Carl F. Doershuk

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.

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

Abstract 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

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.

A 5 YEAR CLINICAL EVALUATION OF A THERAPEUTIC PROGRAM FOR PATIENTS WITH CYSTIC FIBROSIS.

A clinical evaluation of a comprehensive prophylactic therapeutic program for patients with cystic fibrosis is presented. Ninety-six consecutive patients were followed for 18 to 60 months (average 37 months) and evaluated with the use of a modification of the Shwachman scoring system. Eighty-two per cent of these patients showed improvement, 11% remained the same, 4% showed progression beyond their initial status, and only 3% died. None of the deaths occurred before 5 years of age. Evidence is presented supporting the desirability of early diagnosis and the early institution of an intensive prophylactic and therapeutic regimen.

Comparison of a β-lactam alone versus β-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis

We determined whether a β-lactam and an aminoglycoside have efficacy greater than a β-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. Study design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. Results: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P = .034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P < .001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. Conclusion: We conclude that the combination of a β-lactam and an aminoglycoside produces a longer clinical remission than a β-lactam alone and slightly better initial improvement. (J Pediatr 1999;134:413-21)

A THERAPEUTIC REGIMEN FOR PATIENTS WITH CYSTIC FIBROSIS.

A comprehensive therapeutic regimen for patients with cystic fibrosis has been evolved, in part empirically, based on our understanding of the pathogenesis of the pulmonary lesion and in large part supported by the results of clinical and pulmonary function evaluations. The aims of this regimen are the maintenance of adequate pulmonary hygiene both prophylactically and therapeutically, effective control of the pulmonary infection, and comprehensive care of the patient. Prophylactic pulmonary therapy is instituted as soon as the diagnosis is made regardless of whether or not active pulmonary involvement is present. Pulmonary infection when present is treated specifically and intensively and is kept at a minimum by monthly clinical and laboratory evaluation of the patient.

DEVELOPMENTAL SEQUELAE OF LONG‐TERM INFANT TRACHEOSTOMY

The records of 130 children who had had a tracheostomy for more than one month between 1972 and 1982 were reviewed for birth, medical and demographic characteristics, and 32 who were not severely physically or mentally handicapped were followed up at a mean age of 5 · 5 years. Rates of mortality and morbidity were high, and half of the survivors had moderate to severe intellectual and physical impairments. Even those with the most optimal outcome had significant developmental problems, including slower growth‐rate and higher than normal incidences of behavior problems and speech difficulties. Most survivors needed special educational intervention or rehabilitative therapies.

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. Pediatr Pulmonol. 1998;25:304–308.

Longterm histopathologic follow-up of bronchial arteries after therapeutic embolization with polyvinyl alcohol (Ivalon) in patients with cystic fibrosis.

We used light microscopy to examine, at autopsy, bronchial arteries in three patients with cystic fibrosis who died, respectively, 10, 16, and 28 months after bronchial artery embolization with barium sulfate-impregnated polyvinyl alcohol (PVA) to control hemoptysis. PVA was not identified beyond the midsegmental bronchus in any patient. Persistent focal fibrovascular occlusion was noted in two patients, and recanalized and/or partially obstructed vessels were associated with PVA in all. The histologic reaction to PVA included fibrosis, mild chronic inflammation, localized foreign body reaction, and, in two patients, focal calcification of PVA spicules. Within the inflammatory milieu were numerous macrophages containing BaSO4. Extensive vascular mural destruction and fibrosis associated with PVA were also observed. Both PVA and BaSO4 were also frequently present in the perivascular connective tissue. These findings indicate that, although longterm occlusion persists after therapeutic arterial embolization with PVA, focal recanalization also occurs. The extent of vascular mural injury following PVA embolization in humans has been previously underestimated by animal experiments. Finally, perivascular deposition of PVA represents a common reaction to diverse foreign body emboli in both systemic and pulmonary arteries.

Symptomatic Hepatic Disease In Cystic Fibrosis: Incidence, Course, And Outcome Of Portal Systemic Shunting

Fifteen (2.2%) of 693 patients with cystic fibrosis seen over an 18-year period developed clinical hepatic disease. In 13 patients all symptoms were secondary to portal hypertension. Ten had hypersplenism and 6 had variceal bleeding, including 3 who developed both conditions. All 5 patients who survived the initial episode of gastrointestinal bleeding underwent portal systemic shunting. A shunting procedure also was performed on 1 patients with hypersplenism but no variceal bleeding. No subsequent deterioration of intellectual function occurred in either the shunted or unshunted patients. Only 1 of the shunted patients showed progression of hepatic disease after surgery. These results suggest that portal systemic shunting is useful in the treatment of bleeding esophageal varices in cystic fibrosis. A sweat test to rule out cystic fibrosis should be included in the evaluation of any teenage or young adult patient with unexplained portal hypertension.