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BMJ 1994;308:1531-1533 (11 June)

Papers

Contribution of tuberculosis to slim disease in Africa

S B Lucas, K M De Cock, A Hounnou, C Peacock, M Diomande, M Honde, A Beaumel, L Kestens, A Kadio 

Department of Histopathology, University College London Medical School, London WC1E 6JJ Division of HIV/AIDS, NCID, Centers for Disease Control and Prevention, Atlanta, Georgia Projet RETRO-CI, Abidjan,Ivory Coast, University Hospital, Abidjan, Ivory Coast Institute of Tropical Medicine, Antwerp, Belgium Correspondence to: Dr Lucas.

Abstract

Objectives : To assess the contribution of tuberculosis to the aetiology of the HIV wasting syndrome (slim) in Africa, a condition usually considered an enteropathy.
Methods : Clinical examination and representative necropsy study of adult patients positive for HIV.
Setting : Hospital medical wards in Abidjan, Ivory Coast.
Subjects : Adults positive for HIV.
Main outcome measures : CD4 T lymphocyte counts before death, clinical and anthropometric data, and gross and microscopic pathology. Results - Necropsy was done on 212 HIV positive adults. Tuberculosis was found in 41 of 93 with the clinical HIV wasting syndrome and in 32 of 119 without (odds ratio 2.1, 95% confidence interval 1.2 to 4.0). A significant association existed between the prevalence of tuberculosis at necropsy and the degree of cadaveric wasting (no wasting 25% (15/59); moderate wasting 40% (23/58); skeletal wasting 44% (42/95); P=0.02). Wasting was also associated with a history of chronic diarrhoea, but no association existed between diarrhoea and tuberculosis. Median CD4 T lymphocyte counts were lowest in wasted patients irrespective of findings at necropsy and in those with chronic diarrhoea (<60x106/l).
Conclusion : Wasting and chronic diarrhoea are late stage manifestations of HIV disease in Africa. The importance of tuberculosis as a contributing factor in the pathogenesis of the slim syndrome has been underestimated. In nearly half of patients dying with severe wasting, tuberculosis was the dominant pathological finding.

Clinical implications

  • Clinical implications

  • Of all patients positive for HIV dying in a west African hospital nearly half were skeletally wasted (slim)

  • At necropsy 44% of these wasted cadavers had multibacillary tuberculosis, and less wasted patients had less tuberculosis

  • Diarrhoea was not associated with tuberculosis but was independently associated with wasting

  • Earlier diagnosis and better management of tuberculosis is a priority in HIV infection in Africa

Introduction

The typical presentation of AIDS in adults in Africa is with severe wasting, diarrhoea, and fever; the term "slim" was introduced in Uganda in 1985 to describe this.1 More than 80% of patients infected with HIV-1 admitted to hospital have lost over a tenth of their body weight, and over 40% have chronic diarrhoea.2 These features were incorporated into the World Health Organisation's clinical case definition for AIDS surveillance in Africa3 and later refined as the HIV wasting syndrome for resource poor countries.4

Four clinicopathological studies of diarrhoea and slim associated with HIV infection in Africa (Uganda, Zaire, and Zambia) have been published. The prevalence of coccidian infections (Cryptosporidium and Isospora) ranged from 20% to 61% and of microsporidiosis was 9%5,9; these infections were associated with increased permeability of the small intestine. It was concluded that slim has many causes including opportunistic enteropathogens, direct infection of mucosa by HIV, and malnutrition from malabsorption.

There have been no studies of the systemic pathology present in African patients with slim. Because tuberculosis is a common cause of death in African patients with HIV10,11 we wondered whether tuberculosis could be a cause of the HIV wasting syndrome. We examined the relation in adults with HIV of wasting, diarrhoea, CD4 T lymphocyte counts, and pathological findings of tuberculosis at necropsy in west Africa.

Subjects and methods

For 10 months in 1991 consecutive adult patients (>14 years) admitted to the acute medical services of the largest hospital in Abidjan, Ivory Coast, were examined by a clinical team.11 They were evaluated for the HIV wasting syndrome4 and had blood taken for HIV serology12 and for analysis of blood CD4 T lymphocytes.13 No parasitological studies on faeces were performed.

A representative sample (24%) of HIV positive patients who died had necropsies with full histopathological evaluation. Body weight was not measured, but the cadavers were subjectively scored by the pathologists for wasting on a three point scale of no, moderate, and skeletal wasting.11 To validate the assessment of wasting the heart was weighed. The average density of acid fast bacilli in tuberculosis lesions per cadaver was measured in histological sections on a logarithmic scale at magnification of x400.14 The quality of clinical diagnoses before death was too heterogeneous for comparison with necropsy pathology.

Analyses utilised Epi Info, version 5.01.15 Statistical tests were calculations of odds ratio, X2 for trend, and linear regression; all tests were two tailed, and (Alpha) was set at 0.05. The study was approved by the ethics and research subcommittee of the National AIDS Committee of the Ivory Coast.

Results

Two hundred and twelve HIV positive (162 men, 50 women) cadavers had necropsies. CD4 T lymphocyte counts before death were available for 96 (45%). Data on mortality and pathology are published elsewhere.11 The emphasis here is on wasting, CD4 counts, diarrhoea, and tuberculosis.

Wasting, tuberculosis, and CD4 T lymphocyte counts

Of the 212 patients studied, 93 (44%) had been considered before death to have the HIV wasting syndrome. Patients with this syndrome had an increased prevalence of disseminated tuberculosis at necropsy (41/93 v 32/119; odds ratio 2.1, 95% confidence interval 1.2 to 4.0). Evaluation at necropsy showed 95/212 (45%) to be skeletally wasted. A linear decrease was found in heart weight, with increasing severity of wasting in men and women (table I) supporting the validity of the gradation of wasting by the pathologist.


TABLE I - Distribution of weights of hearts measured at necropsy in
patients positive for HIV*
------------------------------------------------------------------------------
                                  Degree of cadaveric wasting
                            --------------------------------------------------
                                None      Moderate      Skeletal
------------------------------------------------------------------------------
Men:
  No of observations             40         40           71
  Mean (SD) heart weight(g)     316 (44)   265 (43)     236 (71)(dagger)
Women:
  No of observations             18          9           20
  Mean (SD) heart weight(g)     233 (37)   218 (33)     200 (60)(double dagger)
-------------------------------------------------------------------------------
 *In 14/212 cadavers hearts not weighed.
 (dagger)Linear regression P<0.001.
 (double dagger)Linear regression P<0.05.

A significant linear trend existed between the degree of cadaveric wasting and the prevalence of tuberculosis at necropsy (table II). The severity of depletion of CD4 T lymphocytes correlated with the degree of wasting (P<0.01) and with the prevalence of tuberculosis at necropsy (table II). Density of acid fast bacilli in tuberculous lesions increased linearly with severity of wasting (P<0.05). The density increased with decreasing CD4 T lymphocyte count (P<0.001). Median densities were >100 per high power field in patients with skeletal wasting or with CD4 T lymphocyte counts <50x106/l, or both.


TABLE II - Prevalence of tuberculosis at necropsy and median CD4 T lymphocytes
counts among 212 patients positive for HIV according to degree of cadaveric
wasting
-----------------------------------------------------------------------
                                       No      Moderate     Skeletal
Measure                             wasting    wasting      wasting
-----------------------------------------------------------------------
Prevalence of tuberculosis*      25% (15/59)  40% (23/58)  44% (42/95)
Median (interquartile range)
 CD4 cell count (x106/l)   123 (57-311) 86 (23-157)  47 (22-104)
-----------------------------------------------------------------------
 *X2 for linear trend=5.2, P<0.02.

Wasting, tuberculosis, and chronic diarrhoea

As shown in table II, cadavers with skeletal wasting assessed at necropsy were more likely to have tuberculosis than those with moderate or no wasting (42/95 v 38/117; 1.7, 0.9 to 3.0). Stratification by previously reported chronic diarrhoea did not influence the direction of this association.

Skeletally wasted patients were more likely to have reported chronic diarrhoea than those without skeletal wasting (47/95 v 41/115) 1.8, 1.0 to 3.2). Stratification for the presence of tuberculosis did not alter the association between wasting and chronic diarrhoea other than reducing the numbers and hence statistical power.

No association existed between tuberculosis and chronic diarrhoea. Intestinal lesions of tuberculosis were more common in skeletally wasted patients (15/95) than in patients without skeletal wasting (3/115; 7.0, 1.9 to 38.6), but their prevalence did not differ significantly in patients with and without diarrohoea when stratified for wasting (data not shown). In summary, these results suggest that tuberculosis and chronic diarrhoea were both significantly associated with skeletal wasting but were not associated with each other.

Table III shows the overall prevalence of tuberculosis and chronic diarrhoea in the 95 skeletally wasted patients. In addition to the 42 who had tuberculosis 25 had a history of chronic diarrhoea and 28 had neither tuberculosis nor chronic diarrhoea but had other AIDS defining pathology at necropsy.11 Of the 42 skeletally wasted patients who had tuberculosis, just over half had given a history of chronic diarrhoea.


TABLE III - Prevalence of tuberculosis and chronic diarrhoea in 95 HIV
positive African patients with skeletal wasting
---------------------------------------
Tuberculosis/chronic
diarrhoea                     No (%)
---------------------------------------
Tuberculosis alone           20 (21)
Chronic diarrhoea alone      25 (26)
Tuberculosis and diarrhoea   22 (23)
No tuberculosis or
diarrhoea                    28 (29)

Wasting, diarrhoea, tuberculosis, and cd4 t lymphocyte counts

Table IV shows the median CD4 T lymphocyte counts in patients with and without skeletal wasting according to whether they also had tuberculosis or chronic diarrhoea. Numbers are inadequate for statistical comparisons but crude trends are described. Severe depletion of CD4 T lymphocytes (<60x106/l) was observed in all categories of patients with skeletal wasting. The patients with chronic diarrhoea had a low count irrespective of the presence or absence of wasting. Patients without skeletal wasting or chronic diarrhoea had higher counts (>95x106/l), indicating that wasting and chronic diarrhoea are end stage manifestations of HIV infection.


TABLE IV - Median (range) CD4 T lymphocyte counts (x106/l) in patients
positive for HIV at necropsy
---------------------------------------------------------------
Condition             Skeletal wasting    Moderate/no wasting
---------------------------------------------------------------
Chronic diarrhoea       44 (19-75)            57 (29-130)
No chronic diarrhoea    50 (22-164)          136 (50-256)
Tuberculosis            47 (4-297)           113 (10-537)
No tuberculosis         47 (2-651)            99 (1-1013)

Other pathologies

Of other potential causes of enteropathy, intestinal cryptosporidiosis was found in seven of 212 (3.3%) cadavers. Intestinal cytomegalovirus infection occurred in 15 of 212 (7%); in all but one it was focal and mild.

Discussion

This is the first study to analyse systemic pathology in relation to the clinical features and immune state of a large number of patients dying with slim disease in Africa. In such patients wasting and chronic diarrhoea were both associated with advanced immunodeficiency. Of patients with skeletal wasting, nearly half had suffered chronic diarrhoea before death and 44% had tuberculosis at necropsy; 29% had neither. Clear associations existed between the degree of immune deficiency, the severity of wasting, the prevalence of tuberculosis, and the density of acid fast bacilli in lesions. We found an association between the severity of wasting and history of chronic diarrhoea but not between chronic diarrhoea and tuberculosis nor between diarrhoea and tuberculosis of the intestine. Although no single cause can explain the pathogenesis of slim disease, these findings suggest that tuberculosis has been underestimated as a contributor to the development of this syndrome, which has been considered primarily an enteropathy.

The earlier studies of diarrhoea and slim associated with HIV infection in Africa were of heterogeneous patients at different stages of disease and immunodeficiency; pathological investigations were limited to intestinal material and results of absorption tests; extraintestinal tuberculosis was not sought or excluded, and a single patient with mycobacterial infection of the gut was noted.5 (The original description of slim, however, did note that four of eight patients tested had acid fast bacilli in the sputum1).

Severe wasting results from reduced nutritional intake, malabsorption, increased catabolism, or a combination of these factors.16 In the United States studies of HIV infection show that death from wasting is related to the magnitude of tissue depletion, independent of the underlying cause.17 Secondary infections are potent causes both of increased resting energy expenditure and of anorexia with decreased energy intake.16 Significant associations were noted between wasting and candidiasis, isosporiasis, and HIV encephalopathy, as were geographical differences in the prevalence of wasting.18

There is an impression that wasting is more severe among HIV positive patients in Africa than in industrialised countries19; because of the higher prevalences of coccidiosis found there it is presumed that the major cause of slim in Africa is infective enteropathy with secondary malabsorption.2,5,8,19 There have been no complementary anthropometric or metabolic studies of HIV infection in Africa; furthermore, evaluations of the effects of dysphagia (due to oro- oesophageal lesions) and of poverty on nutrition are also lacking.20

In Africa the underlying causes of initial wasting associated with HIV infection are not known as natural history studies are lacking. Factors related to HIV infection may operate in the gut to cause malabsorption,21 and food intake may fall for physical and social reasons. Slim undoubtedly has multiple pathogeneses. In our study chronic diarrhoea and tuberculosis were not present in all patients, other AIDS related illnesses can cause wasting, and wasting can occur as an isolated phenomenon in advanced HIV infection. Nevertheless, the high endemicity of tuberculous infection in Africa22 results in an increasing proportion of HIV positive patients with disseminated disease as immunocompetence declines. Anthropometric studies show that tuberculosis is associated with malnutrition, and coinfection with HIV worsens the malnutrition.23 Immunosuppression, dissemination of lesions, increasing bacillary load, and wasting interact and progress to death.

Our study suggests that the HIV wasting syndrome in Africa is not primarily an HIV associated enteropathy. In a substantial proportion of patients the dominant pathology is disseminated multibacillary tuberculosis. The implications are that prophylaxis or earlier diagnosis and treatment of tuberculosis in HIV positive people should be the aim; outcome in skeletally wasted patients is likely to be unfavourable whatever the cause.

We thank the medical, laboratory, and data management staff of the Projet RETRO-CI for their help. The project was supported by the Rockefeller Foundation, the Global Programme on AIDS of the World Health Organisation, and the Centers for Disease Control and Prevention, Atlanta. SBL was supported by the Medical Research Council (UK). Mr R Hayes (London School of Hygiene and Tropical Medicine) gave statistical advice.

  1. Serwadda D, Sewankambo N, Carswell JW, Bayley AC, Tedder RS, Weiss RA, et al. Slim disease: a new disease in Uganda and its association with HTLV-III infection. Lancet 1985;ii:849-52.
  2. Colebunders RL, Latif AS. Natural history and clinical presentation of HIV-l infection in adults. AIDS 1991;5(suppl)1):S103-12.
  3. World Health Organisation. Acquired immunodeficiency syndrome (AIDS). WHO/CDC case definition for AIDS. Wkly Epidem Rec 1986;61:69-76.
  4. De Cock KM, Lucas SB, Coulibaly I-M, Coulibaly D, Soro B. Expanded AIDS surveillance case definitions for use in resource-poor countries. Lancet 1993;342:437-8.
  5. Sewankambo N, Mugerwa RD, Goodgame RW, Carswell JW, Moody A, Lloyd G, et al. Enteropathic AIDS in Uganda. An endoscopic, histological and microbiological study. AIDS 1987;1:9-13. [Medline]
  6. Lucas SB, Papadaki L, Conlon CP, Sewankambo N, Goodgame R, Serwadda D. Diagnosis of intestinal microsporidiosis in patients with AIDS. J Clin Pathol 1988;42:885-7.
  7. Colebunders RL, Lusakumuni K, Nelson AM, Gigase P, Lebughe I, van Marck E, et al. Persistent diarrhoea in Zairian AIDS patients: an endoscopic and histological study. Gut 1988;29:1687-91. [Abstract]
  8. Conlon CP, Pinching AJ, Perera CU, Moody A, Luo NP, Lucas SB. HIV- related enteropathy in Zambia: a clinical, microbiological, and histological study. Am J Trop Med Hyg 1990;42:83-8. [Medline]
  9. Kapembwa MS, Fleming SC, Sewankambo N, Serwadda D, Lucas SB, Moody A, et al. Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects. Clin Sci 1991;81:327-34. [Medline]
  10. Nelson AM, Perriens JH, Kapita B, Okonda L, Lusamuno N, Kalengayi MR, et al. A clinical and pathological comparison of the WHO and CDC case definitions for AIDS in Kinshasa, Zaire: is passive surveillance valid? AIDS 1993;7:1241-5.
  11. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N'Gbichi J-M, et al. The mortality and pathology of HIV disease in a west African city. AIDS 1993;7:1569-79. [Medline]
  12. De Cock KM, Porter A, Kouadio J, Maran M, Gnaove E, Adjorlolo G, et al. Rapid and specific diagnosis of HIV-1 and HIV-2 infections: an evaluation of testing strategies. AIDS 1990;4:875-8. [Medline]
  13. Kestens L, Brattegaard K, Adjorlolo G, Ekpini E, Sibailly T, Diallo K, et al. Immunological comparison of HIV-1, HIV-2, and healthy dually reactive women delivering in Abidjan, Cote d'Ivoire. AIDS 1992;6:803-7. [Medline]
  14. Nambuya A, Sewankambo N, Nugerwa J, Goodgame RW, Lucas SB. Tuberculous lymphadenitis associated with human immunodeficiency virus (HIV) in Uganda. J Clin Pathol 1988;41:93-6. [Abstract]
  15. Dean AD, Dean JA, Burton AH, Dicker RC. Epi Info. Version 5.01. Stone Mountain, Georgia: USD Incorporated, 1990.
  16. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 1992;327:329-37. [Medline]
  17. Kotler DP, Tierney AR, Pierson RN. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 1989;50:444-7. [Abstract]
  18. Nahlen BL, Nwangyanwu OC, Chu SY, Berkelman RL, Martinez SA, Rullan JV. HIV wasting syndrome in the United States. AIDS 1993;7:183-8. [Medline]
  19. Keusch GT, Farthing MJG. Nutritional aspects of AIDS. Annual Review of Nutrition 1990;10:475-501. [Medline]
  20. De Cock KM, Lucas SB, Lucas SE, Agnes J, Kadio A, Gayle HD. Clinical research, prophylaxis, therapy and care for HIV disease in Africa. Am J Public Health 1993;83:1385-9. [Abstract]
  21. Smith PD. Gastrointestinal infections in AIDS. Ann Intern Med 1992;116:63-77. [Medline]
  22. De Cock KM, Soro B, Coulibaly I-M, Lucas SB. Tuberculosis and HIV infection in sub-Saharan Africa. JAMA 1992;268:1581-7. [Abstract]
  23. Scalcini M, Occenac R, Manfreda J, Long R. Pulmonary tuberculosis, human immunodeficiency virus type-1 and malnutrition. Bull Int Union Tuberc Lung Dis 1991;66:37-41. [Medline]
(Accepted 22 March 1994)


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