LeRoy W. Matthews

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.

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.

HUMAN PULMONARY SECRETIONS IN HEALTH AND DISEASE

During the past two and one-half years, work in this laboratory has been directed toward the study of human pulmonary secretions in health and disease. For this purpose the secretions of three groups of patients have been examined: so-called “normal” secretions from a group of laryngectomized patients, secretions from patients with bronchiectasis, and secretions from a group of patients with cystic fibrosis. The pulmonary secretions were collected essentially according to the method of Denton,’ and then stored a t -770” C. prior to use. TABLE 1 shows that the per cent solids in the secretions of the “normal” and bronchiectasis groups is about half the value found for the cystic fibrosis group, whereas ash content is highest in the “normal” group, intermediate in bronchiectasis, and lowest in cystic fibrosis. It was of interest to examine the inorganic constituents of the secretions, and the same table shows that sodium and chloride parallel the relationship observed for total ash content, that is highest in the “normal,” intermediate in bronchiectasis, and lowest in cystic fibrosis. This relationship is reversed when potassium and phosphorus content are considered. Calcium is found in highest amount in bronchiectasis secretions, whereas the cystic fibrosis secretions are intermediate in magnitude and elevated with respect to the “normal” secretions. TABLE 2 summarizes the protein, lipid, and carbohydrate content of the three groups of secretions. Total protein is highest in cystic fibrosis and lower in amount in bronchiectasis secretions. The “normal” secretions contain the smallest amount of protein. About 70 to 80 per cent of the total nitrogen of the three groups is present as protein nitrogen. The values in the table for total carbohydrate represent the additive sum of hexosamine, hexose, methyl pentose, and sialic acid, and parallel the relationship observed for total protein. However the differences between the groups are not significant. The results of analyses for total lipid in the secretions of the three groups of patients show that the values are in the same relationship as total protein and carbohydrate. TABLE 3 summarizes the over-all chemical composition of the secretions of the three groups. The values for deoxyribonucleic acid (DNA) content illustrated in the table were determined by Schmidt-Thannhauser fractionation.2 The table shows that there is a spectrum of values for DNA, protein, lipid, and carbohydrate ranging from the low in the “normal” group to the highest values in the cystic fibrosis group. The values for the bronchiectasis secretions are all intermediate. The experimental data has been uniformly presented on a wet weight basis. Because of the elevated values for total lipid and protein in cystic fibrosis secretions, calculation of the other components of the cystic fibrosis secretions on a dry weight basis yields values which are deceptively low relative to the other two groups of secretions. The similarity between our results and those of Chernick and Barbero3 on secretions

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.

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—A Challenging Long-Term Chronic Disease

Cystic fibrosis, the most frequently seen lethal genetic syndrome, is now increasingly being recognized as a heterogeneous condition. Following a discussion of the many recognizable abnormalities that may be involved in the condition, this article examines the diagnosis, treatment, psychosocial care, and prognosis of cystic fibrosis and encourages greater dialogue between the pediatrician and the mental health consultant.

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.

A Method for Ventilatory Measurements in Subjects 1 Month-5 Years of Age: Normal Results and Observations in Disease

Extract: Using the total body plethysmograph, a method for the measurement of lung volume and airway resistance was developed for infants and young children of 1 month-5 years of age. The subjects were studied in a supine position using a reproducible method of sedation. The procedure providing the most consistent results involved use of a Rendell-Baker mask directly controlled by the operator while the subjects were breathing through the nose. Availability of an oscilloscope permitted immediate detection of pressure leaks, artifacts, and abnormal patterns during each determination and minimized potential errors during the study of each subject. Care was required to avoid pressure on the tip of the nose because an abnormally high airway resistance resulted.The logarithmic relation of thoracic gas volume (TGV) at functional residual capacity (FRC) to body length for 52 normal subjects compared well with results obtained on newborn infants and with those obtained on older subjects. The equation was: TGV at FRC, litters = 1.57 × 10-5 × length, cm2.238 (correlation coefficient = 0.948). The logarithmic relation of airway conductance to TGV was: conductance, liters/sec/cm H2O = 0.1431 TGV, liters0.6441 (correlation coefficient = 0.835). Comparison with older subjects was limited by the difference in airflow rates at which the airway conductance was determined (0.06-0.28 liters/sec versus about 0.5 liters/sec for adults) and by the use of sedation and nasal breathing in this study; adults are studied a wake and during mouth breathing. Comparison of our conductance values with those obtained on unsedated newborns suggests that either sedation alters the airway resistance or that some change occurs in the airway size-lung volume relation during the first weeks of life.Examples of the application of this method to patients with asthmatic bronchitis and cystic fibrosis of the pancreas are provided.Speculation: It is possible that an airflow-lung voliume-airway resistance relation exists throughout life; however, the results presented in this study, combined with those previously presented on newborns for airway resistance, suggest that a change may occur in the relation of the size of the airways to lung volume during early infancy, or that sedation alters airway resistance. Development of this and other methodology should permit more adequate studies of the early changes in pulmonary physiology associated with growth and the acute and chronic pulmonary conditions seen during the first 5 years of life.

Toxic Effects of Oxygen on Cultured Human Neonatal Respiratory Epithelium

Extract: Explants of tracheal epithelium from each of six human neonates were exposed to both 80% and 20% oxygen under otherwise identical culture conditions. Cessation of ciliary movement and carbon particle transport occurred after 48–96 hr of exposure to 80% oxygen, but not after 168 hr of exposure to 20% oxygen.This alteration of ciliary function was related temporally to squamous metaplasia, or to degeneration and sloughing of cells from the surface epithelium. Explants secreted more mucin and lysozyme during the first 24–72 hr of culture in 80% oxygen. Thereafter, diminished secretion was observed, apparently related to loss of goblet cells from the surface epithelium and failure to discharge the secretory products of submucosal glands. These findings indicate that high oxygen concentrations at atmospheric pressure alone can cause marked alterations of structure and function in neonatal large airways epithelium. Onset of these changes corresponds to the time when the earliest clinical and cytologic evidence of bronchopulmonary dysplasia has been detected, suggests that similar oxygen-induced changes are produced in vivo. Loss of mucociliary function may be an important pathogenetic component of bronchopulmonary dysplasia.Speculation: Organ culture of human large airways epithelium appears to be a useful model for study of pulmonary oxygen toxicity. Studies of oxygen concentrations and duration of exposure tolerated by human respiratory epithelium, the cellular mechanisms of oxygen-induced alteration, and the use of pharmacologic agents to prevent or delay onset of toxic changes may be facilitated by using this in vitro technique.

The Vectorcardiogram in Cystic Fibrosis Diagnostic Significance and Correlation with Pulmonary Function Tests

One hundred and one children with cystic fibrosis had detailed studies of the vectorcardiograms and pulmonary function tests. The vectorcardiographic diagnoses were (1) right ventricular hypertrophy (14 patients), (2) right ventricular hypertrophy plus abnormally posterior vector (24 patients), (3) abnormally posterior vector (26 patients), (4) low voltage (nine patients), and (5) tracing within normal limits (35 patients).Right ventricular hypertrophy correlated well with a decreased vital capacity. Abnormally posterior vector correlated well with increased residual volume and functional residual capacity. The presence of the abnormally posterior vector was demonstrated to be the major factor in the difficulty in interpreting right ventricular hypertrophy from the electrocardiogram, for a large terminal rightward vector was often too far posterior to be registered as a terminal R in the right chest leads.The Frank system vectorcardiogram was demonstrated to be better able to detect right ventricular hypertrophy than was the cube system vectorcardiogram. This was particularly true in the presence of an abnormally posterior vector.An abnormally leftward 0.01-second vector, if it is anterior, is frequently seen in right ventricular hypertrophy.