Granulomatous inflammation and transmission of infectious disease

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  • C O M M E N TI M M U N O L O G Y TO D AY

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    analysed in parallel with a molecular epi-demiological study to allow the exogenousor endogenous origin of the infection to bedetermined. Such correlations between epi-demiological data, immunological data andthe infectiousness of HIV/TB co-infected pa-tients, in both industrialized and developingcountries, are important to determine thepotential impact of TB chemoprophylaxisstrategies in HIV-infected patients.

    Eric LedruSylvie LedruMuraz Center-OCCGE, Bobo-Dioulasso,Burkina Faso.

    Alain ZoubgaNational Hospital, Bobo-Dioulasso,Burkina Faso.

    References1 Doenhoff, M.J. (1998) Immunol. Today 19, 462467

    2 Ledru, S., Cauchoix, B., Yameogo, M. et al.

    (1996) Tubercle Lung Dis. 77, 429436

    3 Colebunders, R.L., Ryder, R.W., Nzilambi, N.

    et al. (1989) Am. Rev. Respir. Dis. 139, 10821085

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    Aranda, C.P. (1994) Chest 106, 684686

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    B.W., Gathua, S. and Waiyaki, P. (1993)

    Am. Rev. Respir. Dis. 147, 958961

    7 Karstaedt, A.S., Jones, N., Khoosal, M. and

    Crewebrown, H.H. (1998) Int. J. Tuberc. Lung

    Dis. 2, 312316

    8 Ledru, E., Diagbouga, S., Meda, N. et al.

    (1998) Int. J. STD AIDS 9, 463470

    9 Del Amo, J., Petruckevitch, A., Phillips, A.N.

    et al. (1996) AIDS 10, 15631569

    10 Mukadi, Y., Perriens, J.H., St Louis, M.E. et al.

    (1993) Lancet 342, 143146

    11 Gilks, C.F., Godfrey-Faussett, P., Batchelor,

    B.I. et al. (1997) AIDS 11, 911918

    12 Kubin, M., Riley, L.W., Havelkova, M.,

    Poltoratskaia, N. and Kocova, A. (1998) Int. J.

    Infect. Dis. 2, 155158

    13 Di Perri, G., Cazzadori, A., Vento, S. et al.

    (1996) Tubercle Lung Dis. 77, 244249

    14 Garcia, I., Miyazaki, Y., Marchal, G.,

    Lesslauer, W. and Vassalli, P. (1997) Eur. J.

    Immunol. 27, 31823190

    In his truly brilliant comparison betweenschistosomiasis and tuberculosis (TB), Doenhoff showed how in both diseases thedevelopment of granulomatous inflam-mation is a critical step in creating the patho-logical condition suitable for infection trans-mission1. The association of either diseasewith HIV infection (which leads to progress-ive impairment in the ability to mount agranulomatous reaction) gives additionalsupport to this view because, in some stud-ies, fewer organisms were found to be excreted by co-infected patients2,3.

    However, there are some distinctionsworth being made. In schistosomiasis, thenumber of eggs laid by adult worms pre-sumably remains the same regardless of thehosts immune competence, whereas inHIV1TB1 patients the number of bacilli increases in all infected body tissues (bothpulmonary4 and extra-pulmonary5) in an inverse relationship to the immune status of the individual (represented by the CD41

    T-cell count). This leads to pathologic pic-tures with impressive numbers of bacilli inthe most immunosuppressed AIDS patients.These freely multiplying bacilli are not onlymore numerous but also fully viable, asshown by the comparison of Mycobacteriumtuberculosis isolation rates from specimensbelonging to HIV-infected and uninfectedindividuals higher recovery rates of M. tuberculosis were achieved in cases of HIV1

    TB from various body tissues69. Althoughthe tendency for higher bacillary counts iscounterbalanced by the lower ability to gen-erate open pulmonary lesions (e.g. cavi-tations), the potential for TB transmission bythese subjects remains high, as witnessed bythe many cases of interhuman transmissionin which HIV-infected subjects were foundto play the role of source-case10,11.

    The relationship between increasingbacillary numbers and the downgradingtendency of cell-mediated immunity in

    HIV1TB1 patients is analogous to the re-lationship of TB and another airborne mycobacterial infection, leprosy, whose taxo-nomic position is closer to TB than that ofschistosomiasis.

    The pathological classification of lep-rosy12 distinguishes different disease vari-eties that are characterized by the inverse relationship between granuloma formationand the number of bacilli. In contrast toschistosomiasis, infectiousness of leprosycorrelates with a diminished capacity tomount a granulomatous reaction. Interhu-man transmission usually takes place frompatients with lepromatous leprosy, charac-terized by large numbers of bacilli inter-spersed in a background of unspecific in-flammatory responses, with poorly formedor no granulomas. By analogy, if we focus onthe quantitative microbiological picture, wewould expect immunosuppressed AIDS pa-tients with TB to have a higher infectious-ness, but this only applies when an open lesion is present in the patients respiratorytract, which is rare in these subjects. How-ever, in certain situations, severely immuno-suppressed AIDS patients have caused adramatic spread of tuberculosis both amongpatients13 and among health-care workers14,thus suggesting a circumstantial similarityto leprosy rather than to schistosomiasis.

    In general terms we agree with Doen-hoffs conclusion regarding the similar epi-demiological impact of TB and schisto-somiasis when associated with HIV infection.Nevertheless, we believe that the intrinsicpathophysiological profile of HIV-associatedTB (and especially the progressive increasein size of the bacillary burden) shouldprompt the maintenance of the highest pre-ventive surveillance, especially when noso-comial or other congregate settings are con-cerned. As a result of the long-term patientsurvival rates now possible, it follows thatthere will be a higher chance of HIV-infectedsubjects developing infectious TB forms.

    Giovanni Di PerriStefano BonoraBenedetta AllegranziErcole ConciaDivision of Infectious Diseases of theUniversity of Verona, Ospedale CivileMaggiore, 37126 Verona, Italy.

    Granulomatousinflammation and

    transmission ofinfectious disease

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    References1 Doenhoff, M.J. (1998) Immunol. Today 19,

    462467

    2 Karanja, D.M.S., Colley, D.G., Nahlen, B.L.,

    Ouma, J.H. and Secor, W.E. (1997) Am. J. Trop.

    Med. Hyg. 56, 515521

    3 Kramer, F., Modilevsky, T., Waliany, A.R.,

    Leedom, J.M. and Barnes, P.F. (1990) Am. J.

    Med. 89, 451456

    4 Di Perri, G., Cazzadori, A., Vento, S. et al.

    (1996) Tubercle Lung Dis. 77, 244249

    5 Lucas, S. and Nelson, A.M. (1994) in

    Tuberculosis: Pathogenesis, Prevention and

    Control (Bloom, B.R., ed.), pp. 503512,

    American Society for Microbiology

    6 Shriner, K.A., Mathisen, G.E. and Goetz, M.B.

    (1992) Clin. Infect. Dis. 15, 601605

    7 Shafer, R.W., Goldberg, R., Sierra, M. and

    Glatt, A.F. (1989) Am. Rev. Respir. Dis. 140,

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    8 Prego, V., Glatt, A.E., Roy, V. et al. (1990) Arch.

    Intern. Med. 150, 333336

    9 Berenguer, J., Moreno, S., Laguna, F. et al.

    (1992) New Engl. J. Med. 326, 668672

    10 Di Perri, G., Cruciani, M., Danzi, M.C. et al.

    (1989) Lancet 334, 15021504

    11 Edlin, B.R., Tokars, J.I., Grieco, M.H. et al.

    (1992) New Engl. J. Med. 326, 15141521

    12 Ridley, D.S. and Jopling, W.H. (1966) Int. J.

    Lepr. 34, 255270

    13 Dooley, S.W., Villarino, M.E. and

    Lawrence, M. (1992) J. Am. Med. Assoc.

    267, 26322635

    14 Di Perri, G., Cadeo, G.P., Castelli, F. et al.

    (1993) Infect. Control Hosp. Epidemiol. 14,

    6772

    I am grateful to Ledru and Di Perri and theircolleagues for engaging positively with myhypothesis1 that immune responsiveness isinvolved in the transmission of Mycobac-terium tuberculosis from infected to unin-fected subjects. As well as providing supportfor the original contention, the analysis byLedru et al. indicates that in developed

    countries, concurrent HIV infections reducesputum AFB counts to a lesser extent than indeveloping countries while, paradoxically,the degree of immune suppression (in termsof a reduced blood CD41 T-cell count) seemsto be greater in the former. In addition,Ledru et al. point out that TB in developedcountries might be due to mainly endogen-ous reactivation of an earlier infection,whereas it has a mainly exogenous origin indeveloping countries.

    Examination of further patient groupswill ascertain whether the difference be-tween developed and developing countriesis real, and if so, which of the factors pre-scribing immune status (e.g. granuloma size,T helper cell subpopulation number and ac-tivity, cytokine flux, nitric oxide production)are important in defining the difference. Inthe meantime, it should be remembered thatthe pathogenesis of tuberculosis seems todiffer in populations of different ethnic ori-gin2. Both the transmissibility and the patho-genicity of infectious agents are likely to beprime targets of selective pressure duringthe evolution of a hostpathogen relation-ship. The length of time that has elapsedsince first exposure of a population to en-demic infection could, therefore, have an im-portant bearing on the observation reportedby Ledru et al., even though it does not beginto answer exactly how HIV infection affectssputum AFB counts.

    Di Perri et al. cite references which showthat in HIV1TB1 patients, the number ofbacilli increases in all infected tissues (bothpulmonary and extra-pulmonary). There-fore, the observation that HIV1 patientshave fewer bacteria in their airways thanHIV2 subjects is perhaps all the more strik-ing. However, in formulating the hypoth-esis, it was never my intention to suggest thatHIV1 patients with TB were not secretingany bacteria and therefore could not act assource-cases for transmission of the bacterialinfection. It is reasonable to suppose that inpatients with TB there is a positive corre-lation between the number of bacilli in lungtissue and the number that are released into the airways, and that the much enhanced bacterial growth in tissues of severely immunosuppressed AIDS patients,referred to above, results in proportionately

    increased numbers of organisms secretedinto the airways.

    Di Perri et al. compare TB with leprosy,suggesting that the latter disease is trans-mitted mainly by patients with the leproma-tous (i.e. agranulomatous) forms of the dis-ease. While not wishing to dispute this, Isuspect that less is known about parametersaffecting transmission of leprosy and manyother infectious diseases than those affectingtransmission of TB. Parasites and pathogensare remarkable for the great diversity ofstrategies that they use to increase theirchances of survival3, and in the present con-text there might be many ways in which hostdefence mechanisms can be subverted forsuch exploitation. The leishmanias might be interesting examples to compare withmycobacteria: for example, is transmissionof these intracellular protozoan parasites totheir sandfly vectors facilitated by the cell-mediated immunity responsible for pathol-ogy in vertebrate host skin?

    Michael J. DoenhoffSchool of Biological Sciences, University ofWales, Bangor, Gwynedd, UK LL57 2UW.

    References1 Doenhoff, M.J. (1998) Immunol. Today 19,

    462467

    2 Rich, A.R. (1951) The Pathogenesis of

    Tuberculosis (2nd edn) (Thomas, C.C., ed.),

    Springfield

    3 Barnard, C.J. and Behnke, J.M. (1990)

    Parasitism and Host Behaviour, Taylor and

    Francis

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