End-stage Cystic Fibrosis Research Articles

Association of lung perfusion disparity and mortality in patients with cystic fibrosis awaiting lung transplantation

Background: The risk of death for patients with end-stage cystic fibrosis awaiting lung transplantation remains high and most patients succumb to respiratory failure. This study was conducted to evaluate the usefulness of ventilation-perfusion scintillation scans, obtained during the pre-transplant period, to identify patterns that predict prognosis while on the waiting list. These patterns were compared with other pulmonary physiologic markers of ventilation and perfusion obtained from pulmonary function and cardiopulmonary exercise tests. Methods: From November 1990 to January 1999, 46 patients with cystic fibrosis were listed for bilateral lung transplantation. Fourteen (30.4%) died while waiting for a transplant (Group 1), whereas 32 were transplanted successfully or remain alive and waiting (Group 2). Mean arterial blood gas values, Brasfield radiograph scores, cardiopulmonary exercise data and the degree of scintillation scan abnormalities between lungs were compared for each group. Results: Mean survival for Group 1 was 10.2 ± 1.7 months, and for Group 2 was 23.5 ± 3.0 months ( p < 0.001). The right upper lung zone was the most severely affected segment. The Cox proportional hazards model revealed an increased perfusion disparity and resting hypercapnia as the main predictors of death while on the transplant list. The Kaplan-Meier analysis indicated greater survival for the groups with <30% disparity between lungs on the pre-transplant scintillation scans. Conclusions: The results suggest that severe, unilateral perfusion abnormalities seen on scintillation scans in patients with cystic fibrosis are associated with an increased risk of dying while on the lung transplant waiting list and may be helpful in identifying patients who should be considered for early or living-donor transplantation.

Right Ventricular Dysfunction in Adult Severe Cystic Fibrosis

This study sought to assess the extent of impairment of cardiac function in adult patients with end-stage cystic fibrosis (CF) and to examine the relationship between cardiovascular abnormalities and the degree of hypoxemia and hypercapnia. A retrospective study in a tertiary cardiac and CF center. A total of 103 adult patients with end-stage CF awaiting lung or heart and lung transplantation (mean age [+/- SD], 26+/-7 years; 54 men) underwent Doppler echocardiography and arterial blood gas analysis (mean PaO(2), 54+/-10 mm Hg; mean PaCO(2), 47+/-8 mm Hg). The findings were compared to those of 17 healthy control subjects (mean age, 24+/-7 years; 13 men) who had no history of cardiac or pulmonary disease. All patients were in sinus rhythm with a mean tachycardia of 112+/-18 beats/min (control subjects, 76+/-16; p<0.0001) and had a cardiac output of 5.3 L/min (control subjects, 4.3 L/min; p<0.04). In the patient group, the left ventricular (LV) dimensions, systolic and diastolic function, and wall thickness were all within normal limits. The mean amplitude of long-axis excursion in patients was normal at the LV site, but that of the right ventricular (RV) free wall was significantly reduced as compared with control subjects (1.6+/-0.4 vs. 2.2+/-0.4 cm, respectively; p<0.001), which was found to correlate with the degree of hypoxemia (r = 0.63; p<0.02) and hypercapnia (r = -0.68; p<0.01). RV diastolic function, which was represented by the relative isovolumic relaxation time to cardiac cycle length, was longer in patients than in control subjects (8.7+/-4.8% vs. 5.0+/-3.0%, respectively; p<0.03). The pulmonary flow acceleration time (90+/-22 vs 121+/-34 ms, respectively; p<0.01) and the systolic stroke distance (7.0+/-2.2 vs. 10.5+/-1.9 cm/s(2); p<0.001) were both lower than normal. This study confirms the presence of significant RV systolic and diastolic dysfunction in the setting of consistent tachycardia and increased cardiac output in adult CF patients with severe disease. No specific LV abnormalities were detected in these patients.

Noninvasive Ventilation: Past, Present, and Future: A Focus on Pediatric Applications

Noninvasive ventilation (NIV) is a technique of augmenting alveolar ventilation without requiring an indwelling artificial airway. Use of negative pressure ventilation began in the 1830s and antedates the development of artificial airways by almost a century. It has had a long history of success in the treatment of chronic respiratory failure in patients with neuromuscular disease, thoracic dysplasia, or central hypoventilation. In the 1980s, the concept of body ventilation evolved to include negative pressure ventilation and positive pressure ventilation via nasal mask. Nasal mask positive pressure ventilation has several advantages compared with negative pressure ventilation. It is more portable, easier to use and to fit, causes less discomfort, and avoids upper airway obstruction. Many additional uses of nasal mask positive pressure ventilation have been explored in pediatric practice, including treatment of patients with acute and chronic respiratory failure. NIV has been successfully used in pediatric patients with end-stage cystic fibrosis and hypercapnic respiratory failure, as a bridge to lung transplant, as a bridge to liberation from invasive mechanical ventilation, in children with transient upper airway obstruction, in hypoxemic respiratory insufficiency associated with pneumonia, in acute chest syndrome in patients with sickle cell disease, and for exacerbation of reactive airway disease. It may be particularly useful in patients whose underlying conditions warrant avoidance of tracheal intubation, especially patients who are immune-compromised. As in a review of any technology, potential and reported complications of NIV are discussed, and pediatric indications and relative contraindications are outlined. Clin Pulm Med 2000;7(4):199-207

Palliative Care in Cystic Fibrosis

Although advances in therapy for cystic fibrosis (CF) have dramatically increased the average life span of patients, the disease is still uniformly fatal. Little attention has been paid to methods of palliative care for patients with cystic fibrosis in the medical literature. The primary palliative care issue in end-stage CF is the management of dyspnea. An observational study done at Children's Hospital in Boston suggested that doses of morphine in the range of 5 mg per hour can control the end-stage dyspnea in CF of over 50% of patients; the rest required increasing doses with the highest dose required being 30 mg/hour. The use of mechanical ventilation at the end of life is increasing in CF, particularly for those patients awaiting lung transplantation, and it appears that the consensus against the use of aggressive care at the end of life in CF may be eroding. The use of various modes of assisted ventilation in end-stage CF will add new challenges to the compassionate provision of end-of-life care. In addition to these medical issues, palliative care in CF presents some unique psychosocial issues: there may be more than one family member with the disease, and there is an involved patient community also affected by end-of-life plans. A family-centered approach to end-of-life care for patients with CF is essential.

Lung transplantation and end of life issues in cystic fibrosis.

Lung transplantation has been available as a therapeutic option for patients with end-stage cystic fibrosis lung disease for over 15 years, but the outcome following transplantation remains poor, and the supply of organs limited. For this reason some children opt to continue with medical treatment followed by terminal care rather than undergo transplantation. This article summarizes the current status of lung transplantation, including current referral guidelines and contraindications and also addresses current practice in terminal care.

Neutrophils enhance expression of inducible nitric oxide synthase in human normal but not cystic fibrosis bronchial epithelial cells.

The bronchial epithelium in cystic fibrosis (CF) expresses very low levels of the inducible form of nitric oxide synthase (iNOS). The product of iNOS, nitric oxide (NO), mediates anti-microbial effects and can reduce neutrophil sequestration in the lung. Heavy neutrophilic infiltration of the pulmonary epithelium is a major feature of the end-stage CF lung. This study hypothesized that the system whereby the pulmonary epithelium protects itself against exaggerated neutrophilic infiltration by producing NO is compromised in CF. Human neutrophils were activated by incubation with cytokines, added to monolayers of normal (16HBE14o-) and CF (CFBE41o-) bronchial epithelial cells and co-cultured for up to 72 h. Marked up-regulation of iNOS protein expression was seen in normal bronchial epithelial cells following neutrophil co-culture but the CF cells showed a significantly smaller increase (p<0.001). To determine whether the relative lack of protein was due to a defect in translation, RT-PCR of iNOS mRNA was carried out and a pattern of mRNA expression was seen paralleling that of the protein. The reduced production of NO by CF compared with normal epithelium was shown by the presence of significantly (p<0.001) less accumulated nitrites in medium after co-culture with neutrophils. In summary, this study shows that the normal production of NO by bronchial epithelium in response to contact with neutrophils is lacking in CF. As NO has been shown to oppose neutrophil sequestration, its relative lack in CF may underlie the heavy neutrophilic infiltration that characterizes the disease.

Neutrophils enhance expression of inducible nitric oxide synthase in human normal but not cystic fibrosis bronchial epithelial cells

The bronchial epithelium in cystic fibrosis (CF) expresses very low levels of the inducible form of nitric oxide synthase (iNOS). The product of iNOS, nitric oxide (NO), mediates anti-microbial effects and can reduce neutrophil sequestration in the lung. Heavy neutrophilic infiltration of the pulmonary epithelium is a major feature of the end-stage CF lung. This study hypothesized that the system whereby the pulmonary epithelium protects itself against exaggerated neutrophilic infiltration by producing NO is compromised in CF. Human neutrophils were activated by incubation with cytokines, added to monolayers of normal (16HBE14o-) and CF (CFBE41o-) bronchial epithelial cells and co-cultured for up to 72 h. Marked up-regulation of iNOS protein expression was seen in normal bronchial epithelial cells following neutrophil co-culture but the CF cells showed a significantly smaller increase (p<0.001). To determine whether the relative lack of protein was due to a defect in translation, RT-PCR of iNOS mRNA was carried out and a pattern of mRNA expression was seen paralleling that of the protein. The reduced production of NO by CF compared with normal epithelium was shown by the presence of significantly (p<0.001) less accumulated nitrites in medium after co-culture with neutrophils. In summary, this study shows that the normal production of NO by bronchial epithelium in response to contact with neutrophils is lacking in CF. As NO has been shown to oppose neutrophil sequestration, its relative lack in CF may underlie the heavy neutrophilic infiltration that characterizes the disease.

Neuropsychological Sequelae in a Series of Patients with End-Stage Cystic Fibrosis: Lung Transplant Evaluation

There has been a relative absence of studies that examine the neuropsychological profiles of patients suffering from cystic fibrosis. Data are presented here for 18 individuals with end-stage cystic fibrosis who were also potential candidates for lung transplantation. Neuropsychological test results indicated a diversity of memory and executive control deficits, the most frequent of which were immediate and delayed free recall and retrieval impairments on a memory measure involving noncontextual verbal material. The majority of this sample of patients suffering from cystic fibrosis also exhibited clinically significant elevations on the Minnesota Multiphasic Personality Inventory-2 and Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-2/MMPI-A), which are suggestive of heightened levels of psychological distress (e.g., depressive symptomatology) and multiple somatic complaints. These findings are discussed in light of factors associated with end-stage cystic fibrosis. Implications for clinical practice and future research are also provided.

Neuropsychological Sequelae in a Series of Patients with End-Stage Cystic Fibrosis: Lung Transplant Evaluation

There has been a relative absence of studies that examine the neuropsychological profiles of patients suffering from cystic fibrosis. Data are presented here for 18 individuals with end-stage cystic fibrosis who were also potential candidates for lung transplantation. Neuropsychological test results indicated a diversity of memory and executive control deficits, the most frequent of which were immediate and delayed free recall and retrieval impairments on a memory measure involving noncontextual verbal material. The majority of this sample of patients suffering from cystic fibrosis also exhibited clinically significant elevations on the Minnesota Multiphasic Personality Inventory-2 and Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-2/MMPI-A), which are suggestive of heightened levels of psychological distress (e.g., depressive symptomatology) and multiple somatic complaints. These findings are discussed in light of factors associated with end-stage cystic fibrosis. Implications for clinical practice and future research are also provided.

Assessment for lung transplantation in cystic fibrosis.

Lung transplantation has been available as a therapeutic option for patients with end-stage cystic fibrosis (CF) lung disease from the mid-1980s. Since this time, in excess of 700 CF patients have undergone the procedure worldwide, as recipients of heart-lung, double lung, or more rarely single lung cadaveric transplants. A small number of CF patients have received living donor lobar transplants, but this procedure has been performed rarely in the UK. Survival following heart-lung or double lung cadaveric transplantation is poorer than for other solid organ transplants, with the International Registry reporting survival of 60-70% at 1 year and 30-40% at 5 years for both procedures1 (Figure 1). These survival figures vary little between major centres, and are improving only slowly. However, there is increasing evidence that correctly timed transplantation does provide patients with a significant increase in longevity, in addition to an improved quality of life2'3. As the potential benefits of the procedure become better understood, the number of potential recipients is increasingly outweighing the number of suitable donors. This has the effect of increasing waiting times for organs, with a number of patients not surviving the waiting period. This is an international problem, affecting all solid organ transplants, and is unlikely to be resolved in the near future. As post-transplant survival is relatively poor, patients must not be transplanted too early, or the potential survival benefit from the procedure is reduced. Conversely, if patients are accepted for transplantation too late, the likelihood of them receiving organs is reduced, with the assessment and acceptance for transplantation merely offering them false hope. The first goal of transplant assessment is, therefore, assessment of risk. Furthermore, if patients with particularly poor posttransplant survival potential can be identified, they can either be counselled against transplantation, or offered tailored post-transplant care in an attempt to improve their outcome. The second goal of transplant assessment is, therefore, identification of absolute and relative contraindications. ii

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis.

Mannose-binding lectin (MBL) is a key factor in innate immunity, and lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Accordingly, we investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, we estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. Presence of MBL variant alleles is therefore associated with poor prognosis and early death in patients with CF.

Playing for time: Adolescent perspectives of lung transplantation for cystic fibrosis

A single-case study approach was used to provide an in-depth examination of the special events surrounding the decision of a 21-year-old adolescent to undergo lung transplantation for end-stage cystic fibrosis. The central theme “playing for time” characterized the interplay between the disease progression and adolescent development as illustrated by 3 subthemes: (a) a strange balance; (b) playing chicken; and (c) being listed. The adolescent's developmental needs provided the context for the struggle with the competing demands of physiologic and psychologic readiness for the transplant, quality-of-life issues, and a renewed hope for the future. Developmental needs were more important to the adolescent than the opportunity for increased length of survival provided by lung transplantation. Advanced practice nurses are in an excellent position to provide continuity of care for chronic illness management over time and across settings.

Use of bilevel positive airway pressure (BIPAP) in end-stage patients with cystic fibrosis awaiting lung transplantation.

Nine consecutive end-stage patients with cystic fibrosis (CF) awaiting lung transplantation were admitted to the pediatric intensive care unit (PICU) in respiratory decompensation. They all received noninvasive bilevel positive airway pressure (BIPAP) support and were evaluated to determine whether or not it improved their oxygenation and provided them with long-term respiratory stability. BIPAP was applied to all patients after a brief period of assessment of their respiratory status. Inspiratory and expiratory positive airway pressures (IPAP, EPAP) were initially set at 8 and 4 cm H2O respectively. IPAP was increased by increments of 2 cm H2O and EPAP was increased by 1 cm H2O increments until respiratory comfort was achieved and substantiated by noninvasive monitoring. Patients were observed in the PICU for 48 to 72 hours and then discharged to home with instructions to apply BIPAP during night sleep and whenever subjectively required. Regular follow-up visits were scheduled through the hospital-based CF clinic. The patients' final IPAP and EPAP settings ranged from 14 to 18 cm H2O and 4 to 8 cm H2O, respectively. All nine patients showed a marked improvement in their respiratory status with nocturnal use of BIPAP at the time of discharge from the PICU. Their oxygen requirement dropped from a mean of 4.6 +/- 1.1 L/min to 2.3 +/- 1.5 L/min (P < 0.05). Their mean respiratory rate decreased from 34 +/- 4 to 28 +/- 5 breaths per minute (P < 0.05). The oxygen saturation of hemoglobin measured by pulse oximetry, significantly increased from a mean of 80% +/- 15% to 91% +/- 5% (P < 0.05). The patients have been followed up for a period of 2 to 43 months and have all tolerated the use of home nocturnal BIPAP without any reported discomfort. Six patients underwent successful lung transplantation after having utilized nocturnal BIPAP for 2, 6, 14, 15, 26, and 43 months, respectively. Three patients have utilized home BIPAP support for 2, 3, and 19 months, respectively, and continue to await lung transplantation. An acute development of refractory respiratory failure resulted in the demise of the remaining three patients after having utilized BIPAP for 3, 6, and 10 months, respectively. The authors conclude that BIPAP therapy improves the respiratory status of decompensating end-stage CF patients. It is well tolerated for long-term home use and provides an extended period of respiratory comfort and stability for CF patients awaiting lung transplantation.

Lung transplantation for cystic fibrosis: effective and durable therapy in a high-risk group

Background. The purpose of this study was to review our experience with lung transplantation in patients with end-stage cystic fibrosis. Methods. Eight-two patients with cystic fibrosis have undergone bilateral lung transplantation (n = 76) or bilateral lower lobe transplantation (n = 6) since October 1990. Results. Actuarial survival for the entire cohort is 79% at 1 year and 57% at 5 years. The development of bronchiolitis obliterans syndrome is the leading cause of death after the first year. Freedom from bronchiolitis obliterans syndrome is 84% at 1 year and 51% at 3 years. Pulmonary function tests improve dramatically in recipients. There was no association between death within 1 year and recipient age, weight, graft ischemic time, cytomegalovirus seronegativity, or the presence of panresistant organisms. Similarly, there was no association between the development of bronchiolitis obliterans syndrome within 2 years and ischemic time, number of rejection episodes, cytomegalovirus seronegativity, or the presence of panresistant organisms. Conclusions. Despite their poor nutritional status and the presence of multiply resistant organisms, patients with cystic fibrosis can undergo bilateral lung transplantation with acceptable morbidity and mortality.

Lung transplantation for cystic fibrosis.

Cystic fibrosis (CF) is an inherited disease in which the fundamental physiological defect is failure of cAMP regulation of chloride transport. More than 90% of patients with CF will die of chronic, suppurative, obstructive lung disease, with the median survival in the United States currently being 29 years of age. Currently, although other therapies are being aggressively investigated, bilateral lung transplantation offers the only hope for short-term and mid-term survival in patients with CF and end-stage pulmonary disease. Since 1989, 103 bilateral sequential lung transplants (BLT) for CF have been performed at our institution (46 pediatric, 48 adult, 9 redo) at a mean age of 21+/-10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplantation, and in 15% of adults. The hospital mortality rate was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival rates are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1+/-1.6 years). Mean forced expiratory volume in 1 second increased from 25%+/-9% pretransplantation to 79%+/-35% 1 year posttransplantation. Acute rejection occurred 1.7 times per patient-year, with the majority of these episodes taking place the first 6 months posttransplantation. Need for treatment of lower respiratory infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population, and was associated with an early mortality of 33%. Eight living donor transplants (4 primary transplants, 4 redo transplants) were performed with an early survival of 87.5%. Patients with end-stage CF can undergo BLT with morbidity and mortality comparable with that observed in pulmonary transplantation for other disease entities.

Pediatric And Adult Lung Transplantation For Cystic Fibrosis

Objective: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis. Methods: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 ± 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults. Results: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 ± 1.6 years). Mean forced expiratory volume in 1 second increased from 25% ± 9% before transplantation to 79% ± 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%. Conclusion: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities. (J Thorac Cardiovasc Surg 1998;115:404-14)

End-Stage Cystic Fibrosis: Improved Diabetes Control 2 Years After Successful Isolated Pancreatic Cell and Double-Lung Transplantation

Over a period of years, insulin-dependent diabetes and respiratory insufficiency developed in a 35-year-old patient with end-stage cystic fibrosis. After waiting more than 4 years while receiving maintenance treatment with continuous liquid O2 and nasal ventilation, the patient underwent double-lung and pancreatic islet cell transplantation. Subsequently, the patient has enjoyed a normal life with full employment and much better control of his diabetes. Pancreatic islet cell transplantation is a simple and innocuous technique easily added to the end of lung transplantation. These new pancreatic cells, although locally injected, are still secreting more than 2 years later as assessed by repeated C-peptide measurements.

Internal consistency reliability and predictive validity of a modified N. Huang clinical scoring system in adult cystic fibrosis patients.

We described a modified N. Huang scoring system and its application as a measure of disease status and progression in a population of adult cystic fibrosis patients. We evaluated the scoring for internal consistency reliability and predictive validity. We applied the scoring system to 109 adult cystic fibrosis patients followed at the Montreal Chest Institute. Complete data were available on 36 deceased patients. The total score represented the sum of the clinical, radiological and pulmonary function subscores, minus the complications subscore. It ranged between 0 (worst health) and 100 points (best health). The total score showed a high degree of internal consistency and reliability with an estimated Cronbach coefficient alpha of 0.934. Both total score and forced expiratory volume in one second (FEV1) percentage predicted were significant predictors of survival at 36 and 24 months. However, there was a progressive decrease in the discriminating power of FEV1 percentage pred for predicting survival at 24, 18, 12 and 6 months. The total score showed a progressive and consistent pattern clearly predicting the outcome. A total score < 41, < 38, < 35 and < 30 points was associated with a poor prognosis for survival at 24, 18, 12, and 6 months, respectively. The clinical and complications subscores were the most discriminating components of the total score. The total score of the modified N. Huang scoring system offered a better discriminating scale, as compared to forced expiratory volume in one second % predicted, in the prognostic evaluation of end-stage cystic fibrosis patients. It could be of value in decisions for lung transplantation in these patients.

A prognostic model for the prediction of survival in cystic fibrosis.

BACKGROUND: The treatment for endstage cystic fibrosis is, where appropriate, double-lung, heart-lung or, occasionally, heart-lung-liver transplantation. Optimising the timing of transplantation depends upon an accurate prediction of survival, but while...

Allergic bronchopulmonary aspergillosis in lung allograft recipients

Following lung transplantation for end-stage cystic fibrosis, two male patients presented with shortness of breath, peripheral blood eosinophilia and segmental lung collapse. At bronchoscopy, each had bronchial mucous plugging containing Aspergillus fumigatus. This finding was associated with a systemic eosinophilia and skin test positivity to Aspergillus. Augmented steroid therapy resulted in the successful resolution of the symptoms. We believe that these are the first reported cases of allergic bronchopulmonary aspergillosis in lung allograft recipients.