Betticher, D. C.

Nicole, A.

Pugin, P.

Regamey, C.

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1ID 1990;161 (January) Correspondence 157species (table I)'. Serum (rose bengal-positive, Wright 1:160, im-munofluorescence 1:160) and CSF (rose bengal-positive, im-munofluorescence 1:64) Brucella serology were positive and thepatient was treated with daily rifampin, 900 mg, plus doxycycline,200 mg, for 8 weeks with complete recovery.Brucellosis and tuberculosis are still endemic in our country. Whenthe central nervous system is involved, the clinical picture and CSFanalysis (elevation of protein, decreased glucose, and lymphocyticpleocytosis) may appear similar [6]. Fortunately, CSF and blood se-rology in neurobrucellosis are rarely negative, especially when acomplete battery of tests is available, such as rose bengal and Wrightagglutination, Coombs' test, and indirect immunofluorescence (asis the case in our hospital) or ELISA [7]. However, in the absenceof these examinations, a correct diagnosis may be difficult [8].Increased (>9 units/l) ADA in CSF has been reported to have asensitivity of 1 and specificity of O.99 in the diagnosis of tuberculousmeningitis [9]. However, patients with neurobrucellosis were notincluded in the control groups. False-positive results have beenreported in cases of purulent meningitis [9, 10], but that conditioncould hardly be confused with tuberculous meningitis. However,neu-robrucellosis can easily be mistaken for tuberculous meningitis.On the basis of our data, we think that physicians in countrieswhere brucellosis and tuberculosis are endemic should take care wheninterpreting increased ADA in CSF, at least until neurobrucellosiscan be definitively excluded.Saraiva da Cunha, E. Gaspar, A. Meli~o-Silvestre,R. Azevedo-Bernarda, and Carrington da CostaInfectious Diseases Clinic, University Hospital,and General Pathology Institute, Faculty of Medicine,Coimbra, PortugalThe Hyperreactive Malarial Splenomegaly Syndromein a European: Has the Treatment a ModulatoryEffect on the Immune System?COLLEAGUEs-The hyperreactive malarial splenomegaly (HMS) syn-drome, also known as tropical splenomegaly syndrome, is believedto represent an aberrant immunologic response to repeated malarialinfections and occurs in adultlong-term residents of malarious areas.The syndrome is characterized by a gross splenomegaly with hyper-splenism, high titers of malarial IgM antibodies, a high polyclonalIgM level, hepatic and medullary lymphocytic proliferation, and nor-mal phytohemagglutination response oflymphocytes [1]. We reporta case of HMS syndrome in a white male patient once a residentof Madagascar.A 60-year-old Swiss man had lived for 30 years in Madagascar.He had taken antimalarial prophylaxis (chloroquine) irregularly. InReprints and correspondence: Dr. Daniel Betticher, Med. Klinik, Insel-spital, CH-3010 Bern, Switzerland.The Journal of Infectious Diseases 1990;161:157-159© 1990 by The University of Chicago. All rights reserved,0022-1899/90/6101-0041$01.00References1. Ogawa SK, Smith MA, Brennessel DJ, Lowy FD. Tuberculous menin-gitis in an urban medical center. Medicine (Baltimore) 1987;66:317-3262. Saraiva da Cunha JG, Ma1cata L, Coelho F. Pombo V, Corte-Real R,Pereira A, Melico-Silvestre A, Carrington da Costa R. Meningitetuberculosa do adulto: analise de 36 casos. Coimbra Medica1988;9:237-2433. Molavi A, LeFrock JL. Thberculous meningitis. Med Clin North Am1985;69:315-3314. Daniel TM. New approaches to the rapid diagnosis of tuberculous menin-gitis. J Infect Dis 1987;155:599-6025. Giusti G, Galanti B. Adenosine deaminase. In: Bergmeyer HU, ed.Methods of enzymatic analysis. 3rd ed. Vol4. Weinheim, FRG: Ver-lag Chemie, 1984:315-3236. Shakir RA, AI-Din ASN, Araj GF, Lulu AR, Mousa AR, Saadah MA.Clinical categories of neurobrucellosis; a report on 19 cases. Brain1987;110:213-2237. Bouza E, Garcia de la Torre M, Parras F, Guerrero A, Rodnguez-CreixemsM, Gobernado 1. Brucellar meningitis. Rev Infect Dis 1987;9:810-8228. Dupont B, Bletry 0, Tucat G, Veyssier P, Philippon AM, Godeau P.Neurobrucelloses chroniques avec serodiagnostic de Wright negatif.Nouvelle Presse Med 1980;9:2721-27249. Ribera E, Martinez-Vazquez JM, Ocana I, Segura RM, Pascual C. Ac-tivity of adenosine deaminase in cerebrospinal fluid for the diagno-sis and follow-up of tuberculous meningitis in adults. J Infect Dis1987;155:603-60710. Donald PR, Malan C, van der Walt A, Schoeman JE The simultaneousdetermination of cerebrospinal fluid and plasma adenosine deaminaseactivity as a diagnostic aid in tuberculous meningitis. S Afr Med J1986;69:505-5071983 he gave a history of malaria which was treated by Fansidar(Roche, Basel, Switzerland). At this time the spleen was not enlarged.At the end of 1986 the complaints were tiredness, anorexia (loss of5 kglyear), fever, and malaise. There was no history of alcoholismor jaundice. In 1987 he returned to Switzerland; 2 months later hedid not feel any improvement and therefore was hospitalized. Onexamination he looked pale, his weight was 73 kg, and his height173 cm. During the hospitalization he was never febrile. The liverwas not enlarged, but the spleen wastender and the lower edge reachedthe umbilicus. There were no stigmata of liver disease or other ab-normal physical signs.Laboratory findings included a hemoglobin concentration of 78 gil(mean corpuscular volume, 85 fl; mean corpuscular hemoglobin,31 pg), white blood cell count of 2.8 x 109/1 (neutrophils 49%,lymphocytes 45 %, monocytes 3.5%, eosinophils 1%), and throm-bocytes diminished to 113 x 109/1. Erythrocyte sedimentation rate(ESR) was 130 mm/h. Plasma urea, creatinine, electrolytes, and liverfunction tests were all in the normal range. The proteins were 91 gil.Electrophoresis showed raised immunoglobulins without monoclo-nal spike: serum IgG, 31 (normal, 8-18) g/I; IgA, 1.1 (0.7-4) gil;and IgM, 14.7 (0.7-2.8) gil.Blood smears for malarial parasites were negative several times.No abnormalities or parasites were found in the stool or urine. Anti-158 Correspondence 110 1990;161 (January)body tests for cytomegalovirus, chlamydia, Epstein-Barr virus, toxo-plasma, schistosoma, and brucella were negative. The malarialantibody titers (IF!, Tropical Institute, Basel, Switzerland) for plas-modium falciparum and vivax were 1:5120. Sonography and com-puted tomography of the abdomen confirmed the splenomegaly(24 x II ern, 2400 em'). A liver biopsy showed marked sinusoi-dal infiltration with lymphocytes but no malarial pigment. Bone mar-row examination showed a hyperplasia of the erythroid cells and anexcess of lymphocytes. No evidence of any malignant cells or pig-ments was seen.Thus, the patient presented a typical picture of HMS syndrome.No improvement could be seen during the first 2 months after hisreturn from Madagascar to Switzerland, so we introduced antimalarialtreatment at a prophylactic dose (chloroquine, 300 mg/week). Thepatient soon began to feel well and had no further complaints. Thespleen diminished progressively, the ESR fell almost to the normalrange, and the pancytopenia disappeared (figure I).This is the first case, to our knowledge, of a white male patientmeeting the accepted criteria of HMS syndrome. It was previouslynot known if this illness would strike only the population of tropicalcountries. Different factors play an important part in the pathogene-sis of this syndrome: a long period of exposure to malaria, the an-timalarial drug prophylaxis [2], and a genetic or environmentalpredisposition [3, 4]. The association of antigens and haplotypes ofHLA-DRZ was found to be more frequent in patients suffering fromgross splenomegaly than in those with moderate splenic enlarge-ment [5]. It is still not known whether a European would have thesame aberrant immunologic response.Two cases that could correspond to HMS syndrome in Europeanshave been reported. The first, a Caucasian residing in Africa, showedall the criteria except the high IgM level, which was not measured[6]. The high IgM level (at least 2 SD above the local mean) allowsdifferential diagnosis from other splenomegalies [2]. Although en-largement ofthe spleen (minimal at 10 em below the costal margin)is a major criterion of this syndrome [2], the second published casein a European [7] reported a barely palpable spleen. Those authorsbelieved that the irregular antimalarial prophylaxis was the causeSPLENICVOLUME(em 3)of the minimal enlargement. However, our case meets all the criteriaof HMS syndrome.Studies explaining the pathogenesis indicate that serum samplesfrom patients with HMS syndrome contain lymphocytotoxic anti-bodies (lgM) triggered by repeated or persistent exposure to malar-ial parasites with specificity for 1'8+ suppressor lymphocytes, thusleaving relatively unopposed the stimulating effect of helper T lym-phocytes on B cells [8]. The high level of B cell activity explainsthe production of protein in high concentrations. The treatment con-sists in the inhibition of the triggering mechanism of IgM produc-tion. Antimalarial therapy (in prophylactic dose) is usually followedby disappearance of the symptoms [2].As blood smears for malarial parasites were negative several timesand as our patient was never febrile, we were interested to see hisspontaneous course in the absence of new malarial infection in Swit-zerland. Because he felt no improvement during the first 2 months,administration of chloroquine, in an antimalarial prophylactic dose,was necessary. This treatment induced a progressive disappearanceof the clinical and laboratory signs.Chloroquine seems to have a modulatory effect on the immunesystem. In addition to our case, studies recently published [9] showthat this drug in doses recommended for malarial prophylaxis reducesthe antibody response to primary immunization with intradermalhuman diploid-cell rabies vaccine. These results are explained bythe impaired secretion of a lymphocyte-activatingfactor, interleukin-l[10]. However, the precise mechanism of chloroquine activity is notknown, and further studies are necessary to understand the effectof this drug on the immune system in HMS syndrome.D. C. Betticher, A. Nicole, P. Pugin, and C. RegameyClinique Medicale, Hopital Cantonal, Fribourg, SwitzerlandReferences1. Hewlett 0, Pitchumoni CS. Tropical splenomegaly syndrome (TSS) andother diseases of the spleen. Baillieres Clin Gastroenterol 1987;1:319-333140 1;17-----------------------...---~~------1~------~~---------------ESR(mm/h).t20~Hb(g/I)+I,"" ....IIIIIII::100+I:l:IIII"".!.II:IIIIIIIII300070001000•....·i:i·.....131 r;g····.·····8"';·····7.87CHLOROQUINE........."'so"1.881100······ ..•.. ······4~···31 ....25TIMEFigure 1. Evolution of splenic volume, hemo-globin (Hb) concentration, and erythrocytesedimentation rate (ESR) after administrationof chloroquine.JID 1990;161 (January) Correspondence 1592. Fakunle YM. Tropical splenomegaly. Part I: Tropical Africa. ClinHae-matol 1981;10:963-9753. Greenwood BM, Groenendaal F, Bradley AK, Greenwood AM, Shen-ton F, Thlloch S, Hayes R. Ethnic differences in the prevalence ofsplenomegaly and malaria in The Gambia. Ann Trop Med Parasitol1987;81:345-3544. Crane G, Gibson D, Verrall J, Barker-Hudson P, Barker-Hudson BET,Charlwood D, Heywood P. Malaria and tropical splenomegaly syn-drome in the Anga of Morobe Province. Papua New Guinea MedJ 1985;28:27-345. Bhatia K, Crane G. HLA and tropical splenomegaly syndrome in theUpper Wattut Valley of Papua New Guinea. Hum Immunol 1985;13:235-2426. Lowenthal MN, Hutt MSR. Tropical splenomegaly syndrome in a Cau-casian in Africa. Br Med J 1970;3:262-263New and Old Drugs for Treating Typhoid FeverCOLLEAGUEs-Typhoid fever continues to bea common public healthproblem and a significant cause of morbidity and mortality in manyparts of the world. Despite the excellent in vitro activity of manyantibiotic drugs against Salmonella species, the clinical efficacy ofsome is unclear and others are now being evaluated. Thus, the besttreatment remains controversial as evidenced by several studies re-cently published in the Journal (1-3]. These studies demonstratedthe clinical efficacy of some third-generation cephalosporins andquinolones in the treatment of typhoid fever. The authors suggestedthat these new drugs may be a good alternative to chloramphenicol,which is cited in all of these studies as remaining the drug of choicefor treatment of typhoid fever. Althou~h most clinicians will agree,we are uncertain that a definitive study of chloramphenicol in thetreatment of typhoid fever has been carried out.The renewed interest in the clinical efficacyof new drugs for treatingtyphoid is justified mainly by the potentially dangerous side effectsof chloramphenicol and the data derived from studies showing thatampicillin is not as active as chloramphenicol, We recently reviewedseveral studies published many years ago [4-7] and observed thatinadequate dosage and route of administration of ampicillin couldhave been responsible for these less favorable results. In fact, morerecent studies have shown that intravenous ampicillin in high doses(150-200mg/kg/day) is highlyeffectivein treating typhoid fever [8, 9].During a recent outbreak of typhoid fever in Israel, we comparedthe clinical efficacy of chloramphenicol with high-dose intravenousampicillin [10]. Our results not only confirmed the above-mentioneddata but also showed a more rapid defervescence and a lower re-lapse rate with this ampicillin regimen. We think that this less toxicReprints and correspondence: Dr. R. Finkelstein, Infectious Diseases Unit,Rambam Medical Center, 31096, Haifa, Israel.The Journal of Infectious Diseases 1990;161:159© 1990 by The University of Chicago. All rights reserved.0022-1899/90/6101-0042$01.007. Bhattacharya DN, Harries JR, Emerson PA. Tropical spleno-megaly syn-drome (T.S.S.) in a European. Trans R Soc Trop Med Hyg 1983;77:221-2228. Piessens WF, Hoffman SL, Wadee AA, Piessens PW, Ratiwayanto S,Kurniawan L, Campbell JR, Marwoto HA, Laughlin LL. Antibody-mediated killing of suppressor T lymphocytes as a possible cause ofmacroglobulinemia in the tropical splenomegaly syndrome. J ClinInvest 1985;75:1821-18279. Pappaioanou M, Fishbein DB, Dreesen DW, Schwartz IK, CampbellGH, Sumner JW, Patchen LC, Brown WJ.Antibody response to preex-posure human diploid-eell rabies vaccine given concurrently with chlo-roquine. N Engl J Med 1986;314:280-28410. Salmeron G, Lipsky PE. Immunosuppressive potential of antimalarials.Am J Med 1983;75:19-24drug, which has all of the advantages of chloramphenicol such asclinical efficacy and oral availability (for continuing treatment afterdefervescence occurs), should be considered in the treatment of ty-phoid fever. Certainly it is a less expensive alternative for the publichealth systems of developing countries.Renato Finkelstein and Arie MarkelInfectious Diseases Unit and Department of Internal Medicine.Rambam Medical Center, Haifa. IsraelReferencesI. Pape JW, Gerdes H, Oriol L, Johnson WD. Typhoid fever: successfultherapy with cefoperazone. J Infect Dis 1986;153:272-2762. Islam A, Butler T, Nath SK, Alam NH, Stoeckel K, Houser HB, SmithAL. Randomized treatment of patients with typhoid fever by usingceftriaxone or chloramphenicol. J Infect Dis 1988;158:742-7473. Carbon C, Weber P, Levy M, Boussougant Y, Cerf M. Short-termciprofloxacin therapy for typhoid fever [letter]. J Infect Dis 1987;155:8334. Robertson RP, Wahab MFA, Raasch Fa. Evaluation of chlorampheni-col and ampicillin in salmonella enteric fever. N Engl J Med 1968;278:171-1765. Patel KM. Ampicillin in typhoid fever. Br Med J 1964;1:19646. Kaye D, Rocha H, Eyckmans L, Prata A, Hook EW. Comparison ofparenteral ampicillin and parenteral chloramphenicol in the treatmentof typhoid fever. Ann NY Acad Sci 1967;145:423-4287. Snyder MJ, Gonzalez 0, Palomino C, Music SI, Hornick RB, PerroniJ, Woodward WE, Gonzalez C, Dupont HL, Woodward TE. Com-parative efficacy of chloramphenicol, ampicillin and co-trimoxazolein the treatment of typhoid fever. Lancet 1976;2:1155-11578. Hoffman TA, Ruiz CJ, Counts GW, Sachs JM, Nitzkin JL. Waterbornetyphoid fever in Dade County, Florida. Clinical and therapeutic evalu-ation of 105 bacteremic patients. Am J Med 1975;59:481-4879. Klotz SA, Jorgensen JH, Buckwold FJ, Craven Pc. Typhoid fever. Anepidemic with remarkably few clinical signs and symptoms. Arch In-tern Med 1984;144:533-53710. Finkelstein R, Markel A, Putterman C, Lerman A, Hashman N, Merz-bach D. Waterborne typhoid fever in Haifa, Israel: clinical, microbi-ologic, and therapeutic aspects of a major outbreak. Am J Med Sci1988;296:27-32

The Hyperreactive Malarial Splenomegaly Syndrome in a European: Has the Treatment a Modulatory Effect on the Immune System?

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