B.C.G. VACCINATION OF TUBERCULIN-POSITIVE (HEAF-TEST GRADE 1) CHILDREN

537

only 4 patients (0-7%) was it necessary to discontinue medication, due to oedema in 1 and to peptic ulcer in 3. 1 of these patients, with chronic hypertensive heart-disease, was being treated for rheumatoid arthritis; mild oedema developed after 4 years of treatment. Although dosage of phenylbutazone was only 100 mg. daily, the drug was discontinued as a precautionary measure. The 3 others who stopped medication because of peptic ulcer had been on therapy for 2-4-5 years. The fourth patient who had a peptic ulcer continued satisfactorily on phenylbutazone (200 mg. daily) in conjunction with an anti-ulcer regimen; it was otherwise difficult to control his In

gout. All other side-effects were mild and caused no disruption in long-term drug administration. Reactions were easily controlled by antacids, by taking food with the drugs, or by dosage adjustment. Although reactions were more frequent on phenylbutazone (25 patients, 11-1%) than on oxyphenbutazone (19 patients, 5-7%), only 2 patients on each drug (less than 1-0%) required withdrawal of medication severe

(tables ill). Further analysis of side-effects showed an almost equal distribution in all of the rheumatic diagnostic categories, with. the lowest incidence in the nonarticular group (table iv). The time pattern of reactions was also similar in the various diagnostic groups. Most mild reactions developed during the first few months of therapy. Then a period of about 21/2 years free of reactions was followed by a 1-year period during which mild side-effects recurred occasionally. The more serious reactions, as mentioned above in 5 patients, were observed after 2 to almost 5 years

on

medication.

disease and other medications may have been contributory factors. Although gastric irritation can frequently be prevented by the use of antacids or taking the drugs with meals, it must be emphaised that other precautions are necessary in the management of patients on these drugs to lessen the risk of untoward reaction. Such measures should include: (1) a careful history and frequent physical examination to disclose present or previous ulcers, or cardiovascular or renal disease; (2) partial limitation of salt intake and repeated check of body-weight to control oedema; (3) frequent complete blood-cell counts to detect any blood dyscrasias; (4) periodic liver and kidney function tests; and (5) prompt reporting by the patient of any untoward symptoms such as sore throat, gastrointestinal disturbance, black stools, or fever. Also, the physician must know the contraindications to the use of these drugs. With careful attention to these procedures, I have rarely met any difficulty in satisfactorily maintaining patients on long-term therapy with phenylbutazone or oxyphenbutazone. In general, I feel that the low doses used have contributed considerably to the mildness of adverse reactions and relative safety of prolonged drug administration. In fact, the percentage of patients discontinuing medication was lower than in earlier seriesin which somewhat larger maintenance doses were used for shorter periods, non exceeding 3 years.

oedema,

REFERENCES

1. 2. 3. 4. 5. 6. 7.

DISCUSSION 8.

Adverse effects from phenylbutazone and oxyphenbutazone have been described by myself and others.1-9 The most common reactions include nausea, oedema, and drug rash. Haematological disturbances such as agranulocytosis, leukopenia, anaemia, and thrombocytopenia occasionally develop. Several cases of leukasmia and leukaemoid reactions have been noted, but cannot be definitely attributed to these drugs. Stomatitis and peptic ulcer have also been reported. Most of the serious reactions that have been published resulted from the large doses, up to 1600 mg. phenylbutazone daily used in early trials.2-4 Later, long-term, well-monitored trials have shown that the incidence of reactions is small.5-9 Potential harmful effects may be minimised if simple precautions are followed. As with other drugs, occasional serious effects may develop as a result of individual hypersensitivity. Such reactions, usually unpredictable, are seen very early in treatment, but may often be avoided by asking each patient about history of drug allergy. Long-term administration of phenylbutazone and oxyphenbutazone show that for the therapy of various arthritis and allied disorders was well tolerated by most patients. In this group of 562 patients treated for periods of 2-10 years, adverse reactions were in most instances mild and easily controlled. The drugs were discontinued in only 4 patients (0-7%), because of oedema in 1 and peptic ulcer in 3. In the patient with

concurrent

9. 10.

Rechenberg, H. K. Phenylbutazone; p. 80. London, 1962. Kuzell, W. C. et al. Schaffarzick, R. W., Naugler, W. E., Gaudin G., Mankle, E. A. A.M.A. Archs intern. Med. 1953, 92, 646. MacKnight, J. C., Irby, R., Toone, E. C., Jr. Geriatrics 1954, 9, 111. Mauer, E. F. New Engl. J. Med. 1955, 253, 404. Sperling, I. L. Arthritis Rheum. 1959, 2, 203. Brooke, J. W. Western Med. 1961, 2, 8. Kuzell, W. C., Glover, R., Gibbs, J. O., Naugler, W. E., Blau, R. A. Arthritis Rheum. 1963, 6, 781. Sperling, I. L. Appl. Ther. 1964, 6, 117. Strandberg, B. Acta rheum. scand. 1965, 10, Suppl. Kuzell, W. C. 8th Congress of the Japanese Rheumatism Association, 1964.

von

Public Health B.C.G. VACCINATION OF TUBERCULINPOSITIVE (HEAF-TEST GRADE 1) CHILDREN A REPORT OF NEWHAM HEALTH

DEPARTMENT, LONDON*

As part of routine B.C.G. vaccination in schools, 239 London children, aged 13-14 years, who were Heaf-test-positive grade 1 were given B.C.G. vaccine, and the lesions were compared with those in 335 Heaf-test-negative children who were vaccinated at the same time. The children were seen 5-8 days and again 42-56 days after vaccination; there was no clinically significant difference between the lesions on either of these occasions. It is recommended that in the United Kingdom B.C.G. vaccine should be

Summary

*

This investigation was undertaken by Dr. M. K. BOLAND, Dr. R. A. CLAY, Dr. G. CROSBY, Dr. E. M. T. NEALE, Dr. M. P. O’DWYER, Dr. B. E. POWE, Dr. R. H. RAYNES, and Dr. U. W. WILLIAMS and the following public-health nurses: Mrs. M. BAKER, Mrs. C. E. MOORE, Mrs. M. O’SULLIVAN, and Mrs. E. R. WOZNIAK. The study was organised, the results analysed, and this report prepared by Dr. N. S. GALBRAITH.

538

given to both Heaf-test-negative and Heaf-test-positive grade-1 reactors in the B.C.G. vaccination programme in schools. Vaccination should be omitted only if there is a previous history of B.C.G. vaccination within the previous ten years and if this can be confirmed by the presence of a scar.

TABLE I-NUMBERS OF CHILDREN INVESTIGATED

INTRODUCTION

THERE is controversy about the local complications following B.C.G. vaccination of children with weakly positive tuberculin reactions. Weak sensitivity to human tuberculin in unvaccinated subjects is now considered to be due, not to previous infection with Mycobacterium tuberculosis, but to infection with other antigenically related mycobacteria.I Children exhibiting this weak tuberculin sensitivity are less likely to develop tuberculosis than are those with a negative tuberculin test, but the

protection conferred by atypical mycobacterial infec-2 tions is less than that resulting from s.c.. vaccination. In the United Kingdom, children with weak tuberculin sensitivity are usually denied B.c.G. vaccination because it has been thought that vaccination would local reactions. However, recent studies of B.c.G. vaccination without prior tuberculin testing, carried out by the World Health Organisation in West Africa, Kenya, and India,3have shown that severe local reactions do not take place; in the United Kingdom Stewart4 vaccinated 85 children aged 13-14 years who were tuberculin-positive, Heaf test grade 1 or 2, and no severe local reactions were observed. The purpose of this investigation was to measure the reactions following B.C.G. vaccination in children aged 13-14 years who had weak tuberculin sensitivity, Heaf-test-positive grade 1, and to compare these with the reactions in children who had negative Heaf tests; the children were being vaccinated in the course of the routine B.C.G. vaccination of schoolchildren.’ cause severe

METHOD

The investigation was carried out in Newham, London, between January and May, 1969. All schoolchildren aged 13-14 years, whose parents wished them to be vaccinated against tuberculosis, were given a Heaf test by nurses trained in this work. The test was read seven days later by medical officers, all of whom had received training in reading the test but whose experience in the school B.C.G. vaccination programme varied from many years to a few weeks. The results of the Heaf tests were recorded as follows: 0: no reaction or six faint marks on the skin without induration. Heaf grade 1: four or more discrete palpable papules at least 1 mm. in diameter. Heaf grade 2: papules forming a ring with normal skin in the middle. Heaf grade 3: a plateau of induration. Heaf grade 4: vesiculation or ulceration.

Heaf grade

Children with readings grade 0 and grade 1 were given vaccine; only when there was a history of B.C.G. vaccination within the previous 10 years, and this could be confirmed by the presence of a vaccination scar, was the vaccine not given. Children with readings grade 2, 3, and 4 were referred for examination by consultant chest B.c.G.

physicians. Children who had grade-1 readings, together with a sample of one-quarter of the children who had grade-0 readings, were seen at 6-8 days after vaccination and again at 42-56 days after vaccination. The transverse random

diameter of the B.c.G. lesion was measured and records were made of pain, discharge, and ulceration. These data were recorded by the same doctor and nurse throughout the

investigation. RESULTS

574 children entered the investigation; before B.c.G. vaccination 239 of them were Heaf-test-positive grade 1 and 335 were Heaf-test-negative. All but 15 of the children were seen 5-8 days after vaccination, and all but 23 again at 42-56 days (table l). In none of the absent children was their absence due to a

vaccination reaction. In the children who

were Heaf-test-positive grade 1 before vaccination the mean transverse diameter of induration 5-8 days after vaccination was 7-2 mm. (range 0-25 mm.); in the children who were Heafnegative before vaccination the diameter of induration The difference was 5-3 mm. (range 0-23 mm.). between these two means is 1-96 times the standard error, and therefore just below the 5% level of statistical significance (table n). At the first visit the children were asked if their arm was painful; 7 of 228 (3-1%) of the children who were Heaf-positive grade 1 before vaccination replied in the affirmative, compared with 4 of 331 (1-2%) of the pre-vaccination Heaf-negative children. This difference is not statistically significant. At 42-56 days the mean transverse diameter of induration was 6-6 mm. (range 0-13 mm.) in the children who were Heaf-test-positive grade 1 before vaccination and 5-5 mm. (range 0-25 mm.) in the children who were Heaf-negative. The difference between these two means is not statistically significant

(table 11). ulcerated in more of the than in the Heafchildren Heaf-test-positive grade-1 but the difference was not statisticnegative children, ally significant (table 11). Significantly more of the The

B.C.G.

lesion

was

TABLE II-CHARACTERS OF B.C.G. LESION

539

children gave a history of lesion than did the Heaffrom the B.C.G. discharge children. negative Only one severe local reaction took place; this was in a child who was Heaf-negative but who had had B.C.G. vaccine about two years previously. The doctor carrying out the vaccination was unaware of the previous vaccination and revaccinated the child near the original vaccination site.

Heaf-positive grade-1

DISCUSSION

This investigation showed that there was no clinically significant difference between the B.c.G. vaccination lesion of the children who were Heaf-test-positive grade 1 before vaccination and those who were Heaf-negative, when inspected at 5-8 days and again at 42-56 days after vaccination. We recommend that in the United Kingdom the B.C.G. vaccination programme of children aged 13-14 years should include children who before vaccination exhibit low-grade sensitivity to tuberculin. Children who are Heaf-test-negative or Heaf-test-positive grade 1 (Mantoux test 10 T.u. 10 mm. induration is approximately equivalent to Heaf-test grade 1) should be vaccinated; vaccination should be omitted only if there is a previous history of B.C.G. vaccination within the previous ten years and this can be confirmed by the presence of a scar. In the W.H.O. studies3 of B.C.G. vaccination of positive reactors of all grades, the diameter of induration of the B.C.G. lesion measured within 7 days after vaccination was larger than in our study in which only

Heaf-positive grade-1 unexpected finding.

reactors were

As in

vaccinated-a not-

investigation the difference in the mean diameter of induration in the reactors and non-reactors was greater when the children were first seen after vaccination and smallest when seen later about 8 weeks after vaccination. It appears that the tuberculin-positive children reacted to the tuberculin in the B.C.G. vaccine and the induration seen in the first week after vaccination is similar to that after a Mantoux test. To the child it is no more troublesome than a positive Mantoux reaction. The B.C.G. lesion which develops later is very similar in the prevaccination tuberculin-positive children and the tuberculin-negative children, although there was evidence in the W.H.O. studies of a slightly greater diameter of tissue destruction in the tuberculin-positive group than in the non-reactors. Our finding of a greater proportion of discharging lesions in the Heaf-test-positive grade-1 children than in the Heaf-negative children (table II) probably indicates also increased tissue destruction, but we do not consider this to be of any clinical importance. our

We thank Dr. Audrey Hanson and Dr. D. J. Lawless for their help in this investigation and the Chief Education Officer and head teachers of secondary schools in Newham for their

willing cooperation. Requests for reprints should be addressed to N.

S. G., Newham Health Department, 99 The Grove, London E.15.

Letters to the Editor PERIWINKLE ALKALOIDS AND PLATELETS SIR,-Dr. Robertson and Dr. McCarthy (Aug. 16, p. 353) have shown that periwinkle alkaloids may cause a rise in the blood platelet-count. They have found that the rise is independent of the oncolytic action of the drug, but they are uncertain of the mechanism by which it occurs. Possibly some observations from the United States 1-3 and from this department4 may help to clarify this

phenomenon. The vinca alkaloids5 and colchicine 6 modify the behaviour of contractile proteins by inhibiting the polymerisation of acting and they also alter the structure of microtubules. Platelets possess an actomyosin-like contractile protein, thrombosthenin,8 and have been shown to contain structures resembling microtubules.9 10 The effect of colchicine and vinca alkaloids on platelet function has therefore been studied. Shepro et al.1 showed that clot-retraction was inhibited by colchicine; White 23 has shown that colchicine and vinca alkaloids can destroy the platelet microtubules and that platelets so treated do not show the usual two-phase aggregation response when challenged with A.D.P. or adrenaline. We have found4 that, in the presence of colchicine, platelet adhesiveness to glass is considerably reduced, and that the aggregation patterns produced by A.D.P. and by noradrenaline are altered, colchicine producing enhancement of disaggregation. At the present time there is no clear correlation between alterations in the various in-vitro platelet-function tests such as clot-retraction, adhesiveness, and aggregation, and the behaviour of platelets in their natural habitat in the intact animal." It seems possible, however, that a reduction in the reactivity of platelets would prolong their lifespan, and Smythe et al.11 have indeed shown that materials (such as sulphinpyrazone) which interfere with platelet behaviour in vitro, prolong the survival of labelled platelets. The rise in platelet-count observed by Dr. Robertson and Dr. McCarthy may therefore reflect a prolongation of platelet life resulting from a reduction in platelet reactivity caused by the vinca alkaloids. We would suggest that, in addition to the studies of the marrow turnover which Dr. Robertson and Dr. McCarthy propose in their article, they might also examine platelet survival, platelet morphology, and platelet behaviour as judged by studies of aggregation and adhesiveness. If they find that the circulating platelets contain few microtubules, and show diminished adhesiveness and enhanced disaggregation, then it is clearly possible to induce, in the intact animal, the same changes which are brought about by in-vitro exposure to the vinca alkaloids.3 The implications of this phenomenon, both for the study of in-vivo platelet behaviour and for the continuing search for potential antithrombotic agents, would be considerable. Department of Medicine, G. D. SOPPITT Nottingham University,

General Hospital, Nottingham. 1.

2. 3. 4. 5.

REFERENCES 1.

Heaf, F. R. G., Muggleton, P. W. in Recent Advances in Respiratory Tuberculosis (edited by F. R. G. Heaf and N. L. Rusby). London,

2. 3. 4. 5.

Rees, R. J. W. Br. med. Bull. 1969, 25, 183. Geser, A., Roy, L. A., Bløcher, C. Bull. Wld Hlth Org. 1966, 35, 609. Stewart, C. J. Tubercle, Lond. 1968, 49, 84. Department of Health and Social Security. Immunisation against Infectious Disease. H.M. Stationery Office, 1968.

1968.

6. 7. 8. 9. 10. 11. 12.

J. R. A. MITCHELL.

Shepro, D., Belamarich, F. A., Chao, F. C. Nature, Lond. 1969, 221, 563. White, J. G. Am. J. Path. 1968, 53, 281. White, J. G. ibid. 1969, 54, 467. Soppitt, G. D., Mitchell, J. R. A. J. atheroscler. Res. (in the press). George, P., Journey, L. J., Goldstein, M. N. J. Natn. Cancer Inst. 1965, 35, 355. Borisy, G. G., Taylor, E. W. J. Cell Biol. 1967, 34, 525. Forsheit, A. B., Hayashi, T. Biochim. Biophys. Acta, 1967, 147, 546. Bettex-Galland, M., Lüscher, E. F. Nature, Lond. 1959, 184, 276. Rodman, N. F. Thromb. Diath. hœm. 1967, suppl. 26, 9. White, J. G., Krivit, W. ibid. p. 29. Hampton, J. R. J. atheroscler. Res. 1967, 7, 729. Smythe, H. A., Ogryzlo, M. A., Murphy, E. A., Mustard, J. F. Can. med. Ass. J. 1965, 92, 818.