Leukocyte degranulation and vacuole formation in patients with chronic granulomatous disease of childhood.

A cellular defect associated with decreased bactericidal activity of the polymorphonuclear leukocyte has been found in a 2(1/2) yr old Negro boy with the typical clinical and pathological findings of chronic granulomatous disease. Unlike previously described patients his polymorphonuclear leukocytes were shown to undergo apparently normal degranulation and vacuole formation after phagocytosis. Metabolic studies of the leukocytes indicated a failure to increase oxygen consumption with phagocytosis or to reduce Nitroblue tetrazolium dye. These metabolic abnormalities are identical with those previously reported in patients with chronic granulomatous disease. Two additional patients with chronic granulomatous disease have also been found to have apparently adequate degranulation of polymorphonuclear leukocytes after phagocytosis. Our studies suggest that failure of degranulation may not be a necessary part of this functional leukocyte abnormality.

Brain ultrastructure in Reye's disease. II. Acute injury and recovery processes in three children.

Acute and recovery biopsies of three patients with Reye's Disease are described. Pleomorphic changes of neuronal mitochondria were identified in all of the acute biopsies, similar in appearance to the characteristic alterations of hepatic mitochondria. Distinctive myelin bleb formation may be directly attributable to the mitochondrial injury. The mitochondrial lesion is reversible. There is morphologic evidence for regeneration and repair of myelin; but the presence of myelin ovoids at long intervals after recovery indicates a loss of some myelinated fibers. The neuronal mitochondrial changes, pleomorphism with matrix expansion, and myelin bleb formation, reflect a specific biochemical injury be attributable to ischemic injury secondary to brain edema.

Brain ultrastructure in Reye's syndrome.

Cerebral biopsies were obtained for electron microscopy 48 and 72 hours after the onset of encephalopathy from a child with severe Reye's syndrome. Gravely ill at the time of craniectomy to relieve cerebral hypertension, the child survived and recovered good brain function; therefore, the biopsy findings appear to reflect the organelle pathology of the brain at a severe yet reversible stage in the disease process. The cardinal ultrastructural changes in the brain in Reye's syndrome are astrocyte swelling and partial deglycogenation, myelin bleb formation and universal injury of neuron mitochondria. The mitochondrial injury consists of matrix disruption with moderate but not massive swelling. Dilatation of rough endoplasmic reticulum and nuclear changes occurred only in neurons with severely altered mitochondria. The organelle pathology of the brain in this case did not resemble the organelle pathology of the brain in human "hepatic encephalopathy" or in experimental ammonia intoxication in primates. The mitochondrial ultrastructure of the cerebral neurons resembled the unique mitochondrial ultrastructural changes seen in the liver parenchyma in Reye's syndrome.

The effect of continuous enteral feeding on cholic acid kinetics in a child.

Continuous enteral feeding is utilized for nutritional support and specific therapy for several pediatric diseases, including protracted infantile diarrhea. Its effects on the enterohepatic circulation of bile acids were studied in a boy during continuous intragastric feeding of a high fat diet at age 42 months and after recovery while on bolus feedings at age 51 months. Cholic acid kinetics measured by the isotopic dilution technique using cholic-COOH-14C acid and meal stimulated intraluminal bile acid concentrations were measured. Cholic acid pool size was unaltered (1294 mg/m(2)) during continuous feeding compared to 999 mg/m(2) during bolus feeds and 1072 plus or minus 243 mg/m(2) (mean plus or minus SE) in nine control children. However, the cholic acid fractional turnover rate was increased 3-fold (0.912 days(-1)) during continuous feeds compared to 0.309 days(-1) during bolus feeding and 0.365 plus or minus 0.163 in controls. Similarly, synthesis rate was increased 3-4 fold during continuous feeds (1180 mg/m(2)/day) compared to controls (363 plus or minus 193 mg/m(2)/day) and the patient during bolus feeding (309 mg/m(2)/day). The intraluminal bile salt concentration was apparently reduced both during treatment (3.86 mM) and when bolus fed (3.85 mM) but were significantly different from controls (7.12 plus or minus 1.74 mM). During continuous enteral feeding with a high fat diet, effective homeostatic mechanisms in the enterohepatic circulation of bile salts ensured intraluminal bile salt concentrations adequate for normal fat solubilization and, consequently, normal fat absorption.

Hepatic and encephalopathic components of Reye's syndrome: factor analysis of admission data from 209 patients.

Factor analysis of admission data from 209 Reye's syndrome patients yielded three factors. Factor 1 was associated with encephalopathy, blood ammonia, creatinine kinase (CK), uric acid and, to a lesser extent, bilirubin. This factor was linked to the encephalopathy and hypermetabolic changes in muscle, possibly prostaglandin-mediated proteolysis. Factor 2 was associated with serum alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT), and was identified as a hepatic lesion component. These factors correspond to two etiologic components of Reye's syndrome. Salicylate was only weakly associated with neuropathic and hypercatabolic indicators and not at all associated with the hepatic damage indicators.

Painful defecation and fecal soiling in children.

Fecal soiling is a common complaint among school-age children. The fecal soiling is often accompanied by chronic constipation and so-called "idiopathic," "functional," or "psychogenic" megacolon, the cause of which is undetermined. The records of all children presenting to a pediatric gastroenterology clinic between 1981 and 1990 with difficult defecation were reviewed to determine the incidence of painful defecation and its relationship to chronic impaction and fecal soiling. There were 227 children; 74 were younger than 36 months of age and 153 were older than 36 months. Of the younger children, 86% presented with pain, 71% with impaction, and 97% with severe withholding. The younger children had painful defecation for a mean of 14 +/- 9 (SD) months before presentation. Of the older children, 85% presented with fecal soiling, 57% with pain, and 73% with fecal impaction, and 96% exhibited withholding; the older children had difficult defecation for a mean of 56 +/- 42 months before presentation. Sixty-three percent of the children presenting with fecal soiling had a history of painful defecation beginning before 36 months of age. Painful defecation frequently precedes chronic fecal impaction and fecal soiling in American children. Early, effective treatment of painful defecation in infancy might reduce the incidence of chronic fecal impaction and fecal soiling in school-age children.

Management of Reye's syndrome: need for early diagnosis and intravenous treatment of stage I non-comatose cases.

Clinicians and nurses should obtain a history of antecedent illness occurring within 2 weeks of the onset of vomiting. Ninety percent of school-age children will give a history of an antecedent illness (varicella or influenza-like respiratory illness) within 1 week of the onset of vomiting. The vomiting of Reye's syndrome is usually persistent, lasting for 24 to 96 hours before the onset of serious brain signs. We believe that any child with the history of flu or chickenpox within 1 week of the onset of vomiting, which lasts for more than 12 hours, and is unusually severe or is associated with lethargy, should have an SGPT (alanine aminotransferase). This laboratory measure is clearly elevated in most cases of Reye's syndrome.

Hepatic encephalopathy and Reye's syndrome.

The encephalopathy of Reye's syndrome is a potentially reversible, treatable problem in many cases. Treatment requires (1) accurate, early diagnosis; (2) the prevention of anoxia; (3) the restitution of body glycogen stores through the administration of glucose; (4) the control of the complicating cerebral edema; (5) the avoidance of counterproductive treatment measures, such as the unwarranted infusion of sodium bicarbonate and the inappropriate use of respiratory depressing anticonvulsants; and (6) the early and aggressive use of exchange transfusion.

Reye's syndrome (encephalopathy and fatty liver). Diagnosis and treatment.

Reye's syndrome is an acute encephalopathy and fatty liver which has mainly been recognized in children through the age of about 16 years. Since the patients are not jaundiced and the liver may be relatively small at the moment of admission, the diagnosis must be sought by a high index of suspicion and the routine use of liver function studies, especially the SGOT, in all unexplained cases of encephalopathy. Early treatment and appropriate management of cerebral edema seem to reduce the over-all mortality of Reye's syndrome from more than 50% to less than 20%. Alert gastroenterologists may find some adult cases of Reye's syndrome masquerading as acute neurological disease or supposed acute drug reactions.

Epidemic influenza myopathy in Cincinnati in 1977.

A distinctive myopathy was observed in 24 children following influenza B infection. The abrupt onset of severe muscle pain and difficulty in walking began as the respiratory symptoms were waning. The lower extremities, particularly the gastrocnemius and soleus muscles, were involved preferentially. Nasopharyngeal cultures were positive for influenza B Hong Kong in 18 of these patients. Serum creatine phosphokinase levels were significantly elevated (mean 55.2 units) when compared to controls and nine patients with Reye syndrome. The cardiac muscle isoenzyme was detected in the serum of 17 myopathy patients. Serum glutamic oxaloacetic transaminase, but not serum glutamic pyruvic transaminase, was elevated compared to controls (P less than 0.01) but less (P less than 0.001) than the patients with Reye syndrome. Twelve patients underwent muscle biopsy; segmental rhabdomyolysis without inflammation was detected in nine patients. Myopathy is a complication of influenza infection that can be diagnosed by clinical, biochemical, and virologic examination.

Bile acid malabsorption--a consequence of terminal ileal dysfunction in protracted diarrhea of infancy.

Fecal excretion of labeled bile acid (14C-24-cholic acid) was distinctly increased in two infants with protracted diarrhea, whereas four patients with steatorrhea due to pancreatic or mucosal abnormalities and five patients with mild chronic diarrhea had no excess fecal loss of bile acid. The loss of 14C-24-cholic acid in our patients with intractable diarrhea was similar to that observed in four infants who had undergone ileal resection. The ratio of mean 24-hour excretion of bile acid to that of a non-absorbable marker, polyethylene glycol, confirmed the malabsorption of bile acid in the patients with intractable diarrhea or ileal resection. These results differ significantly (p less than 0.05) from excretion ratios obtained in patients with either steatorrhea or chronic diarrhea. The extent of the loss of bile acid was not significantly related to the rate of fecal fat excretion. There was no direct correlation of fecal weight with the rate of bile acid excretion. Ileal function, as further assessed by the Schilling test with exogenous intrinsic factor, was grossly abnormal in both of the patients with intractable diarrhea.

Hypocalcemia and steatorrhea--clues to etiology.

Two boys with idiopathic hypoparathyroidism had extensive studies of gastrointestinal function during hypocalcemia accompanied by steatorrhea. No evidence of generalized gastrointestinal moniliasis or abnormal mucosal structure or function was observed. Studies of pancreatic function and bile salt metabolism during hypocalcemia demonstrated deficient meal-stimulated intraluminal pancreatic enzyme concentrations in both subjects and reduced bile salt concentrations in one subject. However, following stimulation with exogenous octapeptide of cholecystokinin, intraluminal pancreatic enzyme and bile salt concentrations were normal in both. Cholic acid pool sizes were markedly increased in both subjects during hypocalcemia (9 and 12 times larger than during normocalcemia) and cholic acid turnover was reduced during hypocalcemia in one subject. Our findings suggest that during hypocalcemia, insufficient endogenous cholecystokinin is released by the duodenal mucosa during a meal stimulus to stimulate normal gallbladder contraction and pancreatic enzyme secretion.

Serum salicylate concentrations in Reye's disease. A study of 130 biopsy-proven cases.

Serum salicylate concentration was measured at admission in 130 children with liver-biopsy-confirmed Reye's disease. Mean serum salicylate was 12.3 mg/dl and mean salicylate concentrations by neurological grade (Lovejoy) were: stage I, 12, stage II, 13, stage III, 11, stage IV, 13, and stage V, 13 mg/dl. However, mean serum salicylate (15 mg/dl) at admission in 21 patients who died or had serious neurological deficits was significantly higher than that in 103 patients who survived without neurological sequelae (10 mg/dl). Serum salicylate in a group of 27 age-matched, community-matched control children collected consecutively over the period 1978-80 was less than 2 mg/dl, and children with varicella or influenza had salicylate concentrations indistinguishable from apparently well classmates or siblings. It is impossible to determine from this data whether salicylates are involved in the aetiology of or in determining the outcome of Reye's disease. Increased concentrations of salicylates at admission could be the result of excessive dosage because of a greater severity of the prodromal illness, or to diminished excretion because of impaired hepatic metabolism. It seems likely that serum salicylate concentrations entered the toxic range in many patients with Reye's disease before they presented for treatment. Most had been vomiting and had diminished oral intake for 33-55 h before hospital admission. Since the average number of hours from the beginning of vomiting to admission was no different in non-comatose and comatose cases, the time at which salicylate concentration was measured in relation to the last dose was probably similar in the two groups and therefore does not account for the higher levels in children with poor outcome. Salicylates are mitochondrial toxins and mitochondria are known to be significantly injured in Reye's disease; therefore, it seems wise to avoid the use of aspirin in children during outbreaks of Reye's disease.

Small intestinal mucosal fatty acid uptake and esterification in infants and children.

Oleic acid uptake and esterification in intact intestinal mucosa were studied in 14 infants and children with chronic non-specific diarrhea, but histologically normal small intestinal mucosal biopsies, using an in vitro technique. The uptake rate was 5.876 +/- 1.942 nmol fatty acid/mg Nigrogen/minute and the esterification rate was 4.060 +/- 1.010 nmol fatty acid/mg Nitrogen/minute, comparable to previous adult esterification studies. No effect of age on either esterification or uptake was present. Mucosal injury resulted in significant reductions in esterification (p less than 0.001) and uptake (p less than 0.05) compared to controls. Bile acid deficiencies led to reductions in mucosal esterification (p less than 0.05) but not uptake.

Reye syndrome: treatment by exchange transfusion with special reference to the 1974 epidemic in Cincinnati, Ohio.

The treatment of 66 children with Reye syndrome proved by hepatic biopsy or autopsy is described. Prior to the utilization of exchange transfusion early in the course of the disease, our case fatality rate was 100% of nine patients. With early diagnosis and early exchange transfusion, the case fatality rate was reduced to 27% of 44 patients. During the 1974 epidemic of Reye syndrome, 26 children were treated. In 18 children the diagnosis was established by hepatic biopsy; 16 received one or more exchange transfusions. There were no deaths among these 26 patients. In the 1974 epidemic, the national case fatality rate was estimated to be 40%. Exchange transfusion appears to have been an important factor in the reduction of the case fatality rate among our patients.

Reye's syndrome: epidemiologic and viral studies, 1963-1974.

Fifty-eight children with Reye's syndrome (RS) confirmed by liver biopsy were treated at the University of Cincinnati between 1963 and 1974. Cases were clustered in the winter and spring with the peak in February and March. These coincided with the occurrence of influenza and, numerically, were associated more closely with influenza B than with influenza A. Six of the 58 cases were associated with chickenpox. Twenty-six children with RS were seen from 1963 to 1971, before the beginning of a systematic epidemiologic and virologic study. Viral infection was documented in either the patient or a contact in only 19% of those studied. Between 1971 and 1973, after the study was initiated, 16 cases of RS were diagnosed and viral infection was confirmed in 56% of these. In 1974, an epidemic of RS occurred during an influenza B epidemic and viral infection was found in either the patient or a contact in 81% of 16 cases. This study demonstrates that an association with viral infection can be proven in the majority of cases of RS when an intensive investigation is undertaken. During this study no significant environmental toxic exposures could be idenified. Most children had taken aspirin and other medications, and seven children had a history of excessive aspirin ingestion.

Abnormal lipid accumulation within the small intestinal mucosa of children with juvenile-onset diabetes mellitus.

The lipid content of the proximal jejunum, as studied by light microscopy with lipid histochemical staining methods, is determined in 14 fasting children with juvenile-onset diabetes mellitus. The results show that four children had greatly increased amounts of lipid, while six others had a mildly to moderately increased amounts of lipid present. The amount of lipid present appears to correlate most closely with the quality of control of the diabetes. These results indicate either that the clearance of exogenous lipid is impaired or that there is an increased endogenous synthesis of lipid within the intestine of the diabetic child, especially in those under poor control.