Emerging Infectious Diseases Volume 2 Issue 4

124 Pages·1996·1.1 MB·English

by  CDC

Emerging Vol. 2, No. 4, October-December 1996
Infectious Diseases
Tracking trends and analyzing new and reemerging infectious disease issues around the world
Evolutionary Biology P.W. Ewald
Social Inequalities and Infectious P. Farmer
Diseases
Molecular Mechanisms of J. Mecsas
Bacterial Virulence
New Vaccines for Pneumococcal H. Käyhty
Infections
A Mathematical Model T. Hraba
Chlamydiae R.W. Peeling
Experimental Inoculation with R. Swanepoel
Ebola Virus
Lyssavirus Encephalitis G.C. Fraser
in Australia
CJD in the United States R.C. Holman
Drug Resistance in Italy G. Cornaglia
Rabies Vaccine Cost-Benefit Model M. I. Meltzer
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Emerging Infectious Diseases
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Contents
Emerging Infectious Diseases
Volume 2 • Number 4 October—December 1996
Perspectives
Guarding Against the Most Dangerous Emerging Pathogens: Insights 245 P.W. Ewald
from Evolutionary Biology
Social Inequalities and Emerging Infectious Diseases 259 P. Farmer
Synopses
Molecular Mechanisms of Bacterial Virulence: Type III Secretion 271 J. Mecsas and E.J. Strauss
and Pathogenicity Islands
New Vaccines for the Prevention of Pneumococcal Infections 289 H. Käyhty and J. Eskola
ô
A Mathematical Model and CD4+ Lymphocyte Dynamics in HIV Infection 299 T. Hraba and J. Dolezal
Chlamydiae as Pathogens: New Species and New Issues 307 R.W. Peeling and R.C. Brunham
Dispatches
Experimental Inoculation of Plants and Animals with Ebola Virus 321 R. Swanepoel, P.A. Leman, F.J.
Burt, N.A. Zachariades, L.E.O.
Braack, T.G. Ksiazek, P.E.
Rollin, S.R. Zaki, and C.J.
Peters
Encephalitis Caused by a Lyssavirus in Fruit Bats in Australia 327 G.C. Fraser, P.T. Hooper, R.A.
Lunt, A.R. Gould, L.J. Gleeson,
A.D. Hyatt, G.M. Russell, and
J.A. Kattenbelt
Creutzfeldt-Jakob Disease in the United States, 1979-1994: Using National 333 R.C. Holman, A.S. Khan, E.D.
Mortality Data to Assess the Possible Occurrence of Variant Cases Belay, and L.B. Schonberger
Rapid Increase of Resistance to Erythromycin and Clindamycin 339 G. Cornaglia, M. Ligozzi, A.
in Streptococcus pyogenes in Italy, 1993-1995 Mazzariol, M.Valentini, G.
Orefici, the Italian Surveil-
lance Group for Antimicrobial
Resistance, and R. Fontana
Assessing the Costs and Benefits of an Oral Vaccine for Raccoon Rabies: 343 M.I. Meltzer
A Possible Model
Commentary
Traditional Healers and Global Surveillance Strategies for Emerging 351 N.E. Groce and M. E. Reeve
Diseases: Closing the Gap
Letters
Widespread Foodborne Cyclosporiasis Outbreaks Present Major Challenges 354 D.G. Colley
Identification of Cyclospora in Poultry 356 H.L. García-López, L.E.
Rodríguez-Tovar, and C.E.
Medina-De la Garza
PCR Confirmation of Infection with Cyclospora cayetanensis 357 N.J. Pieniazek, S.B. Slemenda,
A.J. da Silva, E.M. Alfano, and
M.J. Arrowood
Emerging Infectious Diseases and the Depopulation of French 359 P.M.V. Martin and C. Combes
Polynesia in the 19th Century
Epidemic Zoster and AIDS 361 D.M. Morens, A.K. Agarwal, S.
Sarkar, S. Panda, and R. Detels
Ancient Egypt and Today: Enough Scourges to Go Around 362 D.G. Colley
AIDS and AAA in Egypt? 362 R.J. Littman and D.M. Morens
Addendum 364
News and Notes
ABA Sponsors Program on Law and Emerging Infectious Diseases 365 D.P. Fidler
A Global Theme Issue: Bibliography of References 365 M.A. Winker
Conference on Emerging Foodborne Pathogens 372 D. Dalisera
Perspectives
Guarding Against the Most Dangerous
Emerging Pathogens:
Insights from Evolutionary Biology
Paul W. Ewald
Department of Biology, Amherst College,
Amherst, Massachusetts, USA
Control of emerging infectious diseases will be difficult because of the large number of
disease-causing organisms that are emerging or could emerge and the great diversity of
geographic areas in which emergence can occur. The modern view of the evolution of
pathogen virulence—specifically its focus on the tradeoff between costs and benefits to the
pathogen from increased host exploitation—allows control programs to identify and focus
on the most dangerous pathogens (those that can be established with high virulence in
human populations).
Studies of emerging diseases have focused providing methods for inhibiting the emergence
chiefly on the spectrum of different emerging of particularly virulent variants of pathogens
pathogens, epidemiologic reasons for emer- that are already established in human
gence, and interventions to control emergence. populations (e.g., the pathogen that caused the
The feasibility of disease control is hampered 1918 influenza pandemic and virulent,
by the potentially vast number of emerging and antibiotic-resistant strains of Staphylococcus
reemerging pathogens, the diversity of geo- aureus).
graphic sources, the potential for rapid global Modern understanding of the evolution of
dissemination from these sources, and numer- virulence focuses on a tradeoff to which
ous ecologic and social factors influencing pathogens are subjected: the competitive
emergence (1-4). Disease control could be made benefits that pathogens accrue through in-
more manageable if the most dangerous creased exploitation of hosts and the costs that
pathogens could be singled out for the most result from any effects of disease that reduce
intense study, surveillance, and control efforts. infectious contact between infected and suscep-
Experts who have addressed this problem from tible hosts. The traditional view presumed that
an epidemiologic but not an evolutionary natural selection would favor evolution toward
perspective disagree about the feasibility of benign coexistence between host and parasite
predicting and preventing the emergence of the (9-12). The modern view, however, stresses
most damaging new pathogens (5-8). In this that such benign coexistence will be unstable if
perspective, I argue that improved understand- pathogens that exploit hosts to a greater degree
ing of the evolution of virulence (defined have more overall success across transmission
broadly as the harmfulness of an infection) can cycles than those that achieve benign coexist-
make this goal more feasible in two ways: 1) by ence (13-17).
facilitating identification and blocking of The primary assumption of this evolution-
pathogens that represent the greatest threat ary argument is that increased virulence is
should they become established in human correlated with increased pathogen propaga-
populations (e.g., Yersinia pestis during the tion (manifested as increases in pathogen
Middle Ages and human immunodeficiency reproduction within hosts and/or pathogen
virus [HIV] during recent decades) and 2) by shedding from infected hosts). This correlation
need not be strong across host/pathogen
associations for the arguments to be valid;
differences in pathogenic mechanisms, for
Address for correspondence: Paul W. Ewald, Department of
example, could make the correlation virtually
Biology, Amherst College, Amherst, MA 01002-5000; fax:
413-542-7955; e-mail: [email protected]. undetectable when extremely different kinds of
Vol. 2, No. 4—October-December 1996 245 Emerging Infectious Diseases
Perspectives
pathogens are compared. Rather, the tradeoff generate greater numbers of progeny by
argument states that for a given pathogen interfering with the cell’s mechanisms for
(with its particular tropisms and pathogenic restricting cell division (36). For both viruses,
mechanisms), mutations that increase the level increased viral loads are associated with
of host exploitation tend to increase harmful- increased probability of transmission to
ness. The association between virulence, contacted persons (37-39), and HIV-1, which
exploitation, and pathogen propagation is propagates to higher densities than HIV-2, is
expected among “wild type” mutants, but not more transmissible per contact (40).
among novel laboratory-generated virulent The association between virulence and
ones. Because there are many routes to viral propagation in pathogens circulating
increased virulence and laboratory-generated naturally in human populations therefore
variants are often not selected on the basis of supports the modern emphasis on a tradeoff
competitive superiority in vivo, the increased between the fitness benefits and the costs
virulence of variants generated in the accrued by pathogens as a function of changes
laboratory may not be linked to propagative in host exploitation.
superiority. In contrast, natural selection
should eliminate any variants for which Transmission Associated with High
increases in virulence are not linked to Virulence
increases in pathogen fitness.
The connection between virulence, host
Transmission from Immobile Hosts
exploitation, and pathogen propagation may be
Like the traditional view of host/parasite
indirect or direct. If the pathogenic mechanism
coevolution, the modern view identifies host
involves toxin production, a positive associa-
illness as a potential liability for the pathogen.
tion is expected between toxin production and
When pathogens rely on the mobility of their
pathogen propagation. In Vibrio cholerae, for
current host to reach susceptible hosts, the
example, high toxin production is associated
illness caused by intense exploitation typically
with increased densities of vibrios in the fecal
reduces the potential for transmission. The
material, apparently as a result of the toxin’s
modern perspective on host/parasite coevolu-
flushing of competing organisms from the
tion differs from the traditional one, however,
intestinal tract (17). In other organisms, the
in its emphasis on weighing these setbacks
association between virulence, host exploita-
against the benefits of exploitation: high
tion, and pathogen propagation is more direct.
virulence can contribute to evolutionary
The human plasmodia that reproduce more
stability if the costs incurred by parasites from
extensively often cause more severe illness and
exploitation-induced damage are particularly
are more life-threatening (16). Similarly, more
small and/or the benefits obtained from
virulent strains of vector-borne dengue virus
exploitation are particularly big. Thus, if host
reproduce more extensively in cell culture (18).
immobilization has little negative effect on
Growth rates of Salmonella typhimurium were
transmission, pathogen variants that exploit
reduced by eliminating one of its virulence
the host so intensely that it is immobilized will
plasmids and inhibiting the plasmid’s expres-
reap the benefits of exploitation. Put more
sion; introduction of an 8-kb region encoding
generally, when the costs incurred from
the spv genes restored increased growth rate
transmission associated with immobilization
(19). Comparison of Shigella species suggests a
are small, the costs of exploitation should
similar association between virulence and
outweigh the benefits at a higher level of
pathogen reproduction (20).
exploitation—and hence virulence—than would
Sexually transmitted pathogens show
occur if immobilization severely impaired
analogous associations. For the best studied
transmission (16).
pathogen, HIV, more rapidly replicative HIVs
Recognizing this version of the general
are associated with greater cellular destruc-
tradeoff led to several predictions: Because
tion in vitro, more rapid destruction of the
vector-borne parasites can be transmitted
immune system, and more rapid onset of AIDS
effectively from immobilized hosts, they should
(21-35). Similarly, the more oncogenic sero-
evolve to a higher level of virulence than
types of human papilloma-viruses (HPV)
Emerging Infectious Diseases 246 Vol. 2, No. 4—October-December 1996
Perspectives
directly transmitted parasites (16). Similarly, involve the requirements for sexual transmis-
aspects of human behavior and culture can sion imposed on the pathogens by the sexual
form “cultural vectors,” which transmit behavior of the host. Short durations of
pathogens from immobile to susceptible hosts infections would be ineffective for most
(41). For example, diarrheal pathogens that are sexually transmitted pathogens. If people
largely waterborne should evolve to relatively changed sex partners once per year, for
high levels of virulence because effective example, a pathogen that was rendered
transmission can occur even when infected noninfectious by immunologic defenses or the
hosts are mobilized: persons carrying contami- host’s death within a few weeks would have
nated clothing and bedding, the water used for little chance of being transmitted. To survive,
washing bed sheets, and the movement of the pathogen must be transmissible for a
contaminated water into drinking water period that extends into the time of the next
together act like a swarm of mosquitoes, sexual partnership. To prosper, the pathogen
transmitting pathogens from the immobilized must be transmissible for periods that span
host. Attendant-borne pathogens should also more than one change in sex partners;
become virulent. Attendant-borne transmis- therefore, sexually transmitted pathogens may
sion often occurs in hospitals, when nurses and often need cell and tissue tropisms that keep
physicians transmit pathogens from one them from being eliminated by the immune
immobilized patient to another. A reciprocal system for relatively long periods.
process occurs when parasites rely on the The evolutionary effects of changes in
mobility of susceptible persons rather than the sexual behavior on virulence may be strongly
mobility of the infected hosts to reach the influenced by tropisms that were present
susceptible persons. Parasites that are durable before the behavior change. Increased poten-
in the external environment should thus evolve tial for sexual transmission should favor
toward a higher level of virulence than pathogen variants that reproduce more exten-
nondurable pathogens because durable patho- sively sooner after the onset of infection. If the
gens may remain viable in the environment preexisting tropisms target nonessential cell
until the movement of susceptible individuals types, this selection for earlier reproduction
brings them into contact with the pathogens. will have relatively little effect on virulence. If,
Each of these hypotheses has been for example, people changed sex partners every
evaluated and in each case the expected few days, the sexually transmitted pathogen
association occurred: virulence is positively should evolve virulence levels much like those
associated with vector-borne transmission, of respiratory tract pathogens, which rely on
waterborne transmission, attendant-borne host mobility for transmission. Examples of
transmission, and durability in the external such pathogens are sexually transmitted
environment (Table 1). This evolutionary unicellular pathogens such as Neisseria
framework, therefore, explains the diversity of gonorrheae and Chlamydia trachomatis, which
human parasites in a way that contrasts tend to infect mucosal tissues and, therefore,
starkly with the traditional view. Instead of have relatively minor negative effects on the
being seen as a sign of maladaption, the survival of adult hosts. If, however, the
severity of diseases such as malaria, tuberculo- tropisms involve critical cells, the damage
sis, smallpox, cholera, and typhoid fever is seen associated with increased levels of host
as a consuequence of evolutionary adaptation exploitation should be more severe to the host.
because the causative parasites do not rely on HIV provides an example: HIV has a tropism
host mobility for transmission. The tradeoffs for helper T cells, which are critical regulators
between the benefits and costs of exploitation, of immunologic responses. Although a high
therefore, favor evolution of relatively high level of replication in these cells can be
levels of exploitation for such pathogens and tolerated over short periods, it eventually leads
hence high degrees of harm to the host. (by mechanisms that are still being clarified) to
the decimation of this category of cells and the
Sexual Transmission collapse of the immune system.
The evolutionary tradeoffs associated with If these arguments about evolutionary
virulence in sexually transmitted diseases forces and tissue tropisms are applicable to
Vol. 2, No. 4—October-December 1996 247 Emerging Infectious Diseases
Perspectives
HIV, HIVs should be more virulent in areas transmission (48), type E HIV-1s have recently
where the potential for sexual transmission is been introduced from Southeast Asia. If a low
greater. In accordance with this prediction, potential for sexual transmission favors
HIV-2 tends to be less virulent than HIV-1; evolution toward mildness, the Japanese type
moreover, evidence indicates that during the E viruses should become milder over the next
early years of HIV infection in Africa, HIV-2 few decades.
tended to be transmitted in populations having
a lower potential for sexual transmission Assessing the Threat Posed by Pathogens
(17,20). The overall validity of this approach to
HIV virulence, however, will be better tested as Assessment Goals
different variants of HIV emerge in different
Focusing investigative and intervention
geographic regions. Information about the
efforts on the most significant disease threats
potential for sexual transmission can help
makes sense only if the threats can be reliably
predict the evolution of HIV virulence in
assessed. The long-term threat depends on the
different geographic areas. On the basis of the
evolutionary stability of high pathogen viru-
evolutionary tradeoffs mentioned above, for
lence, and the most dangerous pathogens are
example, the type E HIV-1s that are circulating
those that threaten widespread persistence
in Thailand (where the potential for sexual
with severely damaging manifestations. One of
transmission has been great) are predicted to
the most important tasks in controlling
be particularly virulent (17). Although this
emerging diseases is to identify and block such
prediction needs to be evaluated rigorously,
pathogens during the early stages of emer-
recently gathered data support the prediction:
gence, or better yet, before they emerge. If the
the decline in CD4+ cell counts of persons
most dangerous pathogens—the future analogs
infected with HIV and the progression of illness
of the causes of AIDS, malaria, smallpox,
in these patients appear to be particularly
tuberculosis, and cholera—could be effectively
rapid in Thailand (43-44).
blocked, the effort against emerging diseases
The most important application of this
would be successful. If not, the effort may be
evolutionary approach to HIV, however,
looked on as a failure in spite of successes
pertains to interventions that can be used to
against pathogens that are less able to
control the future evolution of HIV. If the
effectively penetrate human populations or
inherent virulences of HIVs depend evolution-
relatively benign when they do establish
arily on the potential for sexual
transmission, interventions that
Table 1. Categories of pathogens that pose threats of being stably
reduce this potential should have
harmful in human populations because of reduced dependence on
a long-term evolutionary effect, as
host mobility
well as widely recognized short-
term epidemiologic effects—in ad- Characteristics allowing Association with lethality Reference
transmission from
dition to reducing the spread of
immobile hosts
HIV infection, such interventions
arthropod-borne lethality higher among (16)
should reduce the harmfulness per
transmission arthopod-borne pathogens
infection. Follow-up of persons
than among directly
infected with HIV-1 for more than transmitted pathogens
a decade without deterioration of
the immune system indicates that water-borne lethality of diarrheal bacteria (42)
transmission correlated with tendencies for
the mildness of the infections is
waterborne transmission
sometimes attributable to inher-
ently mild viruses (45-47). The
attendant-borne lethality of E. coli correlated (20, 41)
raw material for this evolutionary transmission with duration of
change, therefore, appears to be attendant-borne cycling
already present in the HIV gene
durability in the lethality of respiratory-tract *
pool.
external environment pathogens correlated
In Japan, which has a rela-
with durability
tively low potential for sexual
*B. A. Walther and P. W. Ewald, unpublished manuscript
Emerging Infectious Diseases 248 Vol. 2, No. 4—October-December 1996
Perspectives
Table 2. First-level checklist for identifying the Durability
most dangerous emerging pathogens. If the Although durability in various external
answer to any of the questions is yes, the potential
environments was quantified in detail by
for continuous transmission between humans
microbiologists during the first half of this
should be assessed. If this potential is high, the
century (49), modern studies have paid this
pathogen should be considered particularly
attribute little attention. Evolutionary consid-
dangerous.
erations, however, indicate that it should be
Does it have a tendency for waterborne
one of the first variables quantified when a new
transmission?
pathogen is being studied. If a new, directly
Is it vector-borne with the ability to use
transmitted pathogen can remain viable in the
humans as part of the life cycle?
If it is directly transmitted, is it durable in external environment for many days to many
the external environment? weeks, it falls in the category of especially
Is it attendant-borne? dangerous pathogens. If, for example, Ebola
Is it needle-borne?* virus were viable upon natural desiccation for
If it is sexually transmitted, is it weeks instead of hours, its level of host
mutation-prone with a tropism for
exploitation and potential for transmission
critical cell types or does it have
from exploited hosts would not be so
invasive or oncogenic tendencies?
mismatched, and it, like smallpox virus, would
*The hypothesized importance of needleborne transmission
has not yet been tested; it has been included in this listing on pose a much more serious threat. Durability in
the basis of the harmfulness of needleborne pathogens and the external environment depends largely on
the hypothetical assocations between needleborne environmental conditions (49), and thus
transmission and virulence (17).
assessments of viability should cover all
feasible environmental conditions.
themselves. The emergence, spread, and
persistence of pathogens with the characteris-
Vector-borne Transmission
tics of rhinoviruses, for example, would not be
The most serious threat involved in vector-
looked on as a great failure. The establishment
borne transmission comes from pathogens that
of such pathogens would hardly be noticed
can be maintained by human/mosquito cycles
against the current backdrop of mild to
but are absent from suitable areas because of
moderately severe respiratory tract pathogens.
historical accidents or past eradication cam-
To identify pathogens that must be studied
paigns. Dengue and malaria are members of
and controlled most intensively, each pathogen
this category; they have the potential to spiral
should be assessed for two characteristics that
out of control immediately upon release into
are associated with high virulence: 1) an ability
areas with suitable vectors. Nonevolutionary
to spread well from human to human (directly
analyses of emerging infections recognize the
or indirectly through vectors) rather than
threat posed by these pathogens because their
infecting humans as dead-end hosts, and 2)
damaging effects on human populations are
transmission features that select for high
known.
levels of virulence.
Vector-borne pathogens that have not used
The existing associations between virulence
humans as the primary vertebrate host but
and transmission characteristics (Table 1) can
may be capable of doing so represent less easily
be used to make such identifications. Table 2
recognized threats. Evolutionary consider-
offers a checklist that could be applied to each
ations heighten concern because such vector-
emerging pathogen to determine whether it
borne pathogens are expected to become
makes the first cut in the process of identifying
increasingly harmful as they become adapted
the most dangerous candidates. Subsequent
to human/vector cycles of transmission (16).
analyses of the pathogens would then assess
Rift Valley fever virus provides an
the nature of any barriers that limit the
example. For most of this century, this virus
establishment of pathogens in human popula-
was believed to infect humans only as dead-end
tions (e.g., the absence of suitable arthropod
hosts. Although it was vector-borne in
vectors for large proportions of the year).
ungulates, humans were seen as acquiring the
Vol. 2, No. 4—October-December 1996 249 Emerging Infectious Diseases
Perspectives
infection either when involved in cell lymphotropic virus (HTLV) is in this
the slaughtering process or when bitten by category, even though by nonevolutionary
mosquitoes that had acquired infection from criteria it could be dismissed because it has
other vertebrates. Recent outbreaks have been geographically widespread in humans for
spread to an extent consistent with substantial a long time (1). HTLV type 1 (HTLV-I) is less
human/mosquito cycling, but the existence of damaging than HIV; it kills or severely
such cycling has not been conclusively handicaps 5% to 10% of the people it infects,
documented. If human/mosquito cycling is generally decades after infection. Although
occurring, the door is open for further HTLV-I and HIV infections share many
adaptation to humans and for evolution of characteristics, HTLV does not have HIV’s
increased virulence in humans, increased high mutation rate and hence does not have the
efficiency of human/vector transmission, and potential for staying ahead of immune
increased spread through human populations. responses and eventually decimating the
Rift Valley fever virus viremias seem sufficient immune system. Instead, HTLV relies on
for human/mosquito cycling, and the lethality modes of transmission that do not expose it to
of the largest outbreaks was particularly high, the immune system: proviral replication
as one would expect if some evolution toward through stimulation of host cell proliferation
increased virulence accompanied a temporary and transmission through cell-to-cell contact.
establishment of human/mosquito cycles (50- A concern with HTLV is that a high potential
51). To assess the long-term threat posed by for sexual transmission may favor increased
Rift Valley fever virus and to block this virus rates of viral replication leading to increased
should it prove to be particularly threatening, exposure to the immune system and increased
we need to emphasize the following research mutation rates (48).
priorities: 1) study the transmission of Rift A preliminary step toward evaluating the
Valley fever virus in human/mosquito cycles, 2) threat posed by the emergence of particularly
assess the potential for such transmission over virulent HTLVs is assessing whether HTLVs
extended periods, and 3) evaluate the effects of exposed to different levels of potential for
such transmission on virus virulence. sexual transmission vary in virulence. HTLV-I
All emerging vector-borne pathogens need infections tend to lead to leukemias and
not be viewed as equally threatening. For lymphomas at younger ages in Jamaica, where
example, Borrelia burgdorferi, the agent of the potential for sexual transmission is high,
Lyme disease (an emerging vector-borne than in Japan, where potential for sexual
pathogen in human populations in North transmission is low (48). This difference also
America), does not need to be monitored to occurs among North Americans of Japanese
avoid its establishment as a human pathogen and Caribbean descent (52), who presumably
because once emerged, it does not threaten to are infected predominantly (if not exclusively)
spiral out of control; it is tick-borne, and by Japanese and Caribbean HTLVs, respec-
ongoing human/tick cycles are not feasible tively. The inherent virulence and mutation-
because of the limited exposure of infected proneness of the Japanese and Caribbean
humans to susceptible tick populations of the HTLVs need to be assessed. Similarly, HTLV
appropriate instar. Tick- and mite-borne virulence needs to be better studied in regions
rickettsiae do not present a great threat for of Africa where it has been long endemic to
similar reasons. determine whether variations in HTLV viru-
lence are correlated with the potential for
Sexual Transmission sexual transmission.
The tradeoff concerning sexually transmit- Although mutation-prone sexually trans-
ted pathogens may prove particularly useful in mitted viruses that infect critical cell types are
identifying pathogens that are capable of particularly threatening, sexually transmitted
sexual transmission and have cell tropisms viruses in general deserve special attention.
that would cause severe damage if host Even if a sexually transmitted virus invades
exploitation increased but have not had high only epithelial cells and replicates with low
potential for sexual transmission. Human T- mutation rates, a high potential for sexual
Emerging Infectious Diseases 250 Vol. 2, No. 4—October-December 1996
Perspectives
transmission may lead to evolution of in- into Costa Rica, where water supplies were
creased lethality. Death caused by HTLV- relatively pure (L. J. Mata, pers. comm.).
induced lymphomas and leukemias is one
manifestation of the danger posed by an RNA Attendant-borne Transmission
virus that replicates substantially in its DNA Emerging hospital-acquired pathogens may
form and hence is in a middle area within the pose one of the greatest and most controllable
spectrum of mutation-proneness. HPVs illus- threats to people in countries like the United
trate dangers posed by sexually transmitted States, where more than 5% of hospital
viruses that, because they are DNA viruses, are admissions and about 14% of intensive care
even further away from HIV on the mutation- patients acquire infections during their stay
proneness continuum. The mechanism by (55-57). According to some estimates,
which HPV nudges infectious cells toward nosocomial infections rank among the ten
cancer is associated with increased viral leading causes of death in the United States
replication; moreover, high potential for sexual (56), with dangerous bloodstream infections
transmission (as indicated by the number of approximately doubling during the 1980s (58).
lifetime sex partners) is a strong risk factor for Although high virulence has been docu-
infection with the more oncogenic HPV mented in pathogens involved in nosocomial
serotypes but not for the mild HPV serotypes outbreaks (59-63), the damage caused by
(53). This association supports the idea that nosocomial pathogens has generally been
reductions in the potential for sexual transmis- attributed to the state of hospitalized patients,
sion should cause evolution of reduced HPV who may be compromised by underlying
virulence. Specifically, as the potential for disease, immunosuppressive drugs, and inva-
sexual transmission decreases, the risk for sive procedures. These factors, however, do not
acquiring the oncogenic serotypes (vs benign explain why nosocomial pathogens, such as
serotypes) should disproportionately decrease. Staphylococcus aureus often cause symptom-
Similarly, if interventions prevent the poten- atic infections in hospital staff (60) but rarely
tial for sexual transmission from increasing, in persons in the outside community. They also
the emergence of oncogenic HPV serotypes do not explain the association between the
should be disproportionately suppressed. extent of nosocomial transmission and the
virulence of infection, or the differences in
Waterborne Transmission symptomatic infections among otherwise
Although such pathogens as Vibrio cholerae healthy babies (17,20,41). In a New York City
O139 and Shigella dysenteriae type 1 threaten hospital, for example, where attendant-borne
emergence in countries with inadequate water transmission rates were very low, only
supplies, the threat is much lower in countries approximately one of 30 babies with S. aureus
with safe water supplies. Although such were symptomatic (64). Among nosocomial
pathogens continue to be brought into the outbreaks of endemic disease, the analogous
countries with safe water supplies by travelers proportion may be 5- to 10-fold higher (65).
and commerce, the pathogens show little Without an evolutionary framework for
potential for emergence. For example, a major understanding pathogen virulence, research-
epidemic of S. dysenteriae type 1 spread from ers would have no reason for expecting to find
Guatemala through Central America during particularly virulent endemic pathogens in
the early 1970s. It entered the United States in hospitals. The only serious attempts to explain
several places but dissipated without any great the apparently high-level of pathogen virulence
effort at containment. Its transmission was in hospitals involved the linking of virulence to
studied in a Los Angeles neighborhood, where another characteristic associated with hospi-
each infection gave rise on average to about 0.4 tals: antibiotic resistance. The emergence of
new infections (54). Without amplification by antibiotic-resistant organisms in hospitals in
waterborne transmission, this outbreak, like concert with the use of the antibiotics (66) led
other introductions in the United States, was researchers to conclude that high levels of
self-limited (54). The situation at the other end antibiotic use caused the emergence of
of Central America was similar. The S. resistant organisms and to speculate that
dysenteriae epidemic dissipated as it moved antibiotic-resistant organisms might be inher-
Vol. 2, No. 4—October-December 1996 251 Emerging Infectious Diseases