Implications of
Helicobacter pylori
infection
for stomach cancer prevention
Imp lic aç õ e s d a infe c ç ão p o r
He lic o b ac te r p ylo ri
na p re ve nç ão d o c ânc e r d e e stô mag o
Sch ool of Pu b lic Hea lt h , Un iv ersit y of Tex a s Hea lt h Scien ce Cen t er. P. O. Box 20816, Hou st on , T X 77225, U SA.
Ka ren J. Good m a n
Abst ract Accu m u la t in g ev id en ce h a s im p lica t ed He lico b a cte r p ylo ri, a n est a b lish ed ca u se of ch ron ic gast rit is an d p ep t ic u lcer, in t h e et iology of gast ric can cer. Con t rol of t h is in fect ion w ou ld red u ce t h e occu rren ce of ch ron ic gast rit is an d p ep t ic u lcer an d m igh t su bst an t ially low er t h e risk of st om a ch ca n cer a s w ell. Th e p u b lic h ea lt h im p a ct of t h is in fect iou s a gen t w a rra n t s effort s t o id en t ify p rev en t iv e m ea su res. Th is p a p er rev iew s t h e ev id en ce lin k in g H. p ylo riin fect ion t o ga s-t ric ca n cer a n d eva lu a s-t es s-t h e p os-t en s-t ia l for con s-t rol in h igh -risk p op u la s-t ion s. Cu rren s-t obss-t a cles s-t o H. p yloricon t rol are d iscu ssed , in clu d in g t h e lin k t o p oor socioecon om ic con d it ion s, d ifficu lt y in id en t ifyin g in cid en t ca ses, la ck of n a t u ra l im m u n it y t o rein fect ion , lim it ed effect iv en ess of a n -t ib io-t ic -t h era p y in h igh - p rev a len ce p op u la -t ion s, a n d in com p le-t e k n ow led ge rega rd in g -t h e reservoir of in fect ion , m od e of t ran sm ission , h ost su scep t ibilit y fact ors, an d t h e p ot en t ial for d ev elop -i n g a n ef f ect -i v e v a cc-i n e. W o rt h w h -i le a v en u es o f resea rch -i n clu d e st u d -i es d es-i gn ed t o -i d en t -i f y m od ifiable risk fact ors for acqu isit ion of t h e in fect ion , m od ifiable h ost fact ors t h at m ay in crease resist an ce t o ch ron ic in fect ion , m ore effect iv e an t ibiot ic t h erap ies, an d effect iv e vaccin es. Key words Helicob acter p ylori; Preven t ion ; St om ach ; Can cer; Ep id em iology
Resumo Um a cú m u lo d e ev id ên cia s a p on t a p a ra Helico b a cter p ylo ri, u m a ca u sa com p rov a d a d e gast rit e e ú lcera p ép t ica, n a et iologia d o cân cer gást rico. O con t role d essa in fecção p od eria re-d u z ir a ocorrên cia re-d e ga st rit e crôn ica e ú lcera p ép t ica , a lém re-d e re-d im in u ir o risco re-d e câ n cer re-d e est ôm ago. O im p acest o d esse agen est e in feccioso em n ív el d e saú d e p ú blica ju sest ifica os esforços n o sen -t i d o d e i d en -t i f i ca r m ed i d a s p rev en -t i v a s. Es-t e a r-t i go rev ê a s ev i d ên ci a s li ga n d o o H . p ylo r ia o cân cer d e est ôm ago e av alia o p ot en cial p ara con t role em p op u lações d e alt o risco. A au t ora d is-cu t e os obst á is-cu los a t u a is a o con t role d o H. p ylori, in clu siv e su a a ssocia çã o com con d ições su ir o risco d e cân cer d e est ôm ago. O im p act o d esse agen t e in fecciod en t es, a falt a d e im u n id ad e n at u r-al à rein fecção, a eficácia lim it ad a d a an t ibiot icot erap ia em p op u lações com r-alt a p revr-alên cia e o con h ecim en t o in com p let o sobre o reservat ão com con d ições su ir o risco d e cân cer d e est ôm ago. O im p a ct o d esse a gen t e in fecciop ed eiro e p ossib ilid a d e d e d esen v olv er u m a v a cin a efica z . Lin h a s d e p esq u i sa p ri o ri t á ri a s i n clu em est u d o s p ro jet a d o s p a ra i d en t i f i ca r f a t o res d e ri sco m o d i -ficá v eis p a ra a a q u isiçã o d a in fecçã o, fa t ores m od i-ficá v eis n o h osp ed eiro q u e p ossa m a u m en t a r a resist ên cia à in fecção, an t ibiot icot erap ias e v acin as m ais eficaz es.
Accu m u la tin g evid en ce h a s im p lica ted Heli-cob a ct er p ylori, n ow a n esta b lish ed ca u se o f ch ro n ic ga stritis a n d p ep tic u lcer (Ma rsh a ll, 1986; Korm an & Tytgat, 1995), in th e etiology of gastric can cer (Form an , 1995; Parson n et, 1993; Pa rso n n et et a l., 1994). Su ccessfu l co n tro l o f th is ch ron ic in fection wou ld red u ce th e occu r-ren ce o f ga stritis a n d p ep tic u lcer a n d m igh t su b stan tially lower th e risk of on e of th e world’s d ead liest n eop lasm s. Th e p u b lic h ealth im p act of th is in fectiou s agen t ju stifies efforts to id en -tify an d im p lem en t p reven tive m easu res. Cu r-ren tly, h owever, lim ited kn owled ge rega rd in g th e n a tu ra l h isto r y o f H . p ylori in fectio n in a sym p to m a tic ca rriers, su scep tib ility fa cto rs, an d th e p recise m od e of tran sm ission p resen t o b sta cles to p reven tio n (Go o d m a n & Co rrea , 1995). Fu rth erm o re, it is u n clea r h ow to trea t th is in fectio n in p a tien ts fro m p o p u la tio n s o f low socioecon om ic statu s wh o are m ost at risk of gastric can cer; erad ication trials con d u cted in su ch p op u lation s h ave en cou n tered lim ited su ccess, a n d th e risk o f rein fectio n a p p ea rs h igh . Th is p a p er reviews th e evid en ce lin kin g H . p yloriin fectio n to ca n cer o f th e sto m a ch an d evalu ates th e p oten tial for con trol in h igh -risk p op u lation s.
Background
H. p yloriis a h elical or cu rved b acillu s th at col-o n izes th e ga stric m u ccol-o sa . It tra n sfcol-o rm s tcol-o a n on cu ltu rab le coccoid form u n d er ad verse en -viro n m en ta l co n d itio n s, n o ta b ly in th e p res-en ce o f a n tib io tics (Bo d e et a l., 1992). Detec-tion of H. p ylorih as b een p rob lem atic; sp ecial m icro b io lo gica l tech n iq u es a re req u ired fo r su ccessfu l growth fro m ga stric b io p sy sp eci-m en s (Good win &aeci-mp; Worsley, 1993). Atteeci-m p ts to isolate H. p ylorifrom b od ily secretion s or en vi-ron m en ta l sou rces h a ve b een u n su ccessfu l in gen era l. Th is p ro b lem a tic d etectio n h a s p resen ted ob stacles to p in p oin tin g p ortals of en -try an d exit as well as im p licatin g or ru lin g ou t en viron m en tal reservoirs. In n ovation s in lab o-ratory p roced u res h ave b een grad u ally im p rov-in g th e sen sitivity of d etection tech n iqu es.
Sero lo gy h a s b een th e m o st exten sively u sed d ia gn o stic p ro ced u re fo r exa m in in g th e d istrib u tio n o f H. p yloriin fectio n in h u m a n s. Th e p resen ce of H. p ylorian tib od ies in d icates cu rren t in fection with reason ab le accu racy, excep t in in d ivid u a ls recen tly clea red o f th e in -fection , d u e to th e p ersisten ce of elevated an ti-b o d y levels fo r so m e m o n th s a fter clea ra n ce (Kosu n en et al., 1992; Veen en d aal et al., 1991). In fan ts b orn to H. p yloriin fected m oth ers ap
-p ea r to h a ve -p a ssively a cq u ired H . p yloriIgG a n tib o d ies th a t d isa p p ea r with in th e first m o n th s o f life (Blecker et a l., 1994). Th e u rea b reath test, a n on in vasive p roced u re b ased on H. p yloriu rease activity, h as b een d evelop ed in two versio n s, u sin g eith er 13Cla b eled (Gra -h am et al., 1987; Gra-h am & Klein , 1991) or 14C-lab eled (Marsh all & Su rveyor, 1988; Su rveyor et al., 1989) u rea as an altern ative to serology; th e b reath tests d etect active in fection exclu sively a n d ca n b e u sed fo r sh o r t-term fo llow-u p o f an ti-H. p ylorith erapy. In valid ation stu d ies th e u rea b reath tests yield an accu racy th at is com -p arab le to th e gold stan d ard b io-p sy-b ased m icrob iological an d h istological d iagn oses (Van -d en p la s et a l., 1992; Lo ga n et a l., 1991; D ill et al., 1990; Raju et al., 1994; Marsh all et al., 1991; Veld h u yzen van Zan ten et al., 1990). Little valid a tio n o f th e u rea b rea th tests h a s b een co n -d u cte-d in Latin Am erican p op u lation s; Coelh o an d colleagu es (1990) rep orted a sen sitivity of 97 p ercen t a n d a sp ecificity of 100 p ercen t for th e 14C-u rea b reath test valid ated again st cu l-tu re in 41 ga stro sco p y p a tien ts in Bra zil. Th e ra d io a ctive exp o su re o f th e 14C-u rea b rea th test, a lth o u gh m in im a l, m a kes th is test in a p -p ro-p riate for stu d ies in volvin g ch ild ren , -p reg-n areg-n t wom ereg-n , or follow-u p screereg-n ireg-n g at frequ ereg-n t in terva ls, wh erea s th e h igh er co st o f th e 13C-u rea b reath test lim its its 13C-u sef13C-u ln ess in p op 13C-u la-tion -b ased research . Seru m p ep sin ogen s h ave b een p rop osed as m arkers of resp on se to an ti-H. p ylorith erapy (Hu n ter et al., 1993).
Th e p revalen ce of H. p yloriin fection ran ges fro m 20% to over 90% in a d u lt p o p u la tio n s a ro u n d th e wo rld (Po u n d er & Ng, 1995). Th e p revalen ce is h igh est in d evelop in g region s, in -clu d in g th e co u n tries o f La tin Am erica ( Ta b le 1). A b irth coh ort effect n oted in several d evelo p ed cevelo u n tries, wh ere th e p reva len ce is rela -tively low in ch ild ren a n d yo u n g a d u lts b u t com m on ly exceed s 50% in ad u lts over 50 years o f a ge (Po u n d er & Ng, 1995), h a s p ro m p ted sp ecu lation th at tran sm ission h as d ecreased as san itation h as im p roved (Ban atvala et al., 1993; Asaka et al., 1992; Gasb arrin i et al., 1994). With -in cou n tries, H. p yloriin fection is lin ked to low so cio eco n o m ic sta tu s, resid en tia l overcrowd -in g a n d m igra tio n fro m h igh p reva len ce re-gio n s (Eu ro ga st Stu d y Gro u p, 1993; Sm o a k et al., 1994; Blecker & Van d en p las, 1993; Malaty et al., 1992; Sitas et al., 1991; Grah am et al., 1991; Fied orek et al., 1991).
oc-currin g rarely. However, this im p ression is based p rim arily on follow-u p of p revalen t cases, th at is, ca ses with u n kn own tim e o f o n set. Fo llow-u p of n ewly occllow-u rrin g cases h as b een extrem e-ly lim ited (Parson n et, 1995); th erefore, th e p rop ortion of acu te in fection s th at b ecom e ch ron -ic is n ot kn own . Recen t lon gitudin al observation of Peru vian in fan ts su ggests th at sp on tan eou s elim in ation of H. p yloriin fection m ay n ot be un -com m on in youn g children (Klein et al., 1994).
Helicobacter pyloriand gastric cancer
Acco rd in g to Co rrea’s (1995) m o d el o f ga stric ca rcin o gen esis, co n tin u o u s exp o su re to irri-tan ts of th e gastric m u cosa p rod u ces rep eated ep isod es of su p erficial gastritis; wh en th is oc-cu rs in con cert with sp ecific n u trition al deficits, a d egen era tive seq u en tia l p ro cess yield s a t-rop h ic gastritis, in testin al m etap lasia, d ysp la-sia a n d , u ltim a tely, ca rcin o m a . Alth o u gh th e
Tab le 1
Pre vale nc e o f He lic o b ac te r p ylo riin Latin Ame ric an p o p ulatio ns.
Population (Re fe re nc e ) Age n % HP+*
BRAZIL
Be lo Ho rizo nte ab atto ir wo rke rs 18 – 64 160 66 (Ro c ha e t al., 1992) b lo o d d o no rs 18 – 64 160 62 (O live ira e t al., 1994) lo w SES,† lab o rato ry o utp atie nts‡ 3 – 8 104 34 9 – 14 64 47 15 – 18 14 64
CHILE**
Santiag o & Punta Are nas hig h SES, ho use ho ld c luste r samp le 5 – 9 216 30 (Ho p kins e t al., 1993) 10 – 14 86 35 15 – 19 69 58 20 – 34 295 62 lo w SES, ho use ho ld c luste r samp le 5 – 9 118 45 10 – 14 69 55 15 – 19 57 62 20 – 34 121 69 Iq uiq ue mid d le c lass vac c ine trial vo lunte e rs 1 – 5 229 23
(Russe ll e t al., 1993) 6 – 8 47 45
10 – 16 112 70
CO LO MBIA, ANDEAN REG IO N† †
Ald ana rural, lo w SES c e nsus samp le 2 – 9 685 69 (G o o d man e t al., in p re ss)
Ip iale s‡ ‡ he alth p ro fe ssio nals’ c hild re n 2 – 9 57 54
CO STA RICA
Turrub are s & Ho janc ha rural lo w SES sc ho o ls, c e nsus samp le 7 – 10 97 60
(Sie rra e t al., 1992) 11 – 13 106 73
14 – 20 76 75
EL SALVADO R
re fug e e s in Australia ro utine e ntry e xaminatio ns 20 – 59 63 41 (Dwye r e t al., 1988)
PERU
Lima† † hig h SES c o mmunity vo lunte e rs 2 – 12 141 32 (Kle in e t al., 1991) lo w SES he alth p o st p atie nts 2 – 12 266 56
* H. p ylo rip re vale nc e , d e te rmine d b y se ro lo g y e xc e p t as no te d † so c io e c o no mic status
‡ e xc lud e s immuno c o mp ro mise d p atie nts o r tho se having take n antimic ro b ial d rug s in the thre e p re c e d ing mo nths ** p re vale nc e ap p ro ximate d fro m g rap h
† †H. p ylo ristatus d e te rmine d b y 13C-ure a b re ath te st
p recise role of H. p ylori in th is seq u en ce is n ot u n d ersto o d , th e o rga n ism fits in to th e m o d el as an irritan t th at cau ses ch ron ic in flam m ation of th e gastric m u cosa (Correa, 1991).
Co rrea’s m o d el o f ga str ic ca rcin o gen esis evolved largely from lon gitu d in al ob servation s o f a co m m u n ity-b a sed co h o rt recru ited b e-tween 1973 an d 1983 from th ree sm all town s in th e An d ea n regio n o f Na riñ o in so u th ern Co -lo m b ia (Co rrea et a l., 1990b, a ). In p revio u s stu d ies, n a tives o f th is regio n d isp la yed th e h igh est stom ach can cer rates in Colom bia (Cor-rea et al., 1970). Th e Nariñ o coh ort revealed an extrem ely h igh p revalen ce of ch ron ic gastritis a n d m o re a d va n ced d egen era tive lesio n s a s well as a h igh in cid en ce of p rogression of th ese lesio n s a n d o f ga str ic ca rcin o m a itself. Th e p reva len ce o f H . p yloriin fectio n in a ra n d o m sam p le of th is coh ort was over 90 p ercen t (Cor-rea et al., 1989).
Wh ile th e evid en ce estab lish in g H. p ylorias a cau se of ch ron ic gastritis accu m u lated , in ves-tiga to rs b ega n to stu d y th e o ccu rren ce o f th is in fectio n in a sso cia tio n with ca n cer o f th e sto m a ch . Eco lo gica l stu d ies co n tra stin g re gio n s o f h igh a n d low ga stric ca n cer risk co n -d u ct e -d in Co lo m b ia a n -d Ch in a re ve a le -d co r-re la t io n s b e t w e e n ga s t r ic c a n c e r r a t e s a n d H . p ylorisero p reva len ce, a s d id a 13-co u n tr y com p arison (IARC, 1994). Sim ilar stu d ies con -d u cte-d in Co sta Rica , Ita ly, a n -d Ja p a n -d i-d n o t reveal su ch association s, th e ob served ran ge of H. p yloriserop revalen ce b ein g q u ite n arrow in ea ch o f th ese co u n tr ies (IARC, 1994). Th e o b -ser va tio n o f d istin ct ga str ic ca n cer ra tes in p o p u la tio n s o f sim ila r H . p ylori p reva len ce d oes n ot con stitu te evid en ce again st a role for H. p yloriin th e etiology of can cer of th e stom -a ch , b u t r-a th er, su ggests th -a t H. p yloriitself is n o t a su fficien t ca u se o f th is ca n cer ; th e co n tra stin g ga stric ca n cer ra tes in th ese p o p u la -tion s cou ld reflect d ifferen t d istrib u -tion s of co-fa cto rs th a t in tera ct with H . p yloriin th e ca r-cin ogen ic p rocess.
Ca se-co n tro l stu d ies co n d u cted in n in e cou n tries com p arin g H. p yloriserop revalen ce st a t u s in ga st r ic ca n ce r p a t ie n t s t o co n t r o ls m a t ch e d o n a ge a n d se x, sh o w in co n sist e n -cie s b u t overa ll su ggest a p o sitive a sso cia tio n (IARC, 1994). It h a s b een a rgu ed th a t th is d e -sign resu lts in an u n d erestim ate of th e relative risk, h owever, b eca u se H . p ylorico lo n iza tio n ten d s to d im in ish with in creasin g d egen eration of th e gastric m u cosa an d an tib od ies titers d e-clin e followin g clearan ce of th e in fection (For-m a n , 1995). Ga stric ca n cer ca ses wo u ld h a ve in crea sin gly less n o r m a l m u co sa rela tive to con trols an d wou ld b e m ore likely to lose th eir
in fectio n over tim e. To a d d ress th is p ro b lem , n e st e d ca se -co n t ro l st u d ie s d e t e rm in in g H . p yloristatu s from stored sera collected p rior to ca n cer d ia gn o sis were co n d u cted in En gla n d a n d Wa les (o d d s ra tio (OR)=2.8, 95% co n fi-d en ce in ter va l (CI)=1.0-8.0) (Fo rm a n et a l., 1991), Californ ia (OR=3.6, CI=1.87.3) (Parson -n et et a l., 1991), a -n d Ha wa ii (OR=6.0, CI=2.1-17.0) (No m u ra et a l., 1991). In o rd er to a ssess th e p oten tial m isclassification of in fection sta-tu s in can cer cases wh en th e follow-u p is b rief, Form an an d colleagu es (1994) p ooled th e d ata from th ese th ree stu d ies an d stratified th e ob -servation s by tim e in terval b etween collection o f seru m a n d ca n cer d ia gn o sis, o b ser vin g a m on oton ic in crease in th e od d s ratio (2.3 for 5-9 years; 4.4 for 10-14 years; 8.7 for >14 years) as th e follow-u p in terval len gth en s.
Particu larly stron g an d con sisten t evid en ce h a s lin ked H . p ylori in fectio n to ga str ic lym p h om a, a relatively rare form of stom ach can -cer. A h igh H . p ylorip reva len ce h a s b een o b -served in cases of gastric lym p h om a (Form an , 1995). A n ested ca se-co n tro l stu d y u sin g two large coh orts in th e U.S. an d Norway m atch ed 33 ga stric lym p h o m a ca ses, p rim a rily o f th e d iffu se large-cell typ e, to each of fou r con trols on coh ort, d ate of b irth , sex, an d d ate an d site of seru m collection , ob servin g a relative risk of 6.3 (CI=2.0-19.9) fo r H . p ylori se ro p o sit ivit y a n d su b seq u en t d evelo p m en t o f ga str ic n o n Ho d gkin’s lym p h o m a , wh ile n o n ga str ic n o n -Hod gkin’s lym p h om a d id n ot ap p ear related to p revio u s H . p yloriin fectio n (Pa rso n n et et a l., 1994). Th e m ed ian in terval b etween seru m col-lection an d can cer d iagn osis was 14 years an d th e rela tive risk in crea sed to 12.3 (CI=1.5-103.9) a m o n g th o se wh o se ser u m h a d b een co llected 14 yea rs o r m o re p rio r to d ia gn o sis. Th e stron gest su ggestion th at H. p yloricau ses gastric lym p h om a com es from th e follow-u p of severa l series o f H . p ylori-in fected p a tien ts with p rim a r y low-gra d e ga stric lym p h o m a o f th e m u co sa -a sso cia ted lym p h o id tissu e typ e a fter a n ti-H. p ylorith era p y; tu m o r regressio n occu rred in m ost p atien ts wh ose in fection was su ccessfu lly era d ica ted ( Wo th ersp o o n et a l., 1993; Ro ggero et a l., 1995; Ba yerd o rffer et a l., 1995).
-cid en ce o f ga stric ca n cer a d ju sted fo r kn own d ietary risk factors in clu d in g h igh in take of salt a n d n itra tes a n d d eficien t in ta ke o f vita m in C an d b eta-caroten e (Correa, 1991). Th ere is rea-son to su sp ect th at th ese d ietary factors, b ein g m o re co m m o n a m o n g p o p u la tio n s o f low so -cio eco n o m ic sta tu s, m a y co n fo u n d o b ser ved a sso cia tio n s b etween H . p yloriin fectio n a n d gastric can cer, given th e clear lin k b etween th e in fection an d low socioecon om ic statu s.
Perspectives for control
Little p rogress h as b een m ad e toward s id en ti-fyin g p reven tive m ea su res fo r H. p yloriin fec-tio n , p rim a rily d u e to o b sta cles p resen ted b y th e n a tu ra l h isto r y o f th is in fectio n , its ep d em iology, resistan ce to erad ication , an d lim i-tation s of ou r cu rren t state of kn owled ge.
O bstacles to H. pyloriControl
• N atural history
H. p yloriin fection is freq u en tly asym p tom atic an d wh en sym p tom s d o occu r th ese rep resen t n o n sp ecific fo rm s o f sto m a ch d isco m fo r t (Ra u ws & Tytga t, 1989); in cid en t ca ses, th ere-fo re, a re n o t gen era lly d etected a t th e tim e o f o n set. Given th a t a n tib o d y levels d eclin e fo l-lowin g clea ra n ce o f in fectio n (Ku ip ers et a l., 1993), n a tu ra l im m u n ity d o es n o t a p p ea r to p rovid e lastin g p rotection again st rein fection . Co in fectio n with m u ltip le stra in s is n o t u n -co m m o n (Co sta s et a l., 1991), su ggestin g th e p ossib ility of con tin u al rein fection .
• Epidemiology
H . p ylori o ccu rs co m m o n ly th ro u gh o u t th e wo rld , im p lyin g a va st reser vo ir o f in fectio n . Given th a t th e in fectio n is lin ked to p o o r so -cio eco n o m ic co n d itio n s, co n tro l m a y req u ire b road socioecon om ic ch an ges.
• Eradication of infection
Du e to th e p rotection afforded to H. p yloriby its ecologica l n ich e u n d er th e m u cu s la yer of th e ga stric m u cosa , effective a n tib iotic trea tm en t requ ires costly an d bu rden som e m u ltidru g reg-im en s th at h ave sh own lreg-im ited effectiven ess in p op u lation s wh ere th e in fection is m ost p reva-len t (Bu iatti et al., 1994; Glu p czyn ski & Bu rette, 1990). Fa cto rs th a t m a y co n trib u te to th is re-du ced effectiven ess in clu de h igh bacterial loads in in d ivid u a ls fro m su ch p o p u la tio n s d u e to
con tin u al exp osu re to th e agen t, th e h igh p reva-len ce of d ru g resistan t strain s, an d lifestyle fac-tors in clu din g deficien t diet, lim ited edu cation , econ om ic con strain ts, an d alcoh olism th at d o n o t fa vo r co m p lia n ce a n d / o r d ru g to lera n ce. Fu rth erm ore, even wh en treatm en t is su ccess-fu l in h igh p reva len ce p o p u la tio n s, th e risk o f rein fection ap p ears h igh . Alth ou gh few follow-u p stfollow-u d ies h ave b een con d follow-u cted in d evelop in g cou n tries, Brazilian in vestigators ob served th e rein fection rate in th e first year after stan d ard trip le th era p y a m o n g 269 p a tien ts wh o h a d b een su ccessfu lly cleared of H. p yloriin fection as con firm ed by n egative u rea b reath tests at a m ed ia n tim e o f 83 d a ys fo llowin g trea tm en t (Coelh o et al., 1995). Th e p rop ortion of p atien ts wh o b eca m e rein fected by a p p roxim a tely on e year after treatm en t was 31 p ercen t am on g 223 p a rticip a n ts o f low so cio eco n o m ic sta tu s in con trast to n in e p ercen t am on g 46 p articip an ts of h igh socioecon om ic sta tu s. Th e rein fection ra te a m o n g Bra zilia n s o f h igh so cio eco n o m ic sta tu s a p p roxim a tes ra tes o b served in d evel-op ed cou n tries; rep orted rein fection rates fol-lowin g co n firm ed era d ica tio n in a d u lts fro m th e U.S., Au stra lia , Fin la n d , Au stria , Belgiu m , Fran ce an d th e UK ran ge from 0-5 p ercen t p er yea r (Pa rso n n et, 1995). Asid e fro m so cio eco -n om ic statu s, a-n oth er risk factor for rei-n fectio-n d etected in th e Bra zilia n stu d y wa s receivin g en d oscopy at th e in itial p ost-treatm en t follow-u p visit. Th is fin din g is con sisten t with p reviofollow-u s rep orts im p licatin g gastroscop es disin fected by m a n u a l wa sh in g a s p o t e n t ia l ve h icle s o f H . p yloritran sm ission (Good m an & Correa, 1995).
• Limitations in knowledge
Cu rren tly it is n o t kn own if a reser vo ir exists o u tsid e o f h u m a n s a n d th e p recise m o d e o f tra n sm issio n h a s n o t b een id en tified . Mo d ifi-a b le risk fifi-a cto rs fo r in fectio n h ifi-a ve n o t b een clearly id en tified , with th e excep tion of clin ical p ro ced u res th a t tra n sfer ga stric secretio n s from on e p atien t to an oth er. Fu rth erm ore, vac-cin e resea rch is a t a p relim in a r y sta ge. Th e kn owled ge req u ired fo r p ro p o sin g p reven tive m ea su res, a sid e fro m p reca u tio n s a ga in st ia -trogen ic tran sm ission , is lackin g.
Current state of knowledge relevant to prevention
• Transmission of H. Pylori
associ-ated with H. p yloriin fection in Latin Am erican stu d ies. At p resen t th ere is n o evid en ce of sex-u al tran sm ission or of food b orn e tran sm ission , o th er th a n by m ea n s o f ra w vegeta b les co n ta-m in ated by u n p u rified water (Good ta-m an &ata-mp; Cor-rea , 1995). It is of in terest to n ote th a t th e evi-d en ce su p p ortin g waterb orn e tran sm ission h as co m e p rim a rily fro m An d ea n co u n tries o f So u th Am erica . Co n tra r y evid en ce wa s o b -ser ved in so u th ern Ch in a wh ere H . p ylori p reva len ce wa s n o t a sso cia ted with d r in kin g water sou rce (Mitch ell et al., 1992). It is p ossi-b le th at d ifferen t h ygien ic p ractices regard in g d rin kin g water an d / or clim atic d ifferen ces rel-eva n t to th e su r viva l o f H . p yloriin wa ter a c-cou n t for th is d iscrep an cy.
Acu te o u tb rea ks o f H . p ylori-in d u ced ga s-tritis in clin ical settin gs h ave b een attrib u ted to en d o sco p ic p ro ced u res a n d exp o su re o f re search su b jects to gastric p H electrod es (Good
-m a n &a-mp; Co rrea , 1995). H . p yloriDNA h a s b een d etected in ga stroin testin a l eq u ip m en t d isin fected a cco rd in g to sta n d a rd p ro ced u res (Ka -toh et al., 1993; Roosen d aal et al., 1993). Viab le H . p ylori wa s recovered b y b a cteria l cu ltu re fro m 19% o f wa sh -o u t sa m p les fro m th e ga strofiberscope biopsysuction chan n el after m an -u a l Hya m in e wa sh in g; h owever, n o H. p ylori wa s recovered a fter m ech a n ica l wa sh in g (Ka -toh et al., 1993). Th ese ob servation s alon g with th e p revio u sly cited evid en ce th a t en d o sco p y m ay in crease th e risk of rein fection in p atien ts u n d ergoin g an ti-H. p ylorith erapy p oin ts to th e u rgen cy o f a d o p tin g str in gen t p reca u tio n s a im ed a t p reven tin g in fectio n in th e clin ica l settin g.
• Cofactors for infection
A sm a ll n u m b er o f stu d ies h a ve a ttem p ted to id en tify cofactors lin ked to H. p yloriin fection th at are n ot in d icators of sp ecific tran sm ission p a th wa ys, b u t m a y reflect h o st su scep tib ility. Ver y few stu d ies h a ve exa m in ed co fa cto rs a s-sociated with th e risk of acqu irin g in fection . In a coh ort of U.S. ep id em iologists, frequ en t con -su m p tion of caffein ated b everages was lin ked to a n in crea sed risk o f sero co n versio n , wh ile freq u en t co n su m p tio n o f m ilk a p p ea red p ro -tective (Pa rso n n et et a l., 1992). In a fo llow-u p stu d y o f Peru via n in fa n ts, m a les were m o re likely th a n fem a les to b ecom e in fected a n d to rem ain in fected (Klein et al., 1994). Most stu d -ies lin kin g p o ten tia l co fa cto rs to H . p yloriin fectio n h a ve b een cro sssectio n a l. Fo r exp o -su res th at ch an ge over tim e, it m ay n ot b e clear wh eth er cross-section ally id en tified covariates a re ca u ses o r co n seq u en ces o f in fectio n . Fu r-t h e r m o re, if sp o n r-t a n e o u s e lim in a r-t io n o f H . p ylorioccu rs to an im p ortan t d egree, it can n ot b e d eterm in ed wh eth er su ch covaria tes in flu -en ce th e a cq u isitio n o f th e in fectio n o r its ch ro n icity. In d ica to rs o f d eficien t n u tr itio n a l sta tu s h a ve b een lin ked to in crea sed H. p ylori p revalen ce in b oth d evelop ed an d d evelop in g co u n tries (Go o d m a n et a l., 1996; Klein et a l., 1991; Ra ym o n d et a l., 1994; Pa tel et a l., 1994; Men d a ll et a l., 1994; Eu ro ga st Stu d y Gro u p, 1993), alth ou gh th e im p ortan ce of sp ecific in -d ica to rs va ries a cro ss stu -d ies. A stu -d y o f 249 ch ild ren , 0-18 yea rs o f a ge, sa m p led fro m a n o u tp a tien t clin ic ser vin g p a tien ts o f low so -cio eco n o m ic sta tu s in Belo Ho rizo n te, Bra zil rep o rted n o sta tistica lly sign ifica n t a sso cia -tio n s b etween H . p ylorisero sta tu s a n d n u tri-tion al statu s (Oliveira et al., 1994), alth ou gh it m u st b e n o ted th a t th e stu d y sa m p le wa s n o t
Tab le 2
Evid e nc e fo r He lic o b ac te r p ylo ritransmissio n p athways*.
Person-to-person transmission
c luste ring in familie s and g ro up s re sid e nc e s asso c iatio n with re sid e ntial c ro wd ing
c hild ho o d ac q uisitio n sug g e sts transmissio n re late d to p e rso nal hyg ie ne iso latio n fro m human fe c e s and d e ntal p laq ue (tho ug h mo st atte mp ts unsuc c e ssful) d e te c tio n in human fe c e s, saliva, and d e ntal p laq ue b y p o lyme rase c hain re ac tio n
Waterborne transmission
survival in lab o rato ry aq uatic e nviro nme nts
d e te ctio n b y p o lyme rase chain re actio n in wate r samp le s fro m Co lo mb ia† and Pe ru‡ asso c iatio n with d rinking wate r so urc e in And e an c o untrie s**
asso c iatio n with raw ve g e tab le c o nsump tio n in And e an c o untrie s** asso c iatio n with swimming in rive rs and swimming p o o ls in Co lo mb ia**
Zoonotic transmission
suc c e ssful e xp e rime ntal infe c tio n o f mo nke ys, mic e , c ats, g e rm-fre e p ig s, g e rm-fre e d o g s
o b se rvatio n o f natural infe c tio n in re se arc h mo nke ys and c ats o b se rvatio n o f human infe c tio n b y animal He lic o b ac te rsp e c ie s
Iatrogenic transmission
o utb re aks o f ac ute g astritis amo ng g astro sc o p y p atie nts and re se arc h sub je c ts e xp o se d to g astric p H e le c tro d e s
d e te c tio n o f viab le H. p ylo riin manually d isinfe c te d g astro fib e rsc o p e s
* re fe re nc e d in (G o o d man & Co rre a, 1995) e xc e p t as no te d † (Sc haue r e t al., 1995)
‡ (Hulte n e t al., 1995)
Tab le 3
Fac to rs asso c iate d with He lic o b ac te r p ylo riinfe c tio n in Latin Ame ric an p o p ulatio ns.
Population O utcome measure Associated factor
BRAZIL, Be lo Ho rizo nte
249 o utp atie nts, 0 – 18 ye ars o ld se ro p re vale nc e ag e (O live ira e t al., 1994)
269 d uo d e nal ulc e r p atie nts afte r re infe c tio n rate lo w so c io e c o no mic status
suc c e ssful anti-H. p ylo rithe rap y,* b y 14C-UBT† g astro sc o p y at the first p o stre atme nt visit 18 – 79 ye ars o ld
(Co e lho e t al., 1995)
CHILE, Santiag o & Punta Are nas‡ se ro p re vale nc e ag e 1,815 c o mmunity me mb e rs, ho use ho ld male se x
c luste r samp le , 0 – 34 ye ars o ld lo w so c io e c o no mic status (Ho p kins e t al., 1993) c o nsume s unc o o ke d ve g e tab le s
re sid e s in Santiag o v. Punta Are nas c o nsume s unc o o ke d she llfish
CO LO MBIA, Ald ana‡ p re vale nc e ag e 684 rural re sid e nts, c e nsus samp le , b y 13C-UBT† male se x
2 – 9 ye ars o ld mo re than 1 c hild re sid e s in ho me (G o o d man e t al., 1996) c o nsume s < 2 fruits/ ve g e tab le se rving s/ d ay
c o nsume s < 2 c up s o f milk/ d ay lo w he ig ht/ ag e
no nag ric ultural p are ntal o c c up atio n mo the r no t g ainfully e mp lo ye d ho me has no to ile t/ latrine d rinking wate r o b taine d fro m rive r swims in rive r/ swimming p o o l c are s fo r o r p lays with she e p
re c e nt histo ry o f ame b iasis (p ro te c tive )
CO LO MBIA, Ip iale s (b o rd e r c ity)‡ p re vale nc e ag e
69 c hild re n o f he alth p ro fe ssio nals b y 13C-UBT† infre q ue nt c o nsump tio n o f fruits and ve g e tab le s c e nsus samp le , 2 – 12 ye ars o ld ho use ho ld has p e t(s) (p ro te c tive )
(autho r’s unp ub lishe d d ata) re c e nt histo ry o f p arasitic infe c tio n (p ro te c tive )
PERU, p e ri-urb an Lima inc id e nc e male se x 56 infants, 6 – 30 mo nths o ld b y 13C-UBT†
(Kle in e t al., 1994)
PERU, Lima‡
407 c o mmunity me mb e rs, 0 – 12 ye ars o ld p re vale nc e ag e
(Kle in e t al., 1991) b y 13C-UBT† lo w so c io e c o no mic status
munic ip al v. we ll d rinking wate r so urc e e xte rnal v. inte rnal d rinking wate r so urc e lo w he ig ht/ ag e
lo w we ig ht/ he ig ht
* five d ay tre atme nt with amo xic illin, furazo lid o ne , and me tro nid azo le fo llo we d b y a ne g ative 14C-ure a b re ath te st at a me d ian o f 83 d ays fo llo wing tre atme nt
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• Vaccine prospects
Th e m ou se h as b een estab lish ed as an an im al m o d el th a t ca n b e in fected with H . p ylorifo r th e p u rp ose of vaccin e research ; recen tly, oral im m u n ization with p u rified H. p ylorian tigen s h a s b een rep o rted to p ro tect m ice a ga in st H . p yloriin fection (March etti et al., 1995). Previ-o u s rep Previ-o rts d Previ-o cu m en t su ccessfu l p rPrevi-o tectiPrevi-o n again st in fection by Helicobact er felisin m ice, u sin g th e followin g orally ad m in istered com b i-n atioi-n s: H. felisan tigen p lu s ad ju van t ch olera toxin a s well a s th e n o n toxic ch o lera toxin B su b u n it (Lee, A. & Ch en , 1994); recom b in an t H. p yloriGroESlike h eat sh ock p rotein s in com -b in a t io n wit h t h e B su -b u n it o f H . p yloriu re -ase (Ferrero et a l., 1995); a n d reco m b in a n t H . p yloriu rea se with a d ju va n t E. co li toxin (Lee, C. K. et a l., 1995). Cu rren tly it is n o t kn own wh eth er a sim ila r p ro tectio n a ga in st H. p ylori in fection of ad equ ate d u ration can b e ach ieved in h u m an s.
Conclusions
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