Marijke Proesmans

Pancreatitis Among Patients With Cystic Fibrosis: Correlation With Pancreatic Status and Genotype

Objective. Pancreatitis is an infrequent complication among patients with cystic fibrosis (CF). It has mainly been reported for patients with pancreatic sufficiency (PS). Previous studies involved only a small number of patients because they contained data from single centers. The aim of this study was to evaluate the incidence of pancreatitis in a large heterogeneous CF population, to determine the relationship with pancreatic function, and to assess whether pancreatitis is associated with specific CFTR mutations. Methods. Physicians caring for patients with CF were approached through the CF Thematic Network or through the European Cystic Fibrosis Foundation newsletter. They were asked to provide data on their current patient cohort through a standardized questionnaire and to report how many patients they had ever diagnosed as having pancreatitis. A detailed questionnaire was then sent, to be filled out for all of their patients for whom pancreatitis had ever occurred. We defined pancreatitis as an episode of acute abdominal pain associated with serum amylase levels elevated above the ranges established by each participating centers laboratory. General clinical data included age, genotype, age at diagnosis of CF, sweat chloride concentrations, pancreatic status, biometric findings, and respiratory status. CFTR mutations were also reported according to the functional classification of classes I to V. Patients were categorized as having PS, pancreatic insufficiency (PI), or PI after an initial period of PS. PI was defined as a 72-hour stool fat loss of >7 g/day, fat absorption of <93%, or fecal elastase levels of <200 μg/g feces. Clinical data on pancreatitis included age at the first episode, amylase and lipase levels, possible triggers, and occurrence of relapses or complications. Results. A total of 10071 patients with CF, from 29 different countries, who were undergoing follow-up monitoring in 2002 were surveyed. Among this group, pancreatitis had ever been diagnosed for 125 patients (1.24%; 95% confidence interval [CI]: 1.02–1.46%). There was variability in the reported rates of pancreatitis for different countries. Twenty-six centers in 15 different countries sent detailed clinical data on their patients with pancreatitis and on their whole CF clinic. This involved 3306 patients with CF and 61 cases of pancreatitis, leading to a prevalence of 1.84% (95% CI: 1.39–2.30%). The mean age of the patients with pancreatitis ever was 24.4 years (SD: 10.8 years). The first episode of pancreatitis occurred at a mean age of 19.9 years (SD: 9.6 years). The median serum amylase level at the time of pancreatitis was 746 IU/L (interquartile range: 319–1630 IU/L), and the median lipase level was 577 IU/L (interquartile range: 229–1650 IU/L). The majority of patients had PS (34 of 61 patients, 56%; 95% CI: 43–68%). Pancreatitis occurred for 15 patients with PI (25%; 95% CI: 14–35%). Eight patients developed PI after initial PS. The occurrence of pancreatitis among patients with PS was 34 cases per 331 patients, ie, 10.27% (95% CI: 7.00–13.55%); the occurrence of pancreatitis among patients with PI was 15 cases per 2971 patients, ie, 0.5% (95% CI: 0.25–0.76%). The mean age (in 2002) of the CF cohort with pancreatitis did not differ between the PS and PI subgroups. The forced expiratory volume in 1 second was significantly lower among the patients with PI than among the patients with PS, ie, 65% (SEM: 7%) vs 79% (SEM: 4%). The mean age at the occurrence of pancreatitis and the amylase and lipase levels during pancreatitis were not different for patients with pancreatitis and PI versus PS. In the group with PS, 31 of 34 patients carried at least 1 class IV or V CFTR mutation. In the groups with PI and PI after PS, 5 of 15 patients and 3 of 8 patients, respectively, carried 2 class I, II, or III CFTR mutations. Relapses and/or evolution to chronic pancreatitis occurred for 42 patients. Pancreatitis preceded the diagnosis of CF in 18 of 61 cases. These patients were significantly older than the rest of the cohort, ie, age of 28.4 years (SEM: 3.4 years) vs 22.7 years (SEM: 1.3 years). Their median age at the diagnosis of CF was also significantly greater, ie, 21.5 years (interquartile range: 11.9–31 years) vs 7.6 years (interquartile range: 0.4–17.0 years). However, the ages at the occurrence of pancreatitis were similar, ie, 21.0 years (SEM: 3.0 years) vs 19.5 years (SEM: 1.2 years). Conclusions. This study of 10071 patients with CF from 29 different countries revealed an estimated overall occurrence of pancreatitis among patients with CF of 1.24% (95% CI: 1.02–1.46%). The incidence of pancreatitis was much higher among patients with PS. However, pancreatitis was also reported for 15 patients with PI from 11 centers in 9 different countries. A correct diagnosis of pancreatitis for the reported patients with PI was supported by amylase and lipase levels increased above 500 IU/L, similar to those for patients with PS and pancreatitis. A correct diagnosis of PI for these patients with pancreatitis was supported by the adequacy of the methods used. We chose the cutoff values used to distinguish between patients with PI and control subjects without gastrointestinal disease. For one half of the patients, the diagnosis of PI was established on the basis of low levels of stool elastase (mean: 97 μg/g stool). With a cutoff value of 200 μg/g stool, this noninvasive test has high sensitivity (>95%) and high specificity (>90%) to differentiate patients with PI from control subjects with normal pancreatic function. For the other one half of the patients with PI in the cohort, the pancreatic status was determined on the basis of the 3-day fecal fat balance, with the widely used cutoff value of >7 g of fat loss per day. The most likely reason for pancreatitis occurring among patients with PI is that some residual pancreatic tissue is present among these patients. Pancreatitis is a rare complication among patients with CF. It occurred for 1.24% (95% CI: 1.02–1.46%) of a large CF cohort. Pancreatitis occurs mainly during adolescence and young adulthood. It is much more common among patients with CF and PS (10.3%), but it can occur among patients with PI (0.5%). Pancreatitis can be the first manifestation of CF. Pancreatitis was reported for patients carrying a wide range of mutations.

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.

What’s new in cystic fibrosis? From treating symptoms to correction of the basic defect

Chronic relentless lung infection and pancreatic insufficiency are the cardinal features of cystic fibrosis (CF), a life-shortening autosomal recessive disease. Mutations in the ’cystic fibrosis transmembrane conductance regulator’ (CFTR) are currently classified into five groups according to their repercussion on CFTR protein synthesis and its chloride channel function. Stop codon mutations (class I) result in a truncated nonfunctional CFTR, class II mutations consist of aberrantly folded CFTR protein that is degraded by the cell quality control system, while class III mutations lead to defective regulation of the CFTR protein and, consequently, the absence of CFTR function. These three classes usually lead to a classic CF phenotype with pancreatic insufficiency. CFTR mutations that lead to defective chloride conductance are grouped together in class IV. Class V mutations interfere with normal transcription, thereby reducing the amount of otherwise normal CFTR. These latter two classes are mostly associated with a milder expression of the disease. In the absence of CFTR function, unrestrained Na+ absorption and the failure of active Cl- secretion lead to a decreased airway surface liquid (ASL) volume and subsequent failure of normal mucociliary clearance. This review highlights recent therapeutic strategies that either target the underlying defect or the early steps in CF pathophysiology. To date, gene therapy has failed to demonstrate a clinical benefit after repeated administration. Mutation-specific chloride channel correction pharmacotherapy is currently being developed, an example of which is PTC124, a new chemical compound that selectively induces read-through of premature stop codons. However, clinical efficacy for most of the compounds still has to be proven in large clinical trials. The positive effect of nebulised hypertonic saline on mucociliary clearance is based on the restoration of ASL height. Recent advances in the current treatment of lung infection and inflammation are highlighted in this review. Lung transplantation should be considered in terminally ill patients, but the timing of the transplantation is crucial: transplanting too early shortens survival, while transplanting too late results in patients dying on the waiting list.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

Objectives: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. Patients and Methods: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH ≥ 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. Results: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. Conclusions: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.

Primary ciliary dyskinesia: critical evaluation of clinical symptoms and diagnosis in patients with normal and abnormal ultrastructure

BackgroundPrimary ciliary dyskinesia (PCD) is a rare disorder with variable disease progression. To date, mutations in more than 20 different genes have been found. At present, PCD subtypes are described according to the ultrastructural defect on transmission electron microscopy (TEM) of the motile cilia. PCD with normal ultrastructure (NU) is rarely reported because it requires additional testing. Biallelic mutations in DNAH11 have been described as one cause of PCD with NU.The aim of our study was to describe the clinical characteristics of a large population of patients with PCD, in relation to the ultrastructural defect. Additionally, we aimed to demonstrate the need for biopsy and cell culture to reliably diagnose PCD, especially the NU subtype.MethodsWe retrospectively analyzed data from 206 patients with PCD. We compared the clinical characteristics, lung function, microbiology and imaging results of 68 patients with PCD and NU to those of 90 patients with dynein deficiencies and 41 patients with central pair abnormalities. In addition, we aimed to demonstrate the robustness of the diagnosis of the NU subtype in cell culture by data from genetic analysis.ResultsPCD with NU comprised 33% (68/206) of all patients with PCD. Compared to other subtypes, patients with PCD and NU had a similar frequency of upper and lower respiratory tract problems, as well as similar lung function and imaging. With the currently widely applied approach, without cell culture, the diagnosis would have been missed in 16% (11/68) of patients with NU. Genetic analysis was performed in 29/68 patients with PCD and NU, and biallelic mutations were found in 79% (23/29) of tested patients.ConclusionsWe reported on the clinical characteristics of a large population of patients with PCD and NU. We have shown that systematic performance of biopsy and cell culture increases sensitivity to detect PCD, especially the subtype with NU.PCD with NU has similar clinical characteristics as other PCD types and requires biopsy plus ciliogenesis in culture for optimal diagnostic yield.

Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis

Rationale The lung clearance index (LCI) is a promising endpoint for use in cystic fibrosis (CF) clinical trials, but correlations with validated clinical endpoints have not yet been established. Objective This study aimed to demonstrate that, in young patients with CF, baseline LCI predicts subsequent pulmonary exacerbation (PE) and correlates with the respiratory domain of the CF Questionnaire-Revised (CFQ-Rresp). Methods Baseline LCI, forced expiratory volume in 1 s (FEV1), CFQ-Rresp and PEs over the subsequent year were prospectively recorded in 63 patients aged 5–19 years. The ability of baseline LCI to predict PE was assessed using negative binomial regression models and Kaplan–Meier plots. Results Twenty-six patients (41%) experienced 48 PEs. Baseline LCI and FEV1 were predictors of PE. Compared with the quartile with the lowest LCI, the annual PE rate in increasing LCI quartiles was 2.9 (95% CI 0.5 to 16.5, p=0.238), 5.4 (95% CI 1.0 to 29.0, p=0.045) and 13.6 (95% CI 2.8 to 67.1, p=0.001). Similarly, time to first PE decreased with worsening LCI quartiles (log-rank test for trend, p<0.001). Furthermore, LCI correlated with CFQ-Rresp (r=−0.43, p<0.001). In the subgroup of 53 patients with normal FEV1, LCI was a predictor of PE. In this subgroup, LCI also correlated with CFQ-Rresp (r=−0.282, p=0.043). Conclusions Baseline LCI predicts PE in young patients with CF and correlates with CFQ-Rresp, a validated patient-reported outcome, even in the subgroup with normal FEV1. These data further support the use of LCI as a surrogate outcome measure in CF clinical trials.

Laboratory diagnosis of specific antibody deficiency to pneumococcal capsular polysaccharide antigens by multiplexed bead assay.

We evaluated a multiplexed bead-based assay (xMAP Pneumococcal Immunity assay from Luminex) for the simultaneous determination of antibodies against 14 capsular polysaccharides. Post-vaccination (Pneumovax) antibody concentrations were measured in 35 healthy children, 40 healthy adults, 99 consecutive patients with increased susceptibility to respiratory infection, and 24 patients with a deficient anti-polysaccharide antibody response. The serotype-specific lower 5th percentile (cutoff) value for the post-immunization antibody concentration was determined in healthy individuals. Eleven of 99 patients (11%) failed to mount a response that was >5th percentile of controls for at least 6 of the 14 serotypes tested, whereas only 3 of 75 controls (4%) failed to do so. All patients with known anti-polysaccharide antibody deficiency failed to mount a response that was >5th percentile of controls for at least 6 of the 14 serotypes tested. The XMAP pneumococcal immunity panel appears useful for identifying individuals with a low response to the unconjugated pneumococcal vaccine.

Lung structure–function correlation in patients with primary ciliary dyskinesia

Background Primary ciliary dyskinesia (PCD) is a rare disease, characterised by chronic airway infection. In cystic fibrosis, FEV1 is insensitive to detect patients with structural damage, and Lung Clearance Index (LCI) was proposed as a better marker of early lung damage. In PCD, the relationship between functional and structural abnormalities has been less studied. We aimed to re-examine this in a cohort of children and adults with mild to moderate PCD. Methods Thirty-eight patients with PCD (5.2–25.0 years) and 70 healthy controls (4.4–25.8 years) were recruited to compare LCI, measured by N2 multiple breath washout and FEV1 in a prospective observational trial. In a subset of 30 patients who underwent chest imaging, structural abnormalities were evaluated with cystic fibrosis computed tomography (CFCT) scores. Results LCI was abnormal in 28 of 38 patients and a moderate correlation was observed between LCI and FEV1 (r=−0.519, p=0.001). Moreover, LCI correlated well with CFCT total score (r=0.800, p<0.001) and also with subscores for airway wall thickening (r=0.809, p<0.001), mucus plugging (r=0.720, p<0.001) and bronchiectasis (r=0.494, p<0.001). Concordance was seen between LCI and CFCT in 25 of 30 (83%) patients, but between FEV1 and CFCT in only 16 of 30 (53%) patients. LCI was more sensitive (90.9%, 95% CI 70.8 to 98.6) to detect patients with structural abnormalities than FEV1 (36.4%, 95% CI 17.2 to 59.3). Conclusions We demonstrated that measuring LCI in patients with PCD is of clinical relevance; it was more frequently abnormal than FEV1, correlated well with CFCT and was more sensitive than FEV1 to detect patients with structural abnormalities.

Non-invasive liver elastography (Fibroscan) for detection of cystic fibrosis-associated liver disease

BACKGROUND Cystic fibrosis-associated liver disease (CFLD) is the second cause of mortality in CF. The prevalence is estimated to be 26-45%, but sensitive diagnostic tools are lacking. We investigated whether non-invasive liver elastography (Fibroscan) could serve as a screening tool. METHODS Fibroscan measurements were performed in 66 CF patients. Age-specific cutoff values were determined in a control population (n=59). The measurements were compared to clinical data, bi-yearly biochemistry and ultrasound. RESULTS Fibroscan was easy to perform in this patient population. There were 14 patients (21%) with abnormal liver stiffness measurements. Liver stiffness was significantly increased in patients with clinical CFLD (11.2 kPa versus 5.1 kPa), biochemical CFLD (7.4 kPa versus 5.4 kPa) or ultrasonographical CFLD (8.2 versus 4.3 kPa) (p<0.02 for all). CONCLUSIONS Fibroscan is an objective measure and is easy to perform in CF patients, even in children and could provide a valuable tool to detect, and quantify CFLD.

Bile Acids in Sputum and Increased Airway Inflammation in Patients With Cystic Fibrosis

BACKGROUND Up to 80% of patients with cystic fibrosis (CF) may have increased gastroesophageal reflux and aspiration of duodenogastric contents into the lungs. We aimed to assess aspiration in patients with CF by measuring duodenogastric components in induced sputum and to investigate whether the presence of bile acids (BAs) in sputum was correlated with disease severity and markers of inflammation. METHODS In 41 patients with CF, 15 healthy volunteers, 29 patients with asthma, and 28 patients with chronic cough, sputum was obtained after inhalation of hypertonic saline. Sputum supernatant was tested for BA and neutrophil elastase. Spirometry and BMI were assessed on the day of sputum collection. RESULTS Two of 15 healthy patients (13%), eight of 29 patients (28%) with asthma, four of 28 patients (14%) with chronic cough, and 23 of 41 patients (56%) with CF had BA in sputum. BA concentrations were similar in patients who are positive for BA with genotype F508del homozygote, F508del heterozygote, and other CF mutations and were not related with BMI and age. Patients with CF with BA in sputum had a higher concentration of neutrophil elastase compared with patients without BA in sputum (31.25 [20.33-54.78] μg/mL vs 14.45 [7.11-27.88] μg/mL, P < .05). There was a significant correlation between BA concentrations and dynamic lung volumes (FEV(1) % predicted [r = -0.53, P < .01], FVC% [r = -0.59, P < .01]) as well as with number of days of antibiotic IV treatment (r = 0.58, P < .01). CONCLUSIONS BAs are present in the sputum of more than one-half of patients with CF, suggesting aspiration of duodenogastric contents. Aspiration of BA was associated with increased airway inflammation. In patients with BA aspiration, the levels of BA were clearly associated with the degree of lung function impairment as well as the need for IV antibiotic treatment.