Early airway infection,inflammation, and lung function in cystic fibrosis

Aims: To determine the relation between lower airway infection and inflammation, respiratory symptoms, and lung function in infants and young children with cystic fibrosis (CF). Methods: A prospective study of children with CF aged younger than 3 years, diagnosed by a newborn screening programme. All were clinically stable and had testing as outpatients. Subjects underwent bronchial lavage (BL) and lung function testing by the raised volume rapid thoracoabdominal compression technique under general anaesthesia. BL fluid was cultured and analysed for neutrophil count, interleukin 8, and neutrophil elastase. Lung function was assessed by forced expiratory volume in 0.5, 0.75, and 1 second. Results: Thirty six children with CF were tested on 54 occasions. Lower airway infection shown by BL was associated with a 10% reduction in FEV_0.5 compared with subjects without infection. No relation was identified between airway inflammation and lung function. Daily moist cough within the week before testing was reported on 20/54 occasions, but in only seven (35%) was infection detected. Independent of either infection status or airway inflammation, those with daily cough had lower lung function than those without respiratory symptoms at the time of BL (mean adjusted FEV_0.5 195 ml and 236 ml respectively). Conclusions: In young children with CF, both respiratory symptoms and airway infection have independent, additive effects on lung function, unrelated to airway inflammation. Further studies are needed to understand the mechanisms of airway obstruction in these young patients.     

Treatment of airway inflammation in cystic fibrosis]

Cystic fibrosis airway inflammation is characterized by neutrophilic efflux and high levels of proinflammatory cytokines such as IL-8 and IL-6. Inhaled corticosteroids are widely used despite lack of evidence of efficacity. Despite evidence of efficacity of ibuprofen, many clinicians have chosen not to use this therapy because of concerns regarding potential side effects. Azithromycin has antiinflammatory properties and is effective in cystic fibrosis (CF) patients. Deoxyribonuclease (rhDNase) has been shown to improve lung function in patients with cystic fibrosis and may also have a positive effect on inflammation. Other antiinflammatory drugs are in the process of validation.     

Early detection of lung disease in children with cystic fibrosis using lung function

Measurement of lung function is routine in older children and adults with cystic fibrosis (CF) but not in infants and preschool children. Pulmonary infection, neutrophil-dominated inflammation and clinical exacerbations in young children similar to those seen in older subjects have been identified and highlight the urgent need to evaluate lung function in early life. Mounting evidence suggests lung function techniques sensitive to changes in peripheral lung function may be required to detect the early functional abnormalities in infants and preschool children with CF. In addition, the majority of studies in young children with CF have not reported longitudinal data and therefore the prognostic potential of existing lung function methods to track disease progression is poorly understood. This review aims to describe recent research findings in infants and preschool children and to outline currently available lung function techniques, issues around their standardization and their relative advantages and disadvantages in young children with CF.     

Passive smoking and impaired lung function in cystic fibrosis.

Passive smoking was measured in 57 children with cystic fibrosis and in 51 controls using a questionnaire and a measurement of urinary cotinine concentration. In the cystic fibrosis group, cotinine was significantly lower than in the controls. Also in this group, when the parents smoked the child's forced expiratory volume in one second decreased by 4% and the forced vital capacity by 3% for every 10 cigarettes smoked in the household each day.     

Intestinal inflammation in cystic fibrosis.

BACKGROUND: There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS: To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS: Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha(1) antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1beta) were measured. RESULTS: Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS: These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.     

Growth and lung function in Asian patients with cystic fibrosis.

BACKGROUND: The incidence of cystic fibrosis (CF) in Asians is rare. How these patients fare in terms of morbidity and mortality in the UK compared to their non-Asian peers is not well documented. AIMS: To retrospectively study annual reviews of 31 Asian CF patients from three London paediatric CF centres. METHODS: Disease severity was assessed by lung function, age at first infection with Pseudomonas aeruginosa, and body mass index (BMI). The Asian children were compared with 143 matched non-Asian patients with CF. Matching criteria used were same sex and treatment centre as the Asian index patient. In addition, the controls were matched so that their date of birth, date of diagnosis, and date at annual review were within 12 months of the index patient. RESULTS: There was no significant difference in age at diagnosis or age at annual review between the Asian and non-Asian children. Mean Z-scores for FEV1 and FVC were significantly lower for the Asian girls. There was no significant difference in Z-scores for BMI between the Asian children and their controls. Age at first isolation of Pseudomonas aeruginosa in Asian girls was significantly later than for their controls (8.3 years compared to 5.6 years for non-Asian girls). CONCLUSIONS: While the Asian boys' lung function seems comparable with that of their non-Asian peers, the Asian girls emerge as a potentially vulnerable group and more work is required to discover why this is the case.     

Passive smoking and impaired lung function in cystic fibrosis

Passive smoking was measured in 57 children with cystic fibrosis and in 51 controls using a questionnaire and a measurement of urinary cotinine concentration. In the cystic fibrosis group, cotinine was significantly lower than in the controls. Also in this group, when the parents smoked the child's forced expiratory volume in one second decreased by 4% and the forced vital capacity by 3% for every 10 cigarettes smoked in the household each day.     

Pseudomonas infection,allergy, and cystic fibrosis.

The clinical significance of the high prevalence of positive immediate skin tests in cystic fibrosis is unclear. Using analysis of variance, we have tested the hypothesis that patients with allergic cystic fibrosis have worse lung disease than non-allergic patients. Clinical data, skin prick tests, total or specific IgE antibody levels, chest radiographs, and pulmonary function tests were obtained in 104 cystic fibrosis patients. Patients with positive immediate skin reactions to at least one allergen were more likely to be persistently colonised by Pseudomonas aeruginosa than skin test negative patients. The skin test positive patients were also significantly older (mean difference 2.15 years). Analysis of variance showed that pseudomonas infection was the most significant factor contributing to lung damage and the effect of allergy was not significant. Similar longitudinal analysis of pulmonary function over 5 years and study of the hospital admission rate showed that the only statistically significant factor associated with deterioration was colonisation with P. aeruginosa.     

Haemophilus infection in cystic fibrosis.

Twenty seven patients with cystic fibrosis under the age of 12 years and 27 matched patients with asthma were followed up in a prospective study for one year. The isolation rate of non-capsulated strains of Haemophilus influenzae from cough swabs and sputum specimens taken at routine clinic visits every two months was significantly greater in cystic fibrosis than in asthma. Haemophilus para-influenzae was equally common in both groups. During exacerbations the isolation rate of H influenzae in cystic fibrosis was significantly greater than at other times, whereas in asthma there was no significant difference. The distribution of biotypes of H influenzae and H parainfluenzae was similar in the two groups. In cystic fibrosis, biotype I was associated with exacerbations. Biotype V was more common than in previous studies, but was not associated with exacerbations.     

Intestinal inflammation in cystic fibrosis

BACKGROUND—There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF.AIMS—To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy.METHODS—Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α₁ antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured.RESULTS—Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy.CONCLUSIONS—These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.     

Growth and lung function in Asian patients with cystic fibrosis

Background: The incidence of cystic fibrosis (CF) in Asians is rare. How these patients fare in terms of morbidity and mortality in the UK compared to their non-Asian peers is not well documented. Aims: To retrospectively study annual reviews of 31 Asian CF patients from three London paediatric CF centres. Methods: Disease severity was assessed by lung function, age at first infection with Pseudomonas aeruginosa, and body mass index (BMI). The Asian children were compared with 143 matched non-Asian patients with CF. Matching criteria used were same sex and treatment centre as the Asian index patient. In addition, the controls were matched so that their date of birth, date of diagnosis, and date at annual review were within 12 months of the index patient. Results: There was no significant difference in age at diagnosis or age at annual review between the Asian and non-Asian children. Mean Z-scores for FEV₁ and FVC were significantly lower for the Asian girls. There was no significant difference in Z-scores for BMI between the Asian children and their controls. Age at first isolation of Pseudomonas aeruginosa in Asian girls was significantly later than for their controls (8.3 years compared to 5.6 years for non-Asian girls). Conclusions: While the Asian boys'' lung function seems comparable with that of their non-Asian peers, the Asian girls emerge as a potentially vulnerable group and more work is required to discover why this is the case.     

Edetate sodium aerosol in Pseudomonas lung infection in cystic fibrosis

In vitro and animal experimental data suggest the combination of edetate sodium (EDTA) by aerosol plus oral antimicrobials might be effective in the treatment of chronic Pseudomonas infection in patients with cystic fibrosis (CF). For six months we studied the effects of edetate sodium administered by ultrasonic nebulizer to ten children with CF and chronic Pseudomonas aeruginosa infection in a double-blind, placebo-controlled, crossover study. The children had evidence of mild to moderate disease at entry in the study, with a mean (+/- SD) forced expiratory volume in the first second of 85% (+/- 18%) of the predicted value and a mean (+/- SD) Shwachman-Kulczycki score of 83 (+/- 7)/100. Each child was on a three-month regimen of aerosolized edetate sodium plus oral tetracycline twice daily followed by three months of placebo aerosol plus tetracycline or vice versa. Progress was assessed by measurement of pulmonary function, physical examination, and sputum cultures at four weekly intervals, plus chest roentgenograms on entry and after each of the three-month treatment periods. Daily symptoms were assessed using a diary card system. Two patients could not complete the study, one because of severe respiratory relapse, the other because of antibiotic side effects. Of the remaining eight patients, none showed any improvement in pulmonary function, weight gain, or growth acceleration, and none was rendered free of Pseudomonas lung infection. Daily symptom scores and chest roentgenograms were unaltered by edetate sodium. We conclude that the combination of aerosol edetate sodium plus oral tetracycline over a three-month period does not modify the clinical course nor the pulmonary flora in patients with CF with chronic Pseudomonas lung infection.     

Structural lung changes,lung function,and non‐invasive inflammatory markers in cystic fibrosis

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J‐BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non‐invasive inflammatory markers in cystic fibrosis.
Pediatr Allergy Immunol 2010: 21: 493–500.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non‐invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non‐invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8‐isoprostane, hydrogen peroxide, interferon‐gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non‐invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas‐negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8‐isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non‐invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non‐invasive monitoring of airway inflammation in CF adds to better follow‐up of patients.     

Impact of lung inflammation on bone metabolism in adolescents with cystic fibrosis

Deficits in bone mineral density resulting in premature osteopenia and osteoporosis have been documented in cystic fibrosis patients for over 20 years. A high incidence of fractures and kyphosis in the continually increasing adult patient population and in post-lung transplant patients has highlighted the problems associated with poor bone health.The aetiology of osteoporosis in CF is multifactorial but centres on an uncoupling in the normal balance between bone formation and resorption. Delayed puberty, malabsorption and reduced weight-bearing exercise can result in inadequate bone mineral accretion in childhood and adolescence. Corticosteroid use and pro-inflammatory cytokines associated with infective respiratory exacerbations can accelerate bone loss.Dual energy X-ray absorptiometry is the most commonly available technique to measure bone mineral density. All patients should be scanned at least every 2 years from adolescence. The treatment of established disease with bisphosphonates shows encouraging early results.     

Hospital therapy improves exercise tolerance and lung function in cystic fibrosis

We studied the benefits of in-hospital therapy on exercise capacity and related these changes to improvements in lung function in 17 patients with cystic fibrosis (CF) of moderate to extreme severity, as defined by results of pulmonary function tests performed at admission and discharge. Tolerance and adaptations to exercise were assessed from measures of peak work capacity (PWC), peak heart rate (PHR), and peak ventilation (PVE) obtained during an incremental exercise test. Treatment lasted from nine to 18 days. All measures of lung function improved; there also were significant increases in PWC, PHR, PVE, and PHR/PWC. Exercise-induced arterial desaturation was less at discharge than at admission. The PWC of the most severely affected patients remained abnormally low, and their adaptations to exercise were abnormal at discharge. We concluded that intensive in-hospital therapy will significantly improve exercise tolerance and lung function in patients with CF with moderate to severe pulmonary dysfunction.