Urinary incontinence in 9-16 year olds with cystic fibrosis compared to other respiratory conditions and a normal group.

BACKGROUND: Individuals with cystic fibrosis (CF) are deemed at risk of developing urinary incontinence (UI) due to repeated coughing and other factors causing increased pressure on the pelvic floor. Increased incidence of UI is recognised in women and increasingly in men and children. However, there is little comparison with normal controls and other respiratory conditions with chronic cough. Our aim was to report the incidence, degree and impact of UI in 9-16 year olds related to clinical status in CF, compared to these. METHODS: 9-16 year olds were invited to fill in a self-administered anonymous/confidential questionnaire at clinic. Data recorded were sex, age, height, weight, spirometry expressed as percentage predicted. Normal controls - age and sex only recorded. RESULTS: No significant differences were found between incidence of UI (21% CF; 22% respiratory; and 17% normal controls, P=0.43). No relationship found between respiratory or nutritional status and UI. Laughing, exercise and cough were the most common causes of UI. No difference between groups for age range, physiotherapy, breathlessness, antibiotics, urinary tract infections and menarche. Only 6% reported more than a few drops of UI. CONCLUSION: Incidence of urinary incontinence is no different between 9-16 year old girls and boys with CF, and controls.

Creon 10,000 Minimicrospheres vs. Creon 8,000 microspheres--an open randomised crossover preference study.

Creon 10,000 Minimicrospherestrade mark (Creon) 10,000 MMS) is a pancreatic enzyme formulation that contains smaller spheres of pancreatin in a 50% smaller capsule than conventional microspheres (Creon) 8,000). This three-centre study investigated the preference of cystic fibrosis (CF) patients for these products. In one centre, 72 h stool fat excretion and coefficient of fat absorption (CFA) were also compared. Fifty-nine patients with a mean age 10 years (range 3-17) took Creon 8,000 ms for 14 days and were then randomised to 28 days of Creon 8,000 ms followed by 28 days of Creon 10,000 MMS, or vice versa. Dosing was lipase for lipase according to the labelled declaration. At the end of the second treatment period, 51 of 54 patients who completed the study expressed a preference, with a statistically significant preference in favour of Creon 10,000 MMS (47/51; 87%) vs. Creon 8,000 ms (4/51; 7.4%; P<0.0001). Stool fat (g/day) and CFA (%) were measured in 24 patients at the end of each treatment period: the products were therapeutically equivalent (Creon 10,000: 8.4 g/day, 91.3% CFA; Creon 8,000: 6.7 g/day, 93.5% CFA). Both products were well tolerated. In conclusion, in CF children we found a clear preference for Creon 10,000 MMS compared with Creon 8,000 ms with no difference in fat absorption between the two products. Creon 10,000s smaller capsules are easier to take and should aid patient compliance.

Spontaneous rupture of the diaphragm.

A 2.5 year old girl with metachromatic leukodystrophy presented with acute respiratory distress and was initially wrongly diagnosed with pneumothorax. Barium meal showed bowel loops in the left hemithorax, which prompted surgical intervention; spontaneous rupture of the diaphragm was diagnosed at surgery.

Aminoglycoside-associated hypomagnesaemia in children with cystic fibrosis.

Hypomagnesaemia in children with cystic fibrosis (CF) is under-recognized. We report a child with CF who developed significant hypomagnesaemia following intravenous (i.v.) treatment with aminoglycosides for exacerbations of Pseudomonas aeruginosa infection. Three additional cases have also been observed. Investigations in two patients have revealed excessive renal loss of magnesium. It is postulated that renal tubular damage secondary to the cumulative effects of repeated courses of aminoglycosides resulted in hypomagnesaemia, and we suggest screening for this problem by monitoring serum magnesium regularly in all patients with CF receiving multiple courses of aminoglycosides.

Subspecific differentiation of Burkholderia cepacia isolates in cystic fibrosis.

Thirty clinical isolates of Burkholderia cepacia from cystic fibrosis (CF) patients in the UK and Denmark were characterised, together with other clinical isolates and laboratory strains of B. cepacia, B. gladioli and B. vietnamiensis. Outer-membrane protein (OMP) profiles were determined, and the organisms were typed genotypically by pulsed-field gel electrophoresis after DNA restriction analyses with Xbal and DraI. This latter method revealed four clusters among the clinical isolates studied; one of these contained isolates of the UK and intercontinental CF epidemic lineage ET12, a cluster which appeared to contain three subtypes. Each of the four clusters appeared less closely related to laboratory strains of B. cepacia than were laboratory strains of B. vietnamiensis, but more closely related to both these species than to B. gladioli. Two types of OMP profile were distinguished among the clinical isolates and strains, and were designated A and B. In type A isolates the major proteins had mol.wts of 39, 27 and 18 kDa. Type B strains additionally contained a group of proteins in the size range 80-90 kDa, although detection of these depended upon the conditions for sample denaturation. In most cases, the OMP type correlated with the genotype, suggesting that examination of OMPs might be of value in the initial characterisation of isolates.

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Increasing resistance of planktonic and biofilm cultures of Burkholderia cepacia to ciprofloxacin and ceftazidime during exponential growth.

The change in resistance of Burkholderia cepacia to ceftazidime and to ciprofloxacin during the exponential phase and up to the onset of stationary phase was assessed along the growth curve in batch culture. B. cepacia was grown in planktonic culture and in a biofilm on a membrane support. Resistance increased progressively during the exponential phase, being increased by ten-fold about every four generations. Bacteria grown in a biofilm were about 15 times more resistant than equivalent planktonic-grown bacteria. The growth rate was not the key factor for the development of resistance. The growth phase and the mode of growth have a fundamental impact on the susceptibility of B. cepacia towards antimicrobial agents. Bacteria growing at the same rate may differ greatly in their resistance to antimicrobial agents.

Implications of early inflammation and infection in cystic fibrosis: a review of new and potential interventions.

Airway infection and inflammation occur early in cystic fibrosis (CF) lung disease, suggesting the need for early treatment. Our current approach to routine management of CF includes a comprehensive, CF center-directed program that aims at maintaining normal nutrition and delaying the progression of lung disease. Regular secretion clearance, frequent antibiotics, and bronchodilators are commonly used. However, despite this early, aggressive comprehensive management, airway inflammation and infection progress. Several other recent approaches such as the use of corticosteroids and ibuprofen to decrease inflammation, as well as dornase alfa to thin secretions and improve pulmonary function, are under investigation in young children. Other potential treatments include amiloride/uridine triphosphate and hypertonic saline aerosol. Early treatment offers the promise of reducing morbidity as well as delaying the progression of later disease.

Serum IgG response to an outer membrane porin protein of Burkholderia cepacia in patients with cystic fibrosis.

Early and accurate diagnosis of Burkholderia cepacia infection is important, particularly if segregation is to prevent patient-to-patient transmission. We have examined the serum response to a B. cepacia-specific 80-kDa outer membrane protein. 21 patients colonised with B. cepacia and Pseudomonas aeruginosa for 2-51 months (mean 11 months) were age- and sex-matched with 21 patients colonised with P. aeruginosa but not B. cepacia. The 80-kDa protein was recovered by electroelution from outer membrane proteins, separated by SDS-PAGE, coated onto ELISA plates, reacted with patient sera diluted 1:200, protein A-peroxidase and chromogenic substrate. We found that 19/24 patients colonised with B. cepacia and P. aeruginosa had high values, 2/24 patients had intermediate values, and 2/24 patients had a low value. 20/21 patients colonised with P. aeruginosa alone had low values and 1/21 had an intermediate value. We found that in the longitudinal serum samples studied from four patients only one patient developed high values after the first isolation of B. cepacia suggesting that seroconversion does not occur immediately after the first sputum culture of B. cepacia. We conclude that an ELISA test using B. cepacia-specific 80-kDa outer membrane protein can distinguish B. cepacia colonised and non-colonised patients and may be useful in the early diagnosis of B. cepacia infection.

Combined percutaneous lung biopsy and high-resolution computed tomography in the diagnosis and management of lung disease in children.

Computed tomography-guided percutaneous lung biopsy is a well-recognized procedure for obtaining tissue for diagnosis in adults with interstitial lung diseases. Recently this methodology has been extended to pediatric practice. We have further refined this technique by employing high-resolution computed tomography (HRCT) under general anesthesia to obtain maximum anatomical detail. High-quality images are obtained that accurately define the extent of disease, and percutaneous biopsies are then taken from a suitable area of radiological abnormality using an 18G Monopty needle. Twenty-six investigations have been performed on 24 patients. The diagnosis was established from 14 biopsies, and histological and/or radiological information that contributed to patient management was obtained from a further 4 procedures. In 4 patients the histological findings were inconclusive, and the final diagnosis was only confirmed by open lung biopsy and/or other investigations. The procedure was generally well tolerated, although chest drainage for pneumothorax was required in two patients. HRCT-guided percutaneous lung biopsy is a useful initial approach to the diagnosis of interstitial lung disease in selected patients; the necessity of more invasive procedures such as open, thoracoscopic, or transbronchial lung biopsy can thus generally be avoided.

Comparison of two percutaneous intravenous "midline" catheters in cystic fibrosis.

Administration of intravenous antibiotics in cystic fibrosis has been facilitated by the use of midline catheters; percutaneous lines inserted through a peripheral vein and advanced into a large but noncentral vein. In a randomized study, a 23-gauge silastic catheter (Vygon EC, Cirencester, United Kingdom) was compared with the Hydrocath (Viggo-Spectromed, Swindon, United Kingdom), a 22-gauge hydrophillic coated polyurethane catheter inserted using the Seldinger technique. Fifty eight courses of intravenous antibiotics were given, 28 through the Hydrocath (median age 11 years, range 1.5-17.5 years) and 30 through the silastic catheter, (median age 11 years, range 0.5-17.5). Mean line survival was equal. The Hydrocath took longer to insert and was associated with more pain on insertion. However, administration of antibiotics was easier through the Hydrocath and overall satisfaction was higher in those who had the Hydrocath. Both catheters performed well, but administration of antibiotics was easier through the Hydrocath.

Clinical benefit from nebulized human recombinant DNase in Kartagener's syndrome.

Nebulized recombinant human DNase (rhDNase) reduces sputum viscosity, improves pulmonary function, and results in a small reduction in acute respiratory exacerbations requiring intravenous antibiotics in many patients with cystic fibrosis (CF). rhDNase is now recommended for use in CF patients with moderately severe suppurative lung disease. A 14-year-old girl with suppurative lung disease [forced expiratory volume in 1 second (FEV1) 69% and forced vital capacity (FVC) 81% predicted] secondary to Kartagener's syndrome and severe gastroesophageal reflux had worsening spirometry together with intractable gastrointestinal symptoms over the previous 18 months despite conventional treatment. She was, therefore, started on 2.5 mg rhDNase once daily. Her cough lessened and the volume of sputum decreased within 72 hours of commencement of treatment; this improvement was strongly associated with a dramatic reduction in gastrointestinal symptoms. Spirometry after 4 weeks of treatment demonstrated a 20% improvement in FEV1 and a 13% improvement in FVC. These improvements have been maintained after 4 months of rhDNase therapy. The use of rhDNase should be considered in patients with Kartagener's syndrome and a multicenter trial may be justified.

Comparison of fluticasone propionate and sodium cromoglycate for the treatment of childhood asthma (an open parallel group study).

Inhaled corticosteroids are highly effective in the treatment of asthma at all ages and their use in younger children is increasing. As concerns exist about the long-term systemic side-effects of high dose inhaled corticosteroids, current guidelines continue to recommend sodium cromoglycate (SCG) as first line regular medication for children with frequent symptoms. Few published studies have compared the safety and efficacy of inhaled corticosteroids with SCG in children. This study compares SCG with the new inhaled corticosteroid, fluticasone propionate (FP), which has theoretical advantages over other currently available corticosteroids due to its negligible oral bioavailability. This was a randomized, open, multi-centre, parallel group comparison of 50 micrograms FP twice daily and 20 mg SCG four times daily over 8 weeks, preceded by a 2-week baseline period. Sixty-two general practices and two hospital centres enrolled 225 asthmatic children aged 4-12 years (110 received FP; 115 received SCG). Outcome measures improved in both groups, with a significant difference in favour of FP for the key variables of mean morning and evening % predicted PEFR and % of symptom-free days and nights. No significant difference was observed for FEV1, or relief medication use. Two children taking FP and 10 children taking SCG withdrew because of adverse events. This study showed that low dose FP was effective and superior to SCG in young children with mild-moderate asthma. Safety studies of longer duration are needed before changing the current recommendations for inhaled corticosteroid therapy.

Serum IgG response to Burkholderia cepacia outer membrane antigens in cystic fibrosis: assessment of cross-reactivity with Pseudomonas aeruginosa.

Burkholderia cepacia (Pseudomonas cepacia) is now recognised as an important pathogen in cystic fibrosis patients, and several reports have suggested that sputum-culture-proven colonisation occurs despite the presence of specific antibody. In an attempt to establish the use of antibody studies as diagnostic and prognostic indicators of B. cepacia infection, we have examined the IgG response to B. cepacia outer membrane proteins and lipopolysaccharide in patients also colonised with P. aeruginosa. The B. cepacia strains were grown in a modified iron-depleted chemically defined medium and outer membrane components examined by SDS-PAGE and immunoblotting. IgG antibodies were detected against B. cepacia outer membrane antigens, which were not diminished by extensive preadsorption with P. aeruginosa. The response to B. cepacia O-antigen could be readily removed by adsorption of serum either with B. cepacia whole cells or purified LPS, whereas we were unable to adsorb anti-outer membrane protein antibodies using B. cepacia whole cells. The inability to adsorb anti-outer membrane protein antibodies using B. cepacia whole cells maybe due to non-exposed surface epitopes. Several B. cepacia sputum-culture negative patients colonised with P. aeruginosa had antibodies directed against B. cepacia outer membrane protein. this study suggests that there is a specific anti-B. cepacia LPS IgG response, which is not due to antibodies cross-reactive with P. aeruginosa. Our studies indicate that much of the B. cepacia anti-outer membrane protein response is specific and not attributable to reactivity against co-migrating LPS.

Cystic fibrosis in children from ethnic minorities in the West Midlands.

BACKGROUND: We have observed that Doctors often perceive that cystic fibrosis (CF) is exceptionally rare in non-whites, and that this bias has repeatedly resulted in diagnostic delay. We therefore compared the age at diagnosis, genetic features and relative prevalence of CF in non-whites and white patients in the West Midlands. METHODS: Analysis of data on all CF patients diagnosed in childhood and stored in the West Midlands CF register. RESULTS: Sixteen of the 514 children on the register were not of white European extraction, comprising 13 patients whose families originated from the Indian subcontinent, two of mixed AfroCaribbean/white European extraction and one of mixed Pakistani/white European extraction. The median age of diagnosis was similar in the white European and non-white patients (0.42 vs. 0.33 years, 95% CI for the difference of the medians -0.15, 0.37). However, in five cases with typical clinical features the diagnosis appears to have been delayed because of the child's racial origin (median age of diagnosis 3.87 years), and in five others the diagnosis was obvious (two siblings with CF, three had meconium ileus). There was a degree of consanguinity in nine cases. Five patients were homozygous or heterozygous for the delta F508 mutation, but no mutation could be identified in the remaining 11 patients. CONCLUSIONS: The possibility of CF needs to be considered in any patient with relevant clinical problems, regardless of racial origin. These findings need to be considered when planning any mass population screening programme for CF.

Successful treatment of invasive pulmonary aspergillosis in chronic granulomatous disease with orally administered itraconazole suspension.

A 3-yr-old boy with known chronic granulomatous disease presented with a left-sided chest wall mass. Extensive intrathoracic and extrathoracic aspergillosis was confirmed by CT scan-guided percutaneous biopsy. Initially, he was treated intravenously with liposomal amphotericin and subcutaneous gamma-interferon, but his clinical condition deteriorated over 7 wk of treatment. The amphotericin was therefore discontinued, and itraconazole in an oral suspension was begun. There was progressive clinical improvement after 3 months of this regime, and marked radiologic clearing was apparent after 8 months of treatment. A multicenter trial of this mode of therapy in patients with invasive aspergillosis is indicated.

Crohn's disease with pulmonary involvement in a 3 year old boy.

Extra-intestinal or metastatic Crohn's disease is being recognised increasingly, most commonly in the skin and genitourinary system. Only very rarely has it been reported in the lung. A 3 year old boy who presented with swollen gums and a persistent abnormality on his chest x ray is reported. Lung biopsy specimens showed multiple non-caseating epithelioid granulomas. Subsequent investigation showed the presence of intestinal Crohn's disease. The evidence for abnormal lung function in Crohn's disease and the possible pathogenesis of metastatic pulmonary Crohn's disease are discussed.

Chronic granulomatous disease presenting in childhood with Pseudomonas cepacia septicaemia.

Two children who presented with fever, enlarged liver and spleen and ascites were found to have Pseudomonas cepacia septicaemia which proved fatal despite appropriate antibiotics and maximum supportive care. Chronic granulomatous disease of childhood (CGD) was subsequently diagnosed in both children. The possibility of CGD needs to be considered in any child with unexplained P. cepacia infection.