Infectious Diseases in Latin America

and the Caribbean: Are They Really

Emerging and Increasing?
Duri ng 1995, i nfecti ous di sease epi demi cs i n
Lati n Ameri ca and the Cari bbean r ecei ved wi de
publ i ci ty: dengue throughout the r egi on, Venezue-
l an equi ne encephal i ti s (VEE) i n Venezuel a and
Col ombi a, and hemorrhagi c fever i n Ni caragua.
I ncr eased awareness of these di seases fol l owed
extensi ve reports i n the sci enti fi c communi ty
about the threat of emer gi ng i nfecti ons (1,2). Are
i nfecti ous di seases i ncreasi ng i n the regi on or are
we si mpl y seei ng the resul ts of better r eporti ng of
persi stent probl ems? Anal ysi s suggests that both
factors are at wor k.
Dengue and Dengue Hemorrhagic Fever
Duri ng the 1950s and 1960s, under the l eader-
shi p of the Pan Amer i can Heal th Organi zati on
(PAHO), most countri es i n the Ameri cas success-
ful l y r educed or el i mi nated i nfestati on wi th Aedes
aegypti, the pri nci pal vector of dengue and urban
yel l ow fever. As a resul t, much of the Amer i cas
became free of dengue. Dengue transmi ssi on,
however, persi sted i n many Cari bbean i sl ands and
i n some countri es of norther n South Amer i ca that
fai l ed to control the vector; ther efore, several out-
breaks occur red duri ng the 1960s and i n sub-
sequent decades (3).
Ae. aegypti eradi cati on programs, however,
were not sustai ned and the mosqui to r ei nfested
al l Lati n Amer i can countri es except Chi l e and
Ur uguay. As a consequence, dengue spr ead
throughout the regi on, causi ng sever e epi demi cs
or even pandemi cs duri ng the 1970s and 1980s.
Cur rentl y, dengue i s endemi c i n vi rtual l y al l coun-
tri es wi th Ae. aegypti, and epi demi cs occur peri -
odi cal l y.
Between 1968 and 1980, onl y 60 suspected or
confi rmed cases of dengue hemorrhagi c fever
(DHF) were reported, al l by fi ve countri es i n and
around the Cari bbean. After the 1981 DHF out-
break i n Cuba, r eports of DHF i n the Amer i cas
markedl y i ncr eased. The Cuban epi demi c was the
most notabl e event i n the hi story of dengue i n the
Ameri cas: al most 400,000 cases of dengue, over
10,000 cases of DHF, and 158 deaths were r e-
ported. The Cuban authori ti es i mpl emented a
successful vector control program and the country
i s sti l l vi rtual l y free of Ae. aegypti. After thi s
outbreak, cases of DHF conti nued to occur i n the
Ameri cas, al though at rel ati vel y l ow l evel s, unti l
1989 when another l arge epi demi c wi th 2,500
cases of DHF occurred i n Venezuel a. Si nce then,
Venezuel a has reported l arge numbers of DHF
cases every year, and i n 1995 the country reported
the l argest outbreak of dengue/DHF i n i ts hi story:
al most 30,000 dengue cases and 5,000 DHF cases.
Si nce 1968, 25 countri es of the Ameri cas have
reported more than 35,000 confi rmed or suspected
DHF cases and approxi matel y 500 deaths.
I n 1995, dengue and DHF acti vi ty i n the regi on
was hi gher than i n any year except 1981. As of
November, countri es i n the Ameri cas had reported
more than 200,000 dengue cases and 6,000 DHF
cases, and approxi matel y 90 deaths. Brazi l has
had the l argest number of dengue cases, but more
than 80% of the DHF cases occurr ed i n Venezuel a.
The r ei nvasi on of the Amer i cas by dengue vi rus
type 3, whi ch had been absent for 16 years, has
i ncreased the threat of l arge epi demi cs and conse-
quent ri sk for DHF (4). Thi s serotype was i sol ated
i n Panama and Ni caragua at the end of 1994, and
i n 1995 i t spread to other Central Ameri can coun-
tri es (except Bel i ze) and Mexi co, causi ng severe
outbreaks. Hi gh l evel s of i nfestati on wi th Ae.
aegypti are common from the Uni ted States to
Argenti na, maki ng i t l i kel y that dengue epi demi cs
wi l l i ncr ease i n fr equency and severi ty.
Cholera
Another di sease reemer gi ng i n the Ameri cas i s
epi demi c chol era, whi ch had been absent from thi s
hemi sphere for appr oxi matel y 90 years before i t
was i ntroduced i nto Peru i n January 1991 (5).
Si nce then mor e than 1 mi l l i on cases of chol era
have been reported i n 20 countri es i n the regi on.
Onl y Uruguay and the i sl ands of the Cari bbean
have been spared. Though the annual total of
reported cases has decr eased si nce 1991, the di s-
ease i s persi stent and probl emati c i n several Lati n
Ameri can countri es.
Venezuelan Equine Encephalitis
An outbreak of human i nfecti on wi th VEE vi rus
associ ated wi th a l arge number of equi ne cases
and deaths was detected i n northwestern Vene-
zuel a i n Apri l 1995. The di sease spr ead to the
adjacent Col ombi an state of La Guaji ra i n Sep-
tember (6). Unusual l y heavy rai ns duri ng 1994
an d 1995 con tr i bu ted to th e epi demi c by
Commentary
Vol. 2, No. 1 January-March 1996 59 Emerging Infectious Diseases
i ncreasi ng breedi ng si tes for the mosqui to vectors
Ae. taeniorrhynchus and Psorophora confinnis. Vi -
ral strai ns wi th epi zooti c and epi demi c potenti al
appear to have emerged from enzooti c strai ns
mai ntai ned i n enzooti c r odent-mosqui to cycl es (7).
I n addi ti on, fai l ure to i mmuni ze wi l d and domes-
ti c equi ne popul ati ons al l owed the vi rus to ampl i fy
and spread. By mi d-October 1995, reported hu-
man cases total ed 26,500 i n Venezuel a and 22,300
i n Col ombi a, wi th 24 deaths i n the l atter. Attack
rates i n severel y affected communi ti es were 18%
to 57%.
Thi s epi demi c of VEE i s the l argest si nce that
of 1962-1971, when the di sease extended from
northern South Ameri ca through Central Ameri ca
and Mexi co to the Uni ted States (8). I ntensi fi ed
vector control (i ncl udi ng appl i cati on of adul ti ci des
and l arvi ci des), equi ne vacci nati on, and r estri c-
ti on of equi ne movement appear to have at l east
temporari l y control l ed the epi demi c.
Leptospirosis
I n l ate October 1995, Ni caragua reported sev-
eral hundred cases of a hemorr hagi c febri l e i l l ness
i n and near the communi ty of Achuapa, approxi -
matel y 110 km northwest of Managua; ei ght pa-
ti ents di ed. The affected communi ti es had
experi enced unusual l y heavy rai ns and fl oodi ng
duri ng the 2 weeks before the cases were noted.
Al though dengue was occur r i ng el sewher e i n
Ni caragua at the same ti me, that di agnosi s was
excl uded by negati ve l aboratory tests and the
absence of Ae. aegypti i n the l ocal area. I n addi -
ti on, some of the pati ents had frank pul monary
hemorrhage [not typi cal of dengue]. By the end of
October, the Centers for Di sease Control and Pr e-
venti on had rul ed out dengue, other arbovi ruses,
and hemor rhagi c fever vi ruses as causes but had
i denti fi ed l eptospi ra by i mmunohi stochemi stry i n
ti ssues from four pati ents wi th fatal cases. By
mi d-November, the Mi ni stry of Heal th reported
that 2,480 persons had been i l l , 750 were hospi tal -
i zed, and at l east 16 di ed. (I nvesti gati on to defi ne
the extent of i l l ness and the r esponsi bl e ser ovars
was sti l l i n progress at thi s wri ti ng.)
Of the exampl es di scussed here, dengue and
DHF are certai nl y r eemergi ng. Dengue has been
si gnal i ng i ts r eturn for mor e than 15 years and
DHF si nce 1989; these di seases wi l l l i kel y persi st
as epi demi c pr obl ems unl ess drasti c changes i n
vector control are achi eved. Enzooti c VEE has
persi sted i n northern Venezuel a and Col ombi a
si nce the pr evi ous major epi demi c of 1962-1971.
PAHO had urged the countri es to i ncr ease vacci -
nati on coverage of equi nes because of i ncr eased
vi ral acti vi ty i n 1993 and 1994. The appearance i n
1995 of strai ns si mi l ar to these of the 1962-1971
epi demi cs, wi th l ocal l y i ntense transmi ssi on,
rai sed the possi bi l i ty that VEE woul d r eemerge as
a major epi demi c di sease. Whether vi gorous vec-
tor control measures and i mmuni zati on pr ograms
have contai ned that threat i s not yet known, but
we must conti nue to regard the threat as real .
Leptospi rosi s i s a persi stent, often under-recog-
ni zed, probl em to whi ch the i nternati onal commu-
ni ty has pai d r el ati vel y l i ttl e attenti on. I n
Ni caragua, publ i c heal th i nter est was sparked by
concer n that the epi demi c of a new di sease woul d
pose a threat to other communi ti es and countri es,
but attenti on waned as that threat di mi ni shed.
Yel l ow fever, whi ch i s usual l y present i n rel ati vel y
l ow numbers i n remote areas of South Ameri ca,
reemerged wi th for ce i n Peru duri ng 1995. At l east
seven departments of that country have been af-
fected (470 cases and a 40% case-fatal i ty rate by
September 1995).
Several factors have contri buted to the reemer-
gence of i nfecti ous di seases i n the Ameri cas. I n-
vestments i n publ i c heal th have been decr easi ng
because of economi c recessi on and a shri nki ng
publ i c sector or have been di verted from i nfecti ous
di sease programs to other pr essi ng probl ems (9).
Human popul ati ons throughout the regi on have
gr own and become i ncreasi ngl y urban, wi th many
l i vi ng i n i nadequate housi ng wi thout sani tati on or
potabl e water. At the same ti me, popul ati on and
commerci al pressures have l ed to the i nvasi on of
forests, exposi ng peopl e to exoti c agents and en-
zooti c di seases, i ncl udi ng yel l ow fever, rabi es
transmi tted by vampi re bats, arenavi ruses, and
others. Human behavi or has contri buted to epi -
demi c pl ague i n Per u and the rapi d spread of
di seases such as chol era. To thi s l i st can be added
the effects of deforestati on and habi tat and cl i -
mate change. Unusual l y heavy rai nfal l contri b-
uted to at l east three of the epi demi cs consi der ed
i n thi s commentary (10).
Commentary
Emerging Infectious Diseases 60 Vol. 2, No. 1 January-March 1996
I nfecti ous di seases (whether new or r ee-
mergi ng) are a real and seri ous pr obl em i n Lati n
Ameri ca and the Cari bbean. To combat the threat
of these di seases, PAHO, wi th the parti ci pati on of
other i nsti tuti ons i n the regi on, has prepared a
r egi on al pl an to i mpr ov e s ur vei l l ance for
emergi ng di sease and enhance countri es abi l i ty to
respond effecti vel y by strengtheni ng l aboratory
capaci ty, trai ni ng, and r esearch and by i mpl e-
menti ng preventi on and control strategi es. Mi ni s-
ters of heal th from countri es throughout the
regi on di scussed and endorsed the pl an at a meet-
i ng of PAHOs Di recti ng Counci l i n September
1995. Successful i mpl ementati on of the pl an wi l l
r equi r e commi tted acti on by publ i c heal th
authori ti es and col l aborati on and cooperati on by
many i nsti tuti ons and experts throughout the r e-
gi on.
A. David Brandling-Bennett
Francisco Pinheiro
Pan Ameri can Heal th Organi zati on
Washi ngton, D.C., USA
References
1. I nsti tute of Medi ci ne. Emergi ng i nfecti ons: mi cr obi al
thr eats to heal th i n the Uni ted States. Washi ngton,
DC: Nati onal Academy Pr ess, 1992.
2. Centers for Di sease Contr ol and Preventi on. Address-
i ng emergi ng i nfecti ous di sease threats: a pr eventi on
str ategy for the Uni ted States. Atl anta, GA: Center s
for Di sease Control and Preventi on, 1994.
3. Pan Amer i can Heal th Organi zati on. Dengue and den-
gue hemorrhagi c fever i n the Amer i cas: gui del i nes for
pr eventi on and control . Washi ngton, DC: Pan Ameri -
can Heal th Organi zati on, 1995.
4. Centers for Di sease Contr ol and Preventi on. Dengue
type 3 i nfecti onNi caragua and Panama, October-
November 1994. MMWR 1995;44:21-4.
5. Tauxe RV, Mi ntz ED, Qui ck RE. Epi demi c chol era i n
the New Worl d: transl ati ng epi demi ol ogy i nto new
pr eventi on strategi es. Emergi ng I nfecti ous Di seases
1995;1:141-6.
6. Centers for Di sease Control and Preventi on. Venezue-
l an equi ne encephal i ti sCol ombi a, 1995. MMWR
1995;44:721-4.
7. Centers for Di sease Control and Preventi on. Update:
Venezuel an equi ne encephal i ti sCol ombi a, 1995.
MMWR 1995;44:775-7.
8. Wal ton TE, Grayson MA. Venezuel an equi ne encepha-
l omyel i ti s. I n: Monath TP, ed. The arbovi r uses:
epi demi ol ogy and ecol ogy. Boca Raton, FL: CRC Press,
1989;203-32.
9. Pan Amer i can Heal th Organi zati on. Soci al response
to heal th probl ems. I n: Heal th Condi ti ons i n the
Ameri cas. Washi ngton, DC: Pan Amer i can Heal th Or-
gani zati on, 1994;303-420.
10. Epstei n PR, Pena OC, Racedo JB. Cl i mate and di sease
i n Col ombi a. Lancet 1995:346;1243-4.
Commentary
Vol. 2, No. 1 January-March 1996 61 Emerging Infectious Diseases
Microbial Threats and the Global
Society
The publ i c heal th threat of mi crobi al organi sms
l i vi ng i n what can be regarded as one l arge gl obal
soci ety was the subject of a recent i nteracti ve
workshop sponsored by Tufts Uni versi tys Educa-
ti on for Publ i c I nqui ry and I nter nati onal Ci ti zen-
shi p 10th anni versary cel ebrati on, hel d at Tufts
Uni versi ty i n Medford, Massachusetts. The par-
ti ci pants* di scussed mi crobes as the harbi ngers of
di sease and soci ety as both potenti al vi cti m and
guardi an of heal th. Mi crobi al threats were i denti -
fi ed as new, r eemergi ng, and not yet known.
The for um exami ned the many unanswer ed
questi ons regardi ng the or i gi n and causes of i nfec-
ti ous di sease agents. The fai l ur e of tradi ti onal
treatments due to anti bi oti c resi stance and the
i neffecti ve control and conti nued spread of i nfec-
ti ous agents were al so di scussed. Parti ci pants ad-
dressed envi ronmental and behavi or factors that
foster the ampl i fi cati on and spread of di sease
organi sms: bathhouses conduci ve to the spread of
HI V i nfecti on, homel essness and crowded l i vi ng
promoti ng the spread of tubercul osi s, day-care
centers that are i deal envi ronments for the spr ead
of drug-r esi stant pneumococcus.
I n the context of the workshop at Tufts, anal y-
ses of emergi ng i nfecti ous di sease i ssues gener-
ated i nsi ghts about the pol i ti cal and soci al
framework wi thi n whi ch to address these threats
to heal th: A mi nori ty group may be parti cul arl y
affected by a new or reemergi ng di sease, as was
the case, for exampl e, of AI DS i n the gay popul a-
ti on or tubercul osi s i n the i mmi grant and home-
l ess popul ati on. These groups become val uabl e
resour ces for understandi ng the factors l eadi ng to
the emergence or reemergence of the di sease and
shoul d be the focus of publ i c heal th efforts for
curtai l i ng i ts spread. However, as the hi stor y of
AI DS demonstrates, because of pol i ti cal concerns,
i nvesti gati ve efforts are often del ayed or i nade-
quate to stop the spread of the di sease.
An emer gi ng or r eemergi ng organi sm, however,
propagates and spreads unhi ndered by the soci al
concer ns of i ts potenti al l y i nfectabl e host. To mi -
cr oorgani sms, the worl d i s a si ngl e enti ty wi thout
borders. Mi croorgani sms have mor e freedom than
we do and al so mor e geneti c fl exi bi l i ty. Thus, i n
the contest between humans and mi crobes, we are
at a di sadvantage. We can nei ther easi l y acqui re
resi stance mechani sms against the or gani sms,
nor rapi dl y r espond to an i nfecti ous di sease pr ob-
l em i n another country. The recent di ffi cul ti es i n
deal i ng wi th a possi bl e pl ague epi demi c i n I ndi a
are just one exampl e. Moreover, anti bi oti cs whi ch
have been a front-l i ne weapon agai nst di seases
are becomi ng i ncr easi ngl y i neffecti ve, and new
anti bi oti cs to treat and contai n dr ug-resi stant
bacteri al strai ns are not avai l abl e.
I nadequate mi crobi ol ogi c di agnosti c capabi l -
i tyal so the r esul t of the nati onal and i nterna-
ti onal pol i ti cal cl i mateworks to the advantage
of emergi ng mi cr obes. Duri ng the pl ague outbreak
i n I ndi a, l aborator y faci l i ti es that coul d confi rm
the di agnosi s were l acki ng. I n the Uni ted States,
si mi l ar i nadequaci es i n l aboratory di agnosti c ca-
paci ty i nterfere wi th rapi d reporti ng of common
communi ty-acqui red i nfecti ons and thei r suscep-
ti bi l i ty to anti bi oti cs. I f physi ci ans promptl y knew
what they were treati ng, the need for use of an
anti bi oti c as wel l as the pr oper ki nd of anti bi oti c
woul d be based on data, not guesswork.
The emergence of anti bi oti c r esi stance was not
factored i nto strategi c pl anni ng by publ i c heal th
authori ti es. I f i t had been, perhaps condi ti ons
coul d have been i n pl ace to handl e i t, as wel l as
AI DS, tubercul osi s, and other emergi ng patho-
gens. I nsurance agai nst devastati ng happeni ngs
i n i nfecti ous di sease has never been gi ven the
attenti on i t deserves. Such i nsurance woul d have
been hel pful , not just i n money, but al so i n exper-
ti se to for fend and then cope wi th the cal ami ty,
l i ke i nsurance for earthquake damage to structure
and other unexpected di sasters. Shoul d we not
consi der i nsuri ng our future by putti ng more
money and experti se i nto basi c research, i nto sys-
tems for survei l l ance, and i nto ways to curtai l the
spread of a di sease once i t has emerged?
To meet the demands of i ncreased publ i c heal th
acti vi ty and to i mpl ement an i nsurance pol i cy
for the future, we need to be abl e to communicate
the probl em to a broad audi ence that someti mes
has l i ttl e understandi ng of the sci ence. To some
publ i c heal th offi ci al s, recogni ti on that an i nfec-
ti ous di sease probl em exi sts i s suffi ci ent to ad-
dress the probl em. However, to those not trai ned
i n the fi el d who may be maki ng i mportant pol i cy
deci si ons, the publ i c safety aspect of the pr obl em
can be emphasi zed. Heal th, l i ke cri me and traffi c,
shoul d become once agai n a major soci ety i ssue.
Requests for i ncreasi ng support for survei l -
l ance, educati on, and research must take i nto
account curr ent pol i ti cal and soci al pri ori ti es and
Commentary
Emerging Infectious Diseases 62 Vol. 2, No. 1 January-March 1996
emphasi ze di rect benefi ts to the U.S. popul ati on;
i nter nati onal efforts shoul d i nvol ve the col l abora-
ti on of other countri es.
Nongovernment agenci es need to be enl i sted i n
thi s publ i c heal th effort; thus a l arger porti on of
soci ety wi l l be i nvol ved i n the fi ght agai nst the
ever-i ncreasi ng thr eat of i nfecti ous di seases.
Stuart B. Levy
Center for Adaptati on Geneti cs and Drug Resi stance,
Tufts Uni versi ty School of Medi ci ne, Boston
Massachusetts, USA
*Participants: Stuart B. Levy, Tufts University School of
Medicine, and Ruth L. Berkelman, Centers for Disease Control
and Prevention (co-conveners); Christopher Foreman, The
Brookings Institute; Laurie Garrett, Newsday; Margaret
Hamberg, New York City Department of Health; Joshua
Lederberg, Rockefeller University; Jonathan Mann, Christopher
Murray, Harvard School of Public Health.
Commentary
Vol. 2, No. 1 January-March 1996 63 Emerging Infectious Diseases
Xenotransplantation: Risks, Clinical
Potential, and Future Prospects
The reemergence of xenotranspl antati on as a
therapeuti c opti on for the hundreds of thousands
of peopl e dyi ng each year of heart, ki dney, l ung,
and l i ver fai l ur e has rai sed ethi cal , soci al , and
sci enti fi c questi ons. End-stage organ fai l ure i s one
of the most i mportant publ i c heal th pr obl ems fac-
i ng Ameri cans today. Heart fai l ur e, for exampl e,
ki l l s four ti mes as many peopl e as does HI V i nfec-
ti on and thr ee ti mes as many peopl e as does breast
cancer; i t i s a di sease wi th an i ncreasi ng i nci dence,
and the cost of taki ng care of affected pati ents i s
8 to 35 bi l l i on dol l ars each year. The si ngl e most
effecti ve therapy for i t i s transpl antati on. Preven-
ti ve therapi es have had l i ttl e i mpact on di seases
due to end-stage organ fai l ure and are unl i kel y to
have an i mpact at l east i n the next decade. I n the
meanti me, demand for or gans, whi ch far outstri ps
the suppl y, conti nues to grow. I t has been esti -
mated that approxi matel y 45,000 Ameri cans un-
der age 65 coul d benefi t each year from heart
transpl antati on, yet onl y 2,000 human hearts are
avai l abl e annual l y. Pati ents are mor e l i kel y to di e
wai ti ng for a human donor heart than i n the fi rst
2 years after transpl antati on.
Al though cl earl y an experi mental procedure,
xenotranspl antati on between cl osel y rel ated spe-
ci es, such as baboons and humans, offers an al ter-
nati ve to al l otranspl antati on as a source of human
organ repl acement. Al ternati ves to al l ograft do-
nors, such as baboon or pi g xenografts, requi re
seri ous i nvesti gati on i f cl i ni cal transpl antati on i s
ever to meet the current demand and conti nue the
expl osi ve growth pattern i t has establ i shed over
the past quarter century.
Bi ol ogi c cardi ac repl acement poses the i mmu-
nol ogi c probl ems of rejecti on and i nfecti on associ -
ated wi th transpl antati on. I ncreasi ng cl i ni cal
experi ence worl dwi de has shown that rejecti on
and i nfecti on can be managed successful l y i n most
pati ents who recei ve human cardi ac al l ografts.
Further, the i ntroducti on of cycl ospori ne as the
pri mary i mmunosuppressi ve agent for cardi ac
transpl ant r eci pi ents has resul ted i n excel l ent
survi val rates (85% 1-year survi val at most cen-
ters) and has decr eased i l l ness associ ated wi th
i nfecti on and rejecti on. Al though consi derabl e ad-
vances have been made i n the fi el d of cardi ac
xenotranspl antati on si nce i ts fi rst cl i ni cal appl i -
cati on by Hardy i n 1964 (1), i t remai ns uncertai n
whether xenotranspl antati on as desti nati on ther-
apy can be successful l y appl i ed to humans. How-
ever, heart, ki dney, and l i ver xenografts have been
abl e to support human l i fe for an extended peri od.
I t i s thi s fact that i nvesti gators wi sh to expl oi t i n
cl i ni cal bri dgi ng studi es. By provi di ng temporary
heart, ki dney, or l i ver support as a bri dge-to-
transpl antati on, these bi ol ogi cal devi ces may al -
l ow pati ents to recover end-organ functi on and
awai t al l ograft transpl antati on i n a mor e stabl e
cl i ni cal state, thus i mprovi ng thei r chances of
survi val . Bri dgi ng strategi es cannot al l evi ate the
human organ donor shortage. However, i f one
vi ews bri dgi ng strategi es as a fi rst feasi bi l i ty test,
then cr oss-speci es transpl antati on does offer the
possi bi l i ty of eventual l ong-term or gan repl ace-
ment. Success i n thi s more ambi ti ous goal woul d
hel p al l evi ate the human organ donor shortage.
Nonhuman pri mate organ donors have been
favored by those wi shi ng to mi ni mi ze the geneti c
di spari ty between donors and human reci pi ents.
Chi mpanzees, al though most compati bl e wi th
standard sel ecti on cri teri a (e.g., compati bi l i ty of
si ze and bl ood types), are unavai l abl e as an ac-
ceptabl e sour ce of cl i ni cal xenotranspl antati on.
Another choi ce i s the baboon, whi ch i s not endan-
gered, has an anatomy and physi ol ogy si mi l ar to
those of humans, and gr ows to a wei ght of approxi -
matel y 70 pounds. Baboon si ze woul d l i mi t the
cl i ni cal appl i cati on of xenotranspl antati on wi th
baboon organs to pedi atri c pati ents and smal l
adul ts. Smal l body si ze, the i nfrequency of bl ood
gr oup O (uni versal donor) ani mal s, and the l i m-
i ted number of col ony-bred ani mal s are di sti nct
di sadvantages to the baboon as a donor.
Extended graft survi val i s possi bl e, but ABO
bl ood group compati bi l i ty i s mandator y before
xenotranspl antati on (2). The di stri buti on of ABO
bl ood groups found i n baboons i ndi cates that ap-
proxi matel y one thi rd are group A, one-thi rd
gr oup B, and one-thi rd group AB. Uni versal donor
gr oup O, however, i s exceedi ngl y rare. I n Ameri -
cans of Wester n European descent, the rel ati ve
frequency of bl ood types i s approxi matel y 45%
gr oup A, 8% group B, 4% group AB, and 43% group
O (2).
Al though avai l abl e i n l arge numbers, wi l d ba-
boons are not sui tabl e from an i nfecti ous di sease
perspecti ve. Most experts have suggested that
col ony-bred ani mal s r epresent a more sui tabl e
donor pool . However, these ani mal s number onl y
i n the hundreds and are, therefor e, onl y l i kel y to
Commentary
Emerging Infectious Diseases 64 Vol. 2, No. 1 January-March 1996
parti al l y meet the epi demi ol ogi c demands of the
pedi atri c popul ati on wi th end-stage organ fai l ure.
Xenotranspl antati on between baboons and hu-
mans rai ses the i ssue of xenozoonoses (3,4). The
organi sms of greatest concer n are the her pes-
vi ruses and retrovi ruses, whi ch can be screened
for and el i mi nated fr om the donor pool . Others
i ncl ude Toxoplasma gondii, Mycobacterium tuber-
culosis, and encephal omyocardi ti s vi rus. Less
l i kel y to be found i n ani mal s rai sed i n capti vi ty i n
the Uni ted States are the fi l ovi ruses (Marburg
and Ebol a), monkeypox, and Si mi an hemorrhagi c
fever vi rus. Organi sms that are unl i kel y to be
transmi tted wi th an or gan transpl ant (but shoul d
be scr eened for ) i ncl ude l ymphocyti c chori omen-
i ngi ti s vi rus, gastroi ntesti nal parasi tes, and GI
bacteri al pathogens.
The ri sk for xenozoonoses i s l i kel y to be r e-
stri cted to the xenogenei c ti ssue reci pi ent. Never-
thel ess, one must consi der and anti ci pate the
potenti al for xenozoonoti c transmi ssi on thr ough
the human popul ati on, consti tuti ng a publ i c
heal th concer n. The ri sk for recogni zed zoonoti c
pathogens can be reduced, i f not el i mi nated, by
control l i ng the donor ani mal vendor source and
the i ndi vi dual donor ani mal by empl oyi ng de-
scri bed screeni ng tests and stri ct steri l e pr oce-
dures duri ng or gan harvesti ng and donor autopsy
for ti ssue and bl ood. The ri sk for unrecogni zed
pathogens i s present but i l l defi ned.
Survei l l ance for the transmi ssi on of known or
unknown pathogens among heal th care workers
must be conducted by moni tori ng for unexpected
or unexpl ai ned adverse heal th events. I t i s di ffi -
cul t to moni tor for the unknown; therefor e, sur-
vei l l ance shoul d i ncl ude noti fyi ng the pri nci pal
i nvesti gator s offi ce of any unexpl ai ned i l l ness i n
exposed heal th care workers, as wel l as tel ephone
i nter vi ews of these personnel every 6 months by
the pri nci pal i nvesti gator s offi ce.
Con cu r r ent wi th s ci enti fi c adv ances i n
xenotranspl antati on have been the necessary
ethi cal debates concerni ng the appr opri ateness of
thi s endeavor (5). Di sputes r egardi ng ani mal ex-
peri mentati on notwi thstandi ng, the ethi cal i ssues
rai sed by many of these debates are stri ki ngl y
si mi l ar to those put forth 25 years ago i n r eference
to the (then new) fi el d of human heart transpl an-
tati on. I ndeed, the ti mel ess nature of these que-
ri es i tsel f attests to thei r essence, for such ethi cal
concer ns are appropri ate i n the apprai sal of any
new therapeuti c procedure i n medi ci ne.
Can one ever hope to determi ne i f or when the
cl i ni cal appl i cati on of xenotranspl antati on i s jus-
ti fi ed? The assessment of any experi mental ther-
apy, as Fox and Swazey (6) have suggested, shoul d
encourage the i nvesti gator to address three cri ti -
cal questi ons: 1) i n the l aborator y, what defi nes
success suffi ci ent to warrant advancement to
the cl i ni cal arena? 2) under what cl i ni cal condi -
ti ons shoul d thi s advancement proceed? and 3) i n
the cl i ni cal arena, what defi nes success suffi -
ci ent to warrant further eval uati on (6)? Provi di ng
answers to thi s thr eefol d i nqui ry r equi res a r el i -
ance upon defi ned success, i tsel f an apprai sal of
judgment that can onl y confi dentl y be made i n
retrospect.
Because human heart transpl antati on i s now
consi dered by most justi fi abl e for the treatment of
end-stage heart di sease, I woul d fi rst l i ke to r e-
vi ew the hi story of cardi ac al l otranspl antati on i n
l i ght of i ts abi l i ty to address the above threefol d
i nqui ry. I wi l l al so di scuss the hi stor y of cardi ac
xenotranspl antati on wi th reference to sci enti fi c
advances made i n the fi el d throughout the past
quarter century. Fi nal l y, i n l i ght of these anal yses,
I hope to i l l ustrate the rol e of baboon heart
xenotranspl antati on as an al ternati ve to al l o-
transpl antati on for permanent cardi ac repl ace-
ment i n the treatment of end-stage heart di sease.
After the fi rst human cardi ac al l ograft pr oce-
dure performed by Barnard i n 1967 (7) the fi el d of
cardi ac transpl antati on wi tnessed a sur ge i n both
enthusi asm and attempted tri al s, whi ch was fol -
l owed by a marked drop i n pr ocedur es throughout
the 1970s because of poor survi val rates. Duri ng
the i ni ti al peak, 21 human heart al l otranspl ants
were performed i n the 6-month i nterval between
December 1967 and June 1968 (wi th a cumul ati ve
1-year survi val of 22%), and 105 cardi ac al l o-
transpl antati ons were performed i n 1968 al one
(8-10). However, these earl y cl i ni cal tri al s were
marr ed by numerous fai l ures, as 65% of persons
undergoi ng the pr ocedur e before June 1970 di ed
wi thi n 3 months of transpl antati on (6).
Few centers conti nued ani mal r esearch and
human procedures duri ng the so-cal l ed bl ack
years of cardi ac transpl antati on. The i ni ti al expl o-
si on i n cl i ni cal tri al s accordi ngl y el i ci ted numer-
ous responses suggesti ng that too much was bei ng
attempted too soon.
Some woul d propose that thi s was the pri ce of
eventual success, and that further experi mental
studi es at the ti me coul d not have avoi ded earl y
Commentary
Vol. 2, No. 1 January-March 1996 65 Emerging Infectious Diseases
l osses. And yet, there has been, and may al ways
be, a taci t r ecogni ti on by medi cal i nnovators that
the ul ti mate experi ment must be performed i n
humans, for no ani mal model can trul y refl ect the
human condi ti on. Proponents of al l otranspl anta-
ti on at the ti me of the fi rst heart transpl antati on
ci ted the more than 60-year hi story of experi men-
tal cardi ac transpl antati on, begi nni ng wi th Car-
rel s ori gi nal wor k i n 1905. Al though most of thi s
work began i n the 1930s, subsequent i nvesti ga-
ti ons regardi ng the experi mental transpl antati on
of mammal i an hearts showed that cardi ac trans-
pl antati on was techni cal l y feasi bl e and suggested
the possi bi l i ty of cl i ni cal l y r el evant sur vi val rates.
Duri ng the decade befor e Barnards fi rst cl i ni cal
appl i cati on, cardi ac al l ograft survi val had been
shown to exceed 250 days (mean 103 days) i n adul t
dogs treated wi th an i mmunosuppressi ve regi men
that i ncl uded azathi opri ne and methyl predni sone
used i ntermi ttentl y. The mean survi val i n un-
treated dogs used as control s was 7 days (11).
Si nce that ti me, wi th further expansi on of
knowl edge i n vi rtual l y al l areas of cl i ni cal cardi ac
transpl antati on, 1-year survi val has i ncr eased
from 67% i n 1976, to approxi matel y 85% reported
currentl y at most hospi tal centers (3). Human
reci pi ents have sur vi ved for as l ong as 20 years
after transpl antati on, and the 10-year posttrans-
pl ant survi val rate i s now approxi matel y 45% (12).
Whi l e these fi gur es depi ct a cl ear i mpr ovement i n
raw survi val , cardi ac transpl antati on i s sti l l not a
cure for end-stage heart di sease. Reci pi ents must
take i mmunosuppressi ve medi cati on for l i fe and
be moni tored for i nfecti on, rejecti on, and graft
arteri opathy. However, these r esul ts are i mpres-
si ve consi deri ng that the reci pi ent popul ati on to-
day i s consi derabl y si cker than earl i er al l ograft
candi dates. I n l i ght of these fi ndi ngs, few woul d
deny cardi ac al l otranspl antati on i ts present cl ai m
to success. To further understand the evol uti on
of thi s achi evement, however, we may now l ook
back upon the earl y years of cardi ac al l otranspl an-
tati on and try to address the pr oposed threefol d
i nqui ry.
Fi rst, for Barnard and co-workers what can we
presume as success warranti ng advancement to
the cl i ni cal arena? They performed the fi rst hu-
man adul t cardi ac al l otranspl antati on when the
maxi mum sur vi val i n i mmunosuppressed adul t
dogs had been 250 days (average survi val 103
days) (11) and suggested that agai nst the back-
gr ound of thi s r esearch . . . the ti me arri ved when
a cardi ac transpl ant coul d be contempl ated wi th
hope of success (7). I ndeed, i n thei r report of thi s
case, they further descri bed the sci enti fi c basi s of
thei r cl i ni cal advancement by expl ai ni ng that
thi s achi evement di d not come as a surpri se to
the medi cal worl d. Steady pr ogress toward thi s
goal had been made by i mmunol ogi sts, bi ochem-
i sts, sur geons, and speci al i sts i n other branches of
medi cal sci ence al l over the worl d duri ng the past
decades to ensure that thi s, the ul ti mate i n car-
di ac sur gery, woul d be a success (7). Al though we
may, i n retrospect, consi der them justi fi ed i n thei r
decl arati on, i n fact, at that ti me the endeavor was
hi ghl y controversi al and came as a sur pri se to
much of the medi cal worl d.
Second, under what condi ti ons di d they proceed
wi th thi s cl i ni cal tri al ? Gi ven the hope of suc-
cess, Barnard and col l eagues sel ected a pati ent
consi der ed to have heart di sease of such severi ty
that no method of therapy short of cardi ac trans-
pl antati on coul d succeed (7). The pati ent, a 54-
year -ol d man, had r emai ned i n i ntr actabl e
congesti ve heart fai l ure (fol l owi ng mul ti pl e myo-
cardi al i nfarcti ons) despi te al l medi cal manage-
ment (13).
Fi nal l y, i n thi s cl i ni cal arena, what defi ned for
Barnard and col l eagues success warranti ng fur-
ther i nvesti gati on? A concur rent edi tori al i n the
South African Medical J ournal may provi de some
i nsi ght i nto thei r thi nki ng: The cl ai m successful
can be used even at thi s earl y stage because to-
date i t i s a feat whi ch makes medi cal hi story, no
matter how short the further survi val of the pa-
ti ent mi ght be (4). Success, by such an anal ysi s,
was thus not targeted posttranspl ant sur vi val
ti me, but rather any posttranspl ant survi val ti me
(gi ven the ground-breaki ng nature of the en-
deavor). Further edi tori al s regardi ng the ethi cs of
cardi ac transpl antati on vi ewed the pr ocedur e as
a l egi ti mate experi ment but not a treatment (15),
whi l e i n 1968, the Amer i can Col l ege of Cardi ol ogy
suggested (wi th r egard to the success of al l o-
transpl antati on) that resul ts vari ed: . . . the spec-
tr um of succes s r anges fr om s hor t-ter m
restorati on of ci rcul ati on to compl ete physi cal r e-
covery (16).
I ndeed, success di d vary al ong a spectrum of
resul ts. Barnard and col l eagues fi rst al l otrans-
pl ant reci pi ent l i ved for 18 days and ul ti matel y
di ed of pneumoni a. However, thei r second r eci pi -
ent, 1 month l ater, survi ved more than 19 months
befor e dyi ng of chroni c rejecti on (17). Thei r thi rd
Commentary
Emerging Infectious Diseases 66 Vol. 2, No. 1 January-March 1996
pati ent al so l i ved more than 20 months after al l o-
transpl antati on and ul ti matel y di ed of carci noma
of the stomach wi thout si gns of acute or chroni c
rejecti on (18). One can onl y specul ate how di ffer-
ent the worl d r ecepti on to al l otranspl antati on
woul d have been had the l atter two pati ents rep-
resented the fi rst and second reci pi ents of cardi ac
al l otranspl ants. Woul d these survi val data be con-
si dered success, or woul d they sti l l pal e i n com-
pari son wi th the theor eti cal goal of obtai ni ng a
graft that coul d functi on normal l y i ndefi ni tel y?
Cl i ni cal cr oss-speci es transpl antati on dates to
the ear l y twenti eth cen tu r y, wi th k i dney
xenografts from rabbi t, pi g, goat, non-human pri -
mate and l amb donors (19). After these earl y fai l -
ur es, the sci enti fi c l i terature was l argel y devoi d of
reports of cl i ni cal xenotranspl antati on for nearl y
40 years. I n 1963, Reemtsma and col l eagues
descri bed si x human reci pi ents of chi mpanzee ki d-
neys, the l ongest survi vor of whom di ed of causes
unrel ated to r ejecti on 9 months after xenotrans-
pl antati on (20).
The fi rst car di ac xenotranspl antati on, per-
formed by Hardy i n 1964, al so repr esented the
fi rst attempt at cardi ac transpl antati on i n hu-
mans, predati ng Barnards r eport by nearl y 4
years (1). Si nce 1964, when Hardy and col l eagues
at the Uni versi ty of Mi ssi ssi ppi performed the
worl ds fi rst heart xenotranspl ant usi ng a chi m-
panzee as a donor, there have been ei ght docu-
me n t e d a t t emp t s a t cl i n i ca l h e a r t x en o-
transpl antati on. Fi ve of these donors wer e non-
human pri mates (2 baboons, 3 chi mpanzees) and
three were domesti cated farm ani mal s (1 sheep, 2
pi gs) (21-25). The l ongest survi vor was a newborn
i nfant wi th hypopl asti c l eft heart syndrome.
Baby Fae was the reci pi ent of an ABO-bl ood
gr oup mi smatched baboon heart that functi oned
for 20 days (26). However, by the ti me the fi rst
human neonatal cardi ac xenotranspl antati on was
performed by Bai l ey i n 1984 (the so-cal l ed Baby
Fae case), there had been onl y l i mi ted experi -
mental experi ence wi th prol onged graft sur vi val
i n the newborn xenotranspl ant reci pi ent. Studi es
presented by Bai l ey and co-workers shortl y before
the Baby Fae case descri bed a mean sur vi val ti me
of 72 days i n newborn l amb-to-goat xenotrans-
pl ants, wi th one survi vor l i vi ng to 165 days (27).
Thi s advancement of xenotranspl antati on i nto
the cl i ni cal forum was met wi th resi stance i n the
medi cal communi ty because of a percepti on that
research wi th acceptabl e survi val success had
not been achi eved experi mental l y. As Losman i n
an edi tori al regardi ng the Baby Fae experi ence
stated, I t appears that thi s baboon-to-i nfant
transpl antati on di d not rest on such a [sci enti fi c]
basi s [as di d Barnards earl i er operati on i n 1967]
(28).
Duri ng the past 3 years, i nvesti gators at the
Uni versi ty of Pi ttsburgh reported two cases i n
whi ch they transpl anted a baboon l i ver i nto a
human reci pi ent, obtai ni ng a 70-day sur vi val i n
thei r fi rst reported case, and a 26-day survi val i n
the second (29; J.J. Fung, pers. comm.) The i nves-
ti gators overwhel mi ng effort to prevent rejecti on
l ed them to use a harsh i mmunosuppressi ve regi -
men that permi tted mul ti pl e l i fe-thr eateni ng
i nfecti ons. Rejecti on was not the major cl i ni cal
obstacl e they encountered; ther efore, they r ecom-
mended a more di rected and l ess arduous i mmu-
nosuppressi ve regi men for future pati ents.
More al armi ng have been the attempts to appl y
xenotranspl antati on of di stantl y rel ated speci es
to the cl i ni cal arena. I n 1968, both Cool ey and
Ross transpl anted sheep and pi g hearts, r espec-
ti vel y, i nto dyi ng human reci pi ents (30,31). Both
grafts fai l ed upon reperfusi on, presumabl y be-
cause of hyperacute r ejecti on.
More recentl y, Czapl i cki and co-workers i n
1992 descri bed a case i n whi ch they attempted the
xenotranspl antati on of a pi g heart i nto a human
reci pi ent wi th Marfans syndrome (32). By thei r
report, no evi dence of hyperacute rejecti on was
present at the ti me of death nearl y 24 hours after
xenotranspl antati on. Thei r pr otocol used an un-
usual i mmunosuppressi ve regi men i n whi ch both
donor and reci pi ent recei ved, i n addi ti on to con-
venti onal i mmunosuppressi on, both thymi c ti ssue
extracts and fetal cal f sera. Thi s regi men al so
i ncl uded the extracor poreal per fusi on of two pi g
hearts wi th the r eci pi ents bl ood i n an attempt to
remove human anti -pi g anti bodi es before the or-
thotopi c transpl antati on of the functi onal pi g
heart (33). As astoni shi ng as thi s case may be i n
i ts extensi on to the cl i ni cal arena of a techni que
not yet shown to be effecti ve i n the experi mental
l aboratory, i t i s not uni que. Al so i n 1992, Makowka
and col l eagues transpl anted a pi g l i ver i nto a
26-year-ol d woman dyi ng of acute l i ver fai l ure
from autoi mmune hepati ti s (pers. comm.). De-
spi te the fact that, at present, i t appears unl i kel y
that suffi ci ent success has been achi eved i n the
l aborator y r egar di ng xenotranspl antati on be-
tween di stantl y r el ated speci es to war r ant
Commentary
Vol. 2, No. 1 January-March 1996 67 Emerging Infectious Diseases
advancement to the cl i ni cal arena, these i nvesti -
gators were abl e to obtai n approval from thei r
hospi tal s ethi cs commi ttee and i nsti tuti onal r e-
vi ew board to proceed wi th the cl i ni cal tri al . Most
experts i n the fi el d of xenotranspl antati on share
the opi ni on that pi g-to-human or gan transpl anta-
ti on remai ns at l east 3 to 5 years fr om cl i ni cal
tri al s.
Consi derabl e advances i n the fi el d of cardi ac
xenotranspl antati on have subsequentl y emerged
worl dwi de si nce Hardys fi rst cl i ni cal attempt i n
1964, wi th a better understandi ng of the xenor e-
jecti on process and a mor e sophi sti cated i nsi ght
i nto mechani sms for i ts control . Extended graft
survi val has been achi eved i n a number of di ffer-
ent experi mental model s, i ncl udi ng a greater than
tenfol d graft sur vi val i n non-human pri mates
treated wi th conventi onal cycl ospori ne-based i m-
munosuppr essi on (34,35) a mor e than thi rtyfol d
i ncrease i n survi val over control s descri bed by
Cel l i and col l eagues i n a rodent model (36), and
survi val beyond 1 year r eported by Kawauchi and
col l eagues i n a non-human pri mate model (37).
These fi ndi ngs support the potenti al for achi evi ng
cl i ni cal l y rel evant graft survi val i n humans.
The questi on i s whether we have reached a
stage i n l aborator y experi mentati on to justi fy fur-
ther attempts at advanci ng cardi ac xenotrans-
pl antati on to the cl i ni cal arena. I f we vi ew the
current status of experi mental accompl i shments
i n xenotranspl antati on wi th the same scruti ny as
that of al l otranspl antati on at the ti me of Bar-
nards endeavor, we are l eft wi th si mi l ar concl u-
si ons; fi rst, comparabl e graft sur vi val ti me has
been achi eved i n ani mal model s of xenotranspl an-
tati on as was evi dent for al l otranspl antati on be-
for e 1967. Second, wi th ou r cur r ent
understandi ng of cardi ac al l otranspl antati on has
al so come a greater awareness of i ts l i mi tati ons.
Thus, the condi ti ons for the advancement of
xenotranspl antati on arguabl y coul d be ful fi l l ed by
a pati ent wi th end-stage heart di sease who i s a
candi date for al l otranspl antati on, but for whom a
donor cannot be i denti fi ed i n ti me. Fi nal l y, the
cl i ni cal success of xenotranspl antati on mi ght
al so be consi dered (as was the case for al l otrans-
pl antati on) any graft survi val , and the goal of
xenotranspl antati on to stri ve for extended graft
survi val .
However, pol i ti cal and sci enti fi c sensi bi l i ti es
today cl earl y di ffer from those of the 1960s, and so
the cri ti cal assessment of xenotranspl antati on
must be mor e ri gorous than our previ ous di scus-
si on. I ndeed, the above compari son was put forth
l argel y to underscore the mor e humbl e ori gi ns of
the (now) successful therapy (al l otranspl antati on)
to whi ch xenotranspl antati on i s currentl y com-
pared.
What then defi nes success i n the l aboratory
warranti ng advancement from the l aboratory to
the operati ng room? Havi ng demonstrated dra-
mati c prol ongati on of cardi ac xenograft sur vi val
through experi ments i n r odent and non-human
pri mate model s (27,34-37), whi ch model most
cl osel y approxi mates the human condi ti on (and
thus whi ch therapy wi l l be most successful i n
avoi di ng cl i ni cal rejecti on) remai ns to be estab-
l i shed. Therefore, i t i s reasonabl e to suggest both
that we have reached a formi dabl e l i mi tati on for
preci sel y predi cti ng the appl i cabi l i ty of experi -
mental l aborator y evi dence and that answers may
onl y be sought fr om experi ment i n humans. Thi s
concept was real i zed by the Ameri can Medi cal
Associ ati on wi th regard to al l otranspl antati on, i n
reference to whi ch i t r el eased an offi ci al statement
acknowl edgi ng thi s noti on i n 1969 (38).
Concerns most commonl y voi ced wi th respect
to the cl i ni cal appl i cati on of xenotranspl antati on,
however, pertai n to a l arger ethi cal controversy
regardi ng human experi mentati on. Reemtsma, i n
a rel ated comment concerni ng the Baby Fae case,
suggested the fol l owi ng: There i s a wi despr ead
mi spercepti on that medi cal treatments and surgi -
cal pr ocedur es are easi l y cl assi fi ed as ei ther ex-
peri mental or accepted. I n fact, al l treatments
have an el ement of experi mentati on, and new
surgi cal procedures are based on extrapol ati ons
from pri or wor k. . . . When does a surgeon deci de
to appl y a new operati on to a pati ent? . . . the
deci si on i s based on bal anci ng, on the one hand,
the experi mental evi dence suggesti ng that the
procedure may succeed, and, on the other, the
cl i ni cal urgency. . . (39).
Under what condi ti ons wi l l the cl i ni cal ad-
vancement of xenotranspl antati on proceed? For
those i ni ti al pati ents i n whom cl i ni cal xenotrans-
pl antati on wi l l fi rst be appl i ed, cl i ni cal urgency, i n
the compl ete absence of other sui tabl e al terna-
ti ves, undoubtedl y wi l l r epresent the moti vati ng
factor to proceed. Who wi l l compri se thi s i ni ti al
cohort? As Capl an has poi nted out: There woul d
appear to exi st a pool of termi nal l y i l l persons,
both chi l dren and adul ts for whom no therapeuti c
al ternati ves exi st or are l i kel y to exi st i n the near
Commentary
Emerging Infectious Diseases 68 Vol. 2, No. 1 January-March 1996
future. . . . I t woul d [thus] appear ethi cal l y defen-
si bl e to al l ow research i nvol vi ng xenografti ng i n
human subjects to proceed i n those areas where
no reasonabl e al ternati ve to therapy exi sts (40).
I n thi s context, i nnumerabl e reservati ons have
been voi ced regardi ng the ethi cs of pr oposi ng al -
ternati ve experi mental therapi es to such pati ents
for whom therapy has ei ther fai l ed or i s non-exi s-
tent. However, wi th regard to cl i ni cal experi men-
tati on under these ci rcumstances, one must al so
recal l (as Shi mki n has suggested): To do nothi ng,
or to prevent others from doi ng anythi ng, i s i tsel f
a type of experi ment, for the preventi on of experi -
mentati on i s tantamount to the assumpti on of
responsi bi l i ty for an experi ment di fferent from
the one proposed (41).
What i s the goal of the cl i ni cal appl i cati on of
xenotranspl antati on? The need for donor organs
i rr efutabl y outwei ghs the r esources avai l abl e, and
mechani cal devi ces and xenotranspl antati on have
emerged as the two most pr omi si ng al ternati ves
to al l ograft cardi ac repl acement. Mechani cal l eft
ventri cul ar assi st devi ces (LVADs) have wi tnessed
rel ati ve success as bri dges i n careful l y sel ected
pati ents wi th heart fai l ure. (A bri dge i s a tempo-
rary method of l i fe support desi gned to carry a
pati ent i ndefi ni tel y unti l a human heart can be
found and transpl anted. I t i s not a desti nati on
therapy.)
Cri teri a for LVADs excl ude pati ents wi th bi ven-
tri cul ar fai l ur e, and (because of the rel ati vel y
l arge si ze of the devi ce) pati ents wi th a total body
surface area l ess than 1.5 square meters (~120 l b).
Thus, many women and vi rtual l y al l chi l dren are
not candi dates for mechani cal l eft ventri cul ar as-
si stance. As has been the case for Food and Dr ug
Admi ni strati on pr otocol s usi ng LVADs, proposed
i nvesti gati ons i nvol vi ng bi ol ogi c assi st devi ces
(xenografts), have sought to eval uate a short-term
al ternati ve to al l otranspl antati on i n pati ents for
whom a donor heart i s not i mmedi atel y avai l abl e,
and death i s i mmi nent. Onl y candi dates who meet
cri teri a for heart transpl antati on, but do not meet
cri teri a for LVAD i nserti on, woul d be consi der ed
for a heart xenobri dge. Si mi l ar cl i ni cal scenari os
have been proposed for other sol i d organ trans-
pl ants. Si nce they were fi rst i ntroduced by Cool ey
i n 1969, temporary mechani cal ci rcul ator y sup-
port devi ces have become cri ti cal l y useful tool s i n
the therapeuti c armamentari um avai l abl e to pa-
ti ents awai ti ng transpl antati on (42). Neverthe-
l ess, at present, the wi despread appl i cati on of
mechani cal ci rcul ator y support i s l i mi ted both by
pati ent sel ecti on cri teri a and by the temporary
nature of the devi ce. For excl uded pati ents, as wel l
as many adul t mal e candi dates. For excl uded pa-
ti ents, cardi ac xenotranspl antati on may be the
onl y reasonabl e al ternati ve to cardi ac al l ograft
repl acement.
I nvesti gati ons i n cl i ni cal xenotranspl antati on
have been accused of usi ng the gui se of [bei ng a]
bri dge-to-transpl antati on to appear acceptabl e to
I nsti tuti onal Research/Ethi cal Boards (5). How-
ever, the use of xenografts (or mechani cal devi ces)
sol el y as bri dges to al l otranspl antati on wi l l not
i ncrease the donor pool , and, ther efore, successful
permanent xenotranspl antati on must i tsel f be
seen as the target for future cl i ni cal i nvesti ga-
ti ons. The goal of these studi es i s thus not to
engage, as Hasti l l o and Hess (5) woul d suggest, i n
the prematur e use of unproven pr ocedur es i n
fel l ow humans, but rather to i mpact posi ti vel y on
the curr ent shortage of human donor organs (6).
I n 1996, the cl i ni cal pi cture i s no l ess bl eak and
the concl usi ons no l ess val i d. The questi on that
remai ns i s not how but rather when xenotrans-
pl antati on shoul d advance to the cl i ni cal arena.
Most of the uncertai nti es sur roundi ng i ts ad-
vancement wi l l onl y be answered by i ts undertak-
i ng.
I n the foreseeabl e futur e, cl i ni cal xenotrans-
pl antati on may achi eve i ts targeted goal of ex-
tended graft survi val . As was the case duri ng the
ear l y y ear s of al l otr ans pl antati on, cl i ni cal
xenotranspl antati on must persevere under the
consi derati on of and often i n spi te of scruti ny by
i ts most demandi ng cri ti cs, for whi l e success has
a hundred fathers, fai l ure i s an orphan (43).
Robert E. Michler
Di r ector of Heart Transpl ant Servi ce
Di vi si on of Cardi othoraci c Surgery,
Col umbi a-Presbyteri an Medi cal Center, New York, NY,
USA
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Commentary
Emerging Infectious Diseases 70 Vol. 2, No. 1 January-March 1996