Bettens, Florence

Gottstein, Bruno

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1416 Correspondence JID 1994;169 (June)* DR distribution determined by PCR-SSO [10].Table 1. Distribution of relevant HLA antigens (typed by poly-merase chain reaction sequence-specific oligonucleotides [peR-SSO])in Swiss patients with alveolar echinococcosis and in healthyCaucasian controls.cent assay [9]. The relevant distribution ofHLA-DR antigens inpatients with AE versus a random Caucasian control group isshown in table I.In our patient group, the frequency of HLA-DR 13(DRBI*1301/1302) antigen was significantly increased (pa-tients, 34.4%;controls, 13.6%; x2 = 7.0, P = .008). The associa-tion between an HLA antigen and susceptibility to disease afterinfection with E. multilocularis was highly significant. Sub-grouping of patients with respect to individual clinical status andcourse provided more insight into the distribution of the respec-tive DRI3. In the group of inoperable patients, 2 (12%) of 14expressed DR 13 as did 4 (40%) of 10 of those who had partialsurgery and 6 (75%) of 8 who had radical resection. Our primaryfinding was that persons expressing DR 13 develop AE with amuch higher frequency (and a relative risk factor of 5.7) thanwill persons not expressing DR 13. By subgrouping patients byclinical status and course. it was obvious that once infectionresulted in disease, a DR 13 predisposition was favorable andradical surgery was much more likely. Why this is so remainsunknown. We postulate that in patients with DR 13, due tohigher susceptibility to disease, symptoms may become manifestat an earlier stage of infection when radical surgical resection ismore likely.The present study also shows a reduced frequency of HLA-DR4 antigens among patients versus controls (patients, 15.6%;controls, 41.3%; X2 = 6.5; P = .0 I; protection factor, 0.6). Al-though not highly significant, this finding and knowing fromprevious epidemiologic studies that a certain portion of personsinfected with E. multilocularis will not develop disease [I], orwill cast off organisms spontaneously at an early stage [4], pro-vides the rationale for further HLA-DR studies in families ofpatients at high risk of infection, such as native Yupik popula-Patients Controls(n = 32) (n = 177)* x' p7.0 .0086.5 .0126.031.623.741.325.44.62.80.611.32.813.65.10.65.610.6%phenotypefrequency12.537.515.615.631.39.43.1o12.53.134.40.6o3.118.8DRI, DRBI*0101-0103DR2. DRB5*0 I0 I. 0 I02, 020 I, 0202DR3. DRB 1*030 I, 0302DR4, DRB 1*040 1-0411DR7, DRBI*0701, 0702DR8. DRB 1*080 1-0804DR9, DRBI*0901DR 10, DRBI*IOOIDRII, DRBI*I 101-1 104DRI2, DRBI*1201, 1202DRI3. DRBI*1301, 1302DRBI*1303DRBI*1304DRI4. DRBI*1401, 1404DRx. Not detected or homozygoticHLA, PCR-SSO-determinedgenesReprints or correspondence: Dr. Bruno Gottstein. Institute of Parasitol-ogy. Faculty of Veterinary Medicine, University of Berne, Liinggass-Strasse122. P.O. Box 8466. CH-300 I Berne, Switzerland.The Journal of Infectious Diseases 1994;169:1416- 7© 1994 by The University of Chicago. All rights reserved.0022-1899/94/6906-0049$01.00Association between HLA-DR!3 and Susceptibility toAlveolar EchinococcosisColleagues-Alveolar echinococcosis (AE), caused by infec-tion with the larval stage of the small fox tapeworm Echinococ-cus niultilocularis. is one of the most lethal helminthic infectionsin humans. Its pathology and high mortality rate (56%-94% inuntreated cases; 10%-14% after treatment and early diagnosis[I]) are reasons for public health concern.Prevalence among European fox populations is 35% in Swit-zerland [2], which is similar to rates reported for some endemicareas of France and Germany. The wide distribution of foxesinfected with egg-producing E. multilocularis may represent aconsiderable potential risk for humans in densely populated re-gions, such as Switzerland; however, despite this high preva-lence in the definitive host, the disease in humans is relativelyrare. In Switzerland, the annual morbidity rate has been rela-tively stable at 0.18 AE cases per 100,000 inhabitants for severaldecades [I]. Similar data were reported for France, Germany,and Austria [3].Previous seroepidemiologic studies detected cases ofearly ac-tive, but asymptomatic, AE and provided the first evidence ofself-healed cases of AE in humans and the presence of inactivedead or aborted larval parasites [4], indicating the potential fordifferent courses of AE in humans.Experimental infections in inbred laboratory mouse strainshave shown that susceptibility and resistance to infection withE. multilocularis metacestode and subsequent disease may begenetically controlled [5.6]. Our efforts to understand the mech-anisms and genetics of susceptibility to AE have focused on theidentification ofDNA markers that segregate the disease by pop-ulations living in endemic areas. We addressed this task by de-termining the frequency of the lymphoid cell surface HLA-DRproteins, which are encoded in the region of the major histocom-patibility complex and referred to as class II antigens.Blood samples were collected over 3 years from 32 patientswith hepatic AE. The patients were preselected for the study bytheir homogeneous geographic and ethnic origin (all Swiss) andby their clinical courses (described in detail in [7]). Clinicalcourses included radical resection of the hepatic metacestodelesion without recurrence; partial resection of the hepatic lesion.continuous mebendazole or albendazole treatment, and regres-sive or stationary course of disease; inoperable lesion treatedwith continuous mebendazole or albendazole, and stationary orprogressive development of disease. Although the clinicalcourses of disease differed, the groups matched each other inparameters, such as average age, sex, and disease duration.HLA-DR antigens were determined by oligotyping [8]: Leuko-cyte DNA had DRB genes amplified by the polymerase chainreaction. This was followed by sequence-specific hybridizationwith biotinylated oligonucleotides detected in a chemolumines-JID 1994; 169 (J une) Correspondence 1417tions ofAlaska, and for reversed elucidation ofpotential geneticresistance markers indicating metacestode abortion [4].Bruno Gottstein and Florence BettensInstitute of Parasitology. University ofBerne. and Institute of ClinicalImmunology. Inselspital, Berne. SwitzerlandReferences1. Gottstein B. Echinococcus multilocularis infection: immunology andimmunodiagnosis. Adv ParasitoI1992;31:321-80.2. Ewald D. Eckert J. Gottstein B. Straub M. Nigg H. Parasitological andserological studies on the prevalence of Echinococcus multilocularisLeuckart, 1863 in red faxes (Vulpes vulpes Linnaeus, 1758) in Swit-zerland. Rev Sci Tech 1992;11:1057-61.3. World Health Organization. Report of the WHO informal consultationon Echinococcus multilocularis research. Geneva: WHO 1988.4. Rausch RL. Wilson JF, Schantz PM. McMahon BJ. Spontaneous deathofEchinococcus multilocularis: cases diagnosed serologically by Em2-ELISA and clinical significance. Am J Trap Med Hyg 1987;36:576-85.Nitric Oxide in Cerebral MalariaColleagues-Cerebral malaria is an important complication ofPlasmodium [alciparum infection and a major cause of infantmortality in Africa. The pathophysiology of cerebral malariaremains incompletely understood. Recently, a link between cy-tokines, nitric oxide (NO), and cerebral malaria was proposed[I, 2]. It was hypothesized that intravascular NO, induced bytumor necrosis factor in endothelial cells and vascular smoothmuscle, diffuses through the blood-brain barrier and interfereswith neurologic function. Furthermore, NO is thought to in-crease intracranial pressure, a common feature in cerebral ma-laria in African children [3}, through increased vasodilatation.Our data do not support this concept.We studied the evolution of NO plasma concentrations in 28African children (mean age ± SO, 4.4 ± 3 years) with cerebralmalaria in Yaounde. All children presented with unrousablecoma and P.falciparum parasitemia. Coma depth was assessedaccording to the modified Glasgow coma scale for young chil-dren [4}. Other causes of coma were excluded. After treatmentwith quinine (25 mg of base/kg daily for 8 days), the clinicaloutcome was favorable in 21 cases; 4 children developed neuro-logic sequelae. Three children died: after 12 h, 3 days, and 4days. Mean duration of coma for the 25 surviving children was45.1 ± 31.4 h. NO plasma concentrations were measured on theday of admission (day 1) and on days 2,3,5, and 8 (discharge).Stable NO end products (N02 and NO]") were measured bymeans of an automated procedure, as described previously [5].On day 1, mean NO concentration in 28 children was 44.3 ±Reprints or correspondence: Dr. Pascal Ringwald. ORSTOM/OCEAC,BP288. Yaounde. Cameroon.The Journal of Infectious Diseases 1994;169:1417-8© 1994 by The University of Chicago. All rights reserved.0022-1899/94/6906-0050$0 \.005. Liance M. Vuitton 0, Guerret-Stocker S, Carbillet JP, Grimaud JA,Houin R. Experimental alveolar echinococcosis. Suitability ofa mu-rine model of intrahepatic infection by Echinococcus multilocularisfor immunological studies. Experientia 1984;40: 1436-9.6. Kroeze WK. Tanner CEo Echinococcus multilocularis: susceptibility andresponses to infection in inbred mice. Int J Parasitol 1987;17:873-83.7. Gottstein B. Mesarina B. Tanner I, et aI. Specific cellular and humoralimmune responses in patients with different long-term courses ofalveolar echinococcosis (infection with Echinococcus multi/ocularis).Am J Trop Med Hyg 1991;45:734-42.8. Tiercy JM. Jeannet M, Mach B. A new approach for the analysis ofHLA class II polymorphism: HLA oligotyping. Blood Rev 1990;4:9-15.9. Bettens F, Pichler WJ. de Weck AL. Incorporation ofbiotinylated nu-c1eotides for the quantification of PCR-amplified HIV-I DNA bychemiluminescence. Eur J Chern Clin Biochem 1991;29:685-8.10. Doherty DG. Vaughan RW. Donaldson PT,Mowatt AP. HLA DQA.DQB and ORB genotyping by oligonucleotide analysis: distributionof alleles and haplotypes in British caucasoids. Hum Immunol1992;34: 53-63.36.5 J.LM. Children with favorable outcome presented with ahigher mean NO concentration (49.9 ± 40.3 J.LM) than thosewith neurologic sequelae (30.6 ± 15.5 J.LM) or those who died(23.7 ± 4.6 p.M). NO concentrations were higher in childrenwith a coma score of 3 (n = 11; 63.2 ± 49 J.LM) than in childrenwith a coma score of 1 or 2 (n = 17; 32.2 ± 18.6 J.LM). Thesedifferences were not statistically significant. NO concentrationswere negatively correlated with the duration ofcoma (Spearmanrank test, r = -.49, P < .02), indicating that the duration ofcoma was significantly longer in children with NO plasma levels<44.3 p.M than in those with NO plasma levels superior to themean (53.6 ± 27.5 vs. 32.4 ± 34.0 h; P < .02). No significantcorrelation between NO level and platelet or white blood cellcounts, blood glucose level, parasitemia, hemoglobin level, orbody temperature was found.We observed an increase of mean NO concentration after 24h of quinine treatment in children with favorable outcome(group A); in children with sequelae (group B), this was foundafter 48 h. By day 3, mean NO level was higher in group A (44.2± 50.9 p.M) than in group B (12.8 ± 3.9 J.LM)(Mann-Whitney Utest, P = .03). Similar results were observed at day 5 (62.1 ±68.1 vs. 16.2 ± 7.1 p.M; P < .04; figure 1).Although NO plasma concentrations are higher during cere-bral malaria than during uncomplicated malaria attacks (unpub-lished data), our results seem to refute the hypothesis that in-creased NO levels are detrimental in the development ofcerebral malaria. In a murine model, N-monomethyl-L-arginine,an inhibitor ofNO synthase, prevented neither the developmentof neurologic symptoms nor the death of Plasmodium berghei-infected mice [6, 7]. Furthermore, treatment with a competitiveNO synthase inhibitor had a deleterious effect in complicatedmurine Plasmodium vinckei malaria [8]. Therefore, it has beensuggested that NO has a protective role in cerebral malaria [9}.Further investigations are being done to confirm the protectiveeffectofNO in human pathology as suggested by murine modelsand by our preliminary results.

Association between HLA-DR13 and Susceptibility to Alveolar Echinococcosis

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