Effect of Strongyloides stercoralis Infection and Eosinophilia on Age at Onset and Prognosis of Adult T-Cell Leukemia

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1 HEATOPATHOLOGY Orgnal Artcle Effect of Strongylodes stercorals Infecton and Eosnophla on Age at Onset and Prognoss of Adult T-Cell Leukema YVES PLUELLE, D, CLAIRE GONIN, D, ANDRE EDOUARD, D, 2 BERNARD J. BUCHER, D 3 LAURENT THOAS, D, ALAIN BREBION, D, 5 AND GERARD PANELATTI, D 5 Onset of adult T-cell leukema (ATL) usually follows a long perod of vral latency. Strongylodes stercorals nfecton has been consdered a cofactor of leukemogeness. Hypereosnophla (HE) s also observed and could be assocated wth ether the presence of parastes or the leukemc process. In non-hodgkn's lymphoma, eosnophla may or may not affect prognoss. To determne whether nfecton wth S stercorals and therefore eosnophla has a sgnfcant effect on the development of ATL, we studed two varables n 38 patents: age at onset and medan survval rate. Infected (Ss+) patents (n = 9) were younger (P=.OO02) and survved longer (P=.O0O6) than unnfected (Ss-) patents (n = 9) (medan age, vs 0 years; medan survval, 6 vs days). ean survval of patents wth hypereosnophla (HE+) was not sgnfcantly dfferent from that of patents wthout hypereosnophla (HE-) (P=.5). However, overall survval was longer for Ss+HE+ patents than for Ss-HE- patents (P=.0; vs days) or Ss-HE+ patents (P=.03; vs 5 days). Among patents wth mean survval more than days, Ss+HE+ patents survved longer (P=.028). Our data confrm that cofactors related to the envronment, such as S stercorals and hypereosnophla assocated wth S stercorals or human T-cell leukema vrus, type (HTLV-) mght be mportant n HTLV--assocated leukemogeness and suggest that hypereosnophla affects the prognoss of HTLV--assocated leukema. (Key words: Adult T-cell leukema; Eosnophla; Strongylodes stercorals; Vral latency) Am J Cln Pathol 99;0:8-8. A hgh prevalence of nfecton wth Strongylodes stercorals s noted n healthy carrers of human T-cell leukema vrus, type (HTLV-). ' 2 That S stercorals nfecton s found more often n patents wth adult T- cell leukema (ATL) 3, emphaszes that S stercorals s a cofactor of leukemogeness nduced by HTLV-. ' 5 " Some authors have reported that hypereosnophla (HE) s also frequently found n HTLV- carrers 8 ; others dsagree. 9,0 HE s frequently observed n patents wth perpheral T-cell lymphomas. Conflctng data have been reported regardng the assocaton of HE wth development of non- Hodgkn's T-cell lymphomas, partcularly n rom the Departments of Hematobology, 2 CastroenteroIogy, ^Bochemstry, ^Emergency edcne, and 5 Internal edcne, Unversty Hosptal, artnque, rench West Indes. anuscrpt receved ay 9, 996; revson accepted August 2, 996. Address reprnt requests to Dr Plumelle: Department of Hematobology, Unversty Hosptal, 9200 ort de rance, artnque, rench West Indes. ATL. -8 HE-assocated paraste nfecton was not reported n any publcatons revewed. To determne whether S stercorals nfecton and eosnophla, separately or n conjuncton, are mportant factors n development of ATL, we studed ther relaton to age at onset and medan survval rate n patents wth clncal ATL. ATERIALS AND ETHODS Dagnostc Crtera Between 983 and 995 n artnque, ATL was dagnosed n 38 patents (8 women, 20 men), 26 of whom have been descrbed prevously (Table, patents to 26). Dagnostc crtera for ATL n the group studed ncluded absolute lymphocyte count (>X0 9 /L) wth at least 5% abnormal lymphocytes, perpheral lymphadenopathy, postve antbody to HTLV- at enzyme-lnked mmunosorbent assay and Western blot analyss, and an mmunophenotypc profle (CD2+, CD3+, CD+, CD25+, and CD-) consstent wth ATL. In addton, monoclonal ntegraton of HTLV- vrus n tumor cells, smlar to that 8

2 82 HEATOPATHOLOGY Orgnal Artcle TABLE. INDINGS IN 38 PATIENTS WITH ADULT T-CELL LEUKEIA Patent Age No. Sex (y) LN H S CL Ss * * HE Survval (d) > , >20 LN = lymphadenopathy; H = hepatomegaly; S = splenomegaly; CL = cutaneous lesons; Ss = Strongylodes stercorals; HE = hypereosnophla; + = >X0 9 /L. * Stll alve. examned under a mcroscope. An eosnophl count > X0 9 /L was reported as postve for HE. Patents Age at onset of ATL was compared n two groups: S sfercora/zs-nfected (Ss+) patents and nfecton-free (Ss-) patents. In addton, we compared a group of patents wth hypereosnophla (HE+) wth a group wthout ths hematologc feature (HE-). To assess the effects of S stercorals nfecton on survval rate, we compared the followng groups of patents: Ss+ vs Ss-, HE-Ss+ vs HE-Ss-, and HE+Ss+ vs HE+Ss-. The effect of HE on survval rate also was compared, n the followng patent groups: HE+ vs HE- Ss-HE+ vs Ss-HE-, and Ss+HE+ vs Ss+HE-. In addton, Ss+HE+ vs Ss-HE- patent groups and Ss+HE- vs Ss-HE+ groups were compared. The number of patents ncluded n each group s ndcated n Table 2. There was no dfference n treatment between groups. Statstcal Analyss To evaluate the effects of S stercorals nfecton or eosnophla on age at onset of ATL, we used the ann-whtney U test. Survval tme was calculated from the tme of dagnoss to death. Survval curves were obtaned accordng to the method of Kaplan and eer. The degree of statstcal sgnfcance among survval curves was analyzed wth the log-rank test for the varous hypereosnophla and S stercorals subgroups. Independence of these factors wth regard to patent age was determned wth the Cox proportonal hazards model. The dfference was consdered sgnfcant at P<.05. The relatve mortalty rsk was gven for each group. Statstcal analyss took the number of survvors nto account. Patent was excluded from statstcal computatons of survval because of unusually long survval ( years). Results from the HE+Ss- patent group (n = ) were too small for meanngful analyss and therefore are reported reported n the lterature, 9 was confrmed n 9 patents. The Baermann test was used to detect S stercorals n at least three fecal samples from each patent. Eosnophls were counted wth a Coulter/STKS cell counter (Coulter; am). As a control, ay-grunwald-gemsa staned smears were ATL SS+ ss- Total TABLE 2. NUBER O PATIENTS STUDIED HE+ 5 (*) (*) HE- 26 ATL = adult T-cell leukema; HE = hypereosnophla. 'Number of patents ncluded n analyss of survval rate. Total 9 9 (8*) 38 (3*) AJCP January 99

3 PLUELLE ET AL 83 S stercorals Infecton and Eosnophla n Adult T-Cell Leukema here for nformaton only. Computatons were performed wth the Statvew.5 statstcal program (Abacus Concepts, Berkeley, Calf, 99). RESULTS Clncal data for the 38 patents are reported n Table. Nneteen patents (8 women, men) were nfected wth S stercorals. Patents younger than 0 years were more often nfected (0 of ; women, 6 men) than those older than 0 years. Infecton was usually dagnosed several years before onset of ATL (average, 6.5 years; range, to 2 years) and was resstant to treatment wth tabendazole or albendazole. At onset of dsease, patents had eosnophl counts >X0 9 /L (range,. to 6.5X0 9 /L); were nfected wth S stercorals. Statstcal Analyss Effects of S stercorals nfecton and presence of hypereosnophla on age at dsease onset. edan age of patents n all groups was 8 years (range, 23 to 95 years). Dfference n age between the Ss+ and Ss- groups was sgnfcant (P=.0002): Ss+ patents were younger (medan age, years; range, 23 to 5 years) than Ss- patents (medan, 0 years; range, 3 to 95 years). No sgnfcant dfference was found between HE+ and HE- patents (medan age, 50 vs 6 years; P=.5). Effects of S stercorals nfecton and presence of hypereosnophla on survval. edan survval tme n the 3 patents followed up was 2 days (range, 3 to 20 days) and vared accordng to the age of the patent (P=.0) (g, A). Survval curves for the four patent groups (g, B) demonstrate that nfected patents (e, Ss+HE- or Ss+HE+) survved longer than nonnfected patents (Ss-HE- or Ss-HE+) (P=.0009). Infecton Wth S stercorals and Survval Analyss of survval curves demonstrated a statstcally sgnfcant dfference between the Ss+ and Ss- groups (g 2, A). Patents nfected wth S stercorals survved longer than nonnfected patents (medan survval, 6 vs days; P=.0006), and survval was ndependent of patent age (P'=.68). patent groups clearly survved sgnfcantly longer (P=.008) (g 2, B). No correlaton was found wth patent age (P'=.200). Presence of nfecton seemed to ncrease survval tme n the HE+ group as well (P=.033). Pertnent statstcal data are summarzed n Table 3. Hypereosnophla and Survval In terms of overall survval, no sgnfcant dfference was observed between HE+ and HE- groups (medan survval, 00 vs days; P=.96) (g 3, A). The presence of eosnophla had no sgnfcant effect on survval n ether Ss+ or Ss- patent groups (P=.8 and.5, respectvely) (g 3, B; Table ). However, of the patents who survved days or longer (9 of 0 Ss+ patents), those wthout HE survved longer ( vs 28 days; P=.028) I, I. I. I. I.. 00 lc. A, Survval tme n 3 patents wth ATL. D = Excluded patents. for survval <X> CD O.,. r ' - ' n As\ v '> ' ' B, Survval curves for four groups of patents. A = Ss+HE-, O : Ss+HE+, + = Ss-HE+, = SS-HE-, and 0 = excluded patents. Vol. 0 No.

4 8 HEATOPATHOLOGY Orgnal Artcle IG 2. Effects of S stercorals nfecton on survval wth ATL. A, Survval curves for Ss+ (o) and Ss- (A) patent groups (P=.0006). D and 0 = excluded patents. T 200 " ' ' ' r B, Survval curves for Ss+HE- (o) and Ss-HE- (A) patent groups (P=.008). D and 0 = excluded patents. (Table 5). A sgnfcant dfference was also noted between Ss+HE+ compared wth Ss-HE- patent groups (medan survval, vs days; P=.0). The mortalty relatve rsk for Ss-HE- patents was 3. tmes that n SS+HE+ patents. Intergroup comparson demonstrated that Ss+HE- patents survved longer than SS-HE+ patents (P=.053) (Table 6). DISCUSSION HTLV-, human mmunodefcency vrus, and S stercorals are all endemc n artnque. S stercorals nfecton s found frequently n patents wth ATL, wth an nfecton rate of 50% vs % n the overall Patent Group SS+ ss- SS-HE- SS+HE+ SS-HE+ TABLE 3. EECTS O INECTION WITH S STERCORALIS ON SURVIVAL No. of Patents 9 8 edan Survval d) P' + RR* HE+ = eosnophla (>X0 9 /L). * Regresson analyss of survval as a functon of age. t Relatve rsk for mortalty, HE- vs HE+ patent groups populaton of artnque. or example, a 3% nfecton rate s found n banana plantaton workers and ther famles, a group that has been much studed for S stercorals.,20 In contrast, patents wth acqured mmune defcency syndrome have moderate rates of S stercorals nfecton. 20 The man route of transmsson of HTLV- s from mother to chld durng breast-feedng. Infecton durng chldhood appears to be a prerequste for the development of ATL n adulthood. These fndngs, publshed n the lterature, 2 seem to ndcate that latency begns at brth, when the chld s nfected from maternal mlk. Our study shows that the perod of latency precedng the onset of ATL s substantally shorter n Ss+ patents than n Ss- patents. S stercorals nfecton causes a specfc polyclonal expanson of CD+-actvated lymphocytes (Thl type), 22,23 Whch mght lead to the appearance of a malgnant clone. 5,6 A hgh level of monoclonal ntegraton of HTLV- provral DNA s found n those HTLV- carrers who are also Ss+. 5 The results of our study suggest that patents nfected wth HTLV- at brth and later n lfe wth S stercorals present preferentally wth a monoclonal prolferaton of CD+ cells, compared wth other patents wth HTLV-. No data are currently avalable regardng the prevalence of ATL n HTLV-+Ss+ patents compared wth HTLV-+Ss- patents; a prospectve study s n progress, however. Patents nfected wth S stercorals frequently have eosnophl counts above X0 9 /L. Some fndngs emphasze that a clonal expanson of type 2 helper T AJCP January 99

5 PLUELLE ET AL 85 S stercorals Infecton and Eosnophlc! n Adult T-Cell Leukema 00 IG 3. Effects of hypereosnophla on survval wth ATL. A, Survval curves for HE+ (o) and HE- (A) patent groups (P=.96). 0 = excluded patents. cells assocated wth HE may represent a premalgnant condton. 2,25 These data confrm the hypothess that specfc lnks exst between HTLV--assocated leukema and the presence of S stercorals. TABLE. EECTS O HYPEREOSINOPHILIA ON SURVIVAL Patent Group HE+ SS-HE+ SS+HE+ HE- SS-HE- No. of Patents 26 edan Survval (d) HE+ = eosnophla (> XIO'/L). + Regresson analyss of survval as a functon of age. * Relatve rsk for mortalty, HE- vs HE+ patent groups. RR>.. B, Survval curves for Ss+HE+ (o) and Ss+HE- (A) patent groups (P=.8). 0 = excluded patent. ATL carres a poor prognoss. In our seres, mean survval was less than 3 months n more than 50% of patents. In studes performed n Japan, 26 poor prognostc ndcators ncluded age 0 years or older, hypercalcema, hgh lactc dehydrogenase level, and advanced performans status. Our results clearly ndcate that Ss+ patents survve longer than the others and that ths survval s ndependent of age. HE s frequently noted n perpheral T-cell lymphomas, but overall survval rate, especally n ATL, may or may not be assocated wth the presence of HE. -8 Analyss of our statstcal data, n terms of the effect of HE on survval, dd not yeld unequvocal results. Rather, our fndngs suggest that HE alone has no nfluence on the evoluton of ATL (see Table ). They ndcate, however, that the presence of HE, when assocated wth S stercorals (Ss+HE+), may TABLE 6. EECTS O INECTION WITH S STERCORALIS AND HYPEREOSINOPHILIA ON SURVIVAL Patent Group HE+ TABLE 5. EECTS O HYPEREOSINOPHILIA ON SURVIVAL > DAYS No.of Patents 6 edan Survval (d) 28 f Regresson analyss of survval as a functon of age. P*.028 P'+. edan Patent No. of Survval Group Patents (d) SS+HE+ HE- SS-HE f Regresson analyss of survval as a functon of age. t Relatve rsk for mortalty, HE- vs HE+ patent groups. p-t.88. RR> 3. Vol. 0 No.

6 86 HEATOPATHOLOGY Orgnal Artcle carry a better prognoss n ATL (see Table 6). Among patents who survved longer than days, however, those who dd not develop eosnophla (Ss+HE-) survved longer (see Table 5). Thus the presence of S stercorals nfecton wthout assocated eosnophla would ndcate a better prognoss compared wth other stuatons. Eosnophl producton s controlled by actvated T lymphocytes, through producton of granulocytemacrophage colony-stmulatng factor (G-CS), nterleukn 3 (IL-3), and IL-5. Eosnophla n patents wth T-cell lymphomas has been correlated wth G- CS, IL-3, or IL-5 producton by the lymphomatous cells In addton, HTLV--nfected CD-lymphocytes seem to produce one or several lymphoknes that may stmulate eosnophlopoess. ' 29 ' HE may be ether benefcal or harmful to patents wth S stercorals nfecton or lymphoma, dependng on specfc condtons. 3 Eosnophl functon could dffer n noncomplcated ATL compared wth ATL wth S stercorahs nfecton. The cytokne response, wth subsequent effect on eosnophlopoess, could be dfferent, dependng on the prmary pathologc event. Hence, ntrnsc secreton of G-CS, tumor necross factor, and IL- occurs naturally n ATL cells,,29, whereas IL-5 and IL-3 can be produced by lymphocytes n response to helmnthc antgens. Eosnophls found n malgnant dsease are also more senstve to glucocortcod treatment than others are. Ths confrms the hypothess that a functonally dfferent populaton s nvolved. 3,32 Work on eosnophla n asymptomatc HTLV- carrers 8-0 or patents wth ATL -5 dd not address the queston of parastes, partcularly helmnths. Ths could explan certan dscrepances observed among studes relatve to the frequency of eosnophla n asymptomatc HTLV- carrers 9,0 and the effect of ths on the prognoss of lymphomas. 3- The results of our study confrm the hypothess that cofactors related to the envronment play an mportant, although not exclusve, role n the development of HTLV--assocated leukemogeness. Among these, nfecton wth S stercorals and the eosnophlc response of the nfected host to S stercorals or HTLV- may prove to be key elements. urther studes n a larger group of patents wll be necessary to confrm these results. In partcular, future studes should evaluate the role of cytoknes and the knetcs of the populaton of lymphocyte clones n asymptomatc HTLV- carrers both wth and wthout S stercorals. REERENCES. Nakada K, Kohakura, Komoda H, Hnuma Y. Hgh ncdence of HTLV antbody n carrers of Strongylodes stercorals. Lancet. 98;: Neva A, urphy EL, Gama A, et al. Antbodes to Strongylodes stercorals n healthy Jamacan carrers of HTLV-. N Engl J ed. 989;320: Dxon AC, Yanaghara ET, Kwock DW, Nakamura J. Strongylodes assocated wth human T-cell lymphotropc vrus type I nfecton n a nonendemc area. West J ed. 989;0-3.. Plumelle Y, Pascalne N, Nguyen D, et al. Adult T-cell leukemalymphoma: A clnco-pathologc study of twenty-sx patents from artnque. 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7 PLUELLE ET AL 8 S stercorals Infecton and n Adult T-Cell Leukema 22. Genta R, Otteson EA, Neva A, et al. Cellular responses n human strongylodass. Am } Trop Hyg. 983;32: Sato Y, Shroma Y. Perpheral lymphocyte subsets and ther responsveness n human strongylodass. Cln Immunol Immunopathol. 989;53: Bagot, Bodemer C, Wechsler J, et al. Nonepdermotropc T lymphoma preceded for several years by hypereosnophlc syndrome. Ann Dermatol Venereal. 990;: Cogan E, Schandene L, Crusaux A, Cochaux P, Velu T, Goldman. Clonal prolferaton of type 2 helper T cells n a man wth the hypereosnophlc syndrome. N Engl J ed. 99;3: Lymphoma Study Group (98-98). ajor prognostc factors of patents wth adult T-cell leukema-lymphoma: A cooperatve study. LeukRes. 99;5: ernand JP, tjavla T, Le Couedc JP, et al. Role of granulocyte-macrophage colony-stmulatng factor, nterleukn-3 and nterleukn-5 n the eosnophla assocated wth T cell lymphoma. Br J Haematol. 993;83: Chang H, Jamal N, Wang XH, nden D, essner HA. Consttutve producton of the nterleukns IL5 and IL6 by the lymphoma cell lne OCL-Ly derved from a patent wth malgnant lymphoma and hypereosnophla. Leuk Lymphoma. 992;8: Salahuddn SZ, arkham PD, Lndner SG, et al. Lymphokne producton by cultured human T cells transformed by human T-cell leukema lymphoma vrus I. Scence. 98;223: orta, Sato H, Honjo T, et al. Dfferentaton of a human eosnophlc leukema cell lne (EoL-) by a human T-cell leukema cell lne (HIL-3)-derved factor. Blood. 99;: Prn L, Capron, Tonnel AB, Bletry O, Capron A. Heterogenety of human perpheral blood eosnophls: Varablty n cell densty and cytotoxc ablty n relaton to the level and the orgn of hypereosnophla. lnt Arch Allergy Appl Immunol. 983;2: Prn L, Lefebvre P, Gruart V, et al. Heterogenety of human eosnophl glucocortcod receptor expresson n hypereosnophlc patents: Absence of detectable receptor correlates wth resstance to cortcotherapy. Cln Exp Immunol. 989;8: