Mucociliary clearance in cystic fibrosis

Abnormal mucociliary clearance (MCC) is one of the central hypotheses for the development of lung disease in patients with cystic fibrosis (CF). However, attempts to demonstrate this decrease of MCC in vivo have proved to be somewhat less definitive, with the evidence barely favoring impaired clearance. Any apparent disparities are most likely due to the variety of methodologies used by different laboratories to measure MCC. The limitations of the various methodologies are examined in this review, in an attempt to better facilitate comparison of results. A number of physical and pharmacological therapies have been developed to promote mucus clearance from the CF airway. A summary of the results of interventional studies utilizing the measurement of MCC as an outcome measure is presented.     

Use of extracorporeal membrane oxygenation in cystic fibrosis in an Australian cystic fibrosis centre

Extracorporeal membrane oxygenation (ECMO) support is used in selected patients with cystic fibrosis (CF) as a bridge to transplantation. Our aim was to describe briefly treatment and outcomes of six CF patients who received ECMO. One patient received a lung transplant and another recovered from acute respiratory failure. Four died despite ECMO support. Lack of timely availability of suitable donor lungs and patient selection are contributing factors.     

Developmental paradigm for early features of cystic fibrosis

Cystic fibrosis (CF) is a progressive disease in which the lung is perceived to be normal at birth and is injured by recurrent infection. However, there is increasing evidence that the lung is functionally and structurally abnormal prior to the appearance of clinical infection. The cystic fibrosis transmembrane regulator (CFTR) is highly expressed in fetal tissues, and this review examines the role of CFTR in regulatory cascades during lung development. Early changes in the CF lung are examined from a perspective of disrupted fetal development, explaining a number of paradoxes seen with the disease.     

Aerosolized agents for airway clearance in cystic fibrosis

The outlook for people with cystic fibrosis (CF) has improved considerably as a result of conventional therapies including aerosolized agents for airway clearance. These will continue to play a significant role in maintaining well‐being and improving survival, even as newer agents emerge that correct the underlying CF defect. In this review, we explore the evidence supporting the use of dornase alfa, hypertonic saline, and mannitol in improving mucus clearance in patients with CF from different age groups with differing disease severity. We also discuss the clinical use of these agents in the context of available international guidelines as well as practical considerations in the clinic, highlighting the importance of a multidisciplinary approach and shared decision‐making. Unanswered questions regarding the optimal use of these agents are highlighted.     

Lung resection in cystic fibrosis: a survival analysis

Lung resection may be considered for cystic fibrosis (CF) patients showing localized severe chronic atelectasis and/or bronchiectasis. Nonetheless, literature on survival after surgery is scarce. This study was carried out to assess survival time after partial lung resection. Twenty-one CF patients were operated from 1988 to 2003 and were followed until November 30th, 2004. Survival analysis was performed through Kaplan-Meier method. Mean age at resection was 8.09 years (SD 4.40 years) and two-thirds were females. Z-scores for height, weight, and body mass index as well as FEV1 values showed no statistical significance when comparing values obtained from 2 years before to 2 years after resection. Eleven years after resection, survival probability was 93.8%. Our results suggest that lobectomy or segmentectomy are safe procedures and should be considered in carefully selected patients with unilateral severe symptomatic localized and chronic persistent atelectasis and/or bronchiectasis refractory to conservative management.     

Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience

Liver disease develops in one‐third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.     

Spondylodiscitis after bilateral sequential lung transplantation in a patient with cystic fibrosis

We report the case of a 24-year-old woman with cystic fibrosis in whom spondylodiscitis developed after bilateral sequential transplantation. The diagnostic work-up included magnetic resonance imaging, computed tomography-guided disk biopsy, histological examination, and cultures of disk specimens. The infective organism was D group Streptococcus and the patient was successfully treated with intravenous piperacillin followed by oral ampicillin. To our knowledge, this is the first reported case of spondylodiscitis after lung transplantation.     

An advanced stochastic model for mucociliary particle clearance in cystic fibrosis lungs

Background

A mathematical model describing mucociliary clearance in cystic fibrosis (CF) patients and its development with progressing course of the disease was developed. The approach should support the prediction of the disease state on the basis of measured bronchial clearance efficiencies.

Methods

The approach is based on the assumption of a steady-state steady-flow mucus transport through the tracheobronchial tree which enables the determination of airway generation-specific mucus velocities by using a measured tracheal mucus velocity and a realistic morphometric dataset of the human lung. Architecture of the tracheobronchial tree was approximated by a stochastic model, reflecting the intra-subject variability of geometric parameters within a given lung generation.

Results

As predicted by the appropriately validated mathematical approach, mucociliary clearance efficiency in CF patients is partly significantly decreased with respect to healthy controls. 24-h retention of patients with mild CF (FEV₁ >70% of predicted) is reduced by 10% compared to healthy subjects, whilst 24-h retention of patients with moderate to severe CF (FEV₁ <70% of predicted) differs by 25% from that of the healthy controls. These discrepancies are further enhanced with continuation of the clearance process.

Conclusions

The theoretical results lead to the conclusion that CF patients have a higher risk of inhaled particle accumulation and related particle overload in specific lung compartments than healthy subjects.     

Plastic bronchitis as an unusual cause of mucus plugging in cystic fibrosis

Cystic fibrosis patients are known to produce abundant, purulent sputum consisting mainly of DNA and cellular debris. We present a case of a CF patient with recurrent airway obstruction caused by a rare condition known as plastic bronchitis (PB). PB is characterized by the formation of casts of the airways that cause obstruction. Multiple etiologies have been proposed, but to our knowledge, no CF patient has been reported in any PB classification. Histological analysis and in‐vitro testing of the cast were important factors in choosing the adequate therapy in this patient. Pediatr Pulmonol. 2009; 44:939–940. © 2009 Wiley‐Liss, Inc.     

Inflammatory markers of lung disease in adult patients with cystic fibrosis

BACKGROUND: Progressive pulmonary disease associated with chronic bacterial infection and inflammation is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Identifying markers of inflammation that correlate with lung injury may be useful in monitoring disease progression and response to therapy. We hypothesized that levels of serum biomarkers would correlate with clinical course of CF as defined by pulmonary function testing (FEV1). OBJECTIVE: To determine whether biomarkers of systemic inflammation correlate with lung function in adults with CF. METHODS: Retrospective cross-sectional analysis of 63 individuals > or = 30 years of age diagnosed with CF in childhood and followed at Children's Hospital, Boston. We collected data on demographics, CFTR genotype, percent predicted forced expiratory volume in 1 sec (FEV1), C-reactive protein (CRP), serum IgE nd IgG, alpha1-antitrypsin, total white blood cell and neutrophil counts, and percent neutrophils. We used univariate analyses and multivariate linear regression modeling to examine whether markers of systemic inflammation varied with FEV1 (% predicted). RESULTS: In two-covariate models including CRP and one other marker, CRP (P < 0.001) and IgG (P = 0.02) were significantly associated with FEV1 (% predicted). In the CRP and IgG model, percent predicted FEV1 decreased by 4.91% (P < 0.0001) for each twofold increase in CRP and by 1.56% (P = 0.02) for each 100 mg/dl increase in IgG. Results were unchanged by adjustment for number of DF 508 CFTR alleles. There was no association between any other marker and FEV1 (% predicted) after adjusting for CRP. CONCLUSION: Severity of lung disease in long surviving adult CF patients is correlated with CRP and IgG levels. Our findings relating CRP and IgG levels and lung function provide a foundation for subsequent longitudinal studies and consideration of novel disease mechanisms and outcome measurements.     

Improvements of lung function in cystic fibrosis

Improved care for patients with cystic fibrosis (CF) has led to their improved survival. We analyzed retrospectively whether improvements in lung function (LF) could be detected in our CF patients over the decade 1980-1990. In 72 patients, 153 LF measurements were performed in their first year of life (1980-1991), and then 189 LF measurements were performed again in 60 of those patients during their sixth year of life (1987-1997). Regression analysis was performed on LF parameters at age 6 years. When adjusting for weight, height, gender, and LF in the first year of life, the date of subsequent measurement was positively associated with FEV(1) (P < 0.01) and MEF(50%) (P < 0.05) and negatively with FRC(pleth) (P < 0.05). The proposed model predicts a child's FEV(1) at age 6 to be 75% of predicted if born in 1980, but 108% of predicted when born in 1990. Improved CF care is the most likely explanation for this observation.     

Clostridium difficile colitis in cystic fibrosis patients with and without lung transplantation

Background. Despite a large carriage rate of Clostridium difficile among cystic fibrosis (CF) patients, C. difficile- associated disease (CDAD) is rather rare. In case of lung transplantation, the incidence and clinical aspects of CDAD in this patient population are not well known.
Methods. We reviewed the medical files of all CF patients who presented with symptomatic C. difficile infection from January 1998 to December 2004 and compared the incidence, clinical aspects, severity of disease, and clinical outcome between non-transplanted and transplanted CF patients.
Results. Between 1998 and 2004, 106 adult CF patients were followed at our clinic. Forty-nine patients underwent lung transplantation; 15 before 1998 and 34 after 1998. The incidence density of CDAD was higher in transplanted CF patients as compared with non-transplanted CF patients (24.2 vs. 9.5 episodes/100,000 patient-days; risk ratio: 2.93 [1.41–6.08]; P =0.0044). Diarrhea was a very frequent feature, but was notably absent in 20% of the cases. Rates of moderate and severe colitis were similar in both groups. However, only transplanted patients developed complicated colitis. CT scan and endoscopy were performed more frequently in the transplant group. Two transplant recipients died because of CDAD.
Conclusion. CF patients who undergo lung transplantation are at a higher risk of developing CDAD and seem to present more often atypical and/or complicated disease. CDAD should be part of the differential diagnosis in case of digestive symptoms, even in the absence of diarrhea, and requires early treatment.     

Cystic fibrosis: an unusual neonatal presentation

In mechanically ventilated neonates it is not uncommon to observe obstructive atelectasis from various causes. However it is extremely rare to see mucous plugging and massive pulmonary atelectasis in the absence of infection, aspiration, and respiratory distress syndrome in the first couple of days of life. In this report we describe a neonate born with cystic fibrosis (CF) who presented to us with hypoxic respiratory failure, pulmonary hypertension, and hypercarbia without lactic acedemia from sticky mucous plugging and massive lung collapse. Neonatal respiratory distress and wide spread pulmonary atelectasis has not been reported in infants born with CF.     

BPI-ANCA of pediatric cystic fibrosis patients can impair BPI-mediated killing of E. coli DH5alpha in vitro

Gram-negative bacterial lung infections and chronic bacterial colonization are major threats for pediatric cystic fibrosis (CF) patients. Besides impeded mucociliary clearance, other mechanisms that contribute to increased susceptibility to infections are presumed. The bactericidal/permeability-increasing protein (BPI), which is delivered by neutrophil granulocytes and mucosal epithelial cells, is one of the most potent innate antibiotics against Gram-negative bacteria and endotoxin. Antineutrophil cytoplasmic autoantibodies against BPI (BPI-ANCA) have been found in up to 90% of CF patients, and titers correlated inversely with lung function parameters. As major pulmonary damage is mediated by Gram-negative bacteria and their products, the question was raised as to whether BPI-ANCA can inhibit the antibiotic function of BPI in these patients. Sera of 23 pediatric CF patients were analyzed for the presence of BPI-ANCA by indirect immunofluorescence, ELISA, epitope mapping, and Western blotting. Patients' IgG were tested in a bacterial growth inhibition assay with recombinant BPI (rBPI) and an amino-terminal fragment of BPI (rBPI(21)) that retains antibiotic activity for inhibition of the antibiotic function of BPI against E. coli DH5alpha in vitro. BPI was recognized by 21 of 23 patients' sera in our detection assays. Thirteen of 23 patients' BPI-ANCA (56%) could inhibit the antibiotic function in vitro. Moreover, epitope mapping over the whole BPI sequence revealed that more patients' BPI-ANCA recognize the amino-terminal part of BPI than can be detected by ELISA. Thus, in pediatric CF patients, BPI-ANCA may contribute to diminished bacterial clearance by inhibiting the antibiotic function of BPI.