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Defence against Leishmania donovani is dependent on the oxygen dependent and independent microbicidal mechanisms of the macrophages that are activated by the lymphokines (interleukin-2 and interferon-gamma) secreted by sensitised T-lymphocytes in response to protozoal antigens During active VL, interleukin production is absent, but it is usually restored after successful chemotherapy.12 In highly endemic areas the restoration of interleukin production seems to be impaired in some patients, and as a result leishmanial infection is not controlled and viable amastigotes persist for years in patients with few or no symptoms. 3,4 This latent infection can progress to clinical disease when new adverse events impair the immunological defences. Reactivation of latent VL has been described in old age, in malnutrition, in association with chronic diseases, and in various states of immunosuppression, such as in patients with haematological malignancies, autoimmune diseases, recipients of renal transplants, or patients treated with steroids and other immunosuppressor agents.5,6 Moreover, we have described VL in HIV infection-a common cause of immunosuppression in Spain.’ Since Chaudhuri’s patient lived in an endemic area for VL, latent disease is not improbable. Although VL in his patient could have been an unusual presentation of naturally acquired disease, we believe that the disease developed from latent VL activated by tuberculosis, as also happens in other chronic or immunodepressive disease. Thus we suggest that tuberculosis should be added to the diseases that can induce reactivation of latent VL and that this association should be specially considered in areas where both VL and tuberculosis are endemic. Department of Internal Medicine, Hospital Ramon y Cajal, Madrid 28034, Spain

C. MONTALBAN

J. L. CALLEJA

1. Pearson RD. Wheeler DA, Harrison LH, Kay HD. The immunobiology of leishmaniasis. Rev Infect Dis 1983; 5: 907-27. 2. Carvalho EM, Badaró M, Reed SG, Jones TC, Johnson WD. Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest 1985; 76: 2066-69. 3. Badaró R, Jones TC, Carvalho EM, et al. New perspective on a subclinical form of visceral leishmaniasis. J Infect Dis 1986; 154: 1003-11. 4. Pampiglione S, Manson-Bahr PEC, Giungi F, Giunti G, Parenti A, Trotti GC. Studies on Mediterranean leishmaniasis, 2: asymptomatic cases of visceral leishmaniasis. Trans R Soc Trop Med Hyg 1974; 68: 447-53. 5. Badaró R, Carvalho EM, Rocha H, Queiroz AC, Jones TC. Leishmania donovani: an opportunistic microbe associated with progressive disease in three immunocompromised patients. Lancet 1986; i: 647-49. 6. Femandez-Guerreo ML, Aguado JM, Buzón L, et al. Visceral leishmaniasis in immunocompromised hosts. Am JMed 1987; 83: 1098-102. 7. Montalban C, Martinez-Femandez R, Calleja JL, et al. Visceral leishmaniasis (kala-azar) as an opportunistic infection in patients infected with the human immunodeficiency virus in Spain. Rew Infect Dis 1989; 11: 655-60.

Tumour necrosis factor, steroids, and

meningitis SiR,—The encouraging results of the trials of steroids in meningitis, which you review enthusiastically in your Dec 2 editorial, need to be considered in the context of other data on high-dose glucocorticoids in sepsis and the known effects of these agents on tumour necrosis factor (TNF) synthesis and release. Initial evidence that steroids were of value in septic shock comes from studies on dogs and primates.l Previous trials in patients suggested that steroids have, at best, little beneficial effect,3 and larger studies have shown no benefit at all.4,5 TNF is known to be important in the evolution of the septic shock syndrome and high serum concentrations of this cytokine correlate with clinical outcome in meningococcal meningitis .6 However, TNF was only detectable in the sera of 18 patients out of 79, and these patients had a poor prognosis: 10 died compared with 1 of the remaining 61. Monocyte production of TNF and cellular levels of TNF mRNA following a lipopolysaccharide (LPS) challenge are reported to be greatly reduced by pretreatment with dexamethasone both in vitro7 and in vivo.8 This effect is critically dependent on the time of administration of dexamethasone which should be given before or with LPS. Administration of steroid 20 min after LPS has no effect on the magnitude of the TNF response. The inhibitory effect of steroids on TNF is less striking in alveolar macrophages than in peripheral blood monocytes.9 The

response of other cells thought to synthesise and release cytokines in the central nervous system such as dendritic cells and glial cells is unknown. Although steroids may prove to be beneficial in meningitis, the interpretation of the results from Texas must be viewed with caution since the mean estimate of duration of illness before receiving dexamethasone was at least 35 h. Department of Cellular and Molecular Sciences, Division of Communicable Diseases, St George’s Hospital Medical School, London SW17 0RE, UK

JON FRIEDLAND GEORGE GRIFFIN

LB, Archer LT, Beller-Todd BK, et al. Survival of primates in LD100 septic shock following steroid/antibiotic therapy. J Surg Res 1980; 28: 151-70 White GL, Archer LT, Beller BK, Hinshaw LB. Increased survival with methylprednisolone treatment in canine endotoxm shock. J Surg Res 1978, 25: 357-64. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984, 311: 1137-43. Veterans Administrative Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317: 659-65. Bone RC, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 563-58. Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor m serum and fatal outcome in patients with meningococcal disease. Lancet 1987; 355-57. Beutler B, Krochin N, Milsark IW, Luedke NC, Cerami A. Control of cachectin (tumour necrosis factor) synthesis: mechanisms of endotoxin resistance. Science

1. Hinshaw 2.

3.

4.

5.

6.

7.

1986; 232: 977-80. DG, Streiter RM, Lynch JP, et al. In vivo dynamics of murine tumour necrosis factor-alpha gene expression kinetics of dexamethasone induced

8. Remick

suppression. Lab Invest 1989; 60: 766-71. 9. Streiter RM, Remick DG, Lynch JP, et al. Differential regulation of tumour necrosis factor-alpha in human alveolar macrophages and peripheral blood monocytes: a cellular and molecular analysis. Am J Respir Cell Mol Biol 1989; 1: 57-63.

Antibody to hepatitis C virus in hepatocellular carcinoma SiR,—Professor Colombo and colleagues (Oct 28, p 1006) argue that hepatitis C virus (RCV)! is associated with the development of hepatocellular carcinoma (HCC), especially in patients with liver cirrhosis who are serum anti-HBc positive. HCV is now thought to be the major cause of post-transfusion non-A, non-B hepatitis (PTH-NANB).2 Four cases have been reported, in which patients had well-documented chronic NANB hepatitis acquired after blood transfusion and in whom HCC developed 7-18 years after hepatitis onset. Colombo et al say that such a direct link between PTH and HCC has not been seen in Italy. We have reported a patient with NANB PTH who progressed to chronic hepatitis, then to liver cirrhosis, and finally to HCC7 We report here a short description of this case. The patient (male, 58) was heavily transfused during open heart surgery on June 27, 1975. Before the operation liver tests were normal and there were no clinical signs of liver disease. The patient was anti-HBc and anti-HBs positive. Ten weeks after surgery he had fatigue, malaise, anorexia, and jaundice. Serum HBsAg, anti-HBc IgM, anti-HAV IgM, and cytomegalovirus IgM were negative, and no clinical signs of cardiovascular failure were present. A diagnosis of NANB PTH was made. Jaundice resolved within 4 weeks, and transaminases progressively decreased but did not return to normal. In July, 1976, the patient became jaundiced (table). Viral markers did not show any modification, anti-HBc IgM was always negative. Serum autoantibodies (nuclear, smooth muscle, and mitochondrial) were negative and all identifiable causes of liver disease were excluded. One month later transaminases returned to normal and the patient was symptom-free. In November, 1977, he had abnormal transaminases. A liver biopsy showed chronic active hepatitis (CAH) of moderate degree. In May, 1978, after exacerbation of transaminase activity without symptoms, a second liver biopsy showed histological evidence of CAH with bridging hepatic necrosis. In June, 1981, the patient had fatigue and malaise. The liver edge, palpable at 4 cm beyond the costal rib, was round and firm. Transaminases were only moderately raised; serum electrophoresis showed a mild hypergammaglobulinaemia.

Tumour necrosis factor, steroids, and meningitis.

300 Defence against Leishmania donovani is dependent on the oxygen dependent and independent microbicidal mechanisms of the macrophages that are acti...
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