Jonathan E. Spahr

Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial

PURPOSE To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.

Standardized Treatment of Pulmonary Exacerbations (STOP) study: Observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations

BACKGROUND The Standardized Treatment of Pulmonary Exacerbations (STOP) program has the intent of defining best practices in the treatment of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF). The objective of this analysis was to describe the clinical presentations of patients admitted for intravenous (IV) antibiotics and enrolled in a prospective observational PEx study as well as to understand physician treatment goals at the start of the intervention. METHODS We enrolled adolescents and adults admitted to the hospital for a PEx treated with IV antibiotics. We recorded patient and PEx characteristics at the time of enrollment. We surveyed treating physicians on treatment goals as well as their willingness to enroll patients in various study designs. Additional demographic and clinical data were obtained from the CF Foundation Patient Registry. RESULTS Of 220 patients enrolled, 56% were female, 19% were adolescents, and 71% were infected with P. aeruginosa. The mean (SD) FEV1 at enrollment was 51.1 (21.6)% predicted. Most patients (85%) experienced symptoms for ≥7days before admission, 43% had received IV antibiotics within the previous 6months, and 48% received oral and/or inhaled antibiotics prior to IV antibiotic initiation. Forty percent had ≥10% FEV1 decrease from their best value recorded in the previous 6months, but for 20% of patients, their enrollment FEV1 was their best FEV1 recorded within the previous 6months. Physicians reported that their primary treatment objectives were lung function recovery (53%) and improvement of symptoms (47%) of PEx. Most physicians stated they would enroll patients in studies involving 10-day (72%) or 14-day (87%), but not 7-day (29%), treatment regimens. CONCLUSIONS Based on the results of this study, prospective studies are feasible and physician willingness for interventional studies of PEx exists. Results of this observational study will help design future PEx trials.

Pulmonary Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue Associated with Granulomatous Inflammation in a Child with Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Patients with immunodeficiency disorders have an increased incidence of lymphoproliferative disorders; however, only 4 such patients with DiGeorge/chromosome 22q11.2 deletion syndrome have been reported. We report a case of a pulmonary Epstein-Barr virus-negative extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in a child with this syndrome.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis

BACKGROUND Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Comparison of two aspiration techniques of bronchoalveolar lavage in children.

Although bronchoalveolar lavage (BAL) via flexible bronchoscopy is an essential diagnostic tool, its technique is not standardized in children. Our objective was to compare two different aspiration techniques of BAL in children (continuous wall suction vs. handheld syringe suction) in regards to the percentage of fluid recovered and the odds of performing a technically acceptable procedure (i.e., >40% of volume return).

Malignant pleural mesothelioma in a child with ataxia–telangiectasia†‡

Ataxia–telangiectasia (AT) is a hereditary disorder characterized by progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. Pleural neoplasms are extremely rare in the pediatric population, even in patients with AT. We describe the case of a 16‐year‐old male with AT who developed a malignant pleural mesothelioma (MPM). Benign or infectious lung and pleural diseases are common in those with AT. Hence, delayed diagnosis of respiratory neoplasms can occur in these patients. This report highlights the need of heightened vigilance in patients with AT with recurrent or persistent pleuropulmonary disease. To our knowledge, no other cases of MPM in children with AT have been reported. Pediatr Pulmonol. 2013; 48:94–97.

Site of Bronchoalveolar Lavage Via Flexible Bronchoscopy and Fluid Return in Children.

Background:Despite its widespread use as a diagnostic tool, the procedure for bronchoalveolar lavage (BAL) via flexible bronchoscopy is not standardized in children. Our objective was to examine the dissimilarities in fluid return between the different lobes in children undergoing flexible bronchoscopies with BAL. Methods:We conducted a review of all pediatric flexible bronchoscopies with BAL conducted at a single institution over a 2-year period. Our predictor of interest was the site of the BAL. Our outcome of interest was the percent of fluid return. We used 1-way analysis of variance with subsequent pairwise comparisons for unadjusted analyses and multivariable linear regression for adjusted analyses. Results:We identified 529 procedures that met prespecified criteria. The mean (SD) percent of fluid return was 52.1 (14.4) for the right middle lobe, 50.7 (16.0) for the lingula (LIN), 50.5 (18.6) for the right or left upper lobes other than LIN (R/L-UL), and 42.2 (18.7) for the right or left lower lobes (R/L-LL). The R/L-LL had significantly lower fluid return when compared with each of the other lobes (P<0.05 for all pairwise comparisons); in contrast, there was no significant difference in fluid return between the other lobes. In our main analysis adjusting for potential confounders, performing the BAL in the right middle lobe, LIN, or R/L-UL increased the fluid return by 11.1% [95% confidence interval (CI), 6.2-16.1], 9.5% (95% CI, 3.2-15.8), and 8.7% (95% CI, 0.9-16.5%), respectively, when compared with the R/L-LL. Conclusion:Our results suggest that the lower lobes provide the lowest BAL fluid return in children, whereas the other lobes seem to perform similarly.

Lobar displacement following pediatric heart-lung transplantation: case report and review of literature.

Guglani L, Tadros S, Morell VO, Spahr JE, Webber SA, Kurland G. Lobar displacement following pediatric heart‐lung transplantation: Case report and review of literature.

GER and Aspiration in Children

Whether gastroesophageal reflux (GER) directly causes lung disease in children is often debated within and among pediatric pulmonologists, gastroenterologists, and otolaryngologists [1, 2]. Respiratory symptoms are quite common in infants and children, and reflux is very common in infants and children. Determining whether respiratory disease and reflux are related or just coexistent processes is an inherently difficult task. Often, there is little or no supporting literature in children to support or refute the implication that GER causes or exacerbates certain lung diseases. Furthermore, while treatment for GER is effective in controlling the symptoms of GER, there are few studies in children that show a significant improvement in lung disease when coexistent GER is treated.

62 – Pulmonary Disease in the Pediatric Patient with Acquired Immunodeficiency States

Abstract Children with acquired immunodeficiency are at risk for many infectious and noninfectious pulmonary complications. This chapter will discuss such complications in children who have had solid organ transplantation, hematopoietic stem cell transplantation, and who have undergone treatment for childhood malignancy. Infectious and noninfectious complications will be discussed as well as an approach to the diagnosis of such respiratory complications in the child with an acquired immunodeficiency.