Timing of referral for lung transplantation for cystic fibrosis: overemphasis on FEV1 may adversely affect overall survival.

STUDY OBJECTIVES: (1) Report our experience with referral for lung transplantation. (2) Review survival in cvstic fibrosis (CF) patients without lung transplantation after FEV1 remains < 30% predicted for 1 years. DESIGN: Retrospective review. SETTING: A university hospital CF center. PATIENTS: (1) Forty-five patients referred for lung transplantation evaluation, and (2) 178 patients without Burkholderia sp infection, with the above FEVl criterion. MAIN OUTCOME MEASURE: Survival. MEASUREMENTS AND RESULTS: (1) One- and 2-year survival after transplantation was 55% and 45%, respectively. However, among patients without transplants with FEVl < 30% predicted, median survival, 1986 to 1990, ie, before the transplant era, was 4.6 years with 25% living > 9 years (before 1986, 25% lived > 6 vears). (2) Survival after transplantation was not correlated to any of the following: age, sex, genotype, FEVI percent predicted, insulin-dependent diabetes mellitus, or with waiting time before transplantation, and did not seem to be correlated to serum bicarbonate or percent ideal body weight. Four of five patients already infected with Burkholderia species died within 5 months of transplantation; the fifth died at 17 months. All five died of pulmonary or extrapulmonarv infection with Burkholderia species CONCLUSIONS: Use of FEV! < 30% predicted to automatically establish transplantation eligibility could lead to decreased overall survival for CF patients. Referral for evaluation and transplantation should also be based on oxygen requirement, rate of deterioration, respiratory microbiology, quality of life, frequency of IV antibiotic therapy, and other considerations. If pulmonary status has unexpectedly improved when the patient is at or near the top of the waiting list, total survival may be improved by "inactivating the patient" until progression is again evident.

Stenotrophomonas maltophilia in cystic fibrosis: incidence and prevalence.

Stenotrophomonas maltophilia (SM) was recovered from 211 of 773 cystic fibrosis (CF) patients followed for at least one year, and seen between 1982 and 1994. Yearly prevalence (5.6% to 8.7%) and incidence rates (1.6% to 5.7%) showed no trends. SM persistence varied greatly and was unlike that of Pseudomonas aeruginosa. Fifty percent of SM-positive patients had only one positive culture and only 24 (11%) remained chronically infected. Although SM-positive patients were more likely to be hospitalized than SM-negative patients, for 55% of SM-positive patients, acquisition did not appear to follow hospitalization. Of 40 SM-positive patients who had a CF sibling, only 10 siblings were ever culture positive. When stratified by FEV1, the two-year survival for SM-positive with mild/moderate disease (98%) and severe disease (78%) was similar to that of our SM-negative patients. Five-year survival was only 40% for SM-positive patients with initially severe pulmonary status, compared with 72% for the SM-negative patients. Seventy percent of the original SM isolates were panresistant (susceptible to no more than one antimicrobial agent). Ten years later, panresistance was 84%. Despite our reassuring experience with SM, including lack of sibling concordance, the fact that the majority of our patients had no hospital exposure prior to acquisition, the high incidence of transient infection, and the seemingly unaffected two-year survival, there are insufficient data to definitively conclude that segregation of these patients would be beneficial. The increasing prevalence of multiply resistant gram-negative pathogens in CF patients suggests the need for continued caution with any panresistant pathogen.

Sodium space and intravascular volume: dietary sodium effects in cystic fibrosis and healthy adolescent subjects.

OBJECTIVE: To assess the physiologic response to salt depletion in subjects with cystic fibrosis (CF) and control male adolescents for sodium balance, sodium space, and stimulation of the renin-angiotensin-aldosterone axis. DESIGN: Seven subjects with CF and six controls received a salt-replete (150 or 290 mmol NaCl per day) diet and then a salt-deplete (10 mmol NaCl per day) diet while in a clinical research center. RESULTS: Space maintenance: CF subjects responded to salt depletion with a greater weight loss than did controls (1.9 vs 0.8 kg) and a decrease in 24Na+ space, whereas controls maintained 24Na+ space. Paired (Na-deplete/Na-replete) blood volumes decreased in subjects with CF, but not in controls. Renin-angiotensin-aldosterone axis stimulation: During salt repletion, subjects with CF had significantly higher aldosterone values than did controls in the afternoon, but not at 7:00 AM. During salt depletion, plasma renin activity and aldosterone increased significantly more in subjects with CF than in controls (renin, 35 vs 13 ng/mL/hour [9.7 vs 3.6 ng.L-1 s-1]; aldosterone: 181 vs 101 ng/dL [5021 vs 2802 pmol/L]). Furthermore, the angiotensin antagonist saralasin increased renin much more in subjects with CF (154 vs 36 ng/mL per hour [43 vs 10 ng.L-1 s-1]). Vasomotor functions: Mean arterial pressure was decreased in subjects with CF on both diets and decreased significantly more with low salt only in subjects with CF. During salt depletion, subjects with CF showed enhanced orthostatic tolerance (less heart rate increase with standing) compared with controls, thus obscuring their volume loss. The blood pressure response to an acute infusion of saralasin suggested that in salt-replete subjects with CF, but not in controls, angiotensin receptors were functional in maintaining vascular tone. During salt depletion, angiotensin was more important for maintenance of blood pressure in subjects with CF than in controls, because the saralasin-induced drop in blood pressure was 20%, ie, close to shock levels, in subjects with CF, and only 6% in controls. CONCLUSION: The data suggest that patients with CF are so successful in compensating for volume depletion by vigorous activation of the renin-angiotensin system that salt depletion/dehydration cannot be recognized easily by routine clinical measurements, eg, capillary refill, serum sodium levels, or tachycardia.

Pulmonary intralobar sequestration in a patient with cystic fibrosis.

We report a case in which pulmonary Intralobar Sequestration (ILS) was an incidental finding at autopsy in an adult with Cystic Fibrosis. Two aberrant arteries from the descending thoracic aorta supplied a bronchial cystic lesion in the right lower lobe. Termination of the segmental bronchus and scar formation proximal to the cyst suggested prior bronchial obliteration. The elastic configuration of the aberrant aortic-derived vessels of the sequestration contrasted sharply with massively hypertrophied, muscular, bronchial arteries which supplied the bronchiectatic upper lobe. Sections of inferior pulmonary ligament were studied in five additional patients with CF but without ILS. Small muscular arteries were consistently noted within the inferior pulmonary ligament. These histologic findings support the concept that the vascular portion of ILS is congenital, whereas the bronchocystic component, in some cases, may be acquired.

Nontuberculous mycobacteria in cystic fibrosis. An autopsy study.

We retrospectively studied lung and hilar lymph nodes at autopsy in 18 patients with cystic fibrosis (CF) who had antemortem sputum cultures positive for nontuberculous mycobacteria (NTM). Histologic features were compared with those of 18 patients with CF who had negative antemortem cultures. The most frequent species isolated was M. chelonae group (10 patients). Multiple cultures were positive for NTM in six patients. Three patients were clinically considered to be infected, and two received antimycobacteria drugs. Necrotizing pulmonary granulomas associated with granulomatous organizing pneumonia were found at autopsy in two patients, each of whom had multiple positive sputum cultures and clinical evidence of infection. In one of these, mycobacterial infection was considered to be an important factor in her terminal illness. Neither necrotizing granulomas nor granulomatous organizing pneumonia were seen in the lung tissue of patients whose antemortem cultures were negative for mycobacteria. There was no difference in the prevalence of other granuloma-like lesions between those with and those without positive sputum cultures. No mycobacteria-related granulomas occurred in hilar lymph nodes, although histoplasma granulomas involved hilar lymph nodes of three patients. We conclude that granulomatous mycobacterial lung disease is present in a minority of patients (two of six patients in this study) who have multiple positive cultures. Histologic evidence of infection was not found in patients who had only one of multiple sputum cultures positive for NTM.

Urolithiasis and cystic fibrosis.

PURPOSE: We determined whether cystic fibrosis patients are at increased risk for the development of urolithiasis. MATERIALS AND METHODS: Telephone interviews were conducted with 201 cystic fibrosis patients older than 15 years to identify those with a history of urolithiasis. Histories were confirmed by chart review, and only patients with urolithiasis documented by excretory urography, renal ultrasound or spontaneous passage of a stone were included. RESULTS: A total of 11 patients (5.5%) had documented urolithiasis, with 2 or more episodes in 7. Mean age at initial episode was 27.0 years (range 19 to 33). CONCLUSIONS: Cystic fibrosis patients may be at increased risk for urolithiasis compared to age-specific prevalence rates for stone disease in the general population.

3849+10 kb C-->T mutation and disease severity in cystic fibrosis.

50% of patients with cystic fibrosis (CF) are homozygous for the delta F508 mutation, but the remainder have at least one of many other less common mutations. The 3849 + 10 kb C-->T splice mutation seems to be associated with less severe disease. We report ten CF patients who are hemizygous for this mutation. Three male patients do not have azoospermia (sperm counts 12, 53, and 198 x 10(6)/mL). Another boy died before CF was diagnosed; his genital tract appeared normal at necropsy. All patients had clinically sufficient exocrine pancreatic function. Pulmonary disease was delayed in onset in most of these patients (range < 1 to 16; median 9 years), but then became severe in some, progressing to death (in two) and need for transplantation in one. Sweat chloride concentration was abnormal (80 mmol/L) in one patient but in others was in the intermediate range (45-65 mmol/L). There was substantial variation in pulmonary disease severity within sibships. These observations suggest some dissociation in genetically determined severity between different organs. There was some evidence among these patients of a tendency for disease of the genital tract to become progressively more severe. Perhaps sperm banking should be offered to male patients. We speculate that some normal CF transmembrane conductance regulator is made in patients with this splice abnormality.

Maternal child-rearing behavior in three groups: cystic fibrosis, insulin-dependent diabetes mellitus, and healthy children.

Compared child-rearing behaviors among mothers of children (ages 4-14) with cystic fibrosis (CF) (N = 26), insulin-dependent diabetes mellitus (IDDM) (N = 26), and mothers of physically healthy children (N = 26), on six domains, including involvement, limit setting, responsiveness, reasoning and guidance, free expression, and intimacy using the Iowa Parent Behavior Inventory. Maternal Reports of their child-rearing behavior were comparable across the three groups with one exception: Mothers of children with chronic illnesses (CF and IDDM) were significantly less likely to set limits than mothers of healthy children. The present findings are consistent with those of other studies that have identified few differences in child-rearing practices between mothers of children with chronic illnesses and mothers of healthy children. Future research should identify situation-specific parenting tasks unique to childhood chronic illness.

An expanded scoring system including an index of nutritional status for patients with cystic fibrosis.

Evaluation of success or failure of therapy for patients with cystic fibrosis (CF) commonly relies on the results of a single pulmonary function test (PFT). Most PFT measurements reflect different functional aspects of the lung. Although no single parameter can summarize all aspects of lung function, a combination of several may provide an advantage by reflecting the overall abnormality of lung function in one number. Cropp et al. (1982, Am Rev Respir Dis 126:211-216) developed a multiparameter pulmonary function score (PFS) using the results of six separate parameters obtained from a PFT. In CF, there is also the potential for declining nutritional status (NS), leading to malnutrition and skeletal muscle wasting. Our aim was to expand the PFS by including weighted information on NS, and to determine whether the expanded score (nutritional-pulmonary function score, NPFS) was more sensitive in detecting change in outcome variables than the PFS. Individual PFT parameters, percent ideal body weight (%IBW), and an index of anaerobic performance (AP) were measured in 21 patients on admission to the hospital and again at discharge. In the group as a whole, in-hospital therapy resulted in improvement (P < 0.01) in individual PFT parameters, %IBW, PFS, and NPFS, and no change in AP. While the PFS more effectively reflected improvement in lung function than did any single PFT parameter, the NPFS resulted in an even more sensitive index of change. Based on these results, we believe that the NPFS, which includes both lung and nutritional status, provides an effective and sensitive index of disease severity that can be used as a unifying measure to: 1) detect disease progression; 2) guide rehabilitation and training; 3) stratify patients for clinical trials; or 4) evaluate the effects of a therapeutic intervention.

Efficacy of the Flutter device for airway mucus clearance in patients with cystic fibrosis.

The Flutter is a handheld device designed to facilitate clearance of mucus in hypersecretory lung disorders. Exhalation through the Flutter results in oscillations of expiratory pressure and airflow, which vibrate the airway walls (loosening mucus), decrease the collapsibility of the airways, and accelerate airflow, facilitating movement of mucus up the airways. We studied 18 patients with cystic fibrosis and mild to moderate lung disease to determine the efficacy of the Flutter in clearing mucus from the airways. The amount of sputum expectorated (measured by weight) when the Flutter was used was compared with the amount expectorated with vigorous voluntary coughing and with postural drainage (chest percussion and vibration). The amount of sputum expectorated by subjects using the Flutter was more than three times the amount expectorated with either voluntary cough or postural drainage (p < 0.001). There were no adverse effects. The Flutter is simple to use, inexpensive, and fully portable, and once the patient and family are instructed in its use, it does not require the assistance of a caregiver. For hospitalized patients, elimination of the need for a therapist could reduce health care costs. Long-term studies of the use of the Flutter seem justified to determine its effects on pulmonary function and outcome.

Erosion of the wall of the frontal sinus caused by mucopyocele in cystic fibrosis.

Three patients with cystic fibrosis had complete erosion of one of the walls of a frontal sinus caused by a mucopyocele. Only fibrous tissue then separated the purulent contents of the sinus from the orbit or central nervous system. Initial surgery was unsuccessful, but two patients have remained free of symptoms after a second obliterating procedure. Sinus mucocele must be excluded by appropriate radiographic techniques when patients with cystic fibrosis have severe frontal headache and acute ophthalmologic symptoms.

Spontaneous bacterial peritonitis in cystic fibrosis.

Bacterial peritonitis presents with classic symptoms of fever and abdominal pain. Some patients, however, are completely asymptomatic. Death in the short term is considerable, especially in patients with alcoholic cirrhosis. Cystic fibrosis patients occasionally develop biliary cirrhosis and may have secondary hypersplenism, varices, and ascites. These patients should be at risk for spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is described in two patients with longstanding hepatic cirrhosis secondary to cystic fibrosis. Both had required splenectomy for complications of portal hypertension. This is a previously unreported, but potentially fatal, complication of cystic fibrosis liver disease. Early diagnostic paracentesis is essential so that appropriate acute management, including antimicrobial treatment can be started. In the long term, these patients deserve immediate paracentesis for any evidence of recurrence. Whether the patient is treated with chronic (continuous) antimicrobial prophylaxis or only receives antimicrobial treatment during periods when bacteraemia is possible (for example, dental work, bronchoscopy), it would seem reasonable in patients with cystic fibrosis to use a wide spectrum antimicrobial agent with activity against Pseudomonas aeruginosa, other common Gram negative organisms, and Staphylococcus aureus.

Long-term parenteral nutrition in cystic fibrosis.

The effects of parenteral nutrition (PN) with high lipid content were studied in 18 cystic fibrosis patients in this pilot investigation. The patients were randomly assigned to one of two groups. During the first 4-mo period, group 1 received PN and group 2 received routine therapy. During the second 4-mo period, PN was discontinued in group 1 and instituted in group 2. When the effect of PN was considered for both treatment groups, its general effect was to increase body fat content with little or no impact on respiratory function, exercise tolerance, or recurrent infections. However, subsequent analysis and clinical observation suggested that patients receiving PN responded in two seemingly distinct patterns: some demonstrated apparent clinical improvement and benefit, and others did not. A positive response in pulmonary and exercise function was closely correlated to a rise in serum dihomo-gamma-linolenic acid (DHLA) concentrations during PN. Pulmonary function improved in patients who normalized their DHLA levels (vital capacity increased from 2.2 +/- 0.3 to 2.6 +/- 0.3 area %, p < 0.05), whereas those who continued to have undetectable levels of DHLA deteriorated (forced expiratory volume in 1 s decreased from 0.7 +/- to 0.6 +/- 0.1, p < 0.001). PN applied to malnourished patients with cystic fibrosis results in beneficial effects in a subgroup characterized by the presence of DHLA in serum; for the group as a whole, the positive effects are minimal.

The nasal response to exercise in patients with cystic fibrosis.

This study has evaluated the nasal response to exercise in patients with cystic fibrosis (CF), a genetic disease in which factors such as chronic lung disease and/or nasal polyposis might be anticipated to modify nasal function responses. Measurements of nasal resistance (NAR) by posterior rhinomanometry and specific airway resistance (sRAW) were made before and 1, 5, 10, and 30 min after a 4-min period of exhausting legwork exercise (50% predicted maximal) in 19 CF patients (aged 11-29 years) and 10 healthy subjects (aged 11-31 years). One minute after exercise, healthy subjects showed a 54 +/- 5% (mean +/- SEM; standard error of the mean) relative fall from baseline in NAR and CF patients showed a 31 +/- 8% relative fall from baseline (p < 0.05). There were no significant differences in the magnitude or pattern of recovery in NAR after exercise (1 to 30 min) between the groups, largely because of the variability in NAR responses in CF patients. Exercise did not result in significant changes in sRAW in either group. We also found that a history or presence of nasal polyposis does not significantly affect functional nasal responses to exercise. Our conclusion is that the CF genotype and its airway sequelae do not substantively affect the control of the nasal response to exercise.

The prognostic value of exercise testing in patients with cystic fibrosis.

BACKGROUND: Previous studies have shown female sex, impaired pulmonary function, older age, malnutrition, and colonization of the respiratory tract with Pseudomonas cepacia to be associated with a poor prognosis in patients with cystic fibrosis. We sought to determine the prognostic value of exercise testing in addition to the other prognostic factors. METHODS: A total of 109 patients with cystic fibrosis, 7 to 35 years old, underwent pulmonary-function and exercise testing in the late 1970s. They were followed for eight years to determine the factors associated with subsequent mortality. Survival rates were calculated with standard life-table methods. Cox proportional-hazards regression models were used to determine crude relative risks of mortality and relative risks adjusted for age, sex, body-mass index, forced expiratory volume in one second (FEV1) end-tidal partial pressure of carbon dioxide (PCO2) at peak exercise, and oxygen consumption at peak exercise (VO2 peak). RESULTS: Patients with the highest levels of aerobic fitness (VO2 peak, > or = 82 percent of predicted) had a survival rate of 83 percent at eight years, as compared with rates of 51 percent and 28 percent for patients with middle (VO2 peak, 59 to 81 percent of predicted) and lowest (VO2 peak, < or = 58 percent of predicted) levels of fitness, respectively. After adjustment for other risk factors, patients with higher levels of aerobic fitness were more than three times as likely to survive than patients with lower levels of fitness. Colonization with P. cepacia was associated with a risk of dying that was increased fivefold. Age, sex, body-mass index, FEV1, and end-tidal PCO2 at peak exercise were not independently correlated with mortality. CONCLUSIONS: Higher levels of aerobic fitness in patients with cystic fibrosis are associated with a significantly lower risk of dying. Although better aerobic fitness may simply be a marker for less severe illness, measurement of VO2 peak appears to be valuable for predicting prognosis. Further research is warranted to determine whether improving aerobic fitness through exercise programs will result in a better prognosis.

Use of nonmedical treatment by cystic fibrosis patients.

To determine frequency, perceived effectiveness, and cost of religious, physical, and other nonmedical practices, we interviewed all (n = 402; 100% participation) of our cystic fibrosis patients/families [age, 0-45 (median, 18) years]. At least one type of nonmedical therapy was used by/on 264 (66%), two-thirds of which was religious. Most respondents perceived benefit (e.g., group prayer, 95%; religious articles, 81%; chiropractic, 69%). Only 17 (4.2%) invested over $200 lifetime (minimal compared with medical costs). These treatments, apparently used by most patients/families, rarely interfered with medical care. Physician openness and empathy toward patients' beliefs might enhance rapport and facilitate discussion of possible helpful or adverse effects of nonmedical treatment.

Medical and social factors as predictors of outcome in infant tracheostomy.

We examined the relative impact of infant tracheostomy in comparison to associated medical and social factors, on developmental outcome as part of a cross-sectional follow-up of 32 children. These children had no mental retardation, physical handicap, or severe neurological problems, but had a history of long-term tracheostomy in infancy, ranging from 3 to 146 months duration. Medical factors evaluated included prematurity, neurological status, severity of illness, and number of weeks hospitalized. Social factors included parental education and occupation. Outcome measures included IQ, language quotient, growth parameters, and behavioral competence. Correlation analyses, stepwise multiple regression analyses, and t-tests were used. Early medical illnesses were significant predictors of cognitive, language, and growth outcome. Severity of medical complications at birth and the presence of any neurological problem predicted 49% of the variance in IQ at follow-up. Social class was the only variable to predict behavioral outcome, accounting for 28% of the variance. For children without confounding medical conditions, tracheostomy had a negative impact on overall language and auditory comprehension. Once children with confounding medical risk factors were removed from the sample, children with history of infant tracheostomy exhibited significantly lower overall mean language scores (106 versus 120), and lower mean language comprehension scores (104 versus 119) than a matched comparison group.

The spectrum of appendiceal disease in cystic fibrosis.

A retrospective review of 1,220 cystic fibrosis (CF) patients between 1965 and 1989 identified 60 patients who underwent appendectomy. Ten had appendectomy prior to referral and 16 had an incidental appendectomy (primarily meconium ileus). Among the remaining 34 patients, acute appendicitis was present in 19 (1.8% incidence). "Classic appendicitis"--acute abdominal pain shifting to the right lower quadrant (RLQ), focal RLQ tenderness, and elevated white blood cell (WBC) count--was present in 15. Four additional inflamed appendixes were removed in patients following incorrect preoperative diagnosis. Thirteen of these 19 were perforated. Complications included wound infection (2), pelvic abscess (1), ileal obstruction requiring ileostomy (1), and pelvic hematoma (1). There were no deaths. One patient with acute RLQ pain and tenderness had a normal appendix. Seven patients (mean, 20 years) had chronic, intermittent, focal RLQ pain and tenderness not originating periumbilically with a normal WBC count and temperature. At exploration, these appendixes were enlarged and tensely distended with inspissated mucus. Microscopic examination showed no inflammation. Appendectomy resulted in resolution of symptoms without complications. Four additional patients with intermittent RLQ pain and tenderness and a history of recurrent intussusception presented with ileocolic intussusception. Persistent postreduction symptoms in three and failure of reduction in the fourth necessitated celiotomy at which time tensely distended appendixes were removed. Appendectomy led to resolution of symptoms. Three additional enlarged noninflammed appendixes were incidentally removed in asymptomatic patients undergoing unrelated intraabdominal procedures. Appendiceal disease in CF patients represents a spectrum ranging from simple mucous distention to acute appendicitis with perforation. CF patients with pain secondary to a noninflamed distended appendix represent a distinct syndrome cured by appendectomy.(ABSTRACT TRUNCATED AT 250 WORDS)