580

disagreement, there now is some semblance of

agreement about platelet-function tests. HARKERand SLICHTER, for example, used the standardisedtemplate bleeding-time; the platelet-count and

platelet size; platelet aggregation induced by A.D.P.,thrombin, adrenaline, and collagen; platelet retentionon passage of blood through a column of glass beads;platelet adhesion to collagen; platelet phospholipidavailability (platelet factor 3); and clot retraction.Perhaps heparin-neutralising activity (platelet factor4) might be included without too much controversy.We have come a long way from the simplicity ofDuKE’s bleeding-time. Will the next step be a studyof the efficiency of a chain of enzymes and surfacechemistry ?

Mechanisms of Reactions in LeprosyALTHOUGH leprosy is a particularly chronic con-

dition, the course of the disease is often punctuatedby acute reactional episodes which may delayrecovery. The significance and aetiology of thesereactions have until lately remained largely obscure.Thus it is particularly pleasing to see that a combina-tion of experimental, immunological, and clinico-

histological information, assembled by WATERS,TURK, and WEMAMBU, provides an explanation forthe mechanisms of leprosy reactions.To understand reactional episodes in leprosy, it is

essential first to appreciate the remarkable diversityof manifestations in patients infected with Myco-bacterium lepra. The spectrum of clinical, immuno-logical, bacteriological, and histological features isalmost continuous, between the polar lepromatousat one extreme and polar tuberculoid at the other,with some patients at a central position showingfeatures of both polar types (referred to as borderline).There is now substantial evidence that the positionof a patient on the leprosy spectrum is related to hiscapacity to mount a cell-mediated response (cell-mediated immunity, C.M.I.) to M. lepre.2 Thus

patients with tuberculoid leprosy, who carry veryfew leprosy bacilli, have a high degree of C.M.I.reflected in infiltration of their lesions and the

paracortical areas of their lymph-nodes by lympho-cytes.3 In contrast, lepromatous patients, who carrya massive load of bacilli, have gross depression ofC.M.I., and few lymphocytes in their lesions and theparacortical areas of their lymph-nodes.3 3 Theseobservations are confirmed by GODAL and his

colleagues,4 who have shown that lepromatouspatients lack circulating lymphocytes responding toM. leprca, indicating that their immunological defectis consistent with a state of immunological tolerance.

1. Waters, M. F. R., Turk, J. L., Wemambu, S. N. C. Int. J. Lepr.1971, 39, 417.

2. Turk, J. L. Bull. Wld Hlth Org. 1969, 41, 779.3. Turk, J. L., Waters, M. F. R. Clin. exp. Immun. 1971, 8, 363.4. Godal, T., Myklestad, B., Samuel, D. R., Myrvang, B. ibid. 1971,

9, 821.

Finally, these immunological concepts are supportedby the experimental work of REES et al.,5 who haveshown that mice inoculated with M. lepra developlepromatous-type leprosy when their c.M.i. isobliterated by previous thymectomy and irradiation.Although patients with lepromatous leprosy have aC.M.i. deficiency, they are capable of producing hightitres of circulating antimycobacterial antibodies,6 sbut in patients with tuberculoid leprosy the amountof antibody is zero. The importance of these immuno-logical processes in determining the pattern of leprosyhas led to new work on the two well-defined types ofleprosy reactions-namely, erythema nodosum lep-rosum (E.N.L.) and " lepra reactions ".7

E.N.L. occurs only in patients with the lepromatousor near-lepromatous form of the disease: crops oftender and erythematous papules appear in the skinfor 24-48 hours and are accompanied by fever. Inmore severe cases the lesions may pustulate or

necrose. Although rare in untreated patients, E.N.L.has become increasingly common with the advent ofchemotherapy, affecting up to 50% of patients bythe end of their first year of treatment.

8 Histo-

logically the lesions are characterised by an in-tense perivascular polymorph leucocyte infiltration.This picture closely resembles the Arthus reactionin animals, which is known to be due to depositionof immune complexes in and around blood-vessels.9Furthermore, patients with E.N.L. may have systemicmanifestations-arthritis, iridocyclitis, orchitis,neuritis, lymphadenopathy, proteinuria-many ofwhich are also found in chronic serum-sickness,which is known also to be associated with circulatingimmune complexes. Certainly patients with lepro-matous leprosy have the prerequisites for formationof immune complexes, since there is an abundanceof mycobacterial antigenic material, which maybecome more readily available when the bacilli arekilled by chemotherapy, and high titres of anti-

mycobacterial antibodies in the serum. It was onthis basis that WEMAMBU and his colleagues 10applied immunofluorescent techniques for detectingimmune complexes, and they were able to demonstratesuch complexes in E.N.L. skin lesions. They showedthat skin-biopsy specimens from 20 of 38 E.N.L.

patients contained both immunoglobulin and comple-ment-and sometimes also soluble mycobacterialantigen-whereas control specimens from 13 E.N.L.-free lepromatous patients were uniformly negative.Further important evidence in support of an immune-complex setiology for E.N.L. is provided by Dr.

5. Rees, R. J. W., Weddell, A. G. M. Ann. N.Y. Acad. Sci. 1968,154, 214.

6. Rees, R. J. W., Chaterjee, K. R., Pepys, J., Tee, R. R. Am. Rev.resp. Dis. 1965, 92, 139.

7. VIIth International Congress of Leprology, Tokyo, November, 1958.Int. J. Lepr. 1958, 26, 380.

8. Waters, M. F. R., Rees, R. J. W., Sutherland, I. ibid. 1967, 35, 311.9. Cochrane, C. G., Ward, P. A. in Immunopathology. vth int. Symp.

(edited by P. Grabar and P. A. Miescher); p. 433. Basle, 1966.10. Wemambu, S. C. N., Turk, J. L., Waters, M. F. R., Rees, R. J. W.

Lancet, 1969, ii, 933.

581

MoRAN and his co-workers on p. 572 this week.

They used the new technique of AGNELLO et al.,l1by which immune complexes can be precipitated withthe C 1 Q component of complement, and by whichcirculating immune complexes were demonstratedin patients with systemic lupus erythematosus.12Thus 76% of lepromatous patients with active E.N.L.were shown to have circulating immune complexes,compared with only 33% of lepromatous patientswithout E.N.L. While the relation of these circulatingimmune complexes to the aetiology of E.N.L. is not

yet clear, a direct method is now available for

determining the nature of the antigenic constituentsof these complexes.

In contrast, lepra reactions occur in patientsanywhere on the leprosy spectrum save at the twopoles, and cause inflammation and swelling of existingleprosy skin lesions for weeks or months. Leprareactions can happen with or without chemotherapy.Clinically and histologically the lesions are consistentwith the type of leprosy the patient has or is develop-ing ; there is oedema and hyperaemia but no inflam-matory infiltrate. The end-result of lepra reactionsis a shift in the leprosy classification of the patienteither towards the lepromatous pole in untreatedpatients (" downgrading reaction ") or towards thetuberculoid pole in treated or untreated patients(" reversal reaction ").13 While both groups of leprareactions are suppressed by corticosteroids but notby thaiidomide, E.N.L. is suppressed by both drugs.Histologically, reversal reactions are associated withan increase in lymphocytes in the leprosy lesionsand in the paracortical areas of their lymph-nodes,and therefore suggest an increase in c.m.i.1 This

concept is strengthened by experiments in whichreversal reactions have been produced by injectionof syngeneic lymphoid cells to immunologicallysuppressed mice with lepromatous leprosy.14 Accord-ing to this concept, downgrading reactions are

assumed to result from a decrease in C.M.I.

The Management GameWHEN the National Health Service was set up in

1948, its aim was to improve health care. That theaim is still the same is confirmed by the newlypublished report on Management Arrangements forthe Reorganised National Health Service.15 In 1948the orders from the top were contained in a few shortmemoranda. The absence of detailed direction leftcommittee members and administrators free to make

11. Agnello, V., Winchester, R. J., Kunkel, H. G. Immunology, 1970,19, 909.

12. Agnello, V., Koffler, D., Eisenberg, J. W., Winchester, R. J.,Kunkel, H. G. J. exp. Med. 1971, 134, 228.

13. Ridley, D. S. Leprosy Rev. 1969, 40, 77.14. Rees, R. J. W. Proc. R. Soc. Med. 1970, 63, 1060.15. Management Arrangements for the Reorganised National Health

Service. H.M. Stationery Office, 1972 See Lancet, Sept. 9, p. 534.

their own local management arrangements: sometimesthe result was good; sometimes, as when empires werebuilt, honeycombed by subcommittees, the result

proved demoralising to professional staff. This timethe Service is confronted by 174 pages of close print,which could, if too closely followed, inhibit goodflexible management in progressive areas, but shouldat least guard against excessively bad managerialpractice elsewhere.The report has many good features. There will be

few dissenters from the proposition that the opera-tional and planning unit should be the district whichserves about a quarter of a million people, rather thansome more remote area or region. Hard-bittenauthoritarians may complain about the search forconsensus, but most professionals will support thereport’s assumption that the best teamwork is likelyto take place where people of different professionshave an equal regard for one another’s professionalcontribution. Those who have endured the long waitfor decisions on small matters to be processed throughthe bureaucratic machine will welcome the new

emphasis on delegation. Administrators who havehad to sit by in the past whilst a committee memberhelped to appoint a porter, or tasted samples of jam,will be glad that members are to be concerned withwhat is to be done, and with what resources; thatprofessionals are to be concerned with how the thingis to be done; and that members are to judge, onbehalf of the community, whether the thing has beendone. The proposal that the professionals who makeup a district management team will have a right ofaccess to the statutory area health authority will bringa new perspective into relationships between healthprofessionals and committee-men. The distinctionbetween revenue and capital expenditure is to be lessprecisely marked, and unused revenue funds maynow be carried forward from one year to the next:thus, at long last, two of the major financial nonsensesof the N.H. S. are to be removed.

Perhaps the greatest relief for many doctors is thatthe working-party has abandoned the chief-executiveconcept of health-care management, and has choseninstead an approach which favours the equal partici-pation of the health professions. So far, all is sweet-ness and light; but there are some shadows and

complexities.There is great emphasis on the importance of the

district team, but its resources will be controlled bythe area health authority, whose resources will becontrolled in turn by the regional authority and thecentral Department. In reality, he who allocatesresources makes the decisions, however impressivethe consultative apparatus may look; and other

Departmental controls, covering such activities as

personnel, planning, and organisation, appear in thesepages. Veterans who recall the lively independencewhich the new hofpital management committeeswere promised in 1948 will also remember the tapes