SAMJ

Editorial

Adolescent tuberculosisOne of the most intriguing features of the epidemiology oftuberculosis is the well-known variation in the age incidenceof disease and the variation in the nature of the disease withage.

During infancy and early childhood, tuberculous disease isparticularly liable to follow infection and high morbidity andmortality are experienced.' Disseminated forms of disease,such as miliary tuberculosis and tuberculous meningitis, areparticularly likely to develop. Respiratorytuberculosis in young children is mainly related tothe primary complex and the progression of one ormore of its components. Cavitation can occur inyoung children, but is unusual.2

Between the ages of about 5 and 10 years,children enter a period of relative protection fromtuberculous disease, despite a persistent risk ofinfection as evidenced by an uninterrupted rise inthe proportion o~ children with a positive tuberculintest. In South Africa, between 1970 and 1980, thetuberculosis case fatality rate was 7% for children < 1 yearof age falling to 3% for those 1 - 4 years and 1% for those5 - 9 years.3After the age of 10 years, however, an ever­increasing risk of tuberculous disease is experienced andthe nature of the disease changes from primary to adult-typetuberculosis:' In South Africa there is a threefold increase inthe risk of developing tuberculosis as children pass throughadolescence to young adulthood. In the Western Cape thisrisk is increased sixfold.s Disease in adolescence becomescharacteristically that of adult-type pulmonary tuberculosis,also called chronic pUlmonary tuberculosis, post-primary orsecondary tuberculosis. Respiratory disease now involvesmainly the apices of the lungs, and cavitation becomes anintegral part of the disease process, contributing not only tothe destruction of lung tissue, but also to the spread ofinfection in the community.

An equally curious feature of tuberculosis in adolescenceis the female predominance, which is most obvious underepidemic conditions.6The risk of developing adult-typepulmonary tuberculosis in adolescence is 2 - 6 times greaterin females than males and its occurrence is frequentlyassociated with menarche. 7

-9 Notwithstanding this femalepredilection for the development of pulmonary tuberculosis,rates of infection as evinced by a positive tuberculin test areusually similar for males and females and even show a malepredominance in many studies. lo Despite this well­documented female predominance in adolescent pulmonarytuberculosis, tuberculous pleural effusions in adolescenceshow a male predominance. 11

The above epidemiological characteristics of tuberculosiswere well known to earlier generations of researchers, buthave been neglected in recent years. Explanations advancedgenerally drew upon a vague hormonal or endocrinologicalexplanation compounded by the metabolic perturbations ofpUberty.4.6.7 Arvid Wallgren therefore stated: 'It is quite likelythat the liability to pUlmonary tuberculosis (in adolescence)is intimately linked up with endocrine activity. In this waymay also the decreased resistance during pregnancy beexplained ... ." Margaret Smith commented: 'Thedepressing effect of puberty in the girl on the retention of

nitrogen and calcium ... may be determining factors in thehigher rate of chronic pulmonary tuberculosis in youngadolescent females. '7

In discussing the potential importance of the factorsinvolved in this phenomenon, Arnold Rich wrote: 'The mostearnest study should be devoted to an elucidation of thefactors which influence the development of progressivetuberculosis at this time of life, for the precise reasons forthe disastrous effects observed during this period, and laterin life as a result of infection occurring during this period, arestill for the most part obscure and the problem is one not

Commentary and debate

only of extraordinary theoretical interest, but of the utmostimportance from the standpoint of human welfare. '12

Recent developments in our understanding of hormonalinfluences upon the immune system have begun to offermore precise hypotheses for these facts. It now seemspossible that an endocrinological effect upon the capacity ofthe immune system to control stationary-phase dormanttuberculosis bacilli contributes to adolescent susceptibilityto disease and affects the nature of the disease process.13

Two types.of tissue response to the intradermal injectionof tuberculin in an individual previously infected withMycobacterium tuberculosis can be identified. Firstly, thereis a non-necrotising response which correlates withimmunity and secondly, a necrotising response, as in thewell-known Koch phenomenon, which does not correlateclosely with protection. '4 Similarly, two subsets of helperT cells, Th1 and Th2, have been identified, with distinctprofiles of cytokine secretion. '5 In vivo, acting in concert withother cell types, these give rise to two patterns of cytokinerelease known as type 1 (IL-2, IL-12, and gamma-interferon)and type 2 (IL-4, 5, 6, 10 and 13). The balance of the two'families' of cytokines may be critical in determiningresistance or progression of HIV infection to AIDS.16 Thisbalance may be eqUally important in other chronic infectionssuch as tuberculosis.13 Indeed, evidence from in vivocytokine neutralisation experiments and gene knockout micesupports the view that the type 1 response, which stimulatescell-mediated immunity, is also needed (J. Flynn and B. R.Bloom - personal communication), probably as anadditional activator of macrophages. Paradoxically, however,there are also strong arguments for the view that tumournecrosis factor alpha (TNFa) is responsible for some of thenecrosis and weight loss in tuberculosis,17 and the recentobservation that administration of thalidomide causesweight gain and symptomatic relief in tuberculosis patientslends support to this concept (G. Kaplan - personalcommunication), because thalidomide decreases productionof TNFa. The paradox may be resolved by the observationthat whereas TNFa is non-toxic when injected into arelatively 'pure' type 1 inflammatory site, where it

SAMJ Volume 86 No. J March 1996

presumably contributes to macrophage activation, it causesnecrosis when injected into a mixed type 1 + type 2 site. IS

This may explain the dual role of TNFa in tuberculosis,because patients show a clear type 1-lo-type 2 shift. Forinstance the IL-4 gene is expressed in patients' peripheralblood T cells1i2ll and there is IgE antibody, which isdependent on IL-4.21

The balance of type 1-lo-type 2 activity appears to beregulated by adrenal steroids, so it is logical to seekexplanations for adolescent tuberculosis in the strikingchanges in adrenal function that occur at pUberty. At allages, the release of IL-l, IL-6 and TNFa from sites ofimmunological activity activates the hypothaJamic pituitaryadrenal axis and increases glucocorticoid production.Z2

Glucocorticoids for their part inhibit Th1 activity andsynergise with IL-4, and thus create a bias towards Th2activity." In contrast to the glucocorticoids, the adrenalandrogen dehydroepiandrosterone (DHEA), or perhaps ametabolite of DHEA formed in vivo/4 acts as a genuine anti­glucocorticoicj2!l and also promotes a Th1 response.2e Intuberculosis and HIV infection a decrease in theDHEAlcortisol ratio is well documented and in HIV infectionis associated with progression Jo AIDS.1J.21

One would therefore anticipate that a high DHEA/cortisolratio would favour a protective type 1 response. However,what we know of childhood tuberculosis suggests thereverse correlation. DHEA levels are high during the first yearof life when the risk of disease and mortality fromtuberculosis is highest. DHEA levels remain low from 1 yearuntil about 8 years of age, during which time the risk ofdisease is also decreasing although the risk of infectionremains constant. The rise in the incidence of tuberculous

_disease during adolescence correlates with a rise in DHEAlevels. DHEA secretion throughout childhood andadolescence is higher in girls than in boys,2:B.2S correlatingwith a greater risk of disease in girls in this age group.Cortisol secretion, however, apart from its diurnal variation,remains constant during adolescence.

These points lead to some difficu~ but importantquestions. First, what is the mechanism of immunity totuberculosis in children from 1 to 8 years? Is it a type 1response? If so, why does it function so well without DHEA?Is a relevant downstream metabolite of DHEA produced viaa different route in the prepubertal adrenal? The truth is thatwe do not know the final effector mechanism even for theadutt response, since human macrophages have not beenconvincingly shown to kill M. tuberculosis, and we knownothing at all about the mechanisms present in children.This question clearty deserves investigation.

Secondly, does the increase in DHEA at puberty convertthe response to an adu~ type? If so why does it fail so often,leading to adu~-typecavitatory disease rather than adu~­

type immunity? Perhaps the failure is an effect of otherhormones that appear at the same time. For instance, thereis some evidence that dihydrotestosterone candownregulate production of gamma interferon.:JO

A further hormonal factor which may operate during theperiod of rapid bone growth in adolescence, and which mayinfluence the Th1fTh2 balance, is the immunoregulatory roleof vitamin 0 and its metabolites, which functionindependently of the control by parathyroid hormone.Autocrine conversion of 2S-QHD3 to active 1,2S(OH)2D3

(calcitriol) by interleron gamma-activated macrophagesappears to be essential for immunity to tuberculosis.31 Theproduction of 1,25(OH)2D3 may however be a double-edgedsword as excessive amounts may promote a Th2-typeresponse with the release of TNFa and tissue necrosis.1U

2

There are few published data on the production of1.25(OH)2D3 during adolescence, but it is not unlikely that asurfeit generated by active bone metabolism during thisperiod of life may affect immunity to tuberculosis.

As our understanding of the factors promoting tissuenecrosis increases so does the possibility of influencing thisprocess. As it is tissue necrosis and cavitation that promotethe expectoration of large numbers of M. tuberculosis duringcoughing, the epidemiological implications of understandingand controlling the process are considerable. StUdy of theneuro-endocrinological influences operating in HIV infectionand AIDS has already advanced our understanding of thefunctioning of the immune system during chronic diseaseprocesses. The application of similar methodologies inadolescent tuberculosis may prove equally rewarding.

The authors were supported by the Glaxo InternationalTuberculosis Research Initiative and the South African MedicalResearch Council.

P. R. Donald

N. SeversDepartment of Paediatrics and Child HealthTygerberg Hospital andUniversity of StellenboschTygerberg, W. Cape

G.A. W. Rook

Depanment of Medical MicrobiologyUCl Medical Schoollondon, UK

1. Wallgren A. The timetable of tuberculosis. Tubercle 19.:.8: 29: 2':'5-251.2. Solomon A. Rabinowitt L Primary cavitating tube«::uJosis in Childhood. Clm

Radiol1912: 23: ~-~5.3. K(istner HGV. TubEn;:ulosis in children. EpiCemiclogIcaJ Comments 1961: 8(10): 1-19..:.. Wallgren A. Pulmonary tuberculosis. Relation of childhood infectiOn to disease in

adults. LimCl!!! 1938: 1: 417-420.5. KliSlnlY HGV_ TuberculOsis in me Cape PTovince. epidemiOlogical Comments

1991: 18{1}: 3-15.6. Grigg ERN. The arcana of tuberculosis. Am Rev Resplr Dls 1956: 18: 151-112.7. Smith MHD. TuberculOsis in adolescence. CharaCteristics, recognition,

managemeOl. Cfin Pediatr 1961; 6: 9-15.6. Comstock GW, Uvesay VT. Woolpen SF. The prognOSIS of a posittYe tuben:ulln

reaction In childhood adolescence. Am J Ep'detr1lOl1914; 99: 131-136.9. Comstock GW. Frost revisited: The modern eplcemtology of tuberculo$l$. Am J

Epidemtol 1915: 101: 363-382.10. Hall S. The ~evalence of tuberculOSIS. In: Heal FAG, ed. SympoSium of

TubercuJosis. London: Cassell and Company. 1951: 65-107.11. Bentley FJ. Gnybows . S. 8enjamin 8. Pleural effusiofl. In: TuberculoSIS in

Childhood and Adolescence. London: National Assocration for the Prevention ofTuberculOSIS, 1954: 50-64.

12. Rich AA. The ParhogeneSls of TuberculoSis. 2nd eel. Spnngfield: Charles CThomas. 1951: 182-245.

13. Rook GAW, Onyebujoh p. Stanford JL Th1 -> Th2 SWitch and loss of CQ4 celJs inchronic Infections: an immuno-endocrinologlcal hypothesIS not exclUSive to HiV.Immunol Today 1993: 14; 568-569.

14. Bothamley GH. Grange JM. The Koch phenomenon and delayed hypersensitivity:1891·1991. Tubercle 1991; 12; 1-11.

15. Mossmann TA. Aegulatiofl of immune responses by T cells WIth different cytokinesecretor pheru;ltypes. Role of a new cytokme: cytolune synthesIS Inhibitory factor{ll10}. 1nl Arch Allergy Appllmmunol 1991: 94: 110·115.

16. Clericl M. Shearer GM. The Th1·Th2 hypothesis of HIV infeclion: New msights.Immunol Today 1994: 15: 575-561.

11. Rook GAW. Role 01 activated microphages in the Immunopathology oftuberculOSIS. Br Med Bull 1988: 44(3}: 624·634.

18. Hernandez-Pando R. Rook GAW. The role 01 TNFa In T cell-mediatedinflammation depends on the Thltrh2 cytok!ne balance. Immunology 1994: 82;591-595.

19. Barnes PF. Lu S. Abrams JS. Wang E. Vamamura M, Modlln Al. Cylokineproduction at the site of disease in tuberculosis. Infect Immun 1993: 61: 3':'82­3489.

20. Schauf V, Rom WN. Smith KA, er al. Cytokine gene actwation and modifiedresponsiveness 10 imer1eukln-2 In the blood of tuberculosis patients. J Infect o;s1993: 168: 1056-1059.

\"OhtMt 86 No. 3 March 1996 SAJ.\1}

21. Vong AJ, Grange JM, Tee RD, er al. Total and anti-mycobacterial IgE levels inSenJm from patients with tubef"culosis and leprosy. Tubercle 1989; 70: 273-279.

22. Besedovsky HO, del-ReV A, Klusman I, er al. Cytoklnes as modulato~of thehypothatarnus-pituitary-aarenat axiS. J Sreroid Biochem Mol Bioi 1991; 40: 613­618.

23. Fische!' A, Konig W. Influence of c:ytoklnes and cellular interactions on theglucocortiCoid-induced Tg (E,GAM) synthesis of peripheral blood mononuclearcells. Immunology 1991; 14: 228-233.

24. Padgen DA, Loria RM. In vivo polentiation of Iymphocyt:e activation bydel'lydroepiandrosterone, androstenediol and androstenetriol. J ImmlUloll994;153: 1544-1552.

25. Blauel'" KL. Path M, Flogen WM, Sermon 00. Oehyro-epiandrosteroneantagonises the suppressive effec;ts of dexamethasone on Iymphocyteproliferation_ Endocrinology 1991; 129: 3174-3179.

26. Daynes RA, Araneo BA. Dowell TA, Huang K, DudJey D. Rttgulation of murineIymphokine production in vivo. Ill. The lymphoid tissue mil;roenvironment exensregulatory influences OVel'" T helper cell function. J bp Med 1990; 171: 979-996.

27_ Muldef" JW, Frissen PHJ, Knlnen P, er al. Dehydmepianc!rosterone as predictor forprogression to AIDS In asymptomatic human immunodeficiency virus-infec[eCImen. J Infect Di$ 1992; tas: 413418.

28. Parkef" LN. Adrenarche. Endot;rino/ Merab Clin North Am 1991; 20(1): 71-83.29. Dewhurst J. The endocrinology of pubefty. In: Female Puberty 3fId its

Abnormalities. Edinburgh: Churchilllivingstone, 1984: 57-81.30. Araeno BA, Dowell T. Diegel M, Daynes AA.. Oihydrotestoslerone exerts a

dePl'essive influence on the production of inletleukln4 (IL-4). IL-5. and gamma­interferon, bUI no11L-2 by aCtivatecl murine T cells. Blood 1991; 78: 688-1599.

31. Rook GAW, HeI'"nandez·Pando R, Ughtman SL Hormones, peripherally activatedpl'"ohormones. and regulation of the Th11Th2 balance. Immunol Today (in pres.s).

32. Rook GAW. The role of vitamin D in tuben:ulosis. Am Rev Respir Dis 1988; 138:768-770.

OPINION

Compensation fordisabilitiesDetermining just compensation for disabilities is difficulteven when assessment is by competent and experiencedprofessionals.

There is much that is unsatisfactory in the mechanisms forawarding compensation in South Africa As in othercountries which have inherited aspects of English law, thesystem in South Africa is adversarial: the court cannot makejudgements unless the facts are presented by opposingparties. Controversy is necessary to allow the courts to hearthe matter. The system creates adversaries, even wherenone should exist, so that what should be a dispassionatejudgement of disability becomes a contest of strength.

Separate court systems exist for liquor licensing, incometax, industri.al relations, workmen's compensation and wateraffairs because these fields have specialised complexity, butij is the general courts which pass judgement on subtle andintricate medical issues - almost always without the benefitof a medical expert sitting with the jUdge.

A further complication is that the medical aspect (Whichentails the quantification of disability, comprising about 80%of the case) and the legal aspect (determining fau~) tend tofuse. As a result, the medical profession's role in quantifyingdisability has largely yielded to the lawyer's adversarialdetenninations.

The medical assessor, who would be an appropriate andeffective executive authority in assessing disability, has beenreplaced in the adversarial system by the medical wijnesswho plays little more than a subservient role - instructed,recruited or excluded as it best serves the lawyer. Themedical witness is often drawn into the proceedings bychance, civic duty or innocent helpfulness. He is thrust intoan adversariaJ interchange with which he is unaccustomed

SAMJEDITORIAL

and placed under stress in the unfamiliar territory of a courtof law. At times he is unpleasantly harried by cross­examination when legal techniques are used in attempts todiscredit or unsettle his medical judgements_ He is thenexpected to be objectively and articulately instructive towardlawyer. advocate and judge in matters medical.

After this, lawyer and judge claim to have acquired aknowledge of the science, experience, interpretive subtletiesand inturtions necessary to make medical judgements. Notsurprisingly misapprehensions occur, and when courtjudgements are appraised from a medical point of view,inappropriate awards seem to occur trequentty.

As a result of the abovementioned factors, and pertlapsothers. many medical people are reluctant to appear onbehalf of the injured party.

A number of factors further militate against just awards ofcompensation: these include population ignorance, lawyerworkload or lawyer inexperience, fraud and the costs andfinancial risks of Supreme Court action. If, in addition, theclaimant has diffiCUlty in obtaining sincere medical witnessesof an appropriate calibre to support his claim, the currentprocess of claiming compensation may well degenerate. Theoutcome could be an increase in fraudulent claims,contingency litigation (percentage of award to lawyer) andthe use of 'hired gun' medical witnesses.

I believe that, under the present system, there is a gravedanger that the disincentives to make claims for disabilitiescould become so great as to jeopardise just compensationof the disabled.

It is the medical profession's responsibility to close thisunsatisfactory gap in the health sciences and to reclaim therole of impartial assessors of disability and compensation ­with appropriate legal assistance (rather than legal controO.The realist will recognise that it is far easier to familiarise amedical expert with the adjunctive areas of law - which arefairly consistent - than it is for a medical expert repetitiVelyto instruct a court on matters medical, a different (andexpensive) exercise with each different injury and eachdrtferent case.

The appropriate route for the medical profession could bevia techniques of dispute mediation or arbitration. 'No faulfcompensation has many commendable advantages andstrong support from the medical profession will benecessary for the concept to gain ground.

To improve the accuracy and expedition of disabilitycompensation the medical profession needs to address thetraining of medical personnel as assessors of disability. Theskills and science of appraising handicap requiredevelopment along with awareness of the monetary andimpedimentary value of the losses caused by disablement.These needs would best be served by the establishment ofan institute for the measurement of disability, whereobjective methods of measuring disability could beresearched, developed and taught, and disability appraisedby skilled, eclectic professionals. Support from theinsurance industry would more than pay for itself and benefitthat industry and society as a whole.

J, p, Driver-JowittOrthopa.edic Surgeon

3 Norfolk ReadNewlandsCape Town

SAMJ Voll.lm!' 86 No. 3 March 1996