Lena Hjelte

Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials.

Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensus view is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensus view is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of an exacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are being discussed.

Prospective study of mycobacterial infections in patients with cystic fibrosis.

Fifty four patients with cystic fibrosis, aged 3-67 years, were studied prospectively for pulmonary mycobacterial infection. Sputum smears and cultures were carried out and intradermal skin tests performed. Mycobacteria were cultured from six patients in association with clinical deterioration; four patients had positive direct smears. Mycobacterium tuberculosis, M aviumintracellulare, M kansasii, and M gordonae were isolated. There were no deaths and all improved with chemotherapy. A third of the other 48 patients had positive skin test responses (greater than 6 mm) to purified protein derivative (PPD) tuberculin and 21 to one or more antigens prepared from non-tuberculous mycobacteria. Sensitisation increased with age; before the age of 11 only one patient had a positive response to PPD tuberculin and none to any other antigen. This was less than in healthy control subjects of similar age. After age 11 the reactions in sensitised patients were stronger than in positive healthy control subjects. Our study indicates that it is important to consider mycobacterial infection in patients with cystic fibrosis who deteriorate without obvious cause.

Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report

Chronic pulmonary infection with P. aeruginosa develops in most patients with cystic fibrosis (CF); by adulthood 80% of patients are infected and chronic P. aeruginosa infection is the primary cause of increased morbidity and mortality in CF. Chronic infection is preceded by an intermittent stage of infection. The initial stage is characteristically followed by the gradual emergence of mucoid variants of the colonizing strains and a rise in anti-Pseudomonas antibodies. In addition to optimizing existing therapeutic strategies, effective new agents need to be identified. Studies in patients with CF are particularly challenging: the progressive nature of the disease and the wide variation in severity influence considerably the outcome of drug testing. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, is needed that can be used as both a criterion for patient selection for clinical trials and as a study endpoint.

Home intravenous antibiotic treatment of patients with cystic fibrosis.

We report one‐years experience of home iv antibiotic treatment in 31 patients with cystic fibrosis chronically colonized with Pseudomonas aeruginosa. The patients were aged 4–67 years and had a mild to severe disease as indicated by a Shwachman score of 46–95 (mean 77). Ninety‐two courses of iv antibiotic therapy were given (mean 3.0 per patient). The mean duration of the courses was 15.4 days. The entire antibiotic course, except for the first dose, was administered at home in 70% of the courses. Most patients (94%) were given a combined treatment of a β‐lactam and an aminoglycoside, administered by the patients themselves or their parents. One inserted venous cannula could be used for the whole treatment period in 30% of the courses. There were no complications. The clinical and bacteriological outcome was good to excellent in 89% of the courses, with temporary eradication or semi‐quantitative decrease of Pseudomonas growth in sputum. Lung function (forced expiratory volume at 1 s) and blood gases improved significantly (p < 0.001 and p < 0.01, respectively). Most patients were able to attend work or school as usual, and 96% of the patients preferred this type of treatment to hospitalization. Apart from the psychosocial advantages, the economical savings were substantial. In comparison to traditional treatments in hospital (21 patients, 41 courses) home iv antibiotic treatment was safe and effective.

Mutations in the Amiloride-Sensitive Epithelial Sodium Channel in Patients With Cystic Fibrosis-Like Disease

We investigated whether mutations in the genes that code for the different subunits of the amiloride‐sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)‐like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.F61L in SCNN1A. More importantly, a more than three‐fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. Specifically, a significantly higher number of patients carried c.–55+5G>C or p.W493R in SCNN1A in the heterozygous state, with odds ratios (ORs) of 13.5 and 2.7, respectively.The p.W493R‐SCNN1A polymorphism was even found to result in a four‐fold more active ENaC channel when heterologously expressed in Xenopus laevis oocytes. About 1 in 975 individuals in the general population will be heterozygous for the hyperactive p.W493R‐SCNN1A mutation and a cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in very low amounts (0–10%) functional CFTR. These ENaC/CFTR genotypes may play a hitherto unrecognized role in lung diseases. Hum Mutat 30:1–11, 2009.

Nasal Polyps in Cystic Fibrosis: Clinical Endoscopic Study With Nasal Lavage Fluid Analysis

STUDY OBJECTIVES Nasal polyps frequently appear in patients with cystic fibrosis (CF). The aims of this study were to focus on what problems (symptoms, endoscopic findings, and laboratory correlates) nasal polyps cause the CF patient, and how these correlate to the total health situation of this patient group. PATIENTS AND STUDY DESIGN The clinical histories, endoscopic investigations of the nasal cavity, and analyses of nasal lavage fluid of 44 patients with CF complicated with nasal polyposis have been compared with those of 67 CF control subjects. The patients were examined at annual control examinations (with pulmonary tests, working capacity, liver tests, and bacterial and blood tests) from 1995 to 1996 at Stockholm Cystic Fibrosis Center, Huddinge University Hospital. All patients were > 2 years of age. The endoscopic findings were related to the actual pulmonary function, inflammatory blood parameters, colonizing pathogens, antibodies (Staphylococcus aureus and Pseudomonas aeruginosa), and genotype. RESULTS The patients with nasal polyps differed with respect to chronic colonization of P aeruginosa in sputum samples and had a higher occurrence of serum antibodies against the same species. The two groups did not differ in pulmonary functions, inflammatory parameters, or genotype. The polyps found were mainly small (within the meatus media) and gave no significant increase in ongoing clinical symptoms such as rhinorrhea, nasal obstruction, or hyposmia. Neither was any significantly marked finding concerning the nose (mucosal swellings, secretion, etc.) made in the polyp patients. The patients with CF scored slightly lower in a smell identification test in comparison with the healthy control group. The nasal lavage fluid was analyzed (in 93 of the 111 patients) for the occurrence of P aeruginosa (by polymerase-chain reaction [PCR]), interleukin [IL]-5, IL-8, and lysozyme. The lysozyme and IL-8 content was equal in the two CF groups but increased in comparison with the healthy control group. P aeruginosa was not detected with PCR in any nasal lavage fluid. No measurable levels of IL-5 in the nasal lavage were found. CONCLUSIONS There was a higher frequency of chronic colonization of P aeruginosa in the lower respiratory tract in patients with nasal polyps. Otherwise, nonsevere nasal polyposis was not an indicator of lower respiratory tract morbidity in CF patients.

Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis

Background: In patients with symptoms suggestive of cystic fibrosis (CF) and intermediate sweat chloride values (30–60 mmol/l), extensive CFTR gene mutation analysis and nasal potential difference (NPD) measurement are used as additional diagnostic tests and a positive result in either test provides evidence of CFTR dysfunction. To define the phenotype of such patients and confirm the validity of grouping them, patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. Methods: The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). Results: The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. Conclusion: Patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.

BACTERIAL COLONISATION WITH XANTHOMONAS MALTOPHILIA : A RETROSPECTIVE STUDY IN A CYSTIC FIBROSIS PATIENT POPULATION

SummaryXanthomonas maltophilia was isolated from 25 of 150 patients with cystic fibrosis during a period of 10 years (1983–1992). Twelve patients harbouredX. maltophilia chronically, i.e. repeatedly for more than 6 months. No predisposing factors for the colonisation could be identified by studying the clinical and laboratory data of the patients, including preceding and concurrent bacterial colonisation with other bacteria, antibacterial treatments, pulmonary function and biochemical markers. Up to 2 years after the chronic colonisation was established no clinical deterioration could be verified, but the patients withX. maltophilia generally had a worse lung function at the latest follow-up (2–7 years after colonisation) than controls colonised withPseudomonas aeruginosa (p<0.05). Our data imply thatX. maltophilia is a pathogen and the colonisation appears to follow the same pattern as the colonisation byP. aeruginosa. The development of resistance to different antibiotics, as revealed by analysis of the inhibition zones, was related to antibacterial treatment courses.X. maltophilia showed reduced sensitivity to the most commonly used antibiotics, ceftazidime and tobramycin.ZusammenfassungXanthomonas maltophilia wurde bei 25 von 150 Patienten während eines Zeitraumes von 10 Jahren (1983–1992) isoliert. 12 Patienten hatten eine chronische Kolonisierung, das heißt bestehend während mehr als 6 Monaten. Prädisponierende Faktoren konnten bei der Analyse der klinischen Daten und Labordaten nicht festgestellt werden, frühere und gleichzeitige Kolonisierung mit anderen Bakterien, Lungenfunktion und biochemische Parameter inbegriffen. Bis zu 2 Jahre nachdem die chronische Kolonisierung etabliert worden war, fanden wir keine klinische Verschlechterung. Die langfristige Verlaufskontrolle (2–7 Jahre) zeigte, daß Patienten mitX. maltophilia meistens eine schlechtere Lungenfunktion hatten als Kontrollfälle, die mitPseudomonas aeruginosa kolonisiert worden waren (p<0,05). Unsere Daten deuten an, daß bei Patienten mit zystischer FibroseX. maltophilia ein pathogener Erreger ist und die Kolonisierung nach demselben Muster zu erfolgen scheint wie die Kolonisierung mitP. aeruginosa. Die Entwicklung der Antibiotikaresistenz wurde durch Bestimmung der Hemmzonen im Verhältnis zu Antibiotikabehandlungen verfolgt.X. maltophilia zeigte eine herabgesetzte Empfindlichkeit gegen die meisten Antibiotika. In unserer Serie gab es eine markante Resistenzentwicklung gegen Ceftazidim und Tobramycin während der chronischen Kolonisierung.Xanthomonas maltophilia was isolated from 25 of 150 patients with cystic fibrosis during a period of 10 years (1983–1992). Twelve patients harbouredX. maltophilia chronically, i.e. repeatedly for more than 6 months. No predisposing factors for the colonisation could be identified by studying the clinical and laboratory data of the patients, including preceding and concurrent bacterial colonisation with other bacteria, antibacterial treatments, pulmonary function and biochemical markers. Up to 2 years after the chronic colonisation was established no clinical deterioration could be verified, but the patients withX. maltophilia generally had a worse lung function at the latest follow-up (2–7 years after colonisation) than controls colonised withPseudomonas aeruginosa (p<0.05). Our data imply thatX. maltophilia is a pathogen and the colonisation appears to follow the same pattern as the colonisation byP. aeruginosa. The development of resistance to different antibiotics, as revealed by analysis of the inhibition zones, was related to antibacterial treatment courses.X. maltophilia showed reduced sensitivity to the most commonly used antibiotics, ceftazidime and tobramycin. Xanthomonas maltophilia wurde bei 25 von 150 Patienten während eines Zeitraumes von 10 Jahren (1983–1992) isoliert. 12 Patienten hatten eine chronische Kolonisierung, das heißt bestehend während mehr als 6 Monaten. Prädisponierende Faktoren konnten bei der Analyse der klinischen Daten und Labordaten nicht festgestellt werden, frühere und gleichzeitige Kolonisierung mit anderen Bakterien, Lungenfunktion und biochemische Parameter inbegriffen. Bis zu 2 Jahre nachdem die chronische Kolonisierung etabliert worden war, fanden wir keine klinische Verschlechterung. Die langfristige Verlaufskontrolle (2–7 Jahre) zeigte, daß Patienten mitX. maltophilia meistens eine schlechtere Lungenfunktion hatten als Kontrollfälle, die mitPseudomonas aeruginosa kolonisiert worden waren (p<0,05). Unsere Daten deuten an, daß bei Patienten mit zystischer FibroseX. maltophilia ein pathogener Erreger ist und die Kolonisierung nach demselben Muster zu erfolgen scheint wie die Kolonisierung mitP. aeruginosa. Die Entwicklung der Antibiotikaresistenz wurde durch Bestimmung der Hemmzonen im Verhältnis zu Antibiotikabehandlungen verfolgt.X. maltophilia zeigte eine herabgesetzte Empfindlichkeit gegen die meisten Antibiotika. In unserer Serie gab es eine markante Resistenzentwicklung gegen Ceftazidim und Tobramycin während der chronischen Kolonisierung.

Plasma phospholipid fatty acids are influenced by a ketogenic diet enriched with n-3 fatty acids in children with epilepsy

The ketogenic diet (KD) is used to treat medically refractory epilepsy in children. Alterations of fatty acid (FA) levels may reflect one mechanism of action. We examined the influence of the KD on FA levels and seizure control. The levels of 17 FAs in plasma phospholipids were determined before and 1, 3, 6, and 12 months after initiation of the KD in 25 children (mean age 6.3 years) with intractable epilepsy. Fluid omega-3 FA was supplemented in the diet after one month. Highly significant changes of the levels of several FAs were found. Linoleic acid (LA) and eicosapentaenoic acid (EPA) increased, whereas arachidonic acid (AA) and Mead acid (20:3 n-9) decreased. Docosahexaenoic acid (DHA) increased insignificantly. However, no correlation of changes in FA levels with seizure response was found. The ratio of omega-6 to omega-3 gradually decreased from 7.0 before to 4.9 at 12 months after starting the diet, presumably a cardiovascular benefit. The composition of the KD differs as to FA content and type between different treating centers but, still, the efficacy reports are very similar. This study demonstrates the possibility of composing the KD in such a way that the FA profile is kept within a normal range, which may reduce cardiovascular risks.

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study

Background/Objectives:The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels.Subjects/Methods:Eight hundred and ninety-six CF patients were included (0.53–65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1λs (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score.Results:Serum total IgG levels were negatively associated with serum 25OHD (adjusted R 2=0.376; beta=−0.02; P<0.001), supplemented vitamin D intake per kg bodyweight (adjusted R 2=0.375; beta=−0.82; P<0.001) and total vitamin D intake per kg bodyweight (adjusted R 2=0.398; beta=−0.60; P=0.002). Serum 25OHD was positively associated with FEV1 (adjusted R 2=0.308; beta=0.0007; P=0.025).Conclusions:Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.