Eosinophilic esophagitis in cystic fibrosis: A case series and review of the literature

Patients with cystic fibrosis (CF) frequently experience gastrointestinal symptoms including nausea, emesis, malnutrition and indigestion; diseases such as gastroesophageal reflux disease (GERD), distal intestinal obstructive syndrome, and cholelithiasis are commonly implicated. We have recently diagnosed eosinophilic esophagitis (EoE) in three patients with CF. EoE is a TH-2 driven, allergen-mediated disease which causes esophageal eosinophilia and presents with symptoms of nausea, feeding intolerance, regurgitation, and dysphagia. EoE is diagnosed when esophageal biopsies reveal greater than 15 eosinophils per high power field in the setting of the appropriate clinical scenario and after exclusion of other causes of esophageal eosinophilia. Although described with increasing frequently in the gastrointestinal literature, there have been no prior cases documenting the co-existence of EoE and CF. We speculate that this is related to lack of familiarity with EoE symptoms by CF providers. We present three patients with CF diagnosed with EoE and review the current literature regarding diagnosis and management, focusing on management issues in patients with CF.     

Characterization of macrophage activation states in patients with cystic fibrosis

BackgroundChronic airway inflammation characterizes patients with cystic fibrosis (CF). The role of alternative macrophage activation in this disease course is unknown.ObjectiveWe evaluated markers of alternative and classical macrophage activation in the lungs of patients with CF and evaluated these characteristics in the context of Pseudomonas aeruginosa (PA) infection, immunomodulatory drug therapy and pulmonary function.MethodsBronchoalveolar lavage or spontaneously expectorated sputum samples were collected from 48 CF patients. Clinical data were related to macrophage surface expression of mannose receptor (MR) (up-regulated in alternatively activated macrophages) and TLR4 (up-regulated in classically activated macrophages). Also, the activity of the alternatively activated macrophage effector molecule arginase was compared among patient groups, and pro- and anti-inflammatory cytokines produced by alternatively and classically activated macrophages were measured.ResultsThere were significant differences between PA-infected and -uninfected patients in several clinical measurements. PA-infected patients exhibited increased use of azithromycin, up-regulation of MR on CD11b+ cells and increased arginase activity in their lung samples, and had a strong inverse relationship between MR and arginase activity to FEV₁. Upon further analysis, PA-infected patients who were treated with azithromycin had the highest arginase activity and the highest number of macrophages that were MR+TLR4−, and both of these markers were inversely related to the FEV₁.ConclusionsOur findings suggest an increase in both MR and arginase expression as pulmonary function declines in PA-infected patients with CF. These markers of an alternatively activated macrophage phenotype give cause for future study to define the function of macrophage activation states in the CF lung.     

Cultural issues in cystic fibrosis.

Although current numbers of non-Caucasian CF patients are small, collectively they represent sizeable groups and increasingly more is becoming known about the spectrum of mutations in the CFTR gene in different populations. As such it is important to acknowledge that there will be certain sociocultural challenges in interacting with and managing such patients. This paper explores such developments and considers some of the current and future challenges facing those who treat the disease. Techniques applied in other illness contexts for establishing and maintaining effective patient-professional relationships, reviewing patient education, resolving treatment conflicts and improving adherence are discussed, as are the implications for future research.     

Clinical trials in cystic fibrosis.

In patients with cystic fibrosis (CF), clinical trials are of paramount importance. Here, the current status of drug development in CF is discussed and future directions highlighted. Methods for pre-clinical testing of drugs with potential activity in CF patients including relevant animal models are described. Study design options for phase II and phase III studies involving CF patients are provided, including required patient numbers, safety issues and surrogate end point parameters for drugs, tested for different disease manifestations. Finally, regulatory issues for licensing new therapies for CF patients are discussed, including new directives of the European Union and the structure of a European clinical trial network for clinical studies involving CF patients is proposed.     

Musculoskeletal involvement in cystic fibrosis.

The purpose of this study was to review the published evidence of the effects of cystic fibrosis (CF) on the musculoskeletal system, and their implications on the quality of life of these patients. With increasing longevity of CF patients, musculoskeletal manifestations have become important. Decreased bone mineral density (BMD) and bone mineral content (BMC) are common at all ages in CF patients, and its cause is probably multifactorial. Risk factors contributing to decreased BMC include age of the patient, imbalance between bone accretion and degradation, body mass, nutrition, activity, exposure to glucocorticoid therapy, and gonadal dysfunction. BMC correlates strongly to fat-free mass in CF patients. Lung transplant, while increasing life span, can worsen osteoporosis. Twenty-nine percent of patients are below the 10th percentile for height. Fracture rates are approximately twofold greater in females aged 16 to 32 years and males aged 25 to 34 years. Female patients aged 6 to 16 have a higher than normal fracture rate and a higher rate than their male counterparts. Spinal consequences of osteoporosis include excessive kyphosis in up to 62% of patients. Back pain was noted in 94% of patients. Arthritis in CF, although less common, can be very incapacitating, and it is mainly of three types: CF arthritis, hypertrophic osteoarthropathy, and arthritis due to co-existent conditions and drug reactions. The treatment of arthritis is mainly symptomatic in the majority of cases.     

Amyloidosis complicating cystic fibrosis.

Two patients with cystic fibrosis developed acute onset nephrotic syndrome and died within three months of presentation. Examination of renal biopsy specimens indicated amyloid. The onset of proteinuria or a fall in baseline renal function should alert the physician to this rare complication.     

Neutrophil cell death, activation and bacterial infection in cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is characterised by chronic endobronchial bacterial infection and neutrophil mediated inflammation. Neutrophil apoptosis is essential for the resolution of inflammation. This study assessed the relationship between levels of neutrophil apoptosis and sputum microbiology in matched clinically stable patients with CF. METHODS: Sputum was induced from 34 patients (nine with no Gram negative infection, 10 colonised with Pseudomonas aeruginosa, 10 with Burkholderia cenocepacia, and five with other infections). Apoptotic neutrophils measured by flow cytometric Annexin V/propidium iodide staining and morphology were similar in all groups. RESULTS: Patients infected with P aeruginosa or B cenocepacia had a significantly lower percentage of viable neutrophils in the sputum than those with no Gram negative infection (Kruskal-Wallis p = 0.01, median (interquartile range (IQR)) 14.2% (9.4-21.6), 15.8% (12.3-19.5), and 48.4% (23.0-66.4); p = 0.003 and p = 0.002, respectively). They also had significantly higher levels of secondary necrotic granulocytes in sputum than patients with no Gram negative infection (Kruskal-Wallis p<0.0001, median (IQR) 55.5% (48.4-64.5), 50.4% (44.6-61.9), and 24.8% (14.4-30.5); p<0.0001 and p<0.0001, respectively). Neutrophils (x 10(6)/g sputum) in P aeruginosa infected patients (Kruskal-Wallis p = 0.05, median (IQR) 6.3 (3.5-12.7)) and B cenocepacia infected patients (5.7 (1.5-14.5)) were significantly higher than in the group with no Gram negative infection (0.5 (0.5-4.3), p = 0.03 and 0.04, respectively). CONCLUSION: These results suggest that cell death and clearance may be altered in patients with CF colonised with P aeruginosa and B cenocepacia compared with those with no Gram negative infection.     

The pulmonary circulation in cystic fibrosis.

The hearts and lungs of 36 patients dying of cystic fibrosis have been studied to establish the relationship between right ventricular hypertrophy (RVH), pathological changes in the pulmonary circulation, and the clinical features. The presence and degree of RVH were measured by Fulton's technique of weighing the ventricles separately. Of the subjects who died after the age of 3 years, one in six had no RVH, although the mean age of this group was not significantly different from that of the remainder. There was no correlation between duration of cyanosis, haemoglobin levels, and RVH. Although not statistically significant, the cases without RVH tended to have had clubbing of the finger-nails for longer periods before death. The electrocardiogram was useful in the diagnosis of RVH. Right ventricular hypertrophy was common in children with lungs of large volume as judged by the radiographic centile of lung length. Cases with RVH show reduced background haze in the arteriogram and fewer arteries per unit area of lung. For the first time thickening of the medial muscle layer proportional to the degree of RVH has been demonstrated, only in the smaller arteries. Arterial subintimal fibrosis is more common in cases with RVH, as is thickening of the walls of small pulmonary veins. The implications of these findings are discussed.     

Respiratory muscle function in cystic fibrosis.

Maximal static expiratory and inspiratory mouth pressures (PEmax and PImax) and quadriceps femoris muscle strength were measured in 25 patients aged 16-28 years with cystic fibrosis (mean FEV1 46% predicted). Mean (SD) PEmax was 64% (18%) predicted (below 75% predicted in 16 of the 25 patients), and PImax was 64% (24%) predicted (below 75% predicted in 14 patients). Quadriceps muscle strength was 68% (20%) predicted (below 75% predicted in 17 patients). The relatively small reduction in respiratory muscle strength in these patients was unlikely to have contributed appreciably to their respiratory problems.     

Ciprofloxacin-induced renal insufficiency in cystic fibrosis.

Acute renal insufficiency is known to occur in patients who are taking ciprofloxacin, particularly the elderly. We report two young patients with cystic fibrosis who presented with acute renal insufficiency after 2-3 weeks of oral ciprofloxacin therapy. The incidence of this adverse effect in children and young adults who have cystic fibrosis is unknown. Multiple mechanisms for ciprofloxacin-induced nephrotoxicity have been proposed.