Similarities in mortality patterns from influenza
in the first half of the 20th century and the rise
and fall of ischemic heart disease in the United
States: a new hypothesis concerning the
coronary heart disease epidemic
Semelhanças entre o padrão de mortalidade
por influenza na primeira metade do século XX
e o padrão de mortalidade por doença isquêmica
do coração no transcorrer do século, nos Estados
Unidos: uma nova hipótese para a epidemia
de cardiopatia isquêmica
1 Dep artam en to d e Med icin a Socia l, Fa cu ld a d e d e M ed icin a , Un iv ersid a d e Fed era l d o Rio Gra n d e d o Su l. Ru a Ra m iro Ba rcelos 2600, 4oa n d a r, Port o Alegre, RS 90035- 003, Bra z il. m ia z a m b u ja @v ia - rs.n et
M a ria In ês Rein ert Az a m b u ja 1 Bru ce B. Du n ca n 1
Abstract Th e cla ssic risk fa ct ors for d ev elop in g coron a ry h ea rt d isea se (CHD) ex p la in less t h a n
50% of t h e d ecrea se in m ort a lit y ob serv ed sin ce 1950. Th e t ra n sit ion cu rren t ly u n d er w a y, from t h e d egen era t ive t o t h e in fect iou s-in fla m m a t ory p a ra d igm , requ ires a n ew ca u sa l in t erp ret a t ion of t em p ora l t ren d s. T h e follow in g is a n ecologica l st u d y b a sed on d a t a from t h e Un it ed St a t es sh ow in g t h at in m en an d w om en an associat ion bet w een t h e age d ist ribu t ion of m ort alit y d u e t o in flu en z a an d p n eu m on ia (I&P) associat ed w it h t h e in flu en z a p an d em ic in 1918-1919 in t h e 10-49- yea r a ge b ra ck et a n d t h e d ist rib u t ion of CH D m ort a lit y from 1920 t o 1985 in su rv iv ors from t h e corresp on d in g birt h coh ort s. It fu rt h er sh ow s a sign ifican t n egat ive correlat ion (r = -0.68, p = 0.042) b et w een ex cess m ort a lit y from I&P a ccu m u la t ed in ep id em ics from 1931 t o 1940 (u sed a s in d ica t or for p ersist en t circu la t ion of H1N 1 v iru s com bin ed w it h v u ln era bilit y t o in fect ion ) a n d t h e ord er of t h e b egin n in g in t h e d eclin e in CH D m ort a lit y in n in e geogra p h ic d iv ision s in t h e Un it ed St a t es. In ligh t of cu rren t b iologica l k n ow led ge, t h e d a t a su ggest t h a t t h e 1918 in flu en z a p an d em ic an d t h e su bsequ en t ep id em ics u p t o 1957 m igh t h ave p layed a d et erm in an t role in t h e ep id em ic of CHD m ort alit y regist ered in t h e 20t h cen t u ry.
Key words M ort alit y; M yocard ial Isch em ia; In flu en z a; Pn eu m on ia
Resumo Os fa t ores d e risco clá ssicos p a ra o d esen v olv im en t o d e d oen ça isq u êm ica d o cora çã o
(DIC) ex p lica m m en os d e 50% d a q u ed a n a m ort a lid a d e ob serv a d a d esd e 1950. A t ra n siçã o em cu rso, d o p a ra d i gm a d egen era t i v o p a ra o i n fla m a t óri o/i n fecci oso, req u er n ov a i n t erp ret a çã o ca u sa l d a s t en d ên ci a s t em p o ra i s. Est e é u m est u d o eco ló gi co, b a sea d o em d a d o s d o s Est a d o s Un id os, qu e m ost ra , em h om en s e m u lh eres, u m a a ssocia çã o en t re a d ist ribu içã o et á ria d a m or-t a lid a d e p or in flu en z a e p n eu m on ia (I&P) a ssocia d a à p a n d em ia d e in flu en z a d e 1918- 1919 n a fa ix a d os 10 a os 49 a n os e a d ist rib u içã o d a m ort a lid a d e p or DIC, en t re 1920 e 1985, em sob re-v ire-v en t es d a s coort es d e n a scim en t o corresp on d en t es. M ost ra a in d a u m a correla çã o n ega t ire-v a sig-n ificat iva (r = -0,68, p = 0,042) esig-n t re o ex cesso d e m ort alid ad e p or I&P acu m u lad o em ep id em ias en t re 1931-1940 (u t iliz ad o com o in d icad or d a p ersist ên cia d a circu lação d e v íru s H1N 1 aliad a à v u ln erabilid ad e à in fecção) e a ord em d o in ício d o d eclín io n a m ort alid ad e p or DIC, em n ove d i-v isões geográficas d os Est ad os Un id os. Os d ad os su gerem , à lu z d o con h ecim en t o biológico at u al, qu e a p an d em ia d e in flu en z a d e 1918 e as qu e se segu iram at é 1957, p u d esse t er t id o p ap el d et er-m in an t e n a ep id eer-m ia d e er-m ort alid ad e p or DIC regist rad a n o sécu lo XX.
In th e cou rse of th e last 70 years, a rise an d fall in m ortality from coron ary h eart d isease (CHD) o ccu rre d in se ve ra l co u n t rie s. In t h e Un it e d States, an gin a em erged as a sign ifican t cau se of d eath in th e m id -1920s (Stallon es, 1980). From th en o n , CHD m o rta lity ro se stea d ily u n til th e ea rly 1960s, wh en it leveled o ff a t a ro u n d 35% o f overa ll m o rta lity (Ha vlick & Fein leib, 1979). Th e d eclin e b ega n in 1968 a n d a ccelera ted a f-ter 1972 (Levi, 1981), resu ltin g in a fall of m ore t h a n 40% in CH D d e a t h ra t e s in t h e la st 30 years (Sytkowski et al., 1996).
Th e CH D m o rta lity tim e tren d h a s still n o t b een exp la in ed sa tisfa cto rily (Meth a et a l., 1998), with tra d itio n a l risk fa cto rs a cco u n tin g for less th an 50% of th e variation in rates regis-tered sin ce 1950 (Sytkowski et al., 1996). As stat-ed b y Mizga la & Sh u lzer (2000), th e resu lts o f th e MONICA stu d y a n d th e d isa p p o in tin g re-su lts o f p rim a r y in ter ven tio n tria ls b a sed o n th ose risk factors su ggest th at “it is p erh ap s tim e t o recogn iz e t h e p ossib ilit y t h a t t ren d s in CHD m ort a lit y seen a cross t h e w orld in t h e p a st 30 years or so, m ay be d riven by forces in d ep en d en t of t h e cla ssic risk fa ct ors” (Eb ra h im & Da vey-Sm ith , 1999, ap u dMizgala & Sh u lzer, 2000:430). Sin ce th e la te 1970s, evid en ce p rovid ed b y exp erim en tal an d clin ical stu d ies (Koen ig et al., 1999; Ko l & Lib b y, 1999; Lin d b e rg e t a l., 1992; Rid ke r e t a l., 1997; Ro ss, 1999; Sch m it z e t a l., 1998) h a s ch a llen ged th e tra d itio n a l n o tio n o f CH D a s a d e ge n e ra tive co n d itio n , su p p o rtin g in st e a d a n a lt e rn a t ive vie w o f CH D a s a n im -m u n e in fla-m -m atory d isease (Meth a et al., 1998; Sch m it z e t a l., 1998; Wa t a n a b e e t a l., 1996). Several au th ors h ave also p ostu lated a role for in fe ct io n in in it ia t io n a n d / o r p ro gre ssio n o f CHD an d risk of m yocard ial in farction or d eath (Ha jja r e t a l., 1986; Ko l & Lib b y, 1999; Nie t o, 1998; Zh u e t a l., 2001). Howe ve r, t h u s fa r fe w attem p ts h ave b een m ad e (An estad et al., 1997; Mo za r e t a l., 1990) t o in co rp o ra t e t h e in fe ctio u sin fla m m a to r y h yp o th e sis in to e xp la n a -tion s for 20th -cen tu ry CHD m ortality tren d s.
Th e d egen era tive p a ra d igm h a s a ttem p ted to e xp la in th e CH D e p id e m ic a s se co n d a r y to tim e-tren d variation in exp osu resto risk factors fo r d e ve lo p m e n t o f d ise a se. An in fe ctio u sin -flam m atory h yp oth esis wou ld su p p ort a som e-wh a t d iffe re n t e xp la n a tio n , th a t is, o n e b a se d m ore on a variation in in d ivid u al su scep tibility
to CHD over tim e.
It h a s b e e n sh own t h a t ce rt a in in fe ct io n s a ffe ct a n in d ivid u a l’s re sp o n se to su b se q u e n t in fection s (Griffin , 1994) as well as to oth er en -viro n m e n t a l ch a lle n ge s (Eva n s & Bra ch m a n , 1986), am on g th em b ein g h igh -fat d iets (Hajjar et al., 1986). Thus, theoretically, a m assive
occur-ren ce of an in fectiou s d isease cou ld h ave led to the em ergen ce of the CHD ep idem ic, even if oth-er en viron m en tal exp osures (e.g.: high fat in take, sm okin g) h ad n ot ch an ged over tim e, by m od i-fyin g in d ivid u als’ su scep tib ility to th eir effects. A m ajor world wid e in fectiou s even t im m e-d iately p recee-d in g th e rise in CHD m ortality was th e 1918 in flu en za p an d em ic. Twen ty-five p er-ce n t o f t h e U S p o p u la t io n (a t le a st 25 m illio n p eop le) h ad overt flu d u rin g th at p an d em ic, re-su ltin g in at least 500,000 excess in flu en za an d p n eu m on ia d ea th s (Crosby, 1989). World wid e, th e m in im u m estim a ted m orta lity wa s 21 m illion p eop le, with th e real n u m b er easily reach -in g 30 to 40 m illion (Crosby, 1989).
In flu e n za viru se s circu la tin g fro m 1918 to 1957 m ain tain ed an im p ortan t overlap in term s of serological an d b ioch em ical lab oratory tests, ecology, an d p u b lic h ealth effects, an d are n ow a ll cla ssified in th e H1N1 su b typ e of in flu en za A viru ses (Dowdle, 1999). Cou ld th e p ath ogen et-ic b u rd e n o f H 1N1 in flu e n za in fe ct io n o n t h e US p op u lation exp lain th e ob served ep id em io-logical p attern in 20th -cen tu ry CHD m ortality?
H1N1 influenza in the United States
Th e Sp an ish flu of 1918 h ad u n iq u e ch aracter-ist ics co m p a re d t o t h e 1958 (H 2N2 su b -t yp e ) an d 1968 (H3N2 su b-typ e) in flu en za p an d em ics (Cro sb y, 1989; Dowd le, 1999): (1) u n u su a lly h igh m orb id ity an d m ortality; (2) h igh m ale/ fe-m ale an d wh ite/ b lack fe-m orb id ity an d fe-m ortality ra t io s; a n d , o d d ly, (3) h igh e st m o rb id it y a n d m ortality b u rd en am on g you n g ad u lts.
As sh own in Figu re 1 (Collin s, 1930; Crosby, 1989; US Bu reau of th e Cen su s, 1955), th e in ci-d en ce of resp iratory illn esses (with at least on e d ay in b ed ) p eaked in b oth sexes at age 10, fol-lowed by a d rop in th e twen ties, a secon d p eak d u rin g th e th irties, a n d a sign ifica n t fa ll in th e forties. However, on e-th ird to on e-h alf of d eath s we re co n ce n t ra t e d in t h e se co n d a n d t h ird d ecad es of life. Th e con sen su s of th e Am erican Pu b lic He a lt h Co n fe re n ce o f De ce m b e r 1918 wa s th a t th e m o st freq u en t victim s o f flu were “th ose w h o h ad been in th e best of p h ysical con -d it ion an -d freest from p rev iou s -d isease” (Cro s-b y, 1989: 216). Acco rd in g t o e xp e rt o p in io n , d eath was d u e n ot to d irect viral d am age b u t to th e stren gth o f th e im m u n e-in fla m m a to r y re-sp o n se t o in fe ct io n , gre a t e r in ro b u st yo u n g (wh ite, m ale) ad u lts (Crosby, 1989).
durin g the pan dem ic (see Figure 1) also “prim ed” survivors in a sim ilar fashion , p redisp osin g them to fu tu re d evelop m en t of CHD. If th at were th e ca se, th en th e rela tive d istrib u tio n o f in flu en -za-related d eath s am on g in d ivid u als ages 15 to 49 in 1918-1919 (a p roxy for th e d istrib u tion of som e p articu lar kin d of im m u n e-in flam m atory re sp o n se t o in fe ct io n a cro ss t h e ra n ge o f e x-p osed b irth coh orts) sh ou ld x-p red ict th e occu r-re n ce o f CH D m o rt a lit y in su r vivo rs fro m t h e corresp on d in g b irth coh orts (from ab ou t 1870 to 1915) in th e su b se q u e n t ye a rs. ( Th e h igh e r 1918-1919 in flu en za an d p n eu m on ia m ortality at th e extrem es of life is p resu m ab ly related to oth er m ech an ism s, irrelevan t to th e h yp oth esis d iscu ssed h ere, as in flu en za ep id em ics u su ally p resen t greater m ortality at th e extrem es of life.) Wh ile flu a ctivity sh owed a co n tin u in g d e-clin e fro m 1918 t o 1957, su ch a t re n d wa s n o t u n iform across th e Un ited States (Collin s, 1930; Gover, 1943). Th u s we fu rth er h yp oth esize th at t h e re p o rt e d ge o gra p h ic va ria t io n in t im e o f on set of th e declin e in CHD death rates dep en d -ed o n th e va ryin g p ersisten ce o f H1N1 viru ses across th e Un ited States, an d , th rou gh th eir ef-fect, on a lower level b u t con tin u in g CHD “in i-tiation” takin g p lace in later b irth coh orts.
Methodology
Th is p ap er p resen ts ecological association s b e-tween in flu en za a n d CH D o ccu rren ces a cro ss
b irt h co h o rt s a n d a cro ss ge o gra p h ic a re a s o f t h e Un it e d St a t e s, in su p p o rt o f t h e t wo h y-p oth eses y-p resen ted ab ove.
Birth cohort correlation
Un ited States gen d er- an d age-sp ecific m ortal-ity d a ta were u sed to gra p h ica lly co m p a re th e b u rd e n o f t h e 1918-1919 in flu e n za p a n d e m ic wit h t h a t o f t h e 1920-1985 CH D e p id e m ic across b irth coh orts.
Influenza data
Sex an d age strata-sp ecific in flu en za m ortality ra t e s we re ca lcu la t e d u sin g t h e n u m b e r o f d eath s from in flu en za an d p n eu m on ia in 1918 (Cro sb y, 1989) a n d a n estim a te o f th e p o p u la -t io n re sid in g in -t h e U S Re gis-t ra -t io n Are a fo r 1917 (U S Bu re a u o f t h e Ce n su s, 1955) u se d a t th at tim e for n ation al tab u lation s of vital even ts a n d cove rin g a p p roxim a t e ly 80% o f t h e U S con tin en tal p op u lation (Collin s, 1930). Death s occu rrin g d u rin g 1918 an d 1919 were assign ed to Jan u ary 1, 1919. Th ey were th en ad ju sted to reflect th e age th e d eceased wou ld h ave h ad in 1920, so t h a t t h e a ge -sp e cific ra t e s co u ld b e p lotted for b irth coh orts accord in g to th e u su al cen ter o f 10-yea r b irth co h o rt in terva ls ( Ju ly 1 o f ye a rs e n d in g wit h 0 o r 5). Sin ce o n e a n d a h a lf ye a rs e la p se d b e t we e n Ja n u a r y 1, 1919, a n d Ju ly 1, 1920, t h is a d ju st m e n t wa s p e r-form ed for each age stratu m , ad d in g, in weigh t-0
2 4 6 8 10 12 14 16 18 20
0 Incidence rates (/1,000), respiratory symptoms
Death rates (/1,000)
50 100 150 200 250 300 350 400
Mortality (females) Mortality (males) Incidence (females) Incidence (males)
60 and + 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 10-14 05-09 < 5
Figure 1
1918-1919 Influenza and pneumonia morbidity and mortality (/1,000) by sex and age. US Registration States.
ed fash ion , th e 19181919 in flu en za an d p n eu -m on ia stratu -m -sp ecific d eath coefficien t of th e a ge stra tu m in q u estio n (weigh t = 0.85) to th e d eath coefficien t of th e n ext you n gest stratu m (weigh t = 0.15).
CHD mortality data
Fo r t h e m o st re ce n t p e rio d , 1960-1985, CH D m o rta lity ra tes were ca lcu la ted b a sed o n gen -d e r- a n -d a ge -sp e cific -d a ta (n u m b e r o f -d e a th s an d p op u lation ) referen t to th e total US p op u -lation (all races), ob tain ed from th e Division of Vital Statistics of th e Nation al Cen ter for Health Statistics (NCHS, 1990). Age-sp ecific CHD m or-tality was d efin ed as th e n u m b er of d eath s clas-sified accord in g to th e In tern ation al Classifica-tio n o f Disea ses (ICD) revisio n effective in th e ye a r o f d e a t h , d ivid e d b y t o t a l p o p u la t io n in t h e sa m e ye a r, in e a ch 10-ye a r st ra t u m . ICD version s p rior to 1950 were too variab le in th eir d efin ition s of h eart d isease to ch aracterize, in a st a n d a rd ize d wa y, t h e U S CH D d e a t h t re n d s (Co u lso n , 1975). Th u s, to d o cu m en t b irth co -h o rt t re n d s d u rin g t -h e a sce n d a n t lim b o f t -h e CHD ep id em ic cu rve, we u sed p u b lish ed tab les on th e n u m b er of d ea th s a scrib ed to coron a ry h eart d isease (an d p op u lation ), by age an d sex, referen t to SeattleKin g Cou n ty (State of Wash -in gton ) on ly (Raven h old t, 1966). In th is su b set o f d a t a , t h e a ssign e d ca u se o f d e a t h re su lt e d fro m a re vie w a n d ta b u la tio n o f a ll d e a th ce r-tificates registered in th at area from 1920-1960, at every fifth year, in accord an ce with th e 1955 in t e rn a t io n a l st a n d a rd s (ICD-7). Usin g b o t h se t s o f d a t a , we t a b u la t e d CH D m o rt a lit y a c-cord in g to 10-year age an d b irth coh ort strata. To m ake th e total CHD m ortality b u rd en com -p arab le across d ifferen t d istrib u tion s of age in su ccessive b irth coh orts, we d efin ed , sep arate-ly for m en a n d wom en , a referen t b irth coh ort h a vin g a m id -p e rio d n u m b e r o f su r vivo rs a t each su ccessive 10-year age in terval (from ages 4049 to 80+) eq u al to th e n u m b er of in d ivid u -a ls -a t t h e re sp e ct ive 10-ye -a r -a ge st r-a t -a o f t h e 1940 U S t o t a l p o p u la t io n (U S Bu re a u o f t h e Ce n su s, 1954). We t h e n e st im a t e d a ge st ra t a -sp ecific sta n d a rd ized n u m b ers of CHD d ea th s for su ccessive b irth coh orts by m u ltip lyin g th e age stratu m -sp ecific d eath rate corresp on d in g to ea ch sp ecific b irth coh ort by th e n u m b er of in d ivid u a ls estim a ted a t m id -p erio d in th e re-sp e ct ive 10 ye a r a ge st ra t u m in t h is st a n d a rd p op u lation . Next, we calcu lated th e total p eri-od age strata-sp ecific stan d ard ized n u m b ers of d eath s, m u ltip lyin g th is m id -p eriod n u m b er of d eath s by 10. In d oin g so, we extrap olate a on e-ye a r m o rta lity e xp e rie n ce to th a t o f a 10-e-ye a r
p e rio d o f o b se r va tio n o f th e co h o rt m e m b e rs a s th ey p a ss th rou gh th e sp ecified 10-yea r a ge in t e r va l. Fin a lly, we gra p h ica lly su m m e d t h e a ge st ra t a -sp e cific st a n d a rd ize d n u m b e rs o f d eath s with in each b irth coh ort in ord er to ob -ta in a s-ta n d a rd ize d e stim a te o f th e to -ta l CH D m ortality b u rd en for each 10-year b irth coh ort.
Geographic correlation
We u sed th e Sp ea rm a n co rrela tio n co efficien t to q u an tify th e association , across th e US geo-gra p h ic d ivisio n s, b etween lo n ger p ersisten ce o f H 1N1 in flu e n za viru se s, e stim a te d b y to ta l excess d eath rate from in flu en za an d p n eu m o-n ia m e a su re d d u rio-n g t h e wh o le o f e a ch e p i-d em ic occu rrin g from 1931-1940 (Gover, 1943) a n d d e la ye d o n se t o f d e clin e in CH D d e a t h rates estim ated by th e p rop ortion of Metrop ol-itan State Econ om ic Areas in wh ich th e d eclin e in CHD m ortality h ad alread y b egu n in 1968, as an alyzed by Win g et al. (1986).
Results
Birth-cohort trends
Figu re 2 grap h ically com p ares th e relative m or-tality associated with th e 1918-1919 p an d em ic with th at from th e CHD ep id em ic in th e p eriod 19201985 across su ccessive b irth coh orts, sep arately for m en an d wom en . Th e solid lin e con -n e ct s p o i-n t s re p re se -n t i-n g t h e d ist rib u t io -n o f m o rt a lit y fro m in flu e n za a n d p n e u m o n ia in 19181919 fo r b irt h co h o rt s ro u gh ly co rre -sp o n d in g t o t h o se wit h 10-50 ye a rs o f a ge in 1918-1919 (see Figu re 1). Th e vertical b ars d is-p la y th e sta n d a rd ized n u m b er of CHD d ea th s, sh ad ed to rep resen t d eath s in d ifferen t age stra-ta, am on g th ose sam e b irth coh orts. As can b e seen , for b oth sexes, for coh orts b orn in th e last th ird o f th e n in eteen th cen tu ry, a s p a n d em icre la t e d m o rt a lit y in cicre a se s so d o e s t h e o b -served CHD m ortality. Both d istrib u tion s attain th eir p eak in coh orts b orn ju st b efore 1900 an d t h e n b e gin t o fa ll t owa rd s t h e la t t e rb o rn co -h orts. In co-h orts b orn su ccessively after 1900, a growin g e xce ss o f o b se r ve d CH D m o rt a lit y in relation to th at exp ected , in relative term s, from t h e p a n d e m ic m o rt a lit y cu r ve, ca n b e se e n , with th is excess b ein g som ewh at larger for m en .
Geographic variability in onset of CHD decline
er-ab ly across th e US Geograp h ic Division s, b ein g less in th e North east, Mid -Atlan tic, East North Ce n t ra l, So u t h At la n t ic, a n d Pa cific Divisio n s co m p a re d t o t h e We st No rt h Ce n t ra l, Ea st Sou th Cen tral, West Sou th Cen tral, an d Mou n -t a in Divisio n s. Th e o n se -t o f d e clin e in CH D m o rta lity a lso va ried co n sid era b ly, h a vin g b e-gu n in 100% of th e North east an d 98.5% of th e
Pa cific Me tro p o lita n Sta te Eco n o m ic Are a s in 1968, b u t in on ly ap p roxim ately 60% of Metro-p o lit a n Are a s o f t h e We st No rt h Ce n t ra l a n d East Sou th Cen tral Division s.
A n otable n egative correlation exists between excess in flu en za a n d p n eu m on ia m orta lity a f-t e r 1930 a n d e a rly d e clin e in CH D m o rf-t a lif-t y across th e Un ited States (rs = -0.68; p = 0.042). 0
standar
dized number of CHD deaths
500.000 1.000.000 1.500.000 2.000.000
0 1918-1919 influenza and pneumonia death rates (/1,000)
2 4 6 8 10 12 14
80 + 70-79 60-69 50-59 40-49
flu 1918-1919
1926-1935
1921-1930 1916-1925 1911-1920
1906-1915
1901-1910 1896-1905 1891-1900
1886-1895
1881-1890
1876-1885 1871-1880 1866-1875
1861-1870
1856-1865 1851-1860
US men
0 250.000 500.000 750.000 1.000.000
0 2 4 6 8 10
80 + 70-79 60-69 50-59 40-49
flu 1918-1919
1926-1935
1921-1930 1916-1925
1911-1920 1906-1915
1901-1910
1896-1905 1891-1900
1886-1895 1881-1890
1876-1885 1871-1880 1866-1875
1861-1870 1856-1865
1851-1860
standar
dized number of CHD deaths
1918-1919 influenza and pneumonia death rates (/1,000)
US women
Figure 2
Relative distributions of 1918-1919 influenza and pneumonia death rates (line) and of 1920-1985 CHD standardizeda number of deaths by age (bars) in successive birth cohorts, according to age and sex, United States.
Sources: CHD mortality data from National Center for Health Statistics, Vital Statistics of the United States, Vol. II, Mortality. Published and Unpublished Data – Selected Yearsand US Bureau of the Census (1954). Influenza data from Crosby (1989) and US Bureau of the Census (1955).
Discussion
Th e ab ove d ata d em on strate two ep id em iologica lly im p o rt a n t e co lo giologica l a sso cia t io n s b e -tween th e b u rd en of H1N1 in flu en za in fection on th e US p op u lation in th e early 20th cen tu ry a n d t h e m id -ce n t u r y rise in CH D m o rt a lit y. Age-related in flu en za an d p n eu m on ia m ortali-t y d u rin g ortali-t h e 1918-1919 p a n d e m ic p re d icortali-t s we ll, se p a ra t e ly in m e n a n d wo m e n , t h e re la -t ive d is-t rib u -t io n o f CH D m o r-t a li-t y a cro ss -t h e co rre sp o n d in g b irt h co h o rt s. Th e b u rd e n o f H 1N1 in flu e n za a ctivity p o st-1930, m e a su re d b y in flu e n za a n d p n e u m o n ia d e a t h ra t e s, sh owe d a stro n g a sso cia tio n with d e la ye d d e -clin es in CHD m ortality across US Geograp h ic Division s. In fact, it m igh t h elp exp lain th e ob -served p ersisten ce of CHD m ortality across th e la t e st -b o rn co h o rt s b e yo n d t h a t e xp e ct e d o n th e b a sis o f a n estim a te wh ich co n sid ered th e 1918-1919 p an d em ic alon e (see Figu re 2).
Ad d ition ally, th ere are im p ortan t socio-d e-m ograp h ic sie-m ilarities b etween th ose e-m ost af-fe ct e d b y t h e 1918-1919 in flu e n za a n d t h o se wh o d ied from CHD. CHD m ortality was always
h igh e r in m e n t h a n wo m e n (St a llo n e s, 1980). Male/ fem ale d eath ratios d u rin g th e p an d em ic also varied from 1.2 at ages 10-19 to 1.7 at ages 40-49 (Crosby, 1989) (see Figu re 1). CHD m ortal-ity was h igh er in wh ites th an in b lacks from th e m id -1920s u n til a b o u t 1963, wh en a cro ssover in d eath rates occu rred (Gilliu m , 1982). As m en -t io n e d , o n e o f -t h e u n iq u e ch a ra c-t e r is-t ics o f t h e 1918 p a n d em ic wa s its u n exp ected ly h igh wh ite/ b lack m ortality ratio. Not on ly was m or-ta lity fro m in flu en za a n d p n eu m o n ia lower in b la cks b u t, d u rin g th e p a n d em ic, “d eath -rates for all cau ses of black s betw een 25 an d 45 years of a ge w ere below t h ose of t h eir w h it e cou n t er-p a rt s, er-p rob a b ly for t h e on ly t im e in t h e h ist ory of th e n ation” (Crosby, 1989:229).
As flu e p id e m ics d isa p p e a re d fro m t h e No rt h e a st a n d Pa cific re gio n s a n d in flu e n za m o rt a lit y d e cre a se d a n d b e ca m e m o re lo ca l-ized in th e Mo u n ta in a n d So u th ern regio n s o f th e co u n tr y, (1) sp ecific d em o gra p h ic ch a ra c-teristics of th ose p op u lation s (on average with a h igh er p rop ortion of b lacks com p ared to th e North east an d Pacific), (2) h igh er variab ility in ra tes of exp osu re (d u e to lower levels of circu -latin g viru s), an d (3) differen tial su scep tibility to H1N1 in fection across social strata (as d em on -strated by Syd en striker, 1931) cou ld exp lain th e Eastern / Sou th ern (Stallon es, 1980), wh ite/ b lack (Gilliu m , 1982), a n d so cio e co n o m ic ( Win g e t a l., 1992) cro ssove rs in CH D m o rt a lit y ra t e s registered d u rin g th e d eclin e. Th e d eclin e a n d m o re re ce n t le ve lin g o ff (Ro sa m o n d e t a l., 1998) in CHD in cid en ce is con sisten t with p ro-gre ssive e xh a u st io n o f t h e in flu e n za -p rim in g effect with in th e su rvivin g p op u lation .
Th u s, th ese ep id em io lo gica l fin d in gs su p -p ort ou r h y-p oth esis th at gen d er, race, age, an d geograp h ic d ifferen tials in th e b u rd en of p ath -ogen ic effects d u e to H1N1 in flu en za in fection in t h e U S p o p u la t io n co u ld h e lp e xp la in t h e m a in ep id em io lo gica l ch a ra cteristics (gen d er, ra ce, b irth co h o rt, a n d geo gra p h ic p a ttern ) o f th e 20th cen tu ry CHD m ortality ep id em ic.
Speculations on pathogenic
mechanisms involved in an
influenza/CHD mortality association
Epidemiological clues
Th e p rop ortion of excess d eath s occu rrin g d u r-in g r-in flu en za ep id em ics a ttrib u ted to o rga n ic h eart d iseases grew con sid erab ly d u rin g th e as-ce n d in g p h a se o f t h e CH D e p id e m ic, fro m 1.6% in 1918-1919 t o 18.4% in t h e m in o r e p i-d e m ics o ccu rrin g i-d u rin g 1920-1929 (Co llin s, 50
state economic areas with declining CHD death-rates in 1968 (%)
60 70 80 90 100
0 50 100 150 200 250 1931-1940
cumulative excess influenza death rate (/100,000) NE
P MA
ENC SA WSC
M
ESC WNC
Figure 3
Correlationabetween persistence of H1 influenza activity after 1930 (measured by 1931-1940 influenza excess death rates – Gover, 1943) and timing of the onset of the decline in CHD mortality (measured by proportion of metropolitan SEAb with declining CHD death rates in 1968 and earlier, Wing et al., 1992) across the US Geographic Divisionsc.
aSpearman (rs) correlation. bSEA = State Economic Areas
cNE = Northeast; P = Pacific; MA = Mid-Atlantic; ENC = East North Central; SA = South Atlantic; WSC = West South Central; M = Mountain;
1932), a n d to 51% (ca rd iova scu la r-ren a l ca u s-es) of a total of 86,000 excess d eath s registered du rin g th e 1957-1960 Asian in flu en za ep id em ics (Eickoff et al., 1961).
Be gin n in g in t h e 1960s, a co n t in u in g im -p rovem en t in su rvivorsh i-p, reflectin g m ostly a d eclin in g recu rren ce o f m yo ca rd ia l in fa rctio n su b sequ en t to in itial d iagn osis, was d ocu m en t-e d (Elvt-e b a ck, 1979). Alt h o u gh im p rovt-e d su rvivo rsh ip h a s u su a lly b e e n a t t rib u t e d t o im -p roved m ed ical care, a ch an ge in d isease/ h ost re la t io n sh ip ove r t im e h a s b e e n co n sid e re d a p ossib ility (McKin ley et al., 1989). As first su g-ge st e d b y Go rd o n & Th o m (1975), t h e re d u c-tion in d eath rates from CHD cou ld b e p artially a t t rib u t a b le t o t h e co n t in u in g d e clin e in in -flu e n za a ct ivit y a n d t h e a b se n ce o f e xt e n sive in flu en za ep id em ics after 1968. If th e h yp oth esis p ro p o se d h e re is co rre ct , re d u ct io n in re -p eat ex-p osu re of H1N1 “-p rim ed” in d ivid u als to su b se q u e n t in flu e n za in fe ct io n s m igh t h a ve b e e n t h e d e t e rm in in g fa ct o r in t h e ch a n ge in d isea seh o st rela tio n sh ip rega rd in g CH D p ro -gression an d d eath .
It is worth n otin g th at h istorical record s in -d ica t e t h e p o ssib le o ccu rre n ce o f a p re vio u s rise a n d fa ll in CH D m o rt a lit y in Brit a in ove r th e last th ird of th e eigh teen th cen tu ry (Azam -b u ja, 1995). He-b erd en’s origin al d escrip tion of th e a n gin a l syn d rom e in 1772, a tim e wh en its ca rd ia c o rigin h a d n o t ye t b e e n e st a b lish e d , followed a p eriod of sign ifican t in flu en za activ-ity in Britain , with ep id em ics record ed in 1727, 1732, 1737, an d 1760 (Crosby, 1989).
Clinical/pathological clues
Su d d en d ea th wa s a h a llm a rk o f th e CH D ep i-d e m ic, e sp e cia lly i-d u rin g its a sce n i-d in g p h a se. Acco rd in g t o McKin la y e t a l. (1989), a t t h e h eigh t of th e CHD ep id em ic, alm ost two-th ird s o f CH D d e a t h s we re su d d e n a n d u n e xp e ct e d an d occu rred ou tsid e h osp itals, m ostly as a re-su lt o f a cu te a rrh yth m ia s. Du rin g th e d eclin e, t h is co m p o n e n t o f CH D m o rt a lit y fe ll m o re d ra m a t ica lly t h a n d id in cid e n ce o f a cu t e m y-ocard ial in farction or lon g-term p ost-MI m or-tality (McKin lay et al., 1989). Su d d en d eath was a lso a co m m o n co m p o n e n t o f ca rd iova scu la r d eath s in in flu en za ep id em ics (Oseasoh n et al., 1959), a n d it h a s recen tly b een sh own th a t in -flu en za vaccin ation con fers p rotection again st su d d en d eath (Siscovick et al., 2000). Ob stru c-tio n o f a rteries su p p lyin g th e co n d u cc-tio n sys-tem of th e h eart (first sep tal artery, sin u s n od e a rte r y, a triove n tricu la r n o d e a rte r y, p o ste rio r d e sce n d in g a rt e r y) is a p re p o n d e ra n t fin d in g a m o n g p a t ie n t s wit h su d d e n ca rd ia c d e a t h ,
com p ared to ap p aren tly h ealth y su b jects d yin g of accid en tal cau ses (Velican et al., 1989).
Du rin g t h e 1918 in flu e n za p a n d e m ic, t h e m o st fre q u e n t ly o b se r ve d circu la t o r y d ist u rban ce was bradycardia. Particu larly du rin g con -valescen ce, b rad ycard ia often b ecam e m arked . A sm a ll grou p of p a tien ts sh owed a rrh yth m ia s wit h e it h e r a t ria l o r ve n t ricu la r e xt ra syst o le s an d con d u ction d isord ers, varyin g from sim p le p rolon ged P-R in terval to b rad ycard ia with “es-cap ed sin o-n od al b eats”, p artial b lock (1:2, 1:3; 1:4), an d com p lete h eart b lock. Su ch effects on th e h ea rt we re tra n sito r y a n d n o n -resp o n sive to a tro p in e. At a u to p sy, so m e d ila ta tio n o f th e righ t sid e wa s co m m o n ly o b se r ve d , wit h d if-fu se ch a n ge s su ch a s “clo u d y swe llin g”, e vi-d e n ce o f “p a re n ch ym a l vi-d e ge n e ra tio n”, lo ss o f striation , b u t u su ally n o clear-cu t in flam m ato-r y ch a n ge s o f t h e m yo ca ato-rd iu m (An o n ym o u s, 1958). En dothelial cells were n ot described. How-e vHow-e r, in fHow-e ct io n a n d in fla m m a t io n o f a rt How-e riHow-e s su p p lyin g th e co n d u ctio n system o f th e h ea rt cou ld exp lain b oth arrh yth m ias d u rin g th e 1918 p a n d e m ic a n d su d d e n CH D d e a th s o ccu rrin g d u rin g d ecad es of relatively h igh in flu en za ac-tivity. Cytom egaloviru s an d in flu en za viru s are cap able of m odu latin g th e in vitro p rodu ction of IL-6 by h u m an en d oth elial cells (Visseren et al., 1999). An d th e h igh ly p ath ogen ic avian in flu en -za virus A/ FPV/ Rostock/ 34 (H7N1) was shown to be highly en dotheliotropic (Feldm an et al., 2000).
Biomolecular clues
Be sid e s a re in fe ctio n -d rive n a u to im m u n e reactivation of en d oth elial in flam m ation lead in g t o a cu t e CH D e ve n t s a n d / o r ch ro n ic p ro -gression of vascu lar d isease, an oth er p ossib ili-ty m u st also b e con sid ered : th at flu in fection or th e im m u n e resp on se to it in terfered with lip id m etab olism , lead in g to in creased su scep tib ility to h igh seru m ch o lestero l levels. Pleskov et a l. (1994) d escrib ed , in so m e stra in s o f in flu en za viru ses, a sign ifican t m im icry of th e am in o acid se q u e n ce s in vo lve d in ce ll a t t a ch m e n t o f t h e vira l h em a gglu tin in with th o se o f a p o lip o p ro -tein B in volved in LDL b in d in g to h igh -affin ity LDL recep to rs. Up o n rein fectio n , co lo ca liza -t io n o f a n -t i-a p o B a n -t ib o d ie s a -t si-t e s o f vira l p en etration in th e vascu lar b ed cou ld resu lt in in tim a l LDL a ccu m u la tio n fo llowe d b y oxid a tion an d su bsequ en t foam cell form ation (Stein -b erg & Witzu m , 1990).
Th o u gh sp e cu la tive, a m e ch a n ism in vo lvin g crossreactivity b etween th e H1N1 lvin flu en -za st ra in s a n d a p o B-LDL o r t h e LDL re ce p t o r co u ld b e a lin k fro m in fectio n to h yp erch o les-t e ro le m ia a n d CH D m o rles-t a liles-t y a n d sh e d n e w ligh t on th e “d iet-h eart” con troversy (Blackb u rn & Jacob s, 1984). With in p op u lation s, th e effect of d ietary fat/ ch olesterol in take on seru m ch o-lestero l levels m igh t d ep en d m o re o n th e efficien cy of LDL u p take, th e latter p ossib ly in flu -en ced by a cross-reactive im m u n e resp on se to a p reviou s H1N1 in flu en za in fection .
In sh ort, alth ou gh b iological lin ks b etween in flu e n za a n d CH D re m a in t o b e p rove n , in -trigu in g lead s d o exist.
Conclusions and final remarks
Ecological stu d ies are weak d esign s to estab lish cau sality. However, th e stren gth an d con sisten -cy of th e several d ifferen t ecological correlates sh own h ere, co u p led with a p o ten tia l b io lo gi-cal p lau sib ility of th is ep id em iologigi-cally-d riven h yp o t h e sis wit h in a n im m u n e -in fla m m a t o r y p arad igm of ath erosclerosis, d o m ake th e asso-ciation s p resen ted worth y of fu rth er con sid er-ation .
Cu rren t evid en ce d em on strates th at th e d i-et-h eart p arad igm , wh ich gave su p p ort to m ost of th e research an d in terven tion p olicies related to CHD d u rin g th e 20th cen tu ry, can n ot ad -eq u a tely exp la in a ll th e fea tu res rela ted to th e CHD tim e tren ds (Ku u lasm aa et al., 2000; Meth a e t a l., 1998; Mizga la & Sh u lze r, 2000; Ta u b e s, 2001). Sin ce t h e 1990s, se ve ra l o t h e r d ise a se s trad ition ally associated with d egen eration were sh own to h ave, in stead , an in flam m atory b asis a n d a n in fe ct io u s e t io lo gy (Lo rb e r, 1996). In fla m m a t io n h a s a lso b e co m e t h e m a in p a ra d igm of CHD p ath ogen esis, sin ce Ross & Glom -set (1976a; 1976b ) first d em on strated its d om i-n a i-n t ro le ii-n a t h e ro ge i-n e sis (Ro ss, 1999). We h op e th at th is stu d y, wh ich exp an d s p reviou sly p resen ted (Rein ert-Aza m b u ja , 1994) evid en ce fo r t h e in flu e n za / CH D e p id e m ic h yp o t h e sis, will stim u la te fu rth er in vestiga tion of in flu en -za’s ro le in t h e 20t h -ce n t u r y co u rse o f CH D, p erm ittin g exten sion of th e in flam m atory p ar-a d igm ar-a n d in t ro d u ct io n o f t h e in fe ct io u s h y-p o t h e sis t o t h e in t e ry-p re t a t io n o f t h e rise a n d fa ll in CHD m orta lity, a world wid e occu rren ce d e scrib e d b y t h e WH O (1969, a p u d Go rd o n & Kan n el: 1617) as “th e greatest ep idem ic m an k in d h as faced”.
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Rosely Sich ieri Th e a rticle by Aza m b u ja & Du n ca n is a stim u -lu s for reth in kin g card iovascu lar d isease (CVD) e p id e m io lo gy. As t h e a u t h o rs a ckn owle d ge d , m an y in d ivid u als with ath erosclerosis, a m ajor com p on en t of th e cau sal p ath way for CVD, lack id e n t ifia b le t ra d it io n a l risk fa ct o rs. Th is is a re a so n a b le a rgu m e n t fo r se a rch in g fo r o t h e r p oten tial etiologies, an d a p oten tial in fectiou s risk factor h as recen tly gain ed stron g su p p ort.
Th e au th ors p resen ted ecological evid en ce o f a n a sso cia tio n b etween co ro n a ry h ea rt d is-ea se m orta lity a n d in flu en za in fection . If tru e, p re ve n t io n o f CVD co u ld b e su b st a n t ia lly ch a n ged . However, a s th e a u th o rs sta ted , eco -logica l a n a lysis m a y h a ve m a n y fla ws a n d ep i-d e m io lo gica l i-d a t a la ck ro b u st n e ss i-d u e t o t h e m a n y p o ssib le co n fo u n d in g fa cto rs. Th u s, so -cio e co n o m ic le ve l is a n im p o rt a n t risk fa ct o r for CVD an d also a stron g p oten tial con fou n d er for th e association b etween coron ary h eart d is-e a sis-e m o rta lity a n d in flu is-e n za in fis-e ctio n . In tis-e r-estin gly, as m en tion ed by Azam b u ja & Du n can , th e h igh m ortality rate from in flu en za in wh ites a s com p a red to b la cks su ggests th a t socioeco-n o m ic co socioeco-n fo u socioeco-n d isocioeco-n g fa ct o rs a re socioeco-n o t t h e m a isocioeco-n e xp la n a t io n fo r t h e a sso cia t io n . On t h e o t h e r h a n d , a gea d ju sted m o rta lity ra tes fro m co ro -n ary h eart d isease (CHD) i-n Mi-n -n esota for th e ye a rs 1960-1978 sh owe d t h a t in flu e n za a n d p n eu m on ia d eath rates were u n related to CHD tren d s (Gillu m et al., 1984).
An o t h e r im p o rt a n t co n fo u n d in g fa ct o r is sm okin g. Cigarette sm okin g is associated with d iffe re n ce s in t h e in cid e n ce a n d se ve rit y o f a b ro a d a rra y o f re sp ira t o r y illn e sse s, ra n gin g fro m th e co m m o n co ld to ca n cer. In a d d itio n , wh ile th e gen eral effect of sm okin g on resp ira-t o r y d ise a se s is a d ve rse, in ira-t h e ca se o f h yp e r-sen sitivity p n eu m on itis, sm okin g m ay actu ally b e associated with a d ecrease in th e in cid en ce. Th erefore, sm okin g can m od ify th e association b e t we e n CH D a n d in flu e n za in fe ct io n in a com p lex way.
It sh ou ld also b e n oted th at CHD is n ot th e first con d ition to b e d escrib ed by a m u ltifacto-rial d esign th at in clu d es in fection as on e of th e im p o rt a n t fa ct o rs. Ot h e r n o n -co m m u n ica b le ch ron ic con d ition s su ch as h ep atic can cer, d ys-p eys-p sia, an d gastric can cer h ave also b een
asso-Debate on the paper by Maria Inês
Reinert Azambuja & Bruce B. Duncan
Debate sobre o artigo de Maria Inês
Reinert Azambuja & Bruce B. Duncan
In st it u t o d e M ed icin a Socia l, Un iv ersid a d e d o Est a d o d o Rio d e Ja n eiro, Rio d e Ja n eiro, Bra sil.
cia t e d wit h sp e cific m icro o rga n ism s. In re la -tion to card iovascu lar d iseases, several stu d ies h ave sh own Ch lam yd ia p n eu m on iae, Heliobac-t er p ylori, a n d h erp es sim p lex viru s in fectio n s as risk factors for th e ath erogen ic p rocess. Nev-erth eless, a role for m icroorgan ism s in th e eti-ology of CHD h as gain ed su p p ort by th e u n d er-sta n d in g th a t th e fin a l o cclu sio n o f th e ve sse l in a th erosclerosis resu lts from a com b in ed ef-fe ct o f t h e p la q u e a n d in fla m m a t o r y p ro ce ss, wh e n in fe ct io n o f t h e e n d o t h e lia l ce lls m a y p lay a d ecisive role. Accord in g to th ese fin d in gs, n ew risk factors ad d in g to th e p red ictive valu e o f o ld o n e s su ch a s h igh b o d y m a ss in d e x, sm okin g, seru m lip id s, an d sed en tary life style, are m arkers of th e in flam m atory p rocess. Th u s, Cre a ct ive p ro t e in , a n o n sp e cific in fla m m a -t io n m a rke r, is a n e xce lle n -t p re d ic-t o r o f CH D an d stroke.
In fection can also b e con sid ered a p oten tial effect m odifier of tradition al CVD risk. Azam bu -ja & Du n can d iscu ss th at th e risk of CVD associ-ated with fat/ ch olesterol in take m ay d ep en d on p rio r in flu en za in fectio n . Oth er fin d in gs h a ve su p p o r t e d t h is h yp o t h e sis, a n d it h a s b e e n su ggested th a t p h ysica l a ctivity, sm o kin g, a n d lip id s ca n m o d u la t e im m u n e st a t u s a n d t h u s su scep tib ility to in fection s th at are p oten tially im p ortan t in ath erogen esis (O’Con n or, 2001).
Th e im p ortan ce of th is n ascen t field associ-a tin g ch ro n ic d iseassoci-a ses with in fectio n s wassoci-a s re-ce n t ly h igh ligh t e d in a sym p o siu m t h a t crit i-ca lly exa m in ed th e role of in fectiou s a gen ts in u lcer, can cer, ob esity, ath erosclerosis, an d d iab e te s (Dh u ra n d h a r, 2001). Howe ve r, to e sta iab -lish a ca u sa l lin k b e t we e n in fe ct io n a n d a n y ch ro n ic d isea se is a d ifficu lt ta sk, b eca u se th e p re se n ce o f m icro o rga n ism s m a y b e u n d e -te cta b le b y th e tim e th e d ise a se is d ia gn o se d , an d th e p resen ce of an tib od ies d oes n ot estab -lish a ca u sa l rela tion sh ip. Th ese m eth od ologi-ca l co n st ra in t s we re ove rologi-ca m e in t h e ologi-ca se o f th e a ssocia tion b etween ga stric ca n cer a n d H. p ylori. Th e a sso cia t io n wa s first su gge st e d in t h e 1980s a n d is n ow we ll a cce p t e d , a llowin g t h e p re ve n t io n o f t h is ch ro n ic d ise a se b y a n t im icro b ia l a ge n t s. A sim ila r t h e ra p e u t ic a p p ro a ch h a s b e e n d iscu sse d fo r CVD p re ve n -t io n , b u -t a n in a p p ro p ria -t e -t h e ra p y fo r su ch h igh ly p re va le n t d ise a se s co u ld le a d t o re sistan ce in b oth targeted an d n on targeted organ -ism s (O’Co n n o r e t a l., 2001). In co n clu sio n , m an y n ew p reven tive strategies an d treatm en t o p t io n s co u ld b e d e ve lo p e d if t h is in fe ct io u s p ath way p roves to b e tru e for CVD.
n ascen t field . Jou rn al of Nu trition, 131:2787-2810. GILLU M, R. F.; JACOBS Jr., D. R.; LU EPKER, R. V.; PRINEAS, R. J.; HANNAN, P.; BAXTER, J.; GOMEZ-MARIN, O.; KOTTKE, T. E. & BLACKBU RN, H ., 1984. Ca rd iova scu la r m o rt a lit y t re n d s in Min -n eso ta , 1960-1978. Th e Mi-n -n eso ta Hea rt Su rvey. Jou rn al of Ch ron ic Diseases, 37:301-309.
O’CONNOR, S.; TAYLOR, C.; CAMPBELL, L. A.; EP-STEIN, S. & LIBBY, P., 2001. Po ten tia l in fectio u s etiologies of ath erosclerosis: A m u ltifactorial p er-sp ective. Em ergin g In fectiou s Disease, 7:780-788.
Dep a rt a m en t o d e Pa ra sit ologia , In st it u t o d e Ciên cia s Biom éd ica s, Un iv ersid a d e d e Sã o Pa u lo, Sã o Pa u lo, Bra sil. M a rcelo Urb a n o Ferreira
Asso ciatio n between in fluen za an d co ro n ary heart disease: how co n vin cin g is available eviden ce?
Th e first re p o rt o f a t e m p o ra l a sso cia t io n b e -tween in flu en za ep id em ics an d m ortality from co ro n a r y h e a rt d ise a se (CH D) wa s p u b lish e d b y Brit ish e p id e m io lo gist s in 1978. Howe ve r, t h e a u t h o rs st a t e t h a t t h e y “cou ld n ot h op e t o p rovid e clearcu t evid en ce of a cau sal relation -sh ip , n or t h e seq u en ce of t h e t w o con d it ion s” from th eir d ata (Bain ton et al., 1978:238-239).
Th e old h yp oth esis th at ch ron ic in flam m ation an d in fecation are in volved in th e p ath ogen -esis o f a th ero sclero sis a n d CH D h a s b een re-vived in th e 1980s an d 1990s (Javier Nieto, 1998). Mu ch of th e cu rren t research h as been stim u lat-ed by th e fin d in g th a t CH D p a tien ts m o re fre-q u en tly p resen t a n tib od ies to p a th o ge n s su ch a s Ch la m yd ia p n eu m on ia e, cyt o m e ga loviru s, an d Helicobacter p ylori, as well as seru m m ark-ers of in flam m ation , th an p op u lation con trols (Mu h le st e in , 2001). Mo re ove r, Ch la m yd ia is freq u en tly d etected in ath erosclerotic p laq u es o f co ro n a r y a rt e rie s in CH D p a t ie n t s a n d in -d u ces a th ero sclero tic lesio n s in exp erim en ta l m o d els (Gra ysto n , 2000). Evid en ce su ggestin g t h a t t h is p a t h o ge n is in vo lve d in a ll st a ge s o f CH D is a va ila b le. Ch ro n ic Ch la m yd ia in fe c-tio n s a re a sso cia ted with lym p h o p ro lifera tive in flam m atory resp on ses ch aracterizin g th e ear-ly stages of ath erosclerosis, with ch an ges in th e lip id m e t a b o lism t h a t m a y a cce le ra t e p la q u e fo rm a t io n , a n d wit h in t ra p la q u e in fla m m a -t io n le a d in g -t o p la q u e ru p -t u re a n d a r-t e r y o c-clu sion .
If a st ro n g a n d p la u sib le a sso cia t io n b e -tween Ch lam yd ia in fection an d CHD h as b een fou n d , wh y sh ou ld we look for oth er in fection s p u t a t ive ly a sso cia t e d wit h CH D? Fo r a t le a st two reason s: (a) wh en a carefu l ad ju stm en t for
p oten tial con fou n ders (in clu din g socioecon om -ic fa ct o rs) is m a d e, t h e st a t ist -ica l a sso cia t io n b etween th e p resen ce of an ti-Ch lam yd ia an ti-b od ies an d CHD ti-b ecom es rath er weak (Dan esh et a l., 2000b ), a n d (b ) th e p o sitive a sso cia tio n b etween low-gra d e ch ron ic in fla m m a tion a n d CHD is u n related to th e p resen ce of an tib od ies to Ch lam yd ia or H. p ylori (Dan esh et al., 2000a). Th ese fin d in gs su ggest th at oth er p ath ogen s to wh ich p a t ie n t s h a ve b e e n e xp o se d , o r t h e ir “p a t h o ge n b u rd e n”, m a y b e a sso cia t e d wit h ch ro n ic in fla m m a tio n a n d CH D ( Ja vier Nieto, 1998; Zh u et al., 2001). Here Azam b u ja & Du n -can rep ort an association b etween p rior exp o-su re t o in flu e n za a n d CH D m o rt a lit y in t h e Un ited States.
Th e e co lo gica l d e sign re p re se n t s a m a jo r lim itation of th e stu d y by Azam b u ja & Du n can , sin ce we can n ot com p are th e exp osu re to sev-eral kn own risk factors for CHD an d resp irato-r y in fe ct io n s (in clu d in g so cio e co n o m ic va irato- ri-a b le s) in ri-a ffe ct e d ri-a n d n o n -ri-a ffe ct e d su b je ct s. Th e sp ecificity (in th e sen se u sed b y Bra d fo rd Hill) o f a p u ta tive ca u sa l a sso cia tio n b etween H1N1 in flu en za viru s in fection an d CHD is d is-p u tab le. We can h yis-p oth esize, for exam is-p le, th at a p rop ortion of su b jects in fected with in flu en -za viru s d u rin g m ajor ep id em ics are also m ore su sce p t ib le t o o t h e r re sp ira t o r y t ra ct in fe c-tio n s, in clu d in g Ch la m yd ia, p e rh a p s b e ca u se m a n y o f th e m a re cu rre n t o r p a st sm o ke rs. In t h is e xa m p le, t h e re fo re, Ch la m yd ia in fe ct io n a n d sm o kin g re p re se n t m a jo r p o t e n t ia l co n -fou n d in g factors th at sh ou ld b e con trolled for. Fu rt h e rm o re, t h e d e clin e o f CH D m o rt a lit y over th e last th ird of th e twen tieth cen tu ry h as a ltern a tively b een in terp reted a s a la te co n se-qu en ce of th e in trod u ction of an tib iotics, som e of th em active again st Ch lam yd ia,two to th ree d ecad es earlier ( Javier Nieto, 1998).
cit-ed by Bain ton et al. (1978) as a p ossib le lin k b e-t we e n in flu e n za a n d m yo ca rd ia l in fa rce-t io n , cou ld b e exp lored u sin g m od ern ep id em iologi-cal an d exp erim en tal m eth od s.
After a n a b sen ce o f 21 yea rs, H 1N1 viru ses reap p eared in th e Un ited States in 1977, in fect-in g m o st ly co lle ge -a ge d fect-in d ivid u a ls. It wo u ld b e in terestin g to follow th e in cid en ce of CHD-a sso ciCHD-a t e d e ve n t s in t h is co h o rt o f e xp o se d su b je ct s t o co n firm (o r ru le o u t ) t h e a sso cia -tio n fo u n d by Aza m b u ja & Du n ca n . Mo reover, th e availab ility of vaccin es an d am an tad in e or rim an tad in e p rop h ylaxis p rovid es th e b asis for clin ical trials to ad d ress th is top ic.
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Pós- Gra d u a çã o em Sa ú d e Colet iv a , N ú cleo d e Est u d os d e Sa ú d e Colet iv a , Un iv ersid a d e Fed eral d o Rio d e Jan eiro, Rio d e Ja n eiro, Bra sil. Gu ilh erm e L. W ern eck
In th eir in sigh tfu l p ap er, Maria In ês Azam b u ja & Bru ce Du n ca n co n sid er th e p o ssib ility th a t, a t lea st in p a rt, th e p a th o gen b u rd en o f H 1N1 in flu en za in fection m igh t h ave b een an im p ort a n ort d e ort e rm in a n ort in ort h e rise a n d fa ll o f co ro -n ary h eart d isease (CHD) m ortality ob served i-n th e 20th cen tu ry. Alth ou gh I con sid er th e p ap er we ll-fo u n d e d , wit h p la u sib le a rgu m e n t s, t h e e m p irica l e vid e n ce is n o t ve r y co n vin cin g t o m e. My co m m e n t s a re ge n e ra l t h o u gh t s t h a t m ay h op efu lly con trib u te to th e d esign of n ew stu d ies on th e top ic, wh ich I agree is im p ortan t an d d eserves fu rth er con sid eration .
Th e a u th o rs d ra wn o n two m a jo r p ieces o f em p irical evid en ce to su p p ortin g th eir h yp oth -e sis: (1) t h -e sim ila rit y b -e t w-e -e n t h -e r-e la t iv-e m o rt a lit y a sso cia t e d wit h t h e 19181919 in -flu en za p an d em ic an d th e d istrib u tion of CHD d eath s in th e p eriod 1920-1985, across su cces-sive b irth coh orts; a n d (2) th e ecologica l a sso-ciation b etween an in d irect m easu re of lon ger p e rsist e n ce o f H 1N1 in flu e n za viru s a n d d e -layed on set of d eclin e in CHD d eath rates.
Con cern in g th e first p iece of em p irical evi-d en ce, at least two qu estion s m igh t b e raiseevi-d : • Part of th e “d rop” in CHD m ortality th at we se e in t h e gra p h is a ct u a lly d e rive d fro m t h e fact th at m ore recen t coh orts h ave n ot actu ally fin ish e d e vo lvin g ove r t im e. Th e re fo re, t h e re are su ccessive m issin g b ars of m ortality for th e old er ages in th e m ore recen t coh orts, wh ich , if in clu d ed , wou ld m ake th e d eclin e less sh arp. • It d oes n ot seem to m e th a t th e in crea se in CH D m o rt a lit y a m o n g yo u n ge r in d ivid u a ls, wh ich rea lly a p p ea rs to “fo llow” th e in flu en za p an d em ic m ortality, ten d s to retu rn to th e lev-e ls lev-e xp lev-e ct lev-e d fo r a p o p u la t io n n o t lev-e xp o slev-e d t o th e b u rd en of in flu en za.
Regard in g th e secon d p iece of evid en ce, th e ecological correlation is b ased on ly on n in e ar-e a s, a t lar-e a st o n ar-e o f wh ich m a y b ar-e a n ar-e xt rar-e m ar-e ob servation . To get a feelin g of th e u n certain ty u n d erlyin g th e d ata, we ap p roxim ated th e val-u es b y in sp ectin g th e gra p h , a n d p erfo rm ed a sim p le exercise of estim atin g a series of Sp earm a n co rrela tio n co efficien ts fo r ra n d o earm sa earm -p les of th e d ata (with re-p lacem en t, u sin g b oot-st ra p ): in m o re t h a n 40% o f t h e sa m p le s, t h e Sp ea rm a n co rrela tio n co efficien t wa s n o t sta -tistically sign ifican t at th e 0.05 level.
Dep a rt a m en t o d e M ed icin a Prev en t iv a , Fa cu ld a d e d e M ed icin a , Un iv ersid a d e d e Sã o Pa u lo, Sã o Pa u lo, Bra sil. Eu clid es A. Ca st ilh o & N elson Gou v eia
Bio lo gical (an ti)terro rism by m o ther n ature?
Nu m erou s attem p ts h ave b een m ad e to exp lain th e tim e-tren d p a ttern s in coron a ry h ea rt d is-e a sis-e (CH D) m o rt a lit y in Am is-e rica a n d Eu ro p is-e ove r t h e la st ce n t u r y. Th e q u e st io n a s t o wh y CHD m ortality rose steadily u n til ap p roxim ately m id-cen tury an d then began to declin e has been in trigu in g in vestigators for a lon g tim e, an d a se-ries of p ossib le exp lan ation s for su ch a p attern h ave b een d escrib ed . In th eir article, Azam b u ja & Dun can in troduce an other in terestin g hyp oth-esis seekin g to exp lain the rise an d fall in CHD.
Focu sin g on even ts in th e Un ited States, th e a u t h o rs a rgu e t h a t t h e t im e -t re n d p a t t e rn in CH D m o rt a lit y ca n b e e xp la in e d b y t h e in -flu en za ep id em ic strikin g th a t co u n try d u rin g th e first h alf of th e 20th cen tu ry. Th e in fection , t h e y e xp la in , co u ld h a ve ch a n ge d in d ivid u a l su sce p t ib ilit y t o o t h e r kn own risk fa ct o rs fo r CHD, lead in g to in creased m ortality am on g th e exp osed . Sin ce th e flu ep id em ic was restricted to certain tim e p eriod s, n ew gen eration s of u n -exp osed in d ivid u a ls were th en resp on sib le for th e later d eclin e in CHD m ortality.
It is in terestin g to n ote the growin g in terest in in fectiou s d isease th eories for m an y of th e m ost com m on degen erative diseases of ou r tim es. For som e sp ecific can cers, for exam p le, estab lish ed m e ch a n ism s h a ve a lre a d y lin ke d th e d ise a se s to va rio u s in fectio u s a gen ts. So m e even cla im th at every d isease h as an in fectiou s “cau se”, an argu m en t th at h as b een d isp u ted by oth ers th at affirm th at m ost “cau ses” are “en viron m en tal”.
With o u t go in g in to e a ch th e o r y’s p ro s a n d con s, wh ich is b eyon d th e scop e of th is article, it is in t e re st in g t o n o t e t h a t so m e in fe ct io u s agen ts su ch as Ch lam yd ia p n eu m on iaean d cy-t o m e ga loviru s h a ve a lre a d y b e e n a sso cia cy-t e d with coron ary an d p erip h eral arterial d iseases. In a d d it io n , it is kn own t h a t in flu e n za e p i-d e m ics a re a sso cia t e i-d wit h e xce ss m o rb ii-d it y a n d m o rt a lit y, n o t o n ly fro m re sp ira t o r y d is-eases b u t also from oth er cau ses.
Neverth eless, th e con trib u tion of in flu en za to clin ical even ts, in clu d in g clin ical card iovas-cu lar d iseases, is frequ en tly n ot recogn ized (Sis-covick et al., 2000). We id en tified som e articles in t h is re sp e ct sh owin g a sso cia t io n s b e t we e n in flu en za vaccin ation an d b oth red u ced risk of p rim a r y ca rd ia c a rre st (Siscovick e t a l., 2000) a n d re d u ce d m o rta lity fro m in flu e n za a m o n g old er p erson s (Reich ert et al., 2001).
However, th e m ain argu m en t of Azam b u ja’s & Du n ca n’s th e o r y is b u ilt u p o n d a ta fro m in -flu en za an d p n eu m on ia m ortality (a m arker for
in flu e n za a ct ivit y). It is co n ce ive d t h a t a b o u t 99% o f m o rta lity cla ssified a s d u e to p n eu m o n ia a n d in flu e n za a re in fa ct d u e t o p n e u m o n ia , clea rly n ot a ll a ssocia ted with p rim a ry in -flu en za viru s in fection . Th e sou rces of th e d ata th ey u sed a re from d ea th certifica tes a n d h osp it a l d isch a rge d ia gn o se s. Bo t h osp ro b a b ly u n -d erestim ate th e im p act of in flu en za, b u t u sin g p n eu m on ia an d in flu en za can overestim ate th e im p act of in flu en za as well.
Mo re ove r, th e y sta te th a t th e e p id e m ic a f-fe ct e d wh it e s a n d m a le s m o st h e a vily, wh ich we re a lso t h e m a in gro u p s h it b y t h e rise in CHD m ortality in th e US. However, on e can ar-gu e th a t if th e p a n d em ic h a d h it th ese gro u p s th e h ard est, su rvivors of th e p an d em ic, th at is, t h e o n e s “p rim e d ” b y t h e in fe ct io n t o p re d is-p o se t h e m t o fu t u re d e ve lo is-p m e n t o f CH D, wou ld m ore likely b e b lacks an d wom en .
In a d d itio n , in flu en za A (H 1N1) circu la ted in h u m a n p o p u la t io n s fro m 1918 (t h e gre a t p an d em ic) to 1956, an d reem erged ab ou t 1976-1977. Th e a u t h o rs d o n o t d iscu ss, a t le a st n o t very clearly, wh at h ap p en ed to CHD in th e p eri-od from 1956 to 1976, when H1N1 was n ot circu-latin g in h u m an s. Also, th ey d o n ot p rop ose an y association b etween coron ary card iac d iseases sin ce H3N2 em erged in 1968 u n til th e p resen t.
Borrowin g Hill’s criteria for assessin g “cau sal-ity” to illu strate th is com m en tary, we ob served th a t th e Au th o rs p rovid e d a se rie s o f clin ica lp a t h o lo gica l a n d b io m o le cu la r clu e s t o re in -fo rce th eir a rgu m en t, th u s p resen tin g biologi-cal cred ibilityor p lau sibilityfor th eir fin d in gs. However, th is is o n e o f th e m o st criticized cri-t e ria in cri-t h e e p id e m io lo gica l licri-t e ra cri-t u re, give n th at b iological m ech an ism s can easily b e elab -o ra t e d lin kin g a n e xp -o su re t -o a n -o u t c-o m e. If th e ep id em io lo gica l evid en ce p o in ted exa ctly in th e op p osite d irection it wou ld n ot b e d iffi-cu lt to fin d an oth er b iological exp lan ation .
As far as the stren gthof the association is con -cern ed , th e au th ors con sid er a Sp earm an corre-lation = -0.68 with a d escrip tive level of sign ifi-can ce = 0.042 as bein g a NOTABLE (ou r cap itals) n egative correlation . It should be n oted that with n in e observation s, th ey h ad on ly seven observa-tion s to con tribute to the calculaobserva-tion of the resid-ual in the estim ated lin ear equation , an d particu-larly that takin g in to accoun t an R2= 0.46 (-0.682), which m ean s low p recision , they do lacked suffi-cien t evid en ce to con sid er correlation n otab le.
