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tients complied well with the treatment--partly, theybelieve, because of the low incidence of side-effects.The efficacy of a drug is more than its pharmacologi-

cal actions or short-term therapeutic effects. The effi-

cacy of antihypertensive drugs, which have to be takenfor many years in order to influence the long-term com-plications of the condition, can only be judged over asimilar period of time. It is to be hoped that other clin-icians will follow the Edinburgh team in reporting theirlong-term experience.

WHEN DO GALLSTONES MATTER?

GALLSTONE disease is one of the most frequent ofclinical diagnoses, and is responsible for 1% of all deathsin Britain either directly or as a result of complications.Stones are, however, encountered much more commonlyin the postmortem room-currently in a quarter of allsubjects.’ The fact that at necropsy stones are found sixtimes more often than evidence of cholecystectomy sug-gests that they are usually silent or only mildly trouble-some. The great frequency of gallstones means that theywill very often coincide with symptoms arising fromother sources. If the true cause of digestive symptoms isnot sought, or cannot be proved by investigation, theconcurrent presence of a common and readily definablecondition such as gallstones may cause confusion.What symptoms should lead to suspicion that gall-

stone disease is responsible? One complaint often investi-gated by cholecystography is fatty dyspepsia. This im-plies belching, bloating, and mild-to-moderate epigastricdiscomfort after meals. But this has been shown not tobe associated with gallstones,2 3 so that no purpose isserved by proof of cholelithiasis. This is importantbecause symptoms will persist if cholecystectomy is per-formed inappropriately,3 and such patients will then belabelled as having either the post-cholecystectomy syn-drome or X-ray and endoscopy-negative dyspepsia. Only45-70% of patients have complete symptom relief aftercholecystectomy,3 4 and as many as 30% may not benefitat all. These figures can be improved only by more care-ful selection of patients in future. Although the femalesex, advancing age, obesity, and cirrhosis predispose tostone formation, these generalisations do not help in in-dividual patients. Gallstones can occur at any age, ineither sex, in the otherwise completely fit. A radiologicalscreen of 1233 apparently healthy men in 19595 showedthat 14.6% had undergone cholecystectomy, or had gall-stones, or had malfunctioning gallbladder. Even whenclosely questioned 70% of the men with gallstones con-fessed to no symptoms which could possibly be relatedto their cholelithiasis.

Definitely associated with gallstones (but not patho-gnomonic) are obstructive jaundice, right-upper-quad-rant and girdle abdominal pain, and acute pancreatitis.Unless contraindicated by pronounced jaundice or pre-vious cholecystectomy, oral cholecystography is then theinvestigation of choice because it provides the bestdefinition of the gallbladder, where stones are most like-

1. Bateson, M. C., Bouchier, I. A. D. Br. med. J. 1975, iv, 427.2. Price, W. H. ibid. 1963, ii, 138.3. Johnson, A. G. Postgrad. med. J. 1971, 47, 767.4. Stefanini, P., Carboni, M., Patrassi, N., Loriga, P., De Bernardinis, G.,

Negro, P. Surg. Gynec. Obstet. 1974, 139, 734.5. Wilbur, R. S., Bat, R. J. Gastroenterology, 1959, 36, 251.

ly to be. There has been some interest in single-visit cho-lecystography, but at least a quarter of patients withpoor or no opacification will have normal opacificationon the following day.6 Only if oral cholecystographyfails or is contraindicated need one resort to intravenous

cholangiography. Because many patients are not helpedby cholecystectomy it is important to make sure that cal-culi are responsible for symptoms. In addition, the oper-ation is sometimes fatal. There is some alarming evi-dence that high cholecystectomy rates 7 may beassociated with an increased overall death-rate for gall-bladder disease, rather than the decrease for which onewould hope.

THE RADIOALLERGOSORBENT TEST

THE radioallergosorbent test (R.A.S.T.) was devised" todetect specific reaginic antibodies in serum, belonging tothe IgE class of immunoglobulins. It is these IgE anti-bodies that are primarily involved in the immediate

hypersensitivity reactions9 in atopic diseases such as

urticaria, hayfever, and allergic asthma. These anti-bodies become bound to mast cells in the organs con-cerned and, after contact with specific offendingallergens (e.g., grass pollen, animal dander), there isrelease of chemical substances, notably histamine, whichmediate the allergic response. The antibodies are foundin the sera of allergic subjects, but only in extremelysmall amount." The R.A.S.T. is a sensitive method ofdetecting the specific components of this circulating IgEagainst the common provoking allergens, and hence anaid to identification of probable offending allergens inatopic disease. The test system" uses an insoluble cellu-lose carrier to which a specific allergen is coupled. Anyantibodies to this allergen in the test serum will becomebound and those of the IgE class can be detected by theuptake of anti-IgE antibodies labelled with l2sl mea-sured with a gamma counter. The test is semiquantita-tive and results are usually expressed in arbitary unitsrelated to a local standard serum or serum from non-al-

lergic controls.R.A.S.T. results correlate well with clinical provocation

tests.s 12-15 The range of agreement is between 73% and100%, correlations being best when the allergen extracthas been highly purified. But the R.A.s.T. has definiteadvantages over the other tests: clinical history and skintesting will often be a reliable guide,16 but on occasionthey are misleading and positive skin tests may not besupported by positive provocation tests. Provocation, asin the bronchial-challenge test, has risks; it is time-consuming and impossible in young children. The R.A.S.T. isfree from these disadvantages, and results against overtwenty suspected allergens can safely be obtained froma single 5 ml blood-sample, within 48 hours if necessary.Such information is of great value to the busy clinician.Besides its application to common allergens, the test has

6. Rosenbaum, H. D. J. Am. med. Ass. 1974, 229, 76.7. Vayda, E. New Engl. J. Med. 1973, 289, 1224.8. Wide, L., Bennich, H., Johansson, S. G. O. Lancet, 1967, ii, 1105.9. Bennich, H., Ishizaka, K., Johansson, S. G. O., Rowe, D. S., Stanworth, D.

R., Terry, W. D. Bull. Wld. Hlth. Org. 1968, 38, 151.10. Johansson, S. G. O. Lancet, 1967, ii, 951.11. Ceska, M., Eriksson, R., Varga, J. M. J. Allergy clin. Immun. 1972, 49, 1.12. Berg, T., Bennich, H., Johansson, S. G. O. Int. Archs. Allergy, 1971, 40,

770. 13. Aas, K., Johansson, S. G. O. J. Allergy clin. Immun. 1971, 48, 134.14. Aas, K., Lundkvist, U. Clin. Allergy, 1973, 3, 255.15. Berg, T. L. O., Johansson, S. G. O. J. Allergy clin. Immun. 1974, 54, 209.16. Frankland, A. W. Ann. Allergy, 1974, 33, 105.

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been useful in the diagnosis of sensitivity to penicillin,17Aspergillus fumigatus, 18 and some detergents. 19 A ratherdifferent application is in the standardisation of allergenextracts," either by direct coupling of these to the solidphase or by inhibition experiments. The composition ofthese extracts can vary widely between different batchesfrom the same firm as well as between batches from dif-

°

ferent manufacturers. Assessment of purity and activityof these preparations is difficult, but it is only throughstandardisation that precise diagnosis in clinical allergywill become possible. ’

As always, the clinician should beware of placingundue reliance on a single laboratory test, for theR.A.S.T. has limitations. It is only semiquantitive and theresults are not strictly related to the severity of the clini-cal response to any particular allergen. Studies on thecod allergen 14 and animal danders2° suggest that tissuemast cells can have enough attached specific IgE to pro-duce clinical sensitivity to these allergens, even thoughtheir antibodies cannot be detected in serum and theR.A.S.T. will be negative. On the other hand, reaginicantibodies may appear in serum when there is no clinical

sensitivity.21 It has been suggested that the presence ofthese antibodies may precede specifically provokedsymptoms and their detection could be useful in showingthe patient what to avoid.The R.A.S.T. will undoubtedly be used widely, both as

a research procedure and as an aid in clinical practice.For the research-worker, scarcity of the purified anti-IgE antibody, and for the hospital laboratory, the

expense of the commercial kit, have so far restricted itsuse. The test can be modified22 to use commerciallyavailable anti-IgE antiserum, which is much cheaperand more readily obtained, but there is some loss of

sensitivity. However, cost comparison with many otherhospital investigations is favourable and the many ben-efits obtained by more accurate identification of offend-ing allergens-if only in reduction of potentially dan-gerous and expensive drug therapy-ought to be bornein mind.

THE NOSE AND LEPROSY

As regards leprosy, the nose is again in the news. Theearly scientific leprologists were convinced of the impor-tance of the nasal discharge as the vehicle par excellenceof the transmission of the causal organism to sus-

ceptible contacts. At the First International LeprosyCongress, in 1897, Sticker" presented convincing evi-dence that acid/alcohol-fast bacilli left the nasal mucosain mucoid droplets. SchUffer" beautifully illustrated thesame thesis. At the second congress (1909) the president,Hansen himself, suggested that the portal of entry ofthese organisms was the nose.Few investigations of the pathological changes in the

nose caused by direct invasion of mucosa, cartilage, andbone were reported until Barton25 made a systematic

17. Wide, L., Juhlin, L. Clin. Allergy, 1971, 1, 171.18. Arbesman, C. E., Wicher, K., Wypych, J. I., Reisman, R. E., Dickie, H.,

Reed, C. E. ibid. 1974, 4, 349.19. Pepys, J., Wells, I. D., D’Souza, M. F., Greenberg, M. ibid. 1973, 3, 143.20. Johansson, S. G. O., Bennich, H. H., Berg, T. in Progress in Clinical Immu-

nology (edited by R. S. Schwartz); vol. i, p. 157. New York, 1972.21. Foucard, T. Acta pœdiat. Scand. 1973, 62, 633. 22. Sarsfield, J. K., Gowland, G. Clin. exp. Immun. 1973, 13, 619.23. Sticker, G. Dt. med. Wschr. 1897, 44, 1063.24. Schäffer, J. Archs Derm. Syph. 1898, 44, 159.25. Barton, R. P. E. Ann. Otol. 1976, 85, 74.

study of the nose in leprosy. He has confirmed andamplified the early forgotten work of the pioneers, and,by painstaking clinical examination, and histopathologi-cal and bacteriological studies, has brought back thenose into leprosy news.

Apart from a few scattered reports26 27 on the valueof nasal-smear examination in the assessment of the activ-

ity of multibacillary leprosy, scant attention was paidin the intervening years to the importance of the mucoiddischarge from the heavily bacillated mucosa of thenasal septum and anterior extremity of the inferior tur-binate. Then Pedley}2R having drawn attention to thepresence of acid/alcohol-fast bacilli on the surface of theperinasal skin (but not elsewhere), showed29 that thebacillary load of the nasal discharge of patients with un-treated lepromatoud leprosy was immeasurably greaterthan that of any other possible excretion.

It was left to Barton, 21 30 31 working at Dichpalli(India), to provide a convincing observational basis forPedley’s work, and to show that, in India at least, exam-ination of the nasal discharge in patients presenting withsuggestive signs of early lepromatous disease wouldreveal numerous leprosy bacilli, in typical globus forma-tion. Endonasal examination would show specific lesionsof the mucosa, often of unsuspected extent. The vastclinical experience of Davey, 12 13 allied to the laboratoryexpertise of Rees34 and his colleagues, elegantly comple-mented Barton’s rhinological studies. The bacilli wereindeed Mycobacterium leprae; they multiplied in classicfashion in the footpads of laboratory mice, normal andimmunodeficient, and some were found in the nasal dis-charge of the infected mice; and many remained viableoutside the human body for two days.The portal of exit of leprosy bacilli being now well-

established, the portal of entry remains to bedemonstrated. Work is now proceeding on the possibilityof infecting mice by exposure to bacilli-laden aerosols. Inthe human being exposed to bacilli-laden air, particles ofmore than 10 li in diameter are probably entrapped inthe nasal mucus and swallowed. What happens then? Doimmunological factors play a role in the nasal mucus asit entraps leprosy bacilli35? And what happens to themillions of viable M. leprx ingested at each feed by aninfant suckling at the breast of its lepromatoudmother,36 the cells of whose milk ducts may be engorgedto bursting point with organisms?

Barton’s work is the necessary introduction to the in-

vestigations of Job and his colleagues 17 11 on the patho-genesis of specific and non-specific infection of nasal car-tilages and nasal bones in leprosy, and provides theexplanation for the palaeo-osteological revelations ofM0lIer-Christensen. The study of leproud rhinitis inCentral India has already proved to be of germinal im-portance. And there must be more to follow.

26. Browne, S. G. Lepr. Rev. 1959, 30, 174.27. Browne, S. G. Int. J. Lepr. 1966, 34, 23.28. Pedley, J. C. Lepr. Rev. 1970, 41, 31.29. Pedley, J. C. ibid. 1973, 44, 33.30. Barton, R. P. E. ibid. 1974, 45, 135.31. Barton, R. P. E. Ann. R. Coll. Surg. Engl. 1975, 57, 309.32. Davey, T. F. Lepr. Rev. 1974, 45, 97.33. Davey, T. F., Rees, R. J. W. ibid. p. 121.34. Rees, R. J. W., McDougall, A. C., Weddell, A. G. M. ibid. p. 112.35. Br. med. J. 1976, i, 733.36. Pedley, J. C. Lepr. Rev. 1967, 38, 239.37. Job, C. K., Karat, A. B. A., Karat, S. J. Laryng. Otol. 1966, 80, 718.38. Job, C. K., Karat, A. B. A., Karat, S. Lepr. India. 1968, 40, 2.39. Møller-Christensen, V. Bone Changes in Leprosy. Copenhagen, 1961.