Anders Lindblad

Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis

Many children with cystic fibrosis (CF), receiving modern, aggressive CF care, have normal spirometry results. This study aimed to see if homogeneity of ventilation distribution is impaired early in the course of CF lung disease, and if ventilation inhomogeneity is a more frequent finding than abnormal spirometry in children benefiting from modern CF care. The study compared spirometry findings to two indices of ventilation inhomogeneity (mixing ratio (MR) and lung clearance index (LCI)) from multiple-breath inert gas washout in 43 children with CF, aged 3–18 yrs, and 28 healthy children. In total, 10/43 CF subjects (23%) had reduced forced expiratory volume in one second (FEV1) and 14/34 (41%) showed abnormal maximum expiratory flow at 25% of forced vital capacity (MEF25). In contrast, MR was abnormal in 31/43 (72%) and LCI in 27/43 (63%). MR was abnormal in 22/33 CF subjects with normal FEV1, versus 0/28 controls (p<0.001), and abnormal MR was found in 10/20 CF subjects with normal MEF25, versus 0/22 controls (p<0.001). Nine of the 10 CF subjects with reduced FEV1 and 12/14 with abnormal MEF25 showed abnormal MR. Inert gas washout discloses airway dysfunction in the majority of children with cystic fibrosis with normal lung function judged by spirometry. These findings suggest that multiple-breath inert gas washout is of greater value than spirometry in detecting early cystic fibrosis lung disease.

Molecular Epidemiology of Mycobacterium abscessus, with Focus on Cystic Fibrosis

ABSTRACT Mycobacterium abscessus has been isolated increasingly often from the respiratory tracts of cystic fibrosis (CF) patients. It is not known whether these organisms are transmitted from person to person or acquired from environmental sources. Here, colony morphology and pulsed-field gel electrophoresis (PFGE) pattern were examined for 71 isolates of M. abscessus derived from 14 CF patients, three non-CF patients with chronic respiratory M. abscessus infection or colonization, one patient with mastoiditis, and four patients with infected wounds, as well as for six isolates identified as environmental contaminants in various clinical specimens. Contaminants and wound isolates mainly exhibited smooth colony morphology, while a rough colony phenotype was significantly associated with chronic airway colonization (P = 0.014). Rough strains may exhibit increased airway-colonizing capacity, the cause of which remains to be determined. Examination by PFGE of consecutive isolates from the same patient showed that they all represented a single strain, even in cases where both smooth and rough isolates were present. When PFGE patterns were compared, it was shown that 24 patients had unique strains, while four patients harbored strains indistinguishable by PFGE. Two of these were siblings with CF. The other two patients, one of whom had CF, had not had contact with each other or with the siblings. Our results show that most patients colonized by M. abscessus in the airways have unique strains, indicating that these strains derive from the environment and that patient-to-patient transmission rarely occurs.

European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre

Abstract A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.

High Rate of Exophiala dermatitidis Recovery in the Airways of Patients with Cystic Fibrosis Is Associated with Pancreatic Insufficiency

ABSTRACT The black-pigmented fungus Exophiala dermatitidis is considered to be a harmless colonizer of the airways of cystic fibrosis (CF) patients. The aim of this study was to establish the recovery rate of E. dermatitidis in respiratory specimens from CF patients, transplant recipients, and subjects with other respiratory disorders in Sweden. Second, we wished to determine if particular clinical traits were associated with E. dermatitidis colonization of the airways and the antifungal susceptibility profiles of Exophiala strains. Sputum and bronchoalveolar lavage samples (n = 492) derived from 275 patients were investigated. E. dermatitidis was isolated in respiratory specimens from 19% (18/97) of the CF patients but in none of the other patient categories. All isolates were recovered after 6 to 25 days of incubation on erythritol-chloramphenicol agar (ECA) medium. Morphological and genetic analyses confirmed species identity. Pancreatic insufficiency was positively associated with the presence of E. dermatitidis in sputum samples (P = 0.0198). Antifungal susceptibility tests demonstrated that voriconazole and posaconazole had the lowest MICs against E. dermatitidis. In conclusion, E. dermatitidis is a frequent colonizer of the respiratory tract in CF patients in Sweden and appears to be associated with more advanced disease. Whether E. dermatitidis is pathogenic remains to be elucidated.

Lung clearance index: Evidence for use in clinical trials in cystic fibrosis

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the groups work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Decreased bone mineral density in normal-growing patients with cystic fibrosis.

Aim: To study bone mineral density (BMD) in normal‐growing patients with cystic fibrosis (CF) and its relation to clinical and biochemical markers of nutrition and lung function. Methods: Seventy consecutive patients aged 6–49 y with CF were investigated using dual X‐ray absorptiometry and the findings related to anthropometric data. Energy intake was calculated and basal metabolic rate and serum values for calcium, phosphorus, calcitonin and 25(OH) calcidiol measured. Working capacity, lung function and pseudomonas colonization were determined as parameters of physical fitness and severity of pulmonary disease. Results: The average z‐score of BMD was decreased in the lumbar spine in both children and adults, being –0.7 ± 1.0 and –0.5 ± 1.0, respectively, as was the femoral neck BMD z‐score, being –0.3 ± 0.9 and –1.1 ± 1.0 for children and adults, respectively. BMD was correlated to lung function and working capacity, but not to anthropometric data at multiple regression analysis compensating for age and calcitonin. No correlation was found with energy intake, basal metabolic rate or biochemical markers, with the exception of calcitonin.

Report of the European respiratory society/European cystic fibrosis society task force on the care of adults with cystic fibrosis

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management. Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management. The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme. Respiratory physicians, trained in adult CF management, should lead multidisciplinary teams taking care of patients http://ow.ly/SgRgj

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.

Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.

Bile acid kinetics and biliary lipid composition in cystic fibrosis

AIMS/METHODS Bile acid kinetics and biliary lipid composition were studied in seven patients, aged 17-70 years with cystic fibrosis. All patients were of normal height and weight, and were in good clinical condition. Ultrasonography indicated a small gallbladder in one and non-visualized gallbladder in two patients. Serum concentrations of cholesterol and transaminases were essentially normal. Substitution with pancreatic enzymes was discontinued at least 1 week before the investigation. Bile acid kinetics were determined by the isotope dilution technique using [24-14C] cholic and [24-14C] chenodeoxycholic acids. RESULTS The mean pool size of cholic acid was 3.3 (range 0.8-6.9) mmol, and that of chenodeoxycholic acid 2.3 (1.2-2.7) mmol, corresponding to 49 +/- 16 and 36 +/- 4 mumol/kg, respectively. The mean synthesis of cholic acid was 1.3 (0.5-3.6) mmol/day and of chenodeoxycholic acid 0.8 (0.2-1.7) mmol/ day and related to body weight 20 +/- 6 and 12 +/- 3 mumol.kg.day-1, respectively. Fractional turnover rates averaged 0.48 (0.24-0.67) and 0.36 (0.10-0.65) day-1, respectively. The kinetic values were not significantly different from controls, aged 21 to 68 years. The biliary lipid composition of fasting gallbladder bile showed a low-normal molar percentage of cholesterol, and in no case was bile supersaturated. The duodenal bile acid concentration was similar in patients and controls, but the bile acid distribution was significantly different; cholic acid constituted a higher percentage (p < 0.001) and chenodeoxycholic and deoxycholic acid lower percentages (p < 0.05 and p < 0.01, respectively) in cystic fibrosis patients than in controls. CONCLUSIONS The findings of normal concentrations of bile acids in duodenal bile and normal to large pool sizes of bile acids in all patients, despite a marked fat malabsorption, are in contrast to some previous reports. The data indicate that biliary lipid metabolism is normal in well-nourished and well-controlled adult patients with cystic fibrosis.