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. 1998;76(6):651–662.

An approach to the problems of diagnosing and treating adult smear-negative pulmonary tuberculosis in high-HIV-prevalence settings in sub-Saharan Africa.

A D Harries 1, D Maher 1, P Nunn 1
PMCID: PMC2312485  PMID: 10191561

Abstract

The overlap between the populations in sub-Saharan Africa infected with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis has led to an upsurge in tuberculosis cases over the last 10 years. The relative increase in the proportion of notified sputum-smear-negative pulmonary tuberculosis (PTB) cases is greater than that of sputum-smear-positive PTB cases. This is a consequence of the following: the association between decreased host immunity and reduced sputum smear positivity; the difficulty in excluding other HIV-related diseases when making the diagnosis of smear-negative PTB; and an increase in false-negative sputum smears because of overstretched resources. This article examines problems in the diagnosis and treatment of smear-negative PTB in high-HIV-prevalence areas in sub-Saharan Africa. The main issues in diagnosis include: the criteria used to diagnose smear-negative PTB; the degree to which clinicians actually follow these criteria in practice; and the problem of how to exclude other respiratory diseases that can resemble, and be misdiagnosed as, smear-negative PTB. The most important aspect of the treatment of smear-negative PTB patients is abandoning 12-month "standard" treatment regimens in favour of short-course chemotherapy. Operational research is necessary to determine the most cost-effective approaches to the diagnosis and treatment of smear-negative PTB. Nevertheless, substantial improvement could be obtained by implementing the effective measures already available, such as improved adherence to diagnostic and treatment guidelines.

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Selected References

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  1. Abouya L., Coulibaly I. M., Coulibaly D., Kassim S., Ackah A., Greenberg A. E., Wiktor S. Z., De Cock K. M. Radiologic manifestations of pulmonary tuberculosis in HIV-1 and HIV-2-infected patients in Abidjan, Côte d'Ivoire. Tuber Lung Dis. 1995 Oct;76(5):436–440. doi: 10.1016/0962-8479(95)90011-x. [DOI] [PubMed] [Google Scholar]
  2. Abouya Y. L., Beaumel A., Lucas S., Dago-Akribi A., Coulibaly G., N'Dhatz M., Konan J. B., Yapi A., De Cock K. M. Pneumocystis carinii pneumonia. An uncommon cause of death in African patients with acquired immunodeficiency syndrome. Am Rev Respir Dis. 1992 Mar;145(3):617–620. doi: 10.1164/ajrccm/145.3.617. [DOI] [PubMed] [Google Scholar]
  3. Ackah A. N., Coulibaly D., Digbeu H., Diallo K., Vetter K. M., Coulibaly I. M., Greenberg A. E., De Cock K. M. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Côte d'Ivoire. Lancet. 1995 Mar 11;345(8950):607–610. doi: 10.1016/s0140-6736(95)90519-7. [DOI] [PubMed] [Google Scholar]
  4. Atzori C., Bruno A., Chichino G., Gatti S., Scaglia M. Pneumocystis carinii pneumonia and tuberculosis in Tanzanian patients infected with HIV. Trans R Soc Trop Med Hyg. 1993 Jan-Feb;87(1):55–56. doi: 10.1016/0035-9203(93)90418-p. [DOI] [PubMed] [Google Scholar]
  5. Barnes P. F., Verdegem T. D., Vachon L. A., Leedom J. M., Overturf G. D. Chest roentgenogram in pulmonary tuberculosis. New data on an old test. Chest. 1988 Aug;94(2):316–320. doi: 10.1378/chest.94.2.316. [DOI] [PubMed] [Google Scholar]
  6. Batungwanayo J., Taelman H., Dhote R., Bogaerts J., Allen S., Van de Perre P. Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical and radiographic presentation. Am Rev Respir Dis. 1992 Jul;146(1):53–56. doi: 10.1164/ajrccm/146.1.53. [DOI] [PubMed] [Google Scholar]
  7. Briggs I. L., Rochester W. R., Shennan D. H., Riddell R. W., Fox W., Heffernan J. F., Miller A. B., Nunn A. J., Stott H., Tall R. Streptomycin plus thiacetazone (thioacetazone) compared with streptomycin plus PAS and with isoniazid plus thiacetazone in the treatment of pulmonary tuberculosis in Rhodesia. Tubercle. 1968 Mar;49(1):48–69. doi: 10.1016/s0041-3879(68)80007-8. [DOI] [PubMed] [Google Scholar]
  8. Brindle R. J., Nunn P. P., Batchelor B. I., Gathua S. N., Kimari J. N., Newnham R. S., Waiyaki P. G. Infection and morbidity in patients with tuberculosis in Nairobi, Kenya. AIDS. 1993 Nov;7(11):1469–1474. doi: 10.1097/00002030-199311000-00010. [DOI] [PubMed] [Google Scholar]
  9. Cantwell M. F., Binkin N. J. Tuberculosis in sub-Saharan Africa: a regional assessment of the impact of the human immunodeficiency virus and National Tuberculosis Control Program quality. Tuber Lung Dis. 1996 Jun;77(3):220–225. doi: 10.1016/s0962-8479(96)90004-0. [DOI] [PubMed] [Google Scholar]
  10. Centers for Disease Control and Prevention (CDC) Implementation of health initiatives during a cease-fire--Sudan, 1995. MMWR Morb Mortal Wkly Rep. 1995 Jun 16;44(23):433–436. [PubMed] [Google Scholar]
  11. Chaulet P. The supply of antituberculosis drugs and national drugs policies. Tuber Lung Dis. 1992 Oct;73(5):295–304. doi: 10.1016/0962-8479(92)90136-8. [DOI] [PubMed] [Google Scholar]
  12. Chaulet P. The supply of antituberculosis drugs: price evolution. Tuber Lung Dis. 1995 Jun;76(3):261–263. doi: 10.1016/s0962-8479(05)80015-2. [DOI] [PubMed] [Google Scholar]
  13. Daley C. L., Small P. M., Schecter G. F., Schoolnik G. K., McAdam R. A., Jacobs W. R., Jr, Hopewell P. C. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med. 1992 Jan 23;326(4):231–235. doi: 10.1056/NEJM199201233260404. [DOI] [PubMed] [Google Scholar]
  14. De Cock K. M., Gnaore E., Adjorlolo G., Braun M. M., Lafontaine M. F., Yesso G., Bretton G., Coulibaly I. M., Gershy-Damet G. M., Bretton R. Risk of tuberculosis in patients with HIV-I and HIV-II infections in Abidjan, Ivory Coast. BMJ. 1991 Mar 2;302(6775):496–499. doi: 10.1136/bmj.302.6775.496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. De Cock K. M., Wilkinson D. Tuberculosis control in resource-poor countries: alternative approaches in the era of HIV. Lancet. 1995 Sep 9;346(8976):675–677. doi: 10.1016/s0140-6736(95)92284-9. [DOI] [PubMed] [Google Scholar]
  16. Di Perri G., Cruciani M., Danzi M. C., Luzzati R., De Checchi G., Malena M., Pizzighella S., Mazzi R., Solbiati M., Concia E. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet. 1989 Dec 23;2(8678-8679):1502–1504. [PubMed] [Google Scholar]
  17. Dolin P. J., Raviglione M. C., Kochi A. Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ. 1994;72(2):213–220. [PMC free article] [PubMed] [Google Scholar]
  18. Elliott A. M., Halwiindi B., Hayes R. J., Luo N., Tembo G., Machiels L., Bem C., Steenbergen G., Pobee J. O., Nunn P. P. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg. 1993 Feb;96(1):1–11. [PubMed] [Google Scholar]
  19. Elliott A. M., Hayes R. J., Halwiindi B., Luo N., Tembo G., Pobee J. O., Nunn P. P., McAdam K. P. The impact of HIV on infectiousness of pulmonary tuberculosis: a community study in Zambia. AIDS. 1993 Jul;7(7):981–987. doi: 10.1097/00002030-199307000-00012. [DOI] [PubMed] [Google Scholar]
  20. Elliott A. M., Luo N., Tembo G., Halwiindi B., Steenbergen G., Machiels L., Pobee J., Nunn P., Hayes R. J., McAdam K. P. Impact of HIV on tuberculosis in Zambia: a cross sectional study. BMJ. 1990 Sep 1;301(6749):412–415. doi: 10.1136/bmj.301.6749.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Elliott A. M., Namaambo K., Allen B. W., Luo N., Hayes R. J., Pobee J. O., McAdam K. P. Negative sputum smear results in HIV-positive patients with pulmonary tuberculosis in Lusaka, Zambia. Tuber Lung Dis. 1993 Jun;74(3):191–194. doi: 10.1016/0962-8479(93)90010-U. [DOI] [PubMed] [Google Scholar]
  22. Elvin K. M., Lumbwe C. M., Luo N. P., Björkman A., Källenius G., Linder E. Pneumocystis carinii is not a major cause of pneumonia in HIV infected patients in Lusaka, Zambia. Trans R Soc Trop Med Hyg. 1989 Jul-Aug;83(4):553–555. doi: 10.1016/0035-9203(89)90290-3. [DOI] [PubMed] [Google Scholar]
  23. Eriki P. P., Okwera A., Aisu T., Morrissey A. B., Ellner J. J., Daniel T. M. The influence of human immunodeficiency virus infection on tuberculosis in Kampala, Uganda. Am Rev Respir Dis. 1991 Jan;143(1):185–187. doi: 10.1164/ajrccm/143.1.185. [DOI] [PubMed] [Google Scholar]
  24. Gebre N., Karlsson U., Jönsson G., Macaden R., Wolde A., Assefa A., Miörner H. Improved microscopical diagnosis of pulmonary tuberculosis in developing countries. Trans R Soc Trop Med Hyg. 1995 Mar-Apr;89(2):191–193. doi: 10.1016/0035-9203(95)90491-3. [DOI] [PubMed] [Google Scholar]
  25. Gilks C. F., Ojoo S. A., Ojoo J. C., Brindle R. J., Paul J., Batchelor B. I., Kimari J. N., Newnham R., Bwayo J., Plummer F. A. Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet. 1996 Mar 16;347(9003):718–723. doi: 10.1016/s0140-6736(96)90076-8. [DOI] [PubMed] [Google Scholar]
  26. Greenberg S. D., Frager D., Suster B., Walker S., Stavropoulos C., Rothpearl A. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology. 1994 Oct;193(1):115–119. doi: 10.1148/radiology.193.1.7916467. [DOI] [PubMed] [Google Scholar]
  27. Grzybowski S., Barnett G. D., Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc. 1975;50(1):90–106. [PubMed] [Google Scholar]
  28. Harries A. D., Kamenya A., Subramanyam V. R., Salaniponi F. M., Nyangulu D. S. Sputum smears for diagnosis of smear-positive pulmonary tuberculosis. Lancet. 1996 Mar 23;347(9004):834–835. doi: 10.1016/s0140-6736(96)90915-0. [DOI] [PubMed] [Google Scholar]
  29. Harries A. D., Maher D., Mvula B., Nyangulu D. An audit of HIV testing and HIV serostatus in tuberculosis patients, Blantyre, Malawi. Tuber Lung Dis. 1995 Oct;76(5):413–417. doi: 10.1016/0962-8479(95)90007-1. [DOI] [PubMed] [Google Scholar]
  30. Harries A. D. Tuberculosis and human immunodeficiency virus infection in developing countries. Lancet. 1990 Feb 17;335(8686):387–390. doi: 10.1016/0140-6736(90)90216-r. [DOI] [PubMed] [Google Scholar]
  31. Hirschtick R. E., Glassroth J., Jordan M. C., Wilcosky T. C., Wallace J. M., Kvale P. A., Markowitz N., Rosen M. J., Mangura B. T., Hopewell P. C. Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group. N Engl J Med. 1995 Sep 28;333(13):845–851. doi: 10.1056/NEJM199509283331305. [DOI] [PubMed] [Google Scholar]
  32. Ipuge Y. A., Rieder H. L., Enarson D. A. The yield of acid-fast bacilli from serial smears in routine microscopy laboratories in rural Tanzania. Trans R Soc Trop Med Hyg. 1996 May-Jun;90(3):258–261. doi: 10.1016/s0035-9203(96)90239-4. [DOI] [PubMed] [Google Scholar]
  33. Lucas S. B., De Cock K. M., Hounnou A., Peacock C., Diomande M., Hondé M., Beaumel A., Kestens L., Kadio A. Contribution of tuberculosis to slim disease in Africa. BMJ. 1994 Jun 11;308(6943):1531–1533. doi: 10.1136/bmj.308.6943.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lucas S. B., Hounnou A., Peacock C., Beaumel A., Djomand G., N'Gbichi J. M., Yeboue K., Hondé M., Diomande M., Giordano C. The mortality and pathology of HIV infection in a west African city. AIDS. 1993 Dec;7(12):1569–1579. doi: 10.1097/00002030-199312000-00005. [DOI] [PubMed] [Google Scholar]
  35. Malin A. S., Gwanzura L. K., Klein S., Robertson V. J., Musvaire P., Mason P. R. Pneumocystis carinii pneumonia in Zimbabwe. Lancet. 1995 Nov 11;346(8985):1258–1261. doi: 10.1016/s0140-6736(95)91862-0. [DOI] [PubMed] [Google Scholar]
  36. Meeran K. Prevalence of HIV infection among patients with leprosy and tuberculosis in rural Zambia. BMJ. 1989 Feb 11;298(6670):364–365. doi: 10.1136/bmj.298.6670.364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miller R. F., Grant A. D., Foley N. M. Seasonal variation in presentation of Pneumocystis carinii pneumonia. Lancet. 1992 Mar 21;339(8795):747–748. doi: 10.1016/0140-6736(92)90650-r. [DOI] [PubMed] [Google Scholar]
  38. Mukadi Y., Perriëns J. H., St Louis M. E., Brown C., Prignot J., Willame J. C., Pouthier F., Kaboto M., Ryder R. W., Portaels F. Spectrum of immunodeficiency in HIV-1-infected patients with pulmonary tuberculosis in Zaire. Lancet. 1993 Jul 17;342(8864):143–146. doi: 10.1016/0140-6736(93)91346-n. [DOI] [PubMed] [Google Scholar]
  39. Murray C. J., DeJonghe E., Chum H. J., Nyangulu D. S., Salomao A., Styblo K. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet. 1991 Nov 23;338(8778):1305–1308. doi: 10.1016/0140-6736(91)92600-7. [DOI] [PubMed] [Google Scholar]
  40. Nunn P., Gicheha C., Hayes R., Gathua S., Brindle R., Kibuga D., Mutie T., Kamunyi R., Omwega M., Were J. Cross-sectional survey of HIV infection among patients with tuberculosis in Nairobi, Kenya. Tuber Lung Dis. 1992 Feb;73(1):45–51. doi: 10.1016/0962-8479(92)90079-y. [DOI] [PubMed] [Google Scholar]
  41. Nunn P., Kibuga D., Gathua S., Brindle R., Imalingat A., Wasunna K., Lucas S., Gilks C., Omwega M., Were J. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet. 1991 Mar 16;337(8742):627–630. doi: 10.1016/0140-6736(91)92447-a. [DOI] [PubMed] [Google Scholar]
  42. Nunn P., Mungai M., Nyamwaya J., Gicheha C., Brindle R. J., Dunn D. T., Githui W., Were J. O., McAdam K. P. The effect of human immunodeficiency virus type-1 on the infectiousness of tuberculosis. Tuber Lung Dis. 1994 Feb;75(1):25–32. doi: 10.1016/0962-8479(94)90098-1. [DOI] [PubMed] [Google Scholar]
  43. Okwera A., Whalen C., Byekwaso F., Vjecha M., Johnson J., Huebner R., Mugerwa R., Ellner J. Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere University-Case Western University Research Collaboration. Lancet. 1994 Nov 12;344(8933):1323–1328. doi: 10.1016/s0140-6736(94)90693-9. [DOI] [PubMed] [Google Scholar]
  44. Parry C. M., Kamoto O., Harries A. D., Wirima J. J., Nyirenda C. M., Nyangulu D. S., Hart C. A. The use of sputum induction for establishing a diagnosis in patients with suspected pulmonary tuberculosis in Malawi. Tuber Lung Dis. 1995 Feb;76(1):72–76. doi: 10.1016/0962-8479(95)90583-9. [DOI] [PubMed] [Google Scholar]
  45. Pedro-Botet J., Gutiérrez J., Miralles R., Coll J., Rubiés-Prat J. Pulmonary tuberculosis in HIV-infected patients with normal chest radiographs. AIDS. 1992 Jan;6(1):91–93. doi: 10.1097/00002030-199201000-00012. [DOI] [PubMed] [Google Scholar]
  46. Perriëns J. H., St Louis M. E., Mukadi Y. B., Brown C., Prignot J., Pouthier F., Portaels F., Willame J. C., Mandala J. K., Kaboto M. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. N Engl J Med. 1995 Mar 23;332(12):779–784. doi: 10.1056/NEJM199503233321204. [DOI] [PubMed] [Google Scholar]
  47. Post F. A., Wood R., Pillay G. P. Pulmonary tuberculosis in HIV infection: radiographic appearance is related to CD4+ T-lymphocyte count. Tuber Lung Dis. 1995 Dec;76(6):518–521. doi: 10.1016/0962-8479(95)90527-8. [DOI] [PubMed] [Google Scholar]
  48. Raviglione M. C., Snider D. E., Jr, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA. 1995 Jan 18;273(3):220–226. [PubMed] [Google Scholar]
  49. Richter C., Pallangyo K. J., Ndosi B. N., Chum H. J., Swai A. B., Shao J. Chest radiography and beta-2-microglobulin levels in HIV-seronegative and HIV-seropositive African patients with pulmonary tuberculosis. Trop Geogr Med. 1994;46(5):283–287. [PubMed] [Google Scholar]
  50. Russian D. A., Kovacs J. A. Pneumocystis carinii in Africa: an emerging pathogen? Lancet. 1995 Nov 11;346(8985):1242–1243. doi: 10.1016/s0140-6736(95)91854-x. [DOI] [PubMed] [Google Scholar]
  51. Shafer R. W., Bloch A. B., Larkin C., Vasudavan V., Seligman S., Dehovitz J. D., DiFerdinando G., Stoneburner R., Cauthen G. Predictors of survival in HIV-infected tuberculosis patients. AIDS. 1996 Mar;10(3):269–272. doi: 10.1097/00002030-199603000-00005. [DOI] [PubMed] [Google Scholar]
  52. Tuberculosis in a rural population of South India: a five-year epidemiological study. Bull World Health Organ. 1974;51(5):473–488. [PMC free article] [PubMed] [Google Scholar]
  53. Wakefield A. E., Stewart T. J., Moxon E. R., Marsh K., Hopkin J. M. Infection with Pneumocystis carinii is prevalent in healthy Gambian children. Trans R Soc Trop Med Hyg. 1990 Nov-Dec;84(6):800–802. doi: 10.1016/0035-9203(90)90087-u. [DOI] [PubMed] [Google Scholar]

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