Harry Shwachman

The syndrome of pancreatic insufficiency and bone marrow dysfunction

A new entity characterized by pancreaatic insufficiency and bone marrow hypoplasia is described. The first three patients presented in this report had been followed in our cystic fibrosis clinic because of pancreatic insufficiency. These children did not develop respiratory tract difficulties and had normal sweat tests. The hematologic features included anemia; thrombocytopenia, and neutropenia. Attempts to correct all the hematologic abnormalities were unsuccessful. A biopsy of the pancreas in one case revealed intranuclear and intracytoplasmic inclusion bodies. This entity should be suspected in infants who fail to gain weight, have abnormal stools, and neutropenia, as well as those children who are thought to have cystic fibrosis diagnosed on the basis of pancreatic insufficiency with normal sweat electrolytes. Since three patients were observed from one family, it is felt that this is a genetically determined entity.

Reproductive Failure in Males with Cystic Fibrosis

Abstract Adult males with cystic fibrosis are infertile because of failure of normal development of the vas deferens, a finding not previously recognized. Twenty-five patients over 17 years of age ...

Precipitins to antigens of wheat and cow's milk in celiac disease

Sera of 40 subjects with celiac disease were studied by microimmunodiffusion to detect precipitins to the antigens in wheat and cows milk. A high incidence of precipitins to the antigens of both was found. More striking was the finding of precipitins to one component of gliadin in 17 of 212 subjects studied. Sixteen of the 17 had celiac disease and the seventeenth was the father of a child with celiac disease. A definite relationship was found between precipitins to antigens of wheat and gliadin on the one hand and to antigens of cows milk on the other. Once experience has been gained with the technique, tests are easy to perform, inexpensive, and require a minimum of time expenditure and discomfort on the part of the patient. Whenever precipitins to gliadin, and particularly to the constituent of gliadin called Gli I are found, the diagnosis of celiac diesase must be seriously considered. Precipitins to cows milk are less specific but are helpful in the presence of clinical and laboratory evidence of malabsorption.

Gastrointestinal Manifestations of Cystic Fibrosis

Based on experience at the Children’s Hospital Medical Center in Boston, the gastrointestinal complications in cystic fibrosis are described. Methods of diagnosis, with emphasis on indications for the sweat test, and preventive and therapeutic measures are also considered.

Bronchial artery embolization in cystic fibrosis; technique and long-term results.

Severe bronchial hemorrhage in 13 patients with cystic fibrosis was treated by catheter embolization of bronchial arteries. Indications were either excessive bleeding persisting for several days, or bleeding serious enough to interfere with pulmonary drainage and recurring over weeks or months. In follow-up ranging from one to 30 months, cessation of major bleeding was achieved in 12 of 13 patients (93%), although 5 of 13 patients (40%) did have recurrence of minor hemoptysis. No neurologic or other major complications were encountered. However, there are potential risks and this approach at present should be limited to patients with life-threatening bleeding and carried out only by experienced angiographers.

Massive hemoptysis in cystic fibrosis

Massive hemoptysis is occurring with increasing frequency in older patients with cystic fibrosis; it signifies a poor prognosis. Twenty-nine episodes occurring in 19 patients are analyzed. Thirteen of the 19 patients died within 6 months of the initial episode. No single aspect of the pulmonary treatment program has been incriminated. Half of the episodes were associated with a significant exacerbation of pulmonary symptomatology. Active bronchiectasis with blood vessel invasion was felt to be the pathologic process in all cases. Treatment consisted of transfusions and supportive care. Surgical resection was performed on one patient. In view of the poor response to medical therapy, a more aggressive surgical approach might be justified in selected patients.

Progressive diaphyseal dysplasia.

ANUNUSUAL SYNDROME characterized by progressive skeletal changes, wasting, and anomalous neuromuscular signs as observed in four children over a seven-year period is being presented. A preliminary report on the first two of these patients was published by Riley and Shwachman in 1943. Additional information has since been gained on the course of this disease. Descriptions of similar disorders have not been found in the available literature. CASE 1: M. M. (Fig. 1, A and B) was first seen in June 1941 at the age of four years and three months, because of a waddling gait, easy fatigability, and failure to gain weight. The family, birth, and neonatal histories were non-contributory. The childs development was normal, except for some difficulty in walking, up to two and one half years, at which time she had pertussis, followed by loss of appetite and persistent inability to gain weight normally. She was hospitalized at the age of four years and ten months for study. The significant findings were: underweight, ...

The Pancreas in Cystic Fibrosis: Chemical Composition and Comparative Morphology

Extract: Sections of pancreas from 16 individuals who died with cystic fibrosis (CF) were classified by morphometric criteria into four categories in increasing order of pancreatic involvement. The concentration of acini, islets, main ducts, lobular ducts, connective tissue, and fat was compared with control levels. The results show that in the least involved pancreases, from neonates who died under 5 months of age, acini were reduced to 33% of control levels and the following were increased: islets, to 410%; lobular ducts, to 250%; and main ducts, to 1700% of controls.With increasing severity of the pancreatic disease the acini were further reduced to 5% and lobular ducts to 37% of control levels, respectively. Main ducts increased by 19-fold, and fatty infiltration accounted for more than 25% of the fresh weight of the pancreas in 9 of the 16 specimens.Comparative biochemical studies of 35 fibrocystic pancreases were quantitatively related to the severity of the pancreatic involvement as follows. Water and volatile matter, normally accounting for 80±% of the weight of the fresh pancreas, was reduced to less than 30% in the most affected organs. The concentration of zinc diminished from near normal mean levels of 193 μg Zn/g dry pancreas to 10% of this amount in the severely involved pancreas.Elevated concentrations of calcium, amounting to over 10 times control level, were found in obstructed ductal structures. Calcium was depleted from pancreatic sections adjacent to the obstructions. The following biochemical indicators were significantly different in their mean levels in the 35 fibrocystic pancreases when compared with the 17 controls: (P ≤ 0.001) fat, water, zinc, calcium, copper, magnesiu, potassium, and sodium (P ≤ 0.01).Speculation: Morphometric and biochemical studies of the pancreas in cystic fibrosis are interpreted to favor an early and perhaps primary role of ductal and ductular abnormality in the pathogenesis of the pancreatic lesion. The principal basis for this suggestion lies in the demonstration of early massive enlargement of the ductular system and the consequent accumulation of viscous calcium-rich inspissated material responsible for the formation of functional ductal obstructions. Alterations in calcium concentration and binding in the pancreas and in pancreatic juice are believed to be responsible for changes in membrane permeability and the transport of water and electrolytes. The pancreatic disease process begins in utero and the degeneration of the pancreas progresses through life in nearly all patients with cystic fibrosis.

Selective Bronchial Arteriography in Patients with Cystic Fibrosis and Massive Hemoptysis

Massive hemoptysis is a potentially fatal complication of long-standing cystic fibrosis. Lobectomy may prevent a hemorrhagic death if the hemorrhage source can be identified and if involvement of the remaining lung tissue is mild. Selective bronchial arteriography was performed in six patients with cystic fibrosis to localize a lobar source of bleeding. Arteriographic findings correlated with bronchoscopic observations. Bronchial arteriography may be helpful when bronchoscopy cannot be done because of continuous hemorrhage or because the severity of the lung disease precludes general anesthesia, but it is not an adequate substitute for bronchoscopy in most patients.

THE SWEAT TEST IN CYSTIC FIBROSIS

In 1953, Darling, d i Sant’Agnese, and co-workers’ opened a new area of invest igat ion when they discovered a n abnormality in function of t h e eccr ine s w e a t g l a n d s i n children with c y s t i c fibrosis. T h e s e children, when subjec ted t o a s tandard mild thermal s t r e s s for a period of one to two hours while lying quie t ly in a room maintained a t 32.2OC. and 50 per c e n t humidity, produced a s w e a t with a cons is ten t e levat ion of sodium, chloride, and potassium a s cont ras ted with control cases. Sweat from t h e abdominal a r e a w a s absorbed onto a 12 sq. cm. dry gauze pad and subsequent ly e lu ted with d is t i l l ed water for chemical ana lys i s . O n e of u s had t h e good fortune t o v i s i t Darling’s physiology laboratory i n t h e spr ing of 1954, at a t ime when d i Sant’Agnese w a s “sweat ing” two children. I w a s impressed by t h e importance of t h e work; also by t h e c o s t and upkeep of t h e experimental s e t u p a n d t h e need for well-trained technica l a s s i s t a n t s . Numerous ques t ions come t o mind when a new observat ion is made in a genet ical ly determined d i s e a s e of unknown etiology, with multiple clinical manifestations. I s h a l l l i s t a number of ques t ions but d i s c u s s on!y a few. How genera l is t h e defec t? I s i t found in all p a t i e n t s with c y s t i c f ibrosis or in t h e majority of c a s e s ? T h i s quest ion c a n only b e answered by tes t ing large numbers of pa t ien ts with a var ie ty of manifestat ions of c y s t i c f ibros is a t different ages , including infan ts with meconium ileus. Should t h e s w e a t e lec t ro ly te concentrat ions prove t o be suff ic ient ly abnormal when compared with t h e host of c l in ica l condi t ions l ikely t o b e confused with c y s t i c f ibros is and when a method c a n b e devised t o t e s t s u c h pa t ien ts a t all ages, a d iagnos t ic appl icat ion becomes possible. T h u s s u c h a t e s t could a id i n t h e detect ion of cases of c y s t i c f ibrosis in which there is no pancreat ic involvement o r only par t ia l or incomplete pancreat ic insufficiency. T h i s la t te r en t i ty did not represent c y s t i c fibrosis according t o some workers, although we gathered ev idence to indica te that i t occurred i n approximately 15 t o 20 per c e n t of our pat i en ts with c y s t i c fibrosis. In 1954 Higgins, Dooley, and Shwachman,’ a f te r consul ta t ion with Yaglou of t h e Harvard School of P u b l i c Health, developed t h e so-cal led bag method of inducing sweat , t h u s making it poss ib le t o confirm and extend t h e observa t ions of d i Sant’Agnese and h i s a s s o c i a t e s in a relat ively short time. T h e a n s w e r s t o t h e f i rs t two ques t ions appeared a t t h e end of 8 months of bag tes t ing in 239 individuals. T h e bar diagram of F I G U R E 1 i l lus t ra tes t h e e leva ted sodium v a l u e s i n 108 pa t ien ts with c y s t i c fibro-