Ronald Morton

Obstructive Sleep Apnea in Poorly Controlled Asthmatic Children: Effect of Adenotonsillectomy

Asthma and obstructive sleep apnea (OSA) in children share multiple epidemiological risk factors and the prevalence of snoring is higher in asthmatic children, suggesting that the latter may be at increased risk for OSA. Since both asthma and OSA are inflammatory disorders, we hypothesized that polysomnographically demonstrated OSA would be more frequent among poorly controlled asthmatics (PCA), and that treatment of OSA, if present, would ameliorate the frequency of acute asthmatic exacerbations (AAE).

Inhaled corticosteroids in children with asthma: pharmacologic determinants of safety and efficacy and other clinical considerations.

The role of inhaled corticosteroids (ICS) in the treatment of childhood asthma has been well established. An ideal corticosteroid should demonstrate high pulmonary deposition and residency time, in addition to a low systemic bioavailability and rapid systemic clearance. The lung depositions of the ICS have been compared, with beclomethasone (beclometasone)-hydrofluoroalkane (HFA) and ciclesonide showing the highest lung deposition. Lung deposition is influenced by not only the inhalation device and type of propellant (HFA or chlorofluorocarbon), but also by whether the aerosol is a solution or suspension, and the particle size of the respirable fraction. Pulmonary residency time increases when budesonide and des-ciclesonide undergo reversible fatty acid esterification. The bioavailability of the drug depends on the oral bioavailable fraction and the amount absorbed directly from the pulmonary vasculature. The clearance rate of des-ciclesonide is very high (228 L/h), increasing its safety profile by utilizing extra-hepatic clearance mechanisms. Both des-ciclesonide and mometasone have a high protein binding fraction (98–99%). The volume of distribution (Vd) is proportional to the lipophilicity of the drug, with the Vd of fluticasone being 332L compared with 183L for budesonide. Increasing the Vd will also increase the elimination half-life of a drug. The pharmacodynamics of ICS depend on both the receptor binding affinity and the dose-response curve. Among the ICS, fluticasone and mometasone have the highest receptor binding affinity (1800 and 2200, respectively), followed by budesonide at 935 (relative to dexamethasone = 100).Compared with other nonsteroid asthma medications (long-acting β-agonists, theophylline, and montelukast) ICS have proven superiority in improving lung function, symptom-free days, and inflammatory markers. One study suggests that early intervention with ICS reduces the loss in lung function (forced expiratory volume in 1 second) over 3 years. Whether airway remodeling is reduced or prevented in the long term is unknown. Potential adverse drug effects of ICS include adrenal and growth suppression. While in low-to-medium doses ICS have shown little suppression of the adrenal pituitary axis, in high doses the potential for significant adrenal suppression and adrenal crisis exists. Several longitudinal studies evaluating the effect of ICS on growth have shown a small decrement in growth velocity (≈1–2cm) during the first year of treatment. However, when investigators followed children treated with budesonide for up to 10 years, no change in target adult height was noted.In conclusion, the development of optimal delivery devices for young children, as well as optimizing favorable pharmacokinetic properties of ICS should be priorities for future childhood asthma management.

Evaluation of the wheezy infant

BACKGROUND The infant with persistent or recurrent wheezing during the first 2 years of life poses a diagnostic dilemma, which can be a source of anxiety to both physicians and parents. A suggested diagnostic approach to the causes of infantile wheezing is outlined. OBJECTIVES 1. To review the physiologic considerations of the infants airways that predispose to wheezing. 2. To discuss the key physical findings, family history, and risk factors associated with wheezing in infants. 3. To develop a rational approach to the differential diagnosis and management of infantile wheezing. DATA SOURCES The MEDLINE database as well as our clinical experience pertaining to infantile wheezing. CONCLUSIONS This review discusses the diagnostic evaluation and treatment of the wheezing infant. We suggest that infant pulmonary function testing may be used as one diagnostic aid in the workup of the wheezing infant.

Loss of Asthma Control in Pediatric Patients after Discontinuation of Long-Acting Beta-Agonists

Recent asthma recommendations advocate the use of long-acting beta-agonists (LABAs) in uncontrolled asthma, but also stress the importance of stepping down this therapy once asthma control has been achieved. The objective of this study was to evaluate downtitration of LABA therapy in pediatric patients who are well-controlled on combination-inhaled corticosteroid (ICS)/LABA therapy. Clinical and physiologic outcomes were studied in children with moderate-to-severe persistent asthma after switching from combination (ICS/LABA) to monotherapy with ICS. Of the 54 patients, 34 (63%) were determined to have stable asthma after the switch, with a mean followup of 10.7 weeks. Twenty (37%) had loss of asthma control leading to addition of leukotriene receptor antagonists, increased ICS, or restarting LABA. There were 2 exacerbations requiring treatment with systemic steroids. In patients with loss of control, there was a statistically significant decline in FEV1 (−8% versus −1.9%, P = 0.03) and asthma control test (−3.2 versus −0.5, P = 0.03). This did not approach significance for FEF25-75%, exhaled nitric oxide, lung volumes or airway reactivity. No demographic, asthma control measures, or lung function variables predicted loss of control. Pediatric patients with moderate-to-severe persistent asthma who discontinue LABA therapy have a 37% chance of losing asthma control resulting in augmented maintenance therapies. Recent recommendations of discontinuing LABA therapy as soon as control is achieved should be evaluated in a prospective long-term study.

Rational approach to the wheezy infant.

The infant or child presenting to the physicians office with persistent or recurrent wheezing during the first two years of life poses a diagnostic dilemma. A careful medical history should document risk factors for persistent wheezing, including maternal smoking, feeding practices, environmental history, and family history of asthma or cystic fibrosis (CF). A suggested diagnostic approach to the causes of infantile wheezing is outlined. A chest radiograph is non-specific, but may suggest a congenital airway anomaly. Infant pulmonary function testing (IPFT) can help differentiate between central airflow (intrathoracic, extrathoracic, or fixed) and peripheral airflow obstruction. The infant with either intrathoracic, extrathoracic, or fixed airflow obstruction on the PFT may benefit from flexible fiberoptic bronchoscopy. The infant with either an intrathoracic or fixed airway obstruction should undergo an upper gastrointestinal (UGI) series to evaluate the anatomy for extrinsic tracheal compression. The response to treatment with anti-inflammatory therapy may suggest an inflammatory disease such as asthma or CF. The infant with peripheral airflow obstruction and a good response to bronchodilators (> or =25%) using the forced exhalation technique is given the diagnosis of infantile asthma. The infant with peripheral airflow obstruction and no response to bronchodilators should be evaluated further for possible gastroesophageal reflux disease (GERD), and for other causes, which are associated with wheezing symptoms.

Anti-inflammatory dosing of theophylline in the treatment of status asthmaticus in children

Background Low-dose theophylline has been recognized for its ability to restore histone deacetylase-2 activity which leads to improved steroid responsiveness and thus improved clinical outcome. We retrospectively evaluated the effect of low-dose theophylline therapy in pediatric patients hospitalized for an acute asthma exacerbation as a proof of concept study. Methods We compared patients who received low-dose theophylline (5–7 mg/kg/day) in addition to current standard of care to patients who were treated with current standard of care alone. The primary outcome of the study was hospital length of stay (LOS). Generalized linear mixed-effects modeling (GLMM) was used to test whether receiving theophylline independently predicted outcomes. A Cox (proportional hazards) regression model was also developed to examine whether theophylline impacted LOS. Results After adjustment for illness severity measures, theophylline significantly reduces LOS (β=−21.17, P<0.001), time to discontinue oxygen (β=−15.88, P=0.044), time to spirometric improvement (β=−16.60, P=0.014), and time to space albuterol (β=−23.2, P<0.001) as well as reduced costs (β=−US

Lung function changes in asthmatic children treated with HFA-BDP.

2,746, P<0.001). Furthermore, theophylline significantly increased the hazards of being discharged from the hospital (hazards ratio =1.75, 95% confidence interval 1.20–2.54, P=0.004). There was no difference in side effects between patients who receive low-dose theophylline and those who did not. Conclusion The results of this retrospective study suggest low-dose theophylline may have a positive effect in acute status asthmaticus. This study suggests that further research with a prospective, randomized, double-blinded, placebo controlled trial may be warranted to confirm and extend our findings.

Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy

Asthma guidelines suggest that normal or near normal lung function should be one of the goals for good asthma control. Therefore, children with chronic persistent asthma and reduced peripheral airway function were assessed after the replacement of conventional inhaled corticosteroids (ICS) with an extrafine aerosol formulation, hydrofluoroalkane–134a beclomethoasone diproprionate (HFA‐BDP).

Unilateral pulmonary vein atresia: A rare case of hemoptysis

RATIONALE Neuroendocrine cell hyperplasia of infancy (NEHI) is a diffuse lung disease that presents in infancy and improves during childhood. Long-term outcomes have not previously been described. In one familial cohort, we have reported that NEHI is associated with a heterozygous variant of NKX2.1/TTF1. OBJECTIVES Our objective was to determine whether pulmonary abnormalities persist in adults with NEHI, to aid in elucidating the natural history of this disease. METHODS Four adult relatives with heterozygous NKX2.1 mutation and with clinical histories compatible with NEHI enrolled in a prospective study that included questionnaires, pulmonary function tests, and chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS Mild radiologic abnormalities including mosaicism were seen in all four cases. Three individuals had obstruction on pulmonary function tests, two had marked air trapping, and three had symptomatic impairments with exercise intolerance. CONCLUSIONS Although clinical improvement occurs over time, NEHI may result in lifelong pulmonary abnormalities in some cases. Further studies are required to better describe the natural history of this disease and would be facilitated by additional delineation of genetic mechanisms to enable improved case identification.

Granulomatous pleuritis caused by histoplasmosis in a healthy child

We present a rare case of hemoptysis secondary to isolated unilateral pulmonary vein atresia. Isolated pulmonary vein atresia is a rare condition in which patients typically acquire a diagnosis in infancy and early childhood [Mataciunas et al.; Pourmoghadam et al.]. Our patient presented during puberty with several previous episodes of hemoptysis prior to her admission and diagnosis. The initial diagnosis was suspected in our patient from chest computerized tomography (CT), and confirmed with cardiac catheterization and pulmonary angiography. Treatment aim is to preserve lung function and minimize irreversible pulmonary remodeling [Pourmoghadam et al.; Harrison et al.]. Conservative monitoring can be considered with milder or asymptomatic cases, while others may require preoperative collateral artery banding, surgical anastomosis between the pulmonary vein (PV) & left atrium (LA) and even pneumonectomy [Pourmoghadam et al.].