DOES THAT CHILD REALLY HAVE CYSTIC FIBROSIS?

415

Child Health

DOES THAT CHILD REALLY HAVE CYSTIC FIBROSIS?

CHRISTINE A. SMALLEY

D. P. ADDY

Department of Pædiatrics, Dudley Road Hospital, Birmingham B18 7QH CHARLOTTE M. ANDERSON Institute of Child Health,

Summary

University of Birmingham

A diagnosis of cystic fibrosis was rectly made after false-positive

incorsweat

tests in 14 children. 13 of these children had been tested at hospitals where it seems likely that sweat tests were not done very often. All the children had normal sweatvalues when the test was repeated at a 250 regional pædiatric centre where sweat tests are done each year. In 5 cases, detailed test-

electrolyte

approximately

ing of pancreatic function was normal. None of the children had typical chest disease and only 2 had gastrointestinal symptoms. In the absence of the typical clinical features of the disease a diagnosis of cystic fibrosis should be made with extreme caution and only after meticulous testing of both sweat electrolytes and pan-

Patient 14 was diagnosed at the regional hospital in 1964, and is the only such patient known to us in whom the diagnosis of C.F. has subsequently proved false. The hospital laboratory now does approximately 250 sweat tests each year. Detailed pancreatic function tests were done in patients 1, 2, 4, 5, and 6 and all were normal. The children were older at diagnosis than is usual in c.F., half being aged 5 or over. 12 had predominantly chest symptoms, mostly intermittent, without purulent sputum. Chest signs were absent or minimal in all but patients 10 and 14 in whom the final diagnosis was asthma. Both these patients had high blood-eosinophil counts (952 and 973/µl), very high serum-IgE (1650 and 5600 ng/1), and skin sensitivity to a variety of allergens (particularly to egg in patient 14). Bowel history was normal in all but patients 7 and 8, whose parents said that their stools had always been loose, and no child had abdominal distension. Patients 6 and 9 had neither chest symptoms nor abnormal stools and had presented with poor growth. Patients 4 and 5, and patient 8, had some chest symptoms but were investigated because c.F. had been diagnosed in a sibling (patients 3 and 7). Patients 11, 12, and 13 were tested because a first cousin had c.F. 6 patients had no family history of c.F. Patient 6, with poor growth, was the only one in whom a non-respiratory diagnosis was finally made: because of a previous history of dysuria, a midstream specimen of urine was examined and found to be infected. Subsequent urological investigation showed bilateral ureteric reflux and chronic pyelonephritis, but normal renal function as determined by creatinine and chromium-51-E.D.T.A. clearances. Final diagnosis in patient 1 was bronchitis and pneumonia and bronchitis in patients 2, 3, and 4.

creatic function.

METHODS

The

INTRODUCTION

.

THE sweat testl has rightly become established as the reliable single test for the diagnosis of cystic fibrosis (c.F.). However, sweat-electrolyte composition in individuals varies, for example, with the method of stimulation of sweating, weight of sweat collected, sweat secretion-rate, salt intake, and age of the patient.23 Schwarz et a1.4 have pointed out that in a very small percentage of children such variation may produce some abnormal sweat-sodium and sweat-chloride levels. c.F. may then be incorrectly diagnosed. Other diseases in children may be occasionally associated with raised sweat-electrolyte values (e.g., nephrogenic diabetes insipidus, Addison’s disease, adrenogenital syndrome, glucose-6-phosphatase deficiency, fucosidosis, and nephrotic syndrome)5, but these are not likely to be confused clinically with c.F. In our experience, however, much the commonest cause of false-positive sweat-test results leading to an incorrect diagnosis of c.F. is inaccuracy in doing the test, and this seems most likely in laboratories where the test is done only occasionally.6 We here describe 14 children in whom c.F. was wrongly diagnosed on the basis of sweat tests done in 7 different hospitals. most

done by quantitative pilocarpine iontoChloride was measured titrametrically,8 and sodium phoresis.7 by flame emission. Pancreozymin-secretin-stimulated pancreatic function tests were based on the method of Hadorn et al.,9 but a single-lumen pxdiatric duodenal tube was positioned in the duodenum under fluoroscopic control, and gastric contents were continually aspirated by a nasogastric tube to prevent contamination of duodenal juice. Pancreozymin (Boots) (1 unit/kg body-weight) was given intravenously followed after 20 min by secretin (Boots) (2 units/kg). Intravenous diazepam (0.55 mg/kg) was given 5-10 min before intubation. Trypsin was measured by potentiometric titration1O and sweat test was

TABLE I-INVESTIGATIONS IN CHILDREN CONSIDERED NOT TO HAVE C.F.

PATIENTS

Patients 1-5

were seen at the regional paediatric hospital for only. Patients 6-13 were referred from other hospitals to the regional hospital c.F. clinic between 1971 and 1977,

sweat tests

and

were

8-5% of all such

new

referrals

during

those years.

Figures in parentheses are from analyses of sweat Cases 3-5, 7 and 8, and 11 and 12 are siblings.

weights of <

100 mg.

416

amylase with a commercial kit (’Phadebas’ amylase test, Pharmacia). Total faecal fat was measured by the method of Van de Kamer et al. 11I

RESULTS are shown in tables i and 11. Fsecal fat excrenormal in all patients, the highest being 3.2 g/day (11.8mmol/day) in patient 14. The average sweat-weight for 17 tests on 14 children was 238 mg (96-734). No patient required a second test because of insufficient sweat. Sweat-sodium was 17-53 mmol/1 and sweat-chloride 16-50 mmol/1 (upper limit of normal in this laboratory is 60 for both ions). The sweat-electrolyte values from the other hospitals, often very high, contrasted sharply with those from the

Results

tion

was

TABLE II-PANCREOZYMIN-SECRETIN-STIMULATED PANCREATIC

FUNCTION

regional pxdiatric hospital, which were all well within the normal range.. Pancreatic function tests on 5 patients were normal (table II). DISCUSSION

Although there is great variability in sweat-electrolyte values obtained in different hospitals, we maintain the correctness of our own because there is a high incidence of false-positive sweat tests in laboratories where the test is done only occasionally, because we have some clinical evidence that the children did not have c.F., and because pancreatic function was normal in 5 of the patients. Bowel symptoms were absent in all but 2 children. Steatorrhoea was also absent, although steatorrhoea is not found in all c.F. patients. These children were atypical, in that half were aged 5 or over when the diagnosis was made. Most children attending the c.F. clinic were diagnosed as infants or toddlers. While most of the patients had chest-related symptoms none presented with chronic suppurative chest disease typical of c.F. Most had had their coughs or wheezing intermittently for many years (average 4-5 years) and only 2 (patients 10 and 14) had ever had severe respiratory disease. Only these 2 patients had persisting chest signs which might have been mistaken for c.F., and they showed substantial evidence of severe asthma. None of the 14 children had purulent sputum or finger clubbing, and none produced staphylo-

cocci or Pseudomonas aeruginosa from sputum or cough swab cultures, as patients with C.F. often do. c.F. in patients without steatorrhoea can be substantiated with the pancreozymin-secretin stimulated test of pancreatic function:9 enzyme output may be normal, although it is usually rather lower (table 11), but the bicarbonate and volume produced in response to secretin is always poor. Normal values for bicarbonate, volume, and enzymes in the 5 children studied confirm that they did not have c.F. We now test pancreatic function in any child with a positive or borderline sweat test who does not have a clinical picture of pulmonary and alimentary disease fully characteristic of c.F. and, conversely, in any child with a borderline or negative sweat test who has an illness suggestive of c.F. No patient with c.F. has had completely normal pancreatic function. Why should sweat testing be unreliable in less experienced hands? Anderson and Goodchild 13 have recently reviewed the many problems connected with the stimulation and collection of sweat. The technique of Gibson and Cooke7 is not difficult but it is laborious and requires meticulous and constant attention to detail. It is unlikely that an inexperienced house physician, for instance, will do it with acceptable accuracy. To avoid contamination of the sweat the area where pilocarpine is to be iontophoresed must be carefully washed and dried, the area and the filter paper must not be touched, the iontophoresed area must not be burned, and laboratory contamination must be avoided. The filter paper placed on the skin must be occluded by an airtight dressing during collection and transferred in an airtight container to the laboratory to prevent loss of water from the sweat by evaporation. To ensure collection of an adequate weight of sweat for analysis (100 mg or more), iontophoresis must be carried out with the correct equipment and the area used should be kept warm. Depending on the size of the child more than one area may be required for sweat collection, perhaps an area other than the forearm. It is a matter for concern that the diagnosis of c.F.-with all its implications-may be made on uncertain grounds and our experience suggests that false diagnoses may not be uncommon. Where the diagnosis is in doubt repeated sweat analyses should be done, and followed by detailed testing of pancreatic function. Clinicians in units where tests for cystic fibrosis are done only occasionally might prefer to refer to a regional pxdiatric unit for confirmation of the diagnosis. We thank the department of clinical chemistry, Children’s Hospital, for carrying out the sweat tests.

Birmingham

Reprint requests should be addressed to C. A. S., Department of Paediatrics, Dudley Road Hospital, Birmingham B 18 7QH.

REFERENCES 1. di

Sant’Agnese, 1953, 12, 549.

P. A.,

Darling,

R.

C., Perera, G. A., Shea, E. Pediatrics,

Schwarz, V. in Scientific Foundations of Pædiatrics (edited by J. A. Davis and J. Dobbing); p. 545. London, 1974. 3. Gibson, L. E. J. Pediat. 1972, 81, 193. 4. Schwarz, V., Simpson, N. I. M., Ahuja, A. S. Archs Dis. Childh. 1977, 52, 2.

870. 5.

Anderson, C. M., Goodchild, M. C. in Cystic Fibrosis: nosis and Treatment; p. 140. Oxford, 1976.

A Manual of Diag-

417

Hospital

Practice

TISSUE NECROSIS CAUSED BY COMMONLY USED INTRAVENOUS INFUSIONS N. R. GAZE

Department of Plastic Surgery, St Luke’s Hospital, Bradford DESPITE the diversity of intravenous injections and infusions, local complications of intravenous therapy have seldom been reported. Yosowitz et al. reported a series of cases in which skin sloughs followed the extravasation of infusions of calcium and of hypertonic dextrose in children. Important tissue necrosis can, however, be caused by extravasation of more commonly used substances. Cases involving the following solutions have been treated in the plastic surgery services at Leeds and Bradford between 1975 and 1978. Sodium Bicarbonate

Solutions of sodium bicarbonate (15-20 g/litre of were first used to treat metabolic acidosis by Pines in 1951. 8-4%, 4.2% and 2.74% strengths are now used and because of alkalinity (pH 8.15) can cause chemical cellulitis on extravasation. Table i summarises data on those cases in which this process resulted in tissue necrosis. In all of them, sodium bicarbonate was the only intravenous agent used in addition to routine infusions of physiological saline, 5% dextrose, and (in 2 cases) blood. In case 8, a bottle of 5% dextrose was sent for analysis, the true cause of the damage being unrecognised by the clinicians concerned.

water)

Thiopentone Thiopentone sodium, like sodium bicarbonate, can cause tissue damage if it is extravasated during injection. It is even more alkaline (pH 10.5) than sodium bicarbonate. The 2 cases in which skin necrosis followed the leakage outside the vein of thiopentone during induction of anxsthesia are summarised in table u.

PressorAmines Adrenaline and noradrenaline are now rarely used intravenous infusions. Extravasation of adrenaline

as or

6. Committee for a Study for Evaluation of Testing for Cystic Fibrosis. J. Pediat. 1976, 83, 711. 7. Gibson, L. E., Cooke, R. E. Pediatrics, 1959, 23, 545. 8. Schales, O., Schales, S. S. J. biol. Chem. 1941, 140, 879. 9. Hadorn, B., Zoppi, G., Shmerling, D. H., Prader, A., McIntyre, I., Ander-

son, C. M. J. Pediat. 1968, 73, 39. Schwert, G. W., Neurath, H., Kaufman, S., Snoke, J. E. J. biol. Chem. 1948, 172, 221. 11. Van de Kamer, J. H., ten Bokkel Huinink, H., Weijers, H. A. ibid. 1949, 177, 347. 12. Hadorn, B., Johansen, P. G., Anderson, C. M. Can. med. Ass. J. 1968, 98, 10.

377. 13. Anderson, C. M., Goodchild, M. C. in Cystic Fibrosis: A Manual of nosis and Treatment; p. 142. Oxford, 1976.

Diag-

noradrenaline can cause intense local vasoconstriction with ischsemia of the skin leading to necrosis. If pressor amines have to be administered in this way, a large proximal vein should be selected for the infusion. Case 7.—A man of 52 with ischaemic heart-disease became hypotensive after resection of a ventricular aneurysm, and required inotropic support for 5 days. Isoprenaline was ineffective, and on the first day an infusion of 500 ml of 5% dextrose containing 10 mg of adrenaline was administered with a Harvard pump. 20 mg of adrenaline was given on subsequent days. After 5 days a skin slough measuring 10 cm x 6 cm was noted at the site of the cannula in the left medial calf. This separated spontaneously in 2 months with conservative treatment and the wound healed in 5 months, the patient having refused skin grafting. TABLE I-CASES OF TISSUE NECROSIS CAUSED BY SODIUM

BICARBONATE INFUSIONS