Pregnancy in cystic fibrosis. Fetal and maternal outcome.

OBJECTIVE: To assess the effect of pregnancy on pulmonary function and survival in women with cystic fibrosis (CF) and to assess the fetal outcome. DESIGN: Cohort study. The data analyzed were collected from the Toronto CF database, chart review, and patient questionnaire. SETTING: Tertiary-care center. PATIENTS: All women with CF who, at the time of diagnosis or pregnancy, attended the Toronto Cystic Fibrosis Clinics between 1961 and 1998. RESULTS: From 1963 to 1998, there were 92 pregnancies in 54 women. There were 11 miscarriages and 7 therapeutic abortions. Forty-nine women gave birth to 74 children. The mean follow-up time was 11 +/- 8 years. One patient was lost to follow-up shortly after delivery, and one was lost after 12 years. The overall mortality rate was 19% (9 of 48 patients). Absence of Burkholderia cepacia (p < 0.001), pancreatic sufficiency (p = 0.01), and prepregnancy FEV(1) > 50% predicted (p = 0.03) were associated with better survival rates. When adjusted for the same parameters, pregnancy did not affect survival compared to the entire adult female CF population. The decline in FEV(1) was comparable to that in the total CF population. Three women had diabetes mellitus, and seven developed gestational diabetes. There were six preterm infants and one neonatal death. CF was diagnosed in two children. CONCLUSIONS: The maternal and fetal outcome is good for most women with CF. Risk factors for mortality are similar to those for the nonpregnant CF population. Pregnancies should be planned so that there is opportunity for counseling and optimization of the medical condition. Good communication between the CF team and the obstetrician is important.

Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of hypoxemia.

STUDY OBJECTIVES: To determine (1) the prevalence of pulmonary hypertension and cardiac dysfunction in adult cystic fibrosis (CF) patients with severe lung disease, (2) the relationship between these cardiovascular abnormalities and hypoxemia, and (3) the impact of subclinical pulmonary hypertension on survival. DESIGN: Single-blind, cross-sectional study. SETTING: Ambulatory clinic of the Adult CF program at a tertiary-level hospital. PATIENTS: Clinically stable patients with severe lung disease (FEV1 < 40% of predicted normal value) who were not receiving supplemental oxygen. A second cohort of patients in stable condition with less severe lung disease (FEV1 40 to 65% predicted) was also recruited to enable multivariate analysis for the determinants of pulmonary hypertension. MEASUREMENTS AND RESULTS: Eighteen patients with severe lung disease (FEV1 28 +/- 7% of predicted normal value) were initially studied. Each patient had overnight polysomnography, pulmonary function tests, and Doppler echocardiography. Arterial oxygen saturation (SaO2) was reduced during wakefulness (87.1 +/- 6.1%) and fell during sleep (84.0 +/- 6.6%) while transcutaneous PCO2 was normal during wakefulness (41.1 +/- 6.9 mm Hg) and increased during sleep (46.6 +/- 4.7 mm Hg). Left ventricular size, systolic function, and diastolic function were normal except in one patient who had had a previous silent myocardial infarction due to coronary artery disease. Qualitative assessment of right ventricular function was normal in all patients. Pulmonary artery systolic pressure (PASP) was increased (> 35 mm Hg) in seven patients without clinical evidence of cor pulmonale. Regression analysis was performed by combining these data with data from an additional 15 CF patients with moderately severe lung disease (FEV1 56.3 +/- 8.9% predicted normal) who were recruited to a modified study protocol that included overnight oximetry, pulmonary function tests, and Doppler echocardiography. None of these patients had evidence of hypoxemia and only three had mild elevation of PASP (36, 37, and 39 mm Hg). Linear regression analysis revealed that PASP was significantly correlated with FEV1 (r = -0.44; p = 0.013), and SaO2 during wakefulness (r =-0.60; p = 0.0003), during sleep (r = -0.56; p = 0.0008), and after 6 min of exercise (r = -0.75; p < 0.0001). Multivariate analysis revealed that awake SaO2 was a significantly better predictor of PASP than FEV1 (p = 0.0104). Clinical follow-up of the original cohort for up to 5 years revealed that mortality was significantly higher in those with pulmonary hypertension than those without pulmonary hypertension (p = 0.0129). CONCLUSIONS: In adult CF patients with severe stable lung disease, left and right ventricular function is well maintained in the absence of significant coronary artery disease; pulmonary hypertension develops in a significant proportion of patients and is strongly correlated with oxygen status, independent of lung function; and subclinical pulmonary hypertension is associated with an increased mortality.

Comparison of culture and PCR for detection of Burkholderia cepacia in sputum samples of patients with cystic fibrosis.

We investigated the utility of PCR to detect Burkholderia cepacia directly in sputum samples at two cystic fibrosis (CF) centers serving children and adults. Following liquefaction of the sputa by using N-acetyl-L-cysteine, DNA was isolated and analyzed by PCRs with three different primer pairs directed toward bacterial rRNA loci. Two primer pairs were putatively specific for B. cepacia. The other pair, which universally amplifies a band from all bacteria, served as a control. Sputum samples were obtained from 219 patients and analyzed independently by culture and by PCR to detect B. cepacia. The analyses were performed blinded with respect to each other. The results of the PCR with sputa demonstrated that the primers directed to the 16S loci demonstrated approximately 95% concordance with culture results and were more specific than those amplifying the 16S to 23S spacer region. In addition, the 16S primer pair putatively identified B. cepacia in seven patients whose sputa were culture negative at this time. Of these culture-negative patients, five had sputum samples that were culture positive for B. cepacia either prior or subsequent to this study. The results of this study indicate the utility of PCR as a diagnostic method for the rapid identification of B. cepacia in sputum samples of CF patients. We anticipate that improvements in our taxonomic understanding may allow the design of more specific primers for detection of each species of the B. cepacia complex in sputum samples.

Transverse myelitis: a reversible complication of bronchial artery embolisation in cystic fibrosis.

The case history is presented of a young woman with cystic fibrosis and life threatening haemoptysis. Angiography revealed enlarged bronchial vessels, one of which supplied the contralateral lung. Transverse myelitis developed following bronchial artery embolisation but recovery was rapid and nearly complete. Haemoptysis did not recur during four years of follow up.

Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment.

Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase.

Quality of life in cystic fibrosis.

Cystic fibrosis is a chronic, multisystem genetic disease with a wide variability in clinical severity. In recent years, advances in therapy have led to improved patient survival into adulthood. New treatments are rapidly being developed and require evaluation to determine their efficacy. The measurement of health-related quality of life in cystic fibrosis provides additional information about the impact of this disease that cannot be obtained by physiological tests such as pulmonary function. An instrument to measure health-related quality of life is especially useful as an outcome measure for clinical trials. To date, only a few general quality-of-life (QOL) measures have been used in people with cystic fibrosis. There has been some demonstration of validity in 2 measures (the Quality of Well-Being Scale and the Functional Status Index) but the responsiveness of these instruments in this population has not been established. A cystic fibrosis-specific QOL instrument would be valuable as an outcome measure because of its potential for increased responsiveness, but no published measures exist as yet.

Infectious complications following isolated lung transplantation.

STUDY OBJECTIVE: To ascertain the incidence, types, morbidity, and mortality of infectious episodes in isolated lung transplant recipients. DESIGN: Retrospective chart review of patients who have undergone transplants over a six-year period in one institution. PATIENTS: Twenty-three single and 17 double lung transplants followed up between 2 and 68 months. RESULTS: Fifty-one episodes of infection occurred in the group with a slight predominance in the double lung transplants. The 32 episodes of bacterial infection constituted the largest group of infection and more than half of these were pneumonias. Organisms identified were predominantly Gram negative. While bacterial processes made up the bulk of infections, fatalities were rare. Viral and fungal infections were less common, but more often fatal. Of six cases of viral pneumonitis, two were fatal; two of five cases of invasive fungal infection were also fatal. Overall, six patients died of infection. CONCLUSION: Our findings support previous reports from heart-lung centers documenting a high rate of infectious complications, particularly pneumonia, in recipients of lung grafts. In our experience, bacterial infections are the most common (two of three infections), but have the lowest mortality. Efforts should be directed toward establishing effective prophylaxis programs and early detection of infection.

Cytomegalovirus infection in isolated lung transplantations.

The course of 52 isolated single and double lung transplant recipients who survived more than 2 weeks was reviewed to determine the incidence of cytomegalovirus (CMV) infection. In this group 22 patients were seromatched: 11 donor-recipient pairs were seronegative and 11 were seropositive. Of the remaining 30, 13 were donor-positive, recipient-negative and 17 were donor-negative, recipient positive. Diagnosis of CMV infection was made in the event of (1) seroconversion, (2) clinical symptoms consistent with CMV plus a fourfold rise in CMV titer, (3) isolation of CMV from tissue or body fluid by shell vial monoclonal antibody technique. CMV pneumonitis was diagnosed when shell vial culture from bronchoalveolar lavage fluid was positive in the appropriate clinical setting even if cytopathic changes were not yet present. Clinical CMV infection did not develop in any of the 22 seromatched pairs, and none of the seronegative pairs seroconverted. Of 17 recipient-positive, donor-negative pairs, CMV pneumonitis developed in two; one died. Of 13 recipient-negative, donor-positive pairs, seven seroconverted and pneumonitis developed in two but they did not die. The most recent 10 mismatched pairs received hyperimmune globulin prophylaxis, but this did not prevent the development of infection or clinical disease. Morbidity and mortality were greater in the seromismatched groups than in seromatched groups although this difference could not be directly related to CMV infection in most cases. Our experience suggests that both seronegative and seropositive recipients who receive a mismatched graft, but not the usual high-risk seropositive matched pairs, are at significant risk of clinical CMV disease after isolated single and double lung transplantation.