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Summary This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug–drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications. The complexities of these interactions provide a strong rationale for case management by pharmacists and pharmacologists as a routine part of CF care. Pediatr Pulmonol. 2016;51:S61–S70. © 2016 Wiley Periodicals, Inc.

This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug-drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications. The complexities of these interactions provide a strong rationale for case management by pharmacists and pharmacologists as a routine part of CF care. Pediatr Pulmonol. 2016;51:S61-S70. © 2016 Wiley Periodicals, Inc.

Rationale Inhaled tobramycin has been shown to transiently clear Pseudomonas from lower airways in early cystic fibrosis (CF), but does not markedly reduce lung inflammation, a key factor in disease progression. Objective Test the hypothesis that systemic antibiotics are more effective than inhaled antibiotics for reducing lower airways inflammation. Methods Clinically stable CF children with recent Pseudomonas were randomized to receive 4 weeks of inhaled tobramycin or 2 weeks of systemic antibiotics (intravenous ceftazidime and tobramycin). Bronchoalveolar lavage fluid was obtained just before and 4–6 weeks after treatment. The primary outcome was change in % neutrophils in lavage fluid. Results Fifteen subjects (inhaled = 6, systemic = 9) completed the protocol. Three Systemic Group subjects could not have central venous access established and were treated with oral ciprofloxacin (plus inhaled tobramycin) for 2 weeks as an alternative “systemic” regimen, per protocol. Groups were well matched in age, markers of disease severity, and initial % neutrophils. The Systemic Group showed a modest median change in percent neutrophils (−7%) which was not statistically significant compared to inhaled (+5.4%, P = 0.07). However, the Systemic Group had significantly greater reductions in total cells (−50% vs. −3%, P

To determine whether history of chronic lung disease (CLD) in children born at very low birthweight (VLBW) confers additional risk for impaired health, growth, and neurodevelopment, 17 VLBW children born in 1984 who had CLD (requiring supplemental oxygen more than 30 days after birth) in infancy and 28 VLBW children who did not have CLD were assessed at age 7 years. Assessments included a medical history, standard physical and neurological examinations, pulmonary-function tests, and tests of neuropsychological and psychoeducational functioning. Health status did not differ between the groups. In contrast, children with CLD did not perform as well in neuropsychological and psychoeducational assessments. Although CLD confers little added risk to health, it seems to add significantly to risks for poor school performance that are known to be associated with very low birthweight.

Numerous drugs can cause pulmonary reactions in children. Chemotherapeutic agents are most frequently implicated, although toxic effects of other medications have been recognized. Reactions to chemotherapeutic agents may be dose-related; most reactions to noncytotoxic agents develop idiosyncratically. Clinical/pathologic syndromes described include diffuse interstitial pneumonitis and fibrosis, hypersensitivity pneumonitis, noncardiogenic pulmonary edema, pleural effusion, bronchiolitis obliterans, and alveolar hemorrhage. Presenting symptoms vary but often include fever, cough, and dyspnea, and radiologic studies demonstrate diffuse alveolar and/or interstitial abnormalities. Abnormalities in lung function may precede symptoms and radiographic changes. Patterns of abnormalities on chest CT, bronchoalveolar fluid analysis and cultures, and lung histopathology may be useful in categorizing and defining extent of disease but may be nonspecific. Other disorders, including infection, hemorrhage, lung disease related to underlying disease, and radiation damage, must be considered. Criteria for the diagnosis of drug-induced lung disease have been outlined. Although some drug-induced lung injury is reversible, persistent and even fatal dysfunction may occur. Survivors of childhood cancer require follow-up as lung disease may develop remotely from drug exposure and be progressive. More precise information about risk factors, including genetic predisposition and mechanisms of injury, along with more sensitive diagnostic and monitoring approaches are needed for development of improved therapeutic strategies, including early intervention.

Gentamicin and standard-dose ibuprofen were administered to an adolescent with cystic fibrosis who developed renal failure and severe vestibulotoxicity. A contributing factor was possible suboptimal intravascular volume status. Because of the potential severity of this drug interaction, hydration status and renal and vestibular functions should be closely monitored in patients receiving ibuprofen and intravenous aminoglycosides concomitantly.

Inhaled tobramycin has been shown to transiently clear Pseudomonas from lower airways in early cystic fibrosis (CF), but does not markedly reduce lung inflammation, a key factor in disease progression.Test the hypothesis that systemic antibiotics are more effective than inhaled antibiotics for reducing lower airways inflammation.Clinically stable CF children with recent Pseudomonas were randomized to receive 4 weeks of inhaled tobramycin or 2 weeks of systemic antibiotics (intravenous ceftazidime and tobramycin). Bronchoalveolar lavage fluid was obtained just before and 4-6 weeks after treatment. The primary outcome was change in % neutrophils in lavage fluid.Fifteen subjects (inhaled = 6, systemic = 9) completed the protocol. Three Systemic Group subjects could not have central venous access established and were treated with oral ciprofloxacin (plus inhaled tobramycin) for 2 weeks as an alternative "systemic" regimen, per protocol. Groups were well matched in age, markers of disease severity, and initial % neutrophils. The Systemic Group showed a modest median change in percent neutrophils (-7%) which was not statistically significant compared to inhaled (+5.4%, P = 0.07). However, the Systemic Group had significantly greater reductions in total cells (-50% vs. -3%, P0.01) and neutrophils (-74% vs. -10%, P = 0.02) per ml lavage fluid. Both groups had reduced bacterial quantity after treatment, but there was no significant difference between groups.In clinically stable children with CF, systemic antibiotics result in greater short-term reduction in lower airways inflammation than inhaled antibiotics.

We examined the relationship between patterns of mild lower respiratory illness (LRI) experienced in early childhood and lung function in 89 boys and 70 girls 6 to 18 yr of age. The children's histories of outpatient visits for wheezing and nonwheezing LRI during the first 6 yr of life had been documented by physicians in a single pediatric practice. Most children were reported by their parents to have been free of recurrent respiratory symptoms during the 2 yr prior to lung function testing. In sex-specific analyses, average lung function assessed by spirometry was similar in children who had made zero or one physician visit for wheezing LRI during the preschool years. Boys who had experienced two or more episodes of wheezing LRI during the preschool years had lower average FEV1, FEV1/FVC, FEF25-75, Vmax50, and Vmax75 than did boys who had zero or one preschool wheezing illness. The association between recurrent preschool wheezing LRI and later lung function remained after exclusion of data from seven boys who were reported to have wheezed in the 2 yr prior to study. Girls who had experienced two or more preschool wheezing LRI had lower average FEF25-75 and Vmax50 than girls with a history of zero or one such illness, but differences were not statistically significant. Recurrent nonwheezing LRI during the preschool years was not significantly associated with subsequent lung function in either sex, regardless of preschool wheezing LRI history. Detailed information concerning early childhood LRI experience is valuable in epidemiologic studies of factors influencing lung function in children.

Although nontuberculous mycobacteria (NTM) are recognized pathogens in adolescent and adult patients with cystic fibrosis (CF), the role of NTM in younger CF patients is not well-defined. To explore NTM infection in CF patients less than 12 years old, a retrospective review was performed. Prevalence was estimated from routine mycobacterial cultures of bronchoalveolar lavage (BAL) specimens collected over a 3-year period. NTM-positive cultures were obtained from 9 of 258 BALs collected from 7 of 114 different patients (5 months to 11 years of age). Further data were acquired from microbiological and clinical records of all pediatric patients with CF over a 10-year period. A total of 17 patients had at least one positive mycobacterial culture at less than 12 years of age, 5 of whom had positive cultures before age 5. The most commonly identified organisms were Mycobacterium avium-complex and Mycobacterium abscessus. Of the 17 patients, 10 met American Thoracic Society (ATS) microbiological criteria for mycobacterial disease, and 7 did not. The two groups did not differ with respect to age, gender, or presence of other respiratory pathogens. Patients who met ATS microbiological criteria for disease were more likely to have positive smears for acid-fast bacilli and grow Mycobacterium abscessus from culture. These patients also had a greater decline in lung function over time than patients who did not meet the microbiologic criteria. These data suggest that NTM represent a clinically significant pathogen, even in young patients with cystic fibrosis.

Inflammation can be demonstrated in the airway mucosa of asthmatics, even in the absence of overt symptoms, but the pathogenesis of this chronic inflammation is incompletely defined. It has been suggested that inflammatory cytokines produced by epithelium may play important roles in this process. Therefore, we measured the cytokines interleukin-8 (IL-8), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in nasal lavage fluids from school-age children who were (1) "normal" (nonallergic/nonasthmatic), (2) allergic to house-dust mite antigen but nonasthmatic (no history of wheezing), or (3) allergic and asthmatic (history of > or = 10 wheezing episodes). Children underwent a single nasal lavage procedure while asymptomatic and on no anti-inflammatory medications or anti-histamines. In addition to cytokine concentrations, cell counts, differentials, albumin, histamine, and eosinophil cationic protein (ECP) concentrations were determined in nasal lavage fluids. Significant increases in IL-8 and ECP were observed in asthmatics compared with both normals and allergic nonasthmatics. Overall, IL-8 in nasal lavage fluids correlated significantly with ECP. Allergic nonasthmatics did not have significant increases in cytokines or other mediators compared with normal subjects. Concentrations of IL-6 did not differ significantly among the three groups, and GM-CSF was undetectable in all samples tested. We conclude that increased IL-8 production and eosinophil activation are characteristic of the airways of asthmatic children when asymptomatic, and we speculate that IL-8 plays a role in the maintenance of airway inflammation in asthma.

Correlates of recurrent wheezing were examined in a case-control study involving 343 children ranging from 7 to 12 yr of age and recruited from a general pediatric practice. Positive skin tests for allergy were observed in 35% of a random sample of children without recurrent wheezing, and in 77% and 90% of children who had experienced from two to four episodes and five or more episodes, respectively, of recent wheezing. By logistic regression analysis, sensitization to dust mite (odds ratio [OR]: 5.2; 95% CI: 3.0 to 9.0), cat (OR: 15.5; 95% CI: 3.4 to 70.8), and Alternaria (OR: 6.8; 95% CI: 2.1 to 21.5) antigens was consistently associated with recurrent wheezing. Sensitization to pollen antigen(s), observed in 60% of allergic children, was not associated with wheezing. A family history of asthma was a significant predictor of recurrent wheezing (OR: 3.2; 95% CI: 1.7 to 5.9) after adjusting for its association with positive skin tests. Environmental tobacco smoke (ETS) exposure was associated with an increased risk of recurrent wheezing in nonallergic children and in allergic females, but not in allergic males. ETS exposure was not associated with positive skin tests for allergy. A history of wheezing with respiratory illness before 2 yr of age was associated with a modest risk of recurrent wheezing between 7 and 12 yr of age (OR: 2.3; 95% CI: 1.2 to 4.6), a risk that did not differ by allergic status or gender. Theoretically, the prevalence of recurrent wheezing in this population could be reduced approximately 65% by controlling exposure to indoor allergens and ETS.

In a study of 159 school-age children whose histories of outpatient visits for lower respiratory illness (LRI) had been documented from early infancy, we observed lower mean levels of small airway function in boys who had experienced two or more episodes of wheezing-associated LRI before 6 yr of age. To determine whether allergy was an important factor influencing this result, we examined relationships among the results of RAST tests for seven common inhalant allergens and concurrent lung function in 126 subjects who consented to venipuncture. Increasing values for the sum of scores for the seven RAST tests were associated with progressively lower mean levels of small airways function in boys with histories of recurrent wheezing LRI during the preschool years. The association of allergy with lower levels of lung function was largely accounted for by dust mite allergy. RAST results were not correlated with lung function in boys who had experienced zero or 1 wheezing LRI before 6 yr of age or in girls. A history of recurrent wheezing LRI during the preschool years was also associated with significantly lower mean levels of small airways function in boys who had negative RAST tests. A subset of 49 boys was reevaluated after an average interval of 4 yr with RAST tests, spirometry, and methacholine challenge. Dust mite allergy was associated with an increased prevalence of bronchial hyperreactivity independent of early childhood wheezing LRI history.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative analysis of regional interalveolar pore development in the lungs of C3Hf/He mice was performed using scanning electron microscopy. Lungs of male mice ages 7, 10, 14, 21, 28, and 56 days were studied following intratracheal fixation. Interalveolar pores were counted in subpleural, midzonal, and peribronchiolar regions. Interalveolar pores were rarely observed in mice ages 7, 10, and 14 days but appeared abruptly at age 21 days throughout the lung. The number of interalveolar pores increased 2-3 fold from ages 21 to 56 days. By age 28 days and thereafter interalveolar pores were more numerous in subpleural alveoli than in midzonal or peribronchiolar alveoli. We conclude that interalveolar pores appear diffusely in the lungs of mice during the third postnatal week and that regional differences in the number of interalveolar pores are established by age 28 days.

We examined the relationship between lower respiratory illness (LRI) experience in early childhood and lung function and bronchial reactivity in 57 boys, 11 to 22 yr of age, whose histories of outpatient physician visits for wheezing and nonwheezing LRI had been documented prospectively during their first 6 yr of life. These boys were a subpopulation of 159 children whose early childhood LRI experience and spirometric performance had been studied an average of 4 yr previously. The majority of boys had been free of chronic respiratory symptoms in the 2 yr before evaluation. Boys with histories of 2 or more preschool wheezing illnesses had lower mean levels of performance for FEV1, FEF25-75, FEF50, FEF75, and FEV1/FVC than did boys who had zero or 1 preschool wheezing illness, replicating observations that had been made when the boys had been studied 4 yr previously. Boys with lower spirometric performance relative to the study population on initial testing continued to have lower relative levels of spirometric performance 4 yr later. Neither preschool wheezing nor nonwheezing illness experience was associated with the degree of methacholine sensitivity measured in adolescence. Increasing degrees of methacholine sensitivity were associated with lower levels of spirometric performance; however, preschool wheezing illness experience remained a significant correlate of spirometric performance after adjustment for level of methacholine sensitivity. We conclude that recurrent preschool wheezing illness in these adolescent boys was associated with persistently lower lung function, but not enhanced methacholine sensitivity, during the middle to late school years.