Robert C. Stern

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

The Pharmacokinetics of Colistin in Patients with Cystic Fibrosis

The safety and pharmacokinetics ofcolistin were determined after first dose (n = 30) and again under steady‐state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half‐life (t1/2), mean residence time (MRT), steady‐state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first‐dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first‐dose and steady‐state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty‐one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin‐induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin‐induced nephrotoxicity. No relationship between the occurrence of any colistin‐associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.

Purine nucleoside metabolism in the erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency.

Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients...

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.

Pneumothorax in cystic fibrosis: A 26-year experience

We reviewed the records of all patients with cystic fibrosis and radiologically demonstrated pneumothorax at Rainbow Babies and Childrens Hospital between 1959 and 1987. There occurred 144 pneumothoraces, 71 right and 73 left, in 99 patients, 48 female and 51 male. The median survival from the date of the first pneumothorax was 29.9 months. Primary therapy included the following: observation; tube thoracostomy; tube thoracostomy with instillation of quinacrine hydrochloride, tetracycline, silver nitrate, or talc; or partial pleurectomy. Complications were minimal in each group. The surgical group did significantly better than all other groups except the group given talc. We conclude that pneumothorax is a late and ominous complication of cystic fibrosis. The primary treatment of pneumothorax should be partial pleurectomy. Talc instillation should be reserved for patients in respiratory failure who are too ill to undergo operation and for the occasional patient in whom surgical intervention fails.

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.

Demonstration of an adenosine receptor on human lymphocytes in vitro and its possible role in the adenosine deaminase-deficient form of severe combined immunodeficiency☆

Abstract Adenosine receptors have been described in brain, bone, and platelets. Stimulation of this receptor by adenosine results in increased adenyl cyclase activity and accumulation of cyclic AMP. We have identified an adenosine receptor on human peripheral lymphocytes. Adenosine (5–100 μ M ) increased lymphocyte cyclic AMP levels by 100% during a 5-min incubation. Adenine was without stimulatory effect. Theophylline, which did not alter cyclic AMP levels when added alone, reduced the effect of added adenosine by 33% during a 5-min incubation. Norepinephrine alone elevated cyclic AMP levels 500–900% and the effects of adenosine and norepinephrine were additive. These data fulfill the criteria for the demonstration of a specific adenosine receptor. T lymphocytes isolated from a patient with x-linked agammaglobulinemia also demonstrated the presence of the adenosine receptor linked to cyclic AMP accumulation. Persistently elevated levels of cyclic AMP inhibit both lymphocyte proliferation and antibody synthesis. Patients with adenosine deaminase deficiency and severe combined immunodeficiency have markedly impaired lymphocyte proliferation and antibody production. These patients have also been found to have an increased intracellular concentration of ATP and elevated levels of plasma adenosine. Theophylline (0.5 m M ), which decreases cyclic AMP breakdown by inhibiting phosphodiesterase, inhibited normal lymphocyte proliferation by 50%. In contrast, the same concentration of theophylline inhibited adenosine deaminase-deficient lymphocyte proliferation by 89%. These data suggest that the immunologic defects in severe combined immunodeficiency and adenosine deaminase deficiency may result in part from excessive cyclic AMP synthesis associated with overstimulation of the adenosine receptor-adenyl cyclase pathway.

Course of cystic fibrosis in 95 patients

The course of 95 patients with cystic fibrosis is presented. Survivors have a mean follow-up period of over 14 years (minimum: 13 years). Of 45 patients diagnosed prior to extensive irreversible pulmonary involvement, only one has died and none is disabled. In contrast, of the other 50 patients diagnosed after substantial irreversible pulmonary disease was present, 26 have died. Mortality and morbidity has been greater in females. Possible factors contributing to the improving prognosis include early diagnosis, aggressive management with comprehensive care, easy access to specialized care, and improved antimicrobial therapy.

Cystic Fibrosis Diagnosed after Age 13: Twenty-five Teenage and Adult Patients Including Three Asymptomatic Men

Cystic fibrosis was diagnosed after age 13 in 25 patients. All had an elevated sweat chloride and either a sibling with cystic fibrosis or typical pulmonary infection or digestive symptoms caused by exocrine pancreatic deficiency. Fourteen had long-standing pulmonary or digestive symptoms. In contrast, four of eight patients whose symptoms began after age 13 presented with biliary cirrhosis. Three male patients were asymptomatic at diagnosis. Opacification of all paranasal sinuses was found in all patients examined radiologically. At diagnosis, pulmonary-function testing showed obstructive changes in 19 patients and sputum cultures showed Pseudomonas aeruginosa in 15 patients. Delayed menarche in five of seven female patients and infertility in the asymptomatic male patient (two of whom were found to have aspermia) could have led to earlier diagnosis. Teenagers and young adults with long-standing pulmonary or digestive symptoms, unexplained cirrhosis, aspermia, or a sibling with cystic fibrosis should be sweat-tested by pilocarpine iontophoresis.

Hyperreactivity to cow milk in young children with pulmonary hemosiderosis and cor pulmonale secondary to nasopharyngeal obstruction

Six black infants and young children with high titers of milk precipitins were identified by screening the sera of 160 children with idiopathic chronic lung disease. None of the six had immunoglobulin deficiency, elevation of sweat chlorides, SS hemoglobin, or recurrent aspiration. All six children had typical manifestations of milk-induced pulmonary hemosiderosis: recurrent pulmonary infiltrates (6/6), hemosiderin-laden pulmonary macrophages (5/6), intermittent wheezing (5/6), eosinophilia (4/6), anemia (4/6), iron deficiency (4/4), failure to thrive (4/6), and elevated levels of serum IgE (4/4). Three children also had chronic rhinitis and eventually developed large adenoids, hypercapnia and acidosis during sleep, and right heart failure. Elimination of cow milk from the diet, symptomatic therapy, and adenoidectomy when indicated resulted in improvement of all six patients. Pulmonary hemosiderosis and some cases of upper airway obstruction with pulmonary hypertension appear to be two stages, early and delayed, of the same immunophysiologic process. Early dietary intervention may prevent the cardiovascular complications of this process.