment as a source of infection in restrictive lung disease due to the possibility of prolonged NIV device use, greater risk in acquiring infections, and difficulties in managing and clearing infections. NIV devices may draw pathogens through the air inlet port that may contaminate the internal surfaces. These pathogens may then infect children with spinal muscular atrophy. We present a case of 2 genetically identical Pseudomonas aeruginosa cultures from both the patient's NIV device and from nasopharyngeal samples. This infection persisted both in nasopharyngeal aspirate cultures and from NIV equipment cultures despite the use of an eradication program involving both the child and the NIV device.

Manifestations of pulmonary aspergillosis in pediatrics.

PURPOSE OF REVIEW: Aspergillus spp. cause a clinical spectrum of disease with severity of disease dependent on degree of immune compromise, nature and intensity of inflammatory host response, and/or underlying lung disease. Chronic pulmonary aspergillosis encompasses a spectrum of diseases including aspergilloma, Aspergillus nodules, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis. Allergic bronchopulmonary aspergillosis (ABPA) paradoxically is an immune hypersensitivity manifestation in the lungs that almost always occurs in the setting of underlying asthma or cystic fibrosis. These chronic Aspergillus conditions are now becoming more prevalent than invasive Aspergillus, thus it is important to be aware of the current literature of these conditions. RECENT FINDINGS: High-level research assessing the clinical significance and treatment options of these chronic diseases are lacking. Recent literature suggests colonization is antecedent for local airway infection (Aspergillus bronchitis), chronic or allergic bronchopulmonary disease, or invasive and potentially disseminated disease. There have been few advances in assessment of treatment of ABPA. SUMMARY: Research assessing the clinical significance and treatment options is currently needed.

Polysomnography findings in pediatric spinal muscular atrophy types 1-3.

BACKGROUND: Sleep disordered breathing (SDB) causes sleep disturbance and daytime symptoms in children with neuromuscular disorders. Although polysomnography (PSG) findings are well described in many neuromuscular disorders, there are limited reports from children with spinal muscular atrophy (SMA). The aim of this study was to determine the sleep architecture and breathing characteristics and non-invasive ventilation (NIV) use in our pediatric SMA cohort. METHODS: We conducted a cross-sectional cohort study of all children with SMA in Queensland, Australia. Children were Nusinersen naïve and had a full diagnostic PSG in 2018. The PSG was scored and reported by a single pediatric sleep physician in accordance with American Academy of Sleep Medicine Criteria (2012). RESULTS: In sum, 31 children (18 males), Six with Type 1, 16 with Type 2 and nine with Type 3, aged 0.25-18.8 years old were studied. SDB was seen in each SMA type and was more pronounced during rapid eye movement (REM) sleep. Type 1: all patients exhibited SDB, three (50%) with central sleep apnea (CSA) and three (50%) with mixed disease. Type 2: five (31%) had CSA, one (6%) mixed disease, seven (44%) had early SDB and three (19%) had normal sleep breathing. Type 3: four (44%) children had CSA and five had early SDB. No child exhibited obstructive sleep apnea (OSA) alone.Starting NIV significantly reduced mean total PSG Apnea-Hypopnea Index (AHI) scores from a grouped mean of 15.4 events per hour (SD ± 14.6; 95% CI 6.1-24.7) to 4.0 events per hour (SD ± 4.2, 95% CI 1.2-6.5, p = 0.01). CONCLUSION: SDB is common in children with SMA and was present in all types. CSA was the most common disorder; with mixed SDB also present in type 1 and 2 SMA.

Synthesis and Characterization of Valacyclovir HCl Hybrid Solid Lipid Nanoparticles by Using Natural Oils.

BACKGROUND: The Jojoba Simmondsia Chinensis oil is used as one of the main ingredients which has an antioxidant, moisturizing and stabilizing activity. Likewise, grape seed (Vitis vinifera) oil is also used in this preparation which also has some remarkable medicinal properties such as antioxidant, astringent and is also used as a moisturizer. The Valacyclovir Solid Lipid Nanoparticles (SLN) are prepared in combination. OBJECTIVE: The prime objective of the study was to prepare a nanodispersion with good stability indicating zeta potential. The formulations were prepared by varying concentrations of jojoba oil and grape seed oil which form the hybrid nanoparticles with the drug. METHODS: The high-pressure hot-homogenization technique was used to prepare the nanoparticles. The prepared nanoparticles were subjected to characterization analysis such as Mean particle size, Zaverage, and Zeta potential by using Dynamic Light Scattering (DLS) and Photon Correlation Spectroscopy (PCS). The best formulation was subjected to Transmission Electron Microscopy (TEM) technique for surface morphology and other characterizations. The crystalline pattern of the drug alone, drug-loaded nanoparticles and nanoparticles without the drug was studied by XRD. The drug excipients compatibility studies were performed by using Fourier-Transform Infrared Spectroscopy (FTIR) Differential Scanning Calorimetry and (DSC). The other factors such as in vitro drug release, and % drug entrapment efficiency were studied by using suitable methods. RESULTS: The results demonstrated that the particles are in nano range with good stability with appreciable Zeta potential (-48.2±mV). The selected formulations were analyzed for MPS which demonstrated the value of 306.7±183.4 and 416.5±289.3. The best formulation VNP5 demonstrated the Bellshaped curve and confirmed the uniform distribution. CONCLUSION: Based on the patents, it was demonstrated that valacyclovir is widely used in the treatment and prophylaxis of viral infections in human, particularly infections caused by the herpes group of viruses. Valacyclovir is an effective drug for the treatment of cold sores.

Improved Clinical Outcome After Treatment of Mycobacterium abscessus Complex Pulmonary Disease in Children With Cystic Fibrosis.

BACKGROUND: Mycobacterium abscessus complex pulmonary disease (M. abscessus PD) in cystic fibrosis (CF) is challenging to treat. Current guideline therapeutic regimens involving an intensive phase of intravenous (IV) antibiotics followed by a consolidation phase of inhaled and oral antibiotics are not evidence-based. The objectives of this study were to characterize the clinical outcomes and clearance of Mycobacterium abscessus complex (M. abscessus) from respiratory cultures in children with CF M. abscessus PD. METHODS: This retrospective longitudinal cohort analysis evaluated the first course of treatment for M. abscessus PD in 33 children in Queensland, Australia between 2001 and 2015. Spirometry and nutritional outcomes 2 years pretreatment and 1 year posttreatment were compared with clearance or relapse/persistence of Mycobacterium abscessus complex from respiratory cultures. RESULTS: Nine of 18 children who completed therapy, cleared infection. Three of 7 children who completed only intensive therapy cleared sputum compared with 0/8 children who did not. The trajectory of the percent predicted forced expiratory volume in 1 s and age standardized body mass index significantly improved posttreatment in those that cleared sputum (P < 0.0001). CONCLUSIONS: These results suggest that current treatment recommendations for M. abscessus PD are associated with some success in clearing infection in children with CF and improvement in lung function and body mass index. Clinical trials are required to determine the best treatment approaches.

Pooling of bronchoalveolar lavage in children with cystic fibrosis does not adversely affect the microbiological yield or sensitivity in detecting pulmonary inflammation.

BACKGROUND: Bronchoalveolar lavage (BAL) is a potentially useful outcome measure for clinical trials in children with CF but its use is limited by variations in approach internationally. We sought to determine if pooling adversely affected the diagnostic properties of BAL. METHODS: Children undergoing bronchoscopy for clinical reasons were included. A multi-step study protocol ensured BAL was collected and analysed both separately and as a pooled fluid. RESULTS: Eighty-five children (53 CF, 32 control) were recruited. There was a high level of concordance between pooled and non-pooled samples in terms of organism identification (76%). There was good agreement (Bland Altman) between the two methods in terms of detection of inflammation independent of centre, microbiological concordance or disease status. Bi-directional variability in IL-8 levels between pooled and non-pooled samples was seen. Free neutrophil elastase (NE) was detected in 4 cases in pooled lavage when absent in non-pooled lavage. Levels of interleukin-8 (IL-8) were similar between the two groups with pooled samples showing a greater spread of values. CONCLUSIONS: Pooling of BAL in children does not negatively impact on either the detection of pulmonary infection or inflammation or the observed relationship between infection and inflammation. Intra-patient variability in BAL IL-8 levels suggests regional differences in inflammation.

Giant Gastric Bezoar Complicating Congenital Esophageal Atresia Repaired by Gastric Interposition-A Case Report.

We describe a giant gastric phytobezoar in a child with repaired congenital esophageal atresia. At age two, a gastric interposition (pull-up) procedure was performed for severe and recurrent esophageal strictures. For 12 months post-gastric interposition, he experienced frequent respiratory illnesses requiring hospital admissions but it was not initially appreciated that these episodes were likely secondary to recurrent aspiration from a gastric bezoar with "spill-over" aspiration.

Tidal changes in respiratory resistance are sensitive indicators of airway obstruction in children.

RATIONALE: Individual assessment of airway obstruction in preschool-age children requires sensitive and specific lung function methods with low demand of cooperation. Although the forced oscillation technique (FOT) is feasible in young children, conventional measurements of respiratory impedance (Zrs) have limited diagnostic power in individuals. OBJECTIVE: To find descriptors of within-breath Zrs that are sensitive indicators of airway obstruction during tidal breathing in children. METHODS: Zrs was measured with (i) a standard multifrequency FOT (4-26 Hz) to assess the mean values of resistance and reactance for whole breaths and (ii) a 10 Hz signal to track the within-breath changes. Various Zrs measures obtained in healthy children (n=75) and those with acute wheeze (n=31) were investigated with receiver operator characteristic (ROC) analysis. The cut-off values obtained for airway obstruction were then tested in children with recurrent wheeze (n=20) before and after administration of salbutamol. RESULTS: The largest area under the ROC curve (0.95) was observed for the tidal changes of resistance between the zero-flow values (ΔR). The ΔR cut-off value of 1.42 hPa s/L detected airway obstruction with sensitivity of 92% and specificity of 89% in children with acute wheeze and distinguished children with recurrent wheeze (16/20 above the cut-off value) from healthy children (22/23 below the cut-off value). Furthermore, ΔR significantly decreased after salbutamol in wheezy children but remained unchanged in healthy children. CONCLUSIONS: New lung function measure ΔR is able to detect airway obstruction with high sensitivity and specificity and is suitable for use in lung function testing in young children.

Early-life risk factors for chronic nonrespiratory diseases.

We have witnessed a change in disease patterns contributing to the global burden of disease, with a shift from early childhood deaths due to the classic infectious communicable diseases to years lived with disability from chronic noncommunicable diseases. In both developing and developed countries, the years lived with disability attributable to chronic disease have increased: cardiovascular diseases by 17.7%; chronic respiratory disease by 8.5%; neurological conditions by 12.2%; diabetes by 30.0%; and mental and behavioural disorders by 5.0% over the past 20 years. Recognition of the contribution made by adverse environmental exposures in early life to noncommunicable diseases in later life is increasing. These early-life exposures appear to contribute to both chronic respiratory and chronic nonrespiratory diseases. In this State of the Art article, we aim to examine early-life environmental exposures that have an epidemiological association with chronic nonrespiratory diseases, such as obesity and type II diabetes, cardiovascular disease, and neurocognitive and behavioural problems. We will highlight the potential overlap in environmental risks with respiratory diseases, and point out knowledge gaps and research opportunities.