Does Centralized Treatment of Cystic Fibrosis Increase the Risk of Pseudomonas aeruginosa Infection?

ABSTRACT. Two hundred and forty Danish patients with cystic fibrosis (97% of the total CF population in Denmark) participated in a point-prevalence study of Pseudomonas aeruginosa infection. One hundred and ninety-two patients were treated at the Danish CF centre and 48 patients were treated in other places. The age distribution was significantly different as no patients older than 19 years were found in the non-centre group. Pathogenic bacteria were isolated from the sputum of 96% of the patients. P. aeruginosa was more prevalent in patients from the centre, whereas Staphylococcus aureus was more prevalent in the non-centre group. No difference in serogroup and phage pattern of P. aeruginosa was found. There was a tendency that non-centre treated patients acquired chronic broncho-pulmonary P. aeruginosa infection later, but at the age of 16 years 90% of all patients will be chronically infected. Chronic P. aeruginosa infection was significantly more common in the age group 10-14 years at the centre than outside the centre. It is not possible to prevent chronic P. aeruginosa infection in CF patients treated in small groups and because of the better prognosis of centralized treatment the latter must be recommended.     

Estimated Risk of Cross-Infection with Pseudomonas aeruginosa in Danish Cystic Fibrosis Patients

ABSTRACT. During the period 1970–1987 the number of cystic fibrosis (CF) patients treated at the Danish CF Centre increased from 54 to 226. The prevalence of patients with chronic P. aeruginosa infection (CF + P) increased from 35% to 59%, whereafter it decreased to 54%. The yearly incidence of new CF + P patients averaged 8.4% in 1970–1975, 17% in 1976–80, 6.5% in 1981–85, and 3% in 1986–87. These changes correlated to the increased "contact density" between CF + P and non-infected CF patients (CF-P) due to intensified treatment starting in 1976, and the reduced "contact density" due to separation of the two groups starting in 1981. The same trends were observed during an epidemic spread of a multiply resistant P. aeruginosa in the CF + P group, which was also interrupted by separation of two groups of patients, with and without the multiply resistant strain. The observed prevalences of CF + P in different age groups of patients are in accordance with a 20% incidence/year in patients older than three years. The highest probability of aquiring chronic P. aeruginosa infection was calculated to be 2%/day and the lowest 0.09%/day spent in the Centre. By employing a simple mathematical model of the spread of infectious diseases it can be shown, that the highest incidence of CF + P is present when the prevalence of CF + P is 20–80%, and that an increase in the total number of patients also increases the incidence of CF + P unless the patients are divided into smaller groups. The observations in the Danish CF Centre are in accordance with this model.     

Relation between Antibody Response to Pseudomonas aeruginosa Exoproteins and Colonization/Infection in Patients with Cystic Fibrosis

ABSTRACT. Enzyme-linked immunosorbent assay (ELISA) was used to measure the antibody response to Pseudomonas aeruginosa exotoxin A, elastase, alkaline protease and phospholipase C in patients with cystic fibrosis (CF). Only the chronically colonized patients showed elevated antibody titres to phospholipase C (22/22 patients), alkaline protease (16/22 patients), exotoxin A (15/22 patients) and elastase (5/22 patients). In a few patients where serial specimens were available, rising titres were recorded to all four antigens during periods of active infection. Antibiotic treatment resulted in decrease of titres against all four antigens, but only the anti-exotoxin A and anti-elastase titres decreased to normal levels. Titres to phospholipase C were the least influenced by antibiotic treatment. The results imply different roles for these exoproteins in chronic colonization versus active infection. The levels of P. aeruginosa antibodies to exoproteins could probably be used in monitoring treatment of patients with CF.     

Increased IgG2 and IgG3 Concentration Is Associated with Advanced Pseudomonas Aeruginosa Infection and Poor Pulmonary Function in Cystic Fibrosis

ABSTRACT. The concentrations of IgG subclass immunoglobulins were determined by radial immunodiffusion in serum from 126 patients with cystic fibrosis (CF). The results were compared to values from age-matched healthy children and adults and correlated to patients age, duration of chronic Pseudomonas aeruginosa infection and lung function parameters. Fifty-two percent of the patients had an elevated concentration of at least one of the IgG subclasses; IgG1 28%, IgG2 16%, IgG3 18% and IgG4 48%. There was significant correlation between elevated serum levels of IgG2, and to a lesser extent IgG3, with decreased lung function (for FEV₁; p =0.0001, and p =0.001 respectively) and high levels of antipseudomonas precipitins ( p =0.008, and p =0.002). A similar correlation was not found for IgG1 and IgG4. IgG subclasses vary in their ability to promote phagocytosis and to activate complement and it is possible that individual differences in the IgG subclass pattern could explain the variable course of this disease.     

Cystic Fibrosis in Denmark 1945 to 1985

ABSTRACT. The entire population of cystic fibrosis (CF) patients in Denmark diagnosed in the period January 1, 1945, to June 30,1985, comprised 514 persons of whom 62 were diagnosed at autopsy. Of the remaining 452 patients, 372 were probands and 80 were secondary cases. The effect of a centralized treatment on the prognosis was evaluated using a Cox's regression model. Furthermore an incidence analysis was performed using probands including autopsies. Centrab'zed treatment had a significantly beneficial effect on the prognosis ( p =0.02), the death intensity (hazard rate) being decreased by a factor of 0.60. It was calculated that at present 1 out of 4760 newborn Danes may be diagnosed as suffering from CF before the age of 15 years, and 3% of the Danish population are heterozygotes for CF.     

Intensive Treatment of Pseudomonas Chest Infection in Cystic Fibrosis: a Comparison of Tobramycin and Ticarcillin, and Netilmicin and Ticarcillin

ABSTRACT. Seventeen cystic fibrosis patients aged 3.1 years to 19.8 years had 30 courses of intensive treatment for relapse of their pseudomonas chest infection. The combination of netilmicin and ticarcillin was compared with tobramycin and ticarcillin in an open study. A significant subjective and objective improvement occurred in all patients. Pseudomonas was cleared temporarily from the sputum in 11 out of the 30 courses of treatment (37 %). There was no significant difference between the netilmicin and tobramycin groups, nor evidence of sustained renal or ototoxicity. Intensive therapy of pseudomonas chest infection in cystic fibrosis patients is described in detail.     

Immunofluorescence Studies of Lung Tissue in Cystic Fibrosis

Previous studies have suggested that immune mechanisms contribute to lung injury in cystic fibrosis (CF); however, there have been no comprehensive studies of immunofluorescent staining patterns in CF lung tissue. We performed immunofluorescence (IF) studies for immunoglobulins, C3, and fibrinogen on autopsy frozen lung tissue from 21 CF patients. Results were compared with lung findings in patients without CF. In CF-derived lung tissue fibrinogen was ubiquitous along the alveolar wall, alveolar space, and interstitium. Free immunoglobulin G (IgG) and IgA coated the alveolar surface segmentally in 14 and 6 cases, respectively. Unequivocal interstitial deposits were infrequent and IgM was present in blood vessels in one patient only. Intra-alveolar and interstitial inflammatory cells demonstrated cytoplasmic IgG, IgA, and IgM, respectively, in 18, 14, and 6 patients. C3 was seen only segmentally along the alveolar wall in two patients and in blood vessels in one. Antinuclear antibody (ANA) staining of interstitial cells for C3 and immunoglobulins was seen in five patients, four of whom had interstitial pneumonitis. Insignificant amounts of alveolar or interstitial fibrinogen and immunoglobulins in inflammatory cells were seen in controls in the absence of lung inflammation. The IF patterns were similar in the inflammatory lesions of CF and control specimens.

The IF patterns observed in CF lung tissue are consistent with nonspecific vascular leakage and chronic inflammation with little evidence of immune complex deposition in the interstitium or blood vessels. This study confirms previous reports of ANA activity in CF patients, although the significance of this finding is unknown.     

Screening for Cystic Fibrosis

ABSTRACT. A neonatal screening program for CF by determination of albumin in meconium was performed in the north eastern part of the Netherlands from 1973 to 1979. In this period 94043 newborns were screened and 116953 were not. A follow-up study of CF patients in the above cohorts was started in 1980. The purposes of this study were to evaluate the effects of early diagnosis and treatment in CF patients by comparing the outcome in the two groups of patients. Although the results indicate that very early diagnosis and treatment have a beneficial effect on outcome, more studies are needed before a definite answer can be given as to whether or not mass neonatal screening should be started.     

Antimicrobial Therapy of Pseudomonas Pulmonary Exacerbations in Cystic Fibrosis

ABSTRACT. High-dose anti-Pseudomonas chemotherapy is mandatory in the treatment of acute pulmonary exacerbations in patients with advanced cystic fibrosis and Pseudomonas aeruginosa isolated from their sputum. However, neither the regimen itself nor its objective evaluation have been optimized yet. In a prospective controlled evaluation 42 such exacerbations were treated for two weeks with netilmicin combined by randomisation with either azlocillin or ticarcillin. Other aspects of therapy were constant. The two therapy groups were comparable in all aspects. Both regimens produced similar improvements in clinical, radiological, laboratory, bacteriological and pulmonary function measurements. Concentrations of sputum bacteria were significantly reduced; transient eradication was documented in 29% and correlated with antibiotic susceptibility of the initially isolated Pseudomonas strains. The highly dosed antibiotics were well tolerated and emergence of resistance was rarely observed. It is concluded that both antibiotic combinations are beneficial and safe in cystic fibrosis. Monitoring of such intensive hospital treatment must include multiple parameters.     

Evaluation of the PEP Mask in Cystic Fibrosis

ABSTRACT. Twenty-eight patients suffering from cystic fibrosis, with an age range of 8-21 years entered a randomised cross-over trial to study the efficacy of the Positive Expiratory Pressure (PEP) mask as a method of chest physiotherapy, both on its own and in conjunction with other physiotherapy techniques. Twenty-four of these patients completed the trial consisting of 4 treatment programmes each lasting one month and with no wash-out period between them. Five of these patients went on to a fifth programme of Forced Expiratory Technique (FET) alone. At the end of the trial, no significant difference was found between the programmes as regards growth, Shwachman score, Chrispin—Norman score or pulmonary function tests. Twenty-three patients chose to continue using the PEP mask in conjunction with FET long-term as their chest physiotherapy programme as they felt it was an effective treatment allowing increased independence, with postural drainage being kept to a minimum.     

Bile Acid Metabolism in Children with Cystic Fibrosis

ABSTRACT. Recycling of bile acids through the enterohepatic cycle is very efficacious. Bile acids contribute to bile formation and, by forming micelles, participate in lipid solubilization and absorption. The small fraction which escapes in the feces, is synthesized daily by the liver to compensate for losses. In CF, bile acid malabsorption has been documented; these large losses are accompanied by an interruption in the enterohepatic circulation with concomitant reduction in bile acid pool and disturbances in biliary composition. The various intraluminal factors implicated in bile acid malabsorption include: unhydrolysed triglycerides and phospholipids, precipitation of bile acids in acidic duodenal content, adsorption to residues and modification of colonic microflora. A defect in bile acid ileal uptake has also been advocated. These disturbances in bile acid metabolism associated with CF might lead to aggravation of diarrhea and steatorrhea, cholelithiasis and perhaps liver disease.     

Lethal Respiratory Failure in Preterm Infants due to Cystic Fibrosis

ABSTRACT. We present the first report of two preterm infants who died from respiratory failure secondary to cystic fibrosis which presented in the early neonatal period.     

A Review on the Use of Cystic Fibrosis Transmembrane Conductance Regulator Gene Modulators in Pediatric Patients

The literature surrounding the use of cystic fibrosis transmembrane conductance regulator-targeted pharmacotherapies in pediatric patients continues to evolve. These therapies represent a departure from symptom management and infection prevention, which have been the mainstay of cystic fibrosis management in pediatrics, to targeting the genetic defect present within these patients. This article reviews the clinical studies evaluating the safety and efficacy of ivacaftor, ivacaftor/lumacaftor, and ivacaftor/tezacaftor. These medications were initially studied in adults and adolescents but have begun to be studied in younger populations. Further investigation into the use of these drugs with different CFTR mutations and in younger age groups will continue to expand the number of patients who can benefit from these therapies.     

Pulmonary Resection for Localized Bronchiectasis in Cystic Fibrosis

ABSTRACT. Three children with cystic fibrosis and localized bronchiectasis were treated by surgical removal of the affected lobe, after attempts to clear the obstructed bronchus by medical therapy and bronchoscopy with suction and lavage had been unsuccessful. Three to six years after surgery, the results are excellent. Pulmonary disease is mild in all patients, shown by chest radiographs and pulmonary function tests. A review of 102 cases reported in the literature demonstrates that pulmonary surgery is effective and can be performed safely in selected patients.     

The Role of the Small Intestine in Cystic Fibrosis Patients

ABSTRACT. A survey is given of the morphological and biochemical lesions of the small intestine that can he found in cystic fibrosis patients. The available data on the structure and function of the small intestine in CF patients favour the hypothesis that the small intestine itself might contribute to the malabsorption of nutrients in this disease. The most pronounced lesions, i.e. meconium ileus and absent active transport of bile salts are found in the ileum. It might be remembered that the ileum is also the site of intensive exchange of chloride and bicarbonate, a function that is heavily disturbed in the pancreas of CF patients. For this reason, further studies on the ileal function in cystic fibrosis are warranted.     

Scanning Electron Microscopic Study of the Airways in Normal Children and in Patients with Cystic Fibrosis and Other Lung Diseases

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine pulmonary tissue from 9 patients with cystic fibrosis (CF), 12 patients with diseases other than CF, and from two surgically resected specimens with no known airways disease. A region of the human airways, the transition zone, was observed between the end of the terminal bronchiole and the type II alveolar cell lining of the respiratory bronchioles. This region was lined predominantly by nonciliated bronchiolar (NCB) cells. Patients with CF exhibited indistinct transition zones, epidermoid metaplasia, large dilated bronchial gland, copious surface mucus, alveolar destruction, and unusual microvilli; no single lesion specific for cystic fibrosis was identified.     

Decreased Renal Clearance of Sodium in Cystic Fibrosis

ABSTRACT. In 10 patients with cystic fibrosis (CF) and 10 controls of similar age quantitative segmental handling of sodium was estimated by lithium clearance. In the CF group, there was tendency for an increased glomerular filtration rate (GFR) and increased absolute proximal sodium reabsorption. The fractional distal sodium reabsorption was significantly ( p =0.015) increased and sodium clearance was significantly ( p ≤0.01) decreased in CF.     

Glucose Tolerance and Insulin Receptor Binding to Monocytes and Erythrocytes in Patients with Cystic Fibrosis

ABSTRACT. Cystic fibrosis (CF) is the most frequent life threatening hereditary disease in the Western World with an incidence of approximately 1:2000. Due to increasing survival rates the high frequency of abnormal glucose tolerance has become an important problem. We compared insulin concentrations during oral glucose tolerance test and insulin receptor binding to both monocytes and erythrocytes from 9 patients with CF, with results from 10 healthy controls of similar body weight. The insulin: glucose ratio was increased in the fasting state ( p < 0.05) in patients with CF compared to controls, indicating an increased insulin resistance in CF-patients. The total insulin secretion during oral glucose tolerance test as judged by the area beneath the insulin curve was similar in the two groups, but insulin secretion was significantly delayed in patients with CF. Insulin receptor binding to monocytes and the number of receptors were significantly increased ( p < 0.01 and 0.02, respectively) in patients with CF whereas the dissociation constant was similar in patients with CF and controls. No difference was observed in insulin receptor binding to erythrocytes between the two groups. No correlations were found between insulin receptor binding to monocytes or erythrocytes and glucose tolerance or insulin concentrations.     

Acylcarnitine is Low in Cord Blood in Cystic Fibrosis

ABSTRACT. Carnitine metabolites (total, free, short and long chain) were analyzed in cord blood of cystic fibrosis (n=5), non-CF siblings (n=7), and controls (n=8). Total acylcarnitine (short and long chain combined) was significantly lower (<0.001) in CF compared to both control groups. Total and free carnitine showed no significant differences between the three groups. These findings are compatible with disturbed fatty acid metabolism in utero and may be related to the increased energy expenditure characteristic of CF infants.