Demographic and social characteristics of adults with cystic fibrosis in the United Kingdom.

OBJECTIVE--To obtain information about social and demographic characteristics and lifestyle of adult patients with cystic fibrosis, including those who do not attend major specialist clinics. DESIGN--Confidential self completion postal questionnaire to adult patients with cystic fibrosis, asking about social and demographic characteristics, social class and occupation, employment, education, insurance and social security benefits, symptom severity, and medical care. SETTING--National association for adults with cystic fibrosis. SUBJECTS--1052 adult members of the Association of Cystic Fibrosis Adults UK, accounting for 68% of those with cystic fibrosis in the United Kingdom population over 16 years of age and over 80% of those over 25 in June 1990. RESULTS--The response rate was 82% (397 women, 423 men). Most adults with cystic fibrosis were found to be living fulfilling lives into adulthood. Significantly fewer men were married or cohabiting than women (110 (26%) men, 175 (44%) women). 420 (55%) responders were working, and of these 235 (56%) had less than two weeks'' sick leave a year. Half of those not employed gave ill health as the reason. Revealing that they had cystic fibrosis at job interviews reduced likelihood of being employed for those with mild to moderate disease. People with cystic fibrosis had been less successful than the general population in achieving O level or equivalent qualifications, but more successful in achieving A level or higher qualifications. Achievement of any qualifications enhanced employment prospects irrespective of disease severity. CONCLUSION--Contrary to an image of chronic ill health and disability, a high proportion of adults with cystic fibrosis are living full and productive lives.     

Voice Disorder in Cystic Fibrosis Patients

Cystic fibrosis is a common autosomal recessive disorder with drastic respiratory symptoms, including shortness of breath and chronic cough. While most of cystic fibrosis treatment is dedicated to mitigating the effects of respiratory dysfunction, the potential effects of this disease on vocal parameters have not been systematically studied. We hypothesized that cystic fibrosis patients, given their characteristic respiratory disorders, would also present dysphonic symptoms. Given that voice disorders can severely impair quality of life, the identification of a potential cystic fibrosis-related dysphonia could be of great value for the clinical evaluation and treatment of this disease. We tested our hypothesis by measuring vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. We found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When we segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men. Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. Our results show that CF patients exhibit significant dysphonia and suggest they may potentially benefit from voice therapy as a parallel treatment strategy.     

Meconium ileus equivalent in older patients with cystic fibrosis.

Meconium ileus equivalent is one of the lesser known manifestations of cystic fibrosis, and occurs most often in older patients. With the improved overall survival of patients with cystic fibrosis, one would expect to see this condition more often in the future. Of 53 patients attending our cystic fibrosis clinic for adolescents and adults, eight had experienced a total of 25 episodes of meconium ileus equivalent. Recurrent attacks occurred in seven patients, of whom four had at least four separate, well documented episodes: these episodes were associated with obvious recognised precipitating factors in only three patients. All patients responded to appropriate medical treatment with acetylcysteine or sodium diatrizoate, including three who had previously undergone surgery for meconium ileus equivalent elsewhere. Controversies remain, however, concerning the role of prophylactic medical management with acetylcysteine, sodium diatrizoate, and pancreatic supplements.     

Pseudo-Foster Kennedy Syndrome due to unilateral optic nerve hypoplasia: a case report

Introduction

The presentation of cystic fibrosis is dependant upon which organs are affected. Common presentations include chronic respiratory infections and malabsorption. Patients with atypical disease tend to present late in childhood or as adults. Eye manifestations of cystic fibrosis are less well known.

Case presentation

A 14-year-old Caucasian boy presented with tiredness and difficulty seeing at night, over a period of 6 months. Good vision was only described in bright conditions. There was no history of jaundice, steatorrhea or diarrhoea.

Conclusion

This is the first reported case of newly diagnosed cystic fibrosis-related liver disease in a teenage boy, whose presenting symptom was night blindness secondary to vitamin A deficiency.     

Sweat tests to diagnose cystic fibrosis in adults.

Twenty five patients with cystic fibrosis and 25 controls were studied to define a sweat sodium concentration in adults that could be taken as diagnostic of cystic fibrosis. Some of the controls had a sweat sodium concentration of over 50 mmol(mEq)/l, and thus cystic fibrosis should be diagnosed in an adult only when two measurements of sweat sodium concentration are above 70 mmol/l. In cases in which the sweat sodium concentration was borderline a suppression test using fludrocortisone improved the accuracy of diagnosis; this test entails recording the lowest concentration reached after administration of the drug. A scatter diagram of the baseline sweat sodium concentrations plotted against the lowest concentration attained after suppression with fludrocortisone may aid the diagnosis further.     

Evidence for the in vivo degradation of human respiratory mucins during Pseudomonas aeruginosa infection

The comparison of distribution of glycopeptides of sputa from patients suffering from various chronic hypersecretions has already shown an increased acidity with a decreased proportion of neutral glycopeptides in the respiratory secretions of patients suffering from cystic fibrosis, as compared to those of patients with chronic bronchitis. In order to find out whether this decrease is specific to cystic fibrosis mucins or whether it is due to a degradation of mucus by Pseudomonas aeruginosa, which infects most of the sputa from patients with this disease, mucus glycopeptides from patients with different chronic bronchial disorders, infected by Pseudomonas or not, were prepared and fractionated by ion-exchange chromatography. The neutral fraction, which has never been studied in detail, was gel-filtered, and provided two fractions, one containing true mucin glycopeptides and the other containing a mixture of peptides and glycopeptides with a lower molecular mass. In the Pseudomonas-infected samples, the true mucin glycopeptide fraction was greatly diminished as compared to this same fraction in non-Pseudomonas-infected samples; this was not specific to cystic fibrosis secretions. In contrast, the glycopeptide fraction with a lower molecular mass was greatly increased in all the Pseudomonas-infected samples. Polyacrylamide gel electrophoresis of this second fraction showed unique glycopeptide bands between 40-50 kDa in the Pseudomonas-infected samples, regardless of the origin of the samples. These bands were revealed by an antibody directed against whole cystic fibrosis mucin. Infected chronic bronchitis sputa and cystic fibrosis samples without P. aeruginosa did not show these bands. These studies therefore suggest that there are P. aeruginosa-associated changes in mucins which may result from degradation of mucins.     

The calcium abnormality in cystic fibrosis mitochondria: Relative role of respiration and ATP hydrolysis

Calcium uptake by mitochondria isolated from skin fibroblasts of patients with cystic fibrosis and controls was studied in the presence and absence of inhibitors. Since mitochondrial calcium accumulation may be supported by ATP hydrolysis or respiration, inhibitors of each were used to characterize the basis of previously described alterations in calcium uptake by mitochondria from patients with cystic fibrosis. Calcium uptake measurements under the influence of oligomycin and antimycin A suggest that the increased calcium uptake by mitochondria from patients with cystic fibrosis is related to altered respiratory system activity. Binding constants of calcium to the carrier system in mitochondria were not different between genotypes.     

The Km of NADH dehydrogenase is decreased in mitochondria of cystic fibrosis cells

The kinetic properties of the NADH dehydrogenase of the mitochondrial respiratory chain, assayed as NADH-dependent rotenone-sensitive cytochrome c reductase have been studied in mitochondria isolated from mononuclear white blood cells in patients affected by cystic fibrosis. Data reported here show that the apparent Km of the enzyme for NADH is significantly decreased in cystic fibrosis mitochondria. These findings are independent of the age or the clinical state of the disease and have also been obtained with mitochondria isolated from cultured skin fibroblasts. These observations support the notion that cystic fibrosis is possibly accompanied by alterations of intracellular membranes and these are evident also in circulating cells and cultured fibroblasts.     

Kinetic analysis of chloride efflux from normal and cystic fibrosis fibroblasts

Chloride permeability in 9 cystic fibrosis- and 11 normal-skin fibroblast lines has been investigated. Chloride efflux, under steady-state conditions, involves two intracellular compartments characterized by slow- and fast-rate constants of efflux. We show here that the fast rate constant in cystic fibrosis cells is reduced by 25% in comparison with controls. The data presented support recent studies indicating that isolated sweat glands and respiratory epithelia of patients suffering from cystic fibrosis have an unusual low permeability to chloride ions compared to control epithelia. It is concluded that variation in chloride transport can successfully be studied in cultured fibroblasts, which are not directly involved in the pathology of the disease.     

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease

Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (delta F508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the delta F508 (23% in this group), G542X, N1303K, and 1717-1G----A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the delta F508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.     

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis.

The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well understood. A clinical phenotype resembling the pulmonary disease seen in cystic fibrosis (CF) patients can occur in some individuals with ABPA. Reports of familial occurrence of ABPA and increased incidence in CF patients suggest a possible genetic basis for the disease. To test this possibility, the entire coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and had normal sweat electrolytes (< or = 40 mmol/liter). One patient carried two CF mutations (deltaF508/R347H), and five were found to carry one CF mutation (four deltaF508; one R117H). The frequency of the deltaF508 mutation in patients with ABPA was significantly higher than in 53 Caucasian patients with chronic bronchitis (P < .0003) and the general population (P < .003). These results suggest that CFTR plays an etiologic role in a subset of ABPA patients.     

Rapid Detection and Immune Characterization of Mycobacterium abscessus Infection in Cystic Fibrosis Patients

Cystic fibrosis patients are highly susceptible to infections with non-tuberculous mycobacteria. Especially Mycobacterium abscessus infections are common but reliable diagnosis is hampered by non-specific clinical symptoms and insensitive mycobacterial culture. In the present study we established novel methods for rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. We performed Mycobacterium abscessus specific DNA-strip- and quantitative PCR-based analyses of non-cultured sputum samples to detect and characterize Mycobacterium abscessus infections. Concomitantly in vitro T-cell reactivation with purified protein derivatives (PPDs) from different mycobacterial species was used to determine Mycobacterium abscessus specific T-cell cytokine expression of infected cystic fibrosis patients. Four of 35 cystic fibrosis patients (11.4%) were Mycobacterium abscessus culture positive and showed concordant DNA-strip-test results. Quantitative PCR revealed marked differences of mycobacterial burden between cystic fibrosis patients and during disease course. Tandem-repeat analysis classified distinct Mycobacterium abscessus strains of infected cystic fibrosis patients and excluded patient-to-patient transmission. Mycobacterium abscessus specific T-cells were detected in the blood of cystic fibrosis patients with confirmed chronic infection and a subgroup of patients without evidence of Mycobacterium abscessus infection. Comparison of cytokine expression and phenotypic markers revealed increased proportions of CD40L positive T-cells that lack Interleukin-2 expression as a marker for chronic Mycobacterium abscessus infections in cystic fibrosis patients. Direct sputum examination enabled rapid diagnosis and quantification of Mycobacterium abscessus in cystic fibrosis patients. T-cell in vitro reactivation and cytokine expression analyses may contribute to diagnosis of chronic Mycobacterium abscessus infection.     

Serum pancreatic lipase activity in cystic fibrosis.

Patients with cystic fibrosis have been found to have abnormal serum concentrations of immunoreactive trypsin and abnormal activities of pancreatic isoamylase. A study was undertaken to discover whether activity of pancreatic lipase is also altered in cystic fibrosis. Serum from 23 patients with cystic fibrosis was assayed for immunoreactive trypsin and pancreatic lipase. Median serum pancreatic lipase activity was significantly lower in patients with cystic fibrosis than in controls, as was immunoreactive trypsin concentration (p less than 0.0001). Some patients had supranormal lipase concentrations but these were not always associated with absence of malabsorption. Serum pancreatic lipase activity is considerably changed in cystic fibrosis.     

Absence congenitale des canaux deferents: Phenotype genital de la mucoviscidose?

Because spermatogenesis is typically normal in men with bilateral agenesis of the vas deferens, epididymal sperm recovery for subsequent use in in-vitro fertilization (IVF) has recently been proposed for such patients. The discovery of the presence of mutations in the cystic fibrosis gene in such patients has indicated that this disease might constitute a genital phenotypie concomitant of cystic fibrosis, and has profound genetic implications if the spouse is heterozygous. Testing for mutations of the cystic fibrosis gene, and the provision of genetic counselling as appropriate, should be performed in patients, and their partners, when IVF is being considered for such couples presenting with infertility. The main characteristics of the cystic fibrosis gene and its mutations are discussed, with particular reference to problems in identifying mutations among the 27 exons encoding the gene’s product     

Modulatoren der Kanalfunktion

Modulators of canal functions Diagnosis and therapy of cystic fibrosis have been completely redefined in recent years. With newborn screening, early diagnosis is now possible and treatment with CFTR modulators tackles the hereditary disease at the basic defect. If used early, many irreversible damages could be avoided and the patientś quality of life and disease burden could be significantly reduced. According to the German Cystic Fibrosis Register, a child born today with cystic fibrosis has an average life expectancy of 53 years [2]. Even today, there are more adult patients than children with cystic fibrosis, which not so long ago was considered a pure childhood disease. But this change also leads to challenges in care, because structures in the health system do not keep pace. Many adult patients have to be treated at children's clinics – there are far too few institutions that specialise in treating adult patients. Despite all the joy about progress, there are still many challenges here. The documentation of the long-term effects of the new drugs is also of great importance. Finally, the patients (approx. 10 %) who carry very rare CFTR mutations should not be forgotten. None of the approved therapies are currently available for them. A personalised approach using organoids, which is already being investigated in the HitCF project, could be applied here.     

Active cascade testing for carriers of cystic fibrosis gene.

OBJECTIVE--To examine the acceptability, practicability, efficiency, and application of active screening for carriers of the cystic fibrosis gene in the extended families of those in whom the disease is present (Cascade screening). DESIGN--Paediatricians and physicians provide details of their affected patients, pedigrees are drawn up, and relatives offered tests after initial contact by the affected nuclear families. Affected patients are genotyped in a laboratory with a special interest in the genetics of cystic fibrosis. SETTING--North Western health region. SUBJECTS--Relatives and partners of 607 people with cystic fibrosis. INTERVENTIONS--Genetic counselling by letter for people found to be carriers; formal genetic counselling and when indicated arrangements for prenatal diagnosis for couples discovered to be carriers. MAIN OUTCOME MEASURES--Number of carrier couples detected; action in pregnancy of detected carrier couples; extent of the uptake of screening by relatives. RESULTS--Of 1563 relatives or partners tested, 15 carrier couples were detected; of nine pregnancies undertaken by these 15, eight had prenatal tests and three terminated pregnancies. An average of 16 people per family have come forward for testing so far. CONCLUSIONS--Cascade screening for carriers of cystic fibrosis is well accepted by relatives, especially on the mother''s side of the family; it is 10 times more efficient in detecting carrier couples than unfocused screening. Detected carrier couples make practical use of the information in pregnancy. Active cascade screening for carriers is effective in cystic fibrosis and widespread application is recommended. These principles could be applied to other recessive disorders.     

Cystic Fibrosis of the Pancreas—Diagnosis by Sodium Electrode Sweat Tests

One of the most difficult and unreproducible procedures in clinical laboratories has been the measurement of electrolytes in sweat. The iontophoresis techniques for the diagnosis of cystic fibrosis of the pancreas, which are widely used, are fraught with difficulties.Measurement of sweat electrolytes with sodium or chloride electrodes is gradually replacing the iontophoresis methods. A simple modification of the sodium electrode technique was used for diagnosis in 11 cystic fibrosis patients and in 260 normal children. The values obtained with the sodium electrode clearly separated the normal children from those with cystic fibrosis.     

Determinants of refusal of A/H1N1 pandemic vaccination in a high risk population: a qualitative approach

Background

Our study analyses the main determinants of refusal or acceptance of the 2009 A/H1N1 vaccine in patients with cystic fibrosis, a high-risk population for severe flu infection, usually very compliant for seasonal flu vaccine.

Methodology/Principal Findings

We conducted a qualitative study based on semi-structured interviews in 3 cystic fibrosis referral centres in Paris, France. The study included 42 patients with cystic fibrosis: 24 who refused the vaccine and 18 who were vaccinated. The two groups differed quite substantially in their perceptions of vaccine- and disease-related risks. Those who refused the vaccine were motivated mainly by the fears it aroused and did not explicitly consider the 2009 A/H1N1 flu a potentially severe disease. People who were vaccinated explained their choice, first and foremost, as intended to prevent the flu''s potential consequences on respiratory cystic fibrosis disease. Moreover, they considered vaccination to be an indirect collective prevention tool. Patients who refused the vaccine mentioned multiple, contradictory information sources and did not appear to consider the recommendation of their local health care provider as predominant. On the contrary, those who were vaccinated stated that they had based their decision solely on the clear and unequivocal advice of their health care provider.

Conclusions/Significance

These results of our survey led us to formulate three main recommendations for improving adhesion to new pandemic vaccines. (1) it appears necessary to reinforce patient education about the disease and its specific risks, but also general population information about community immunity. (2) it is essential to disseminate a clear and effective message about the safety of novel vaccines. (3) this message should be conveyed by local health care providers, who should be involved in implementing immunization.     

Role of polymorphic variants of cytochrome P450 genes (CYP1A1, CYP2E1) and microsomal epoxide hydrolase (mEPHX) in pathogenesis of cystic fibrosis and chronic respiratory tract diseases

Frequencies of CYP1A1, CYP2E1, and mEPHX polymorphic variants were analyzed in cystic fibrosis, chronic obstructive lung disease, bronchiectatic disease, chronic nonobstructive bronchitis, and recurring bronchitis. Mutations in CYP1A1 and mEPHX were shown to modify the severity of respiratory disorders in cystic fibrosis, the combination of CYP1A1 genotype Val/Val with the "very slow" mEPHX phenotype being most unfavorable (odds ratio OR = 12.30). Heterozygosity at both CYP1A1 and CYP2E1 was associated with chronic obstructive lung disease and recurring bronchitis (OR = 4.08 and 11.72, respectively). The "very slow" phenotype of mEPHX was predisposing to chronic respiratory disorders regardless of the CYP1A1 or CYP2E1 alleles (OR = 4.06). Basing on the above correlations, a combination of the "very slow" mEPHX phenotype with elevated cytochrome P450 (CYP1A1 and CYP2E1) activities was assumed to expedite severe respiratory disorders.     

<Emphasis Type="Italic">Exophiala dermatitidis</Emphasis> Revealing Cystic Fibrosis in Adult Patients with Chronic Pulmonary Disease

Cystic fibrosis (CF) is a genetic inherited disease due to mutations in the gene cystic fibrosis transmembrane conductance regulator (CFTR). Because of the huge diversity of CFTR mutations, the CF phenotypes are highly heterogeneous, varying from typical to mild form of CF, also called atypical CF. These atypical features are more frequently diagnosed at adolescence or adulthood, and among clinical signs and symptoms leading to suspect a mild form of CF, colonization or infection of the respiratory tract due to well-known CF pathogens should be a warning signal. Exophiala dermatitidis is a melanized dimorphic fungus commonly detected in respiratory specimens from CF patients, but only very rarely from respiratory specimens from non-CF patients. We described here two cases of chronic colonization of the airways by E. dermatitidis, with recurrent pneumonia and hemoptysis in one patient, which led clinicians to diagnose mild forms of CF in these elderly patients who were 68- and 87-year-old. These cases of late CF diagnosis suggest that airway colonization or respiratory infections due to E. dermatitidis in patients with bronchiectasis should led to search for a mild form of CF, regardless of the age and associated symptoms. On a broader level, in patients with chronic respiratory disease and recurrent pulmonary infections, an allergic bronchopulmonary mycosis or an airway colonization by CF-related fungi like E. dermatitidis or some Aspergillus, Scedosporium or Rasamsonia species, should be considered as potential markers of atypical CF and should led clinicians to conduct investigations for CF diagnosis.