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Cholera: A Classic Epidemic/Pandemic Pathogen

Cholera: A Classic Epidemic/Pandemic Pathogen

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Figure 1. Smooth (left) and rugose (right) colony morphologies for Vibrio cholerae.

More than 200 O-groups have been identified for V. cholerae, with epidemic

cholera cases traditionally linked with O-group 1 (V. cholerae O1). Key virulence

factors necessary for occurrence of cholera include CT and associated genes (carried by

the CTX phage, which is capable of transfer among V. cholerae strains) and the vibrio

pathogenicity island, which includes genes for toxin-coregulated pilus, a key attachment

factor (and the receptor for the CTX phage). However, it appears that the ability to

cause epidemic disease is dependent on additional and still poorly charcterized factors. In

studies conducted in our laboratories using multilocus sequence typing (MLST), all

clinical cholera strains clustered into a single MLST clonal complex, consistent with

the hypothesis that strains capable of causing disease are closely related phylogenetically.

In contrast, there may be striking sequence divergence between epidemic cholera

strains and V. cholerae strains from other O-groups. In work that we have done with V.

cholerae strain NRT-36S, an O31 strain, we found only 89% sequence homology with

epidemic cholera isolates, with absence of a number of putative virulence genes [9].

Epidemiologically, cholera tends to occur in two patterns: it spreads in pandemic

form, moving across continents, and, after introduction into an area, it may settle into

an “endemic” pattern marked by seasonal epidemics. From the perspective of undertanding emergence of pathogens, this leads to two basic questions: what mechanisms

underlie occurrence of pandemic disease, and, once the pandemic wave has passed,

what are the triggers for recurrent seasonal epidemics?

1.1. Pandemic Cholera

The modern history of cholera begins in 1817 with the occurrence of what has been

designated as the first of seven cholera pandemics. It was during the spread of the third

pandemic to London in 1854 that John Snow demonstrated the association between

illness and consumption of sewage-contaminated water. His work established the role

of epidemiology in public health and highlighted the efficacy of simple interventions –

in this case the removal of the handle of the Broad Street pump, which had been linked

with illness. The seventh (and most recent) cholera pandemic began in 1961, with an

outbreak of disease in the Celebes. The strain responsible for this outbreak (V. cholerae

O1 biotype El Tor) subsequently has spread through Asia, Africa, Europe, and the

Americas, resulting in substantial global morbidity and mortality and leaving behind an

endemic pattern of seasonal epidemics (Fig. 2) [10].



Figure 2. Global spread of the seventh pandemic of cholera.

In 1992, against this background and outside of normal seasonal epidemic patterns,

cholera began to spread rapidly across India and Bangladesh, with subsequent spread to

other parts of Asia. In contrast to the traditional endemic pattern of cholera in these

areas, all ages were affected, suggesting a lack of preexisting immunity within the

population [11]. In subsequent studies, we and others found that the strain responsible

for this “new” epidemic was from a different O-group (O139), was encapsulated, and

had undergone a genetic substitution/deletion with the introduction of 35 kb of “new”

DNA encoding the O139 capsule, replacing 22 kb of “original” DNA encoding the O1

antigen [12, 13]. Aside from this one substitution, the epidemic strain appeared to be

identical to seventh pandemic V. cholerae O1 El Tor strains.

Further studies from our laboratory have shown that the gene cluster controlling

expression of the O-antigen and capsule is bounded consistently by two genes – gmhD

and rjg. Genetic substitutions within this region are not uncommon and may account

for the diversity of O-groups within the species [14, 15]. Although the initial epidemic

due to V. cholerae O139 did not progress to pandemic disease (i.e., with involvement of

multiple continents), it is clear that this new strain had pandemic potential, and there

were suggestions that its appearance should be designated as the beginning of the

eighth pandemic. Based on our findings with this strain, we would hypothesize that

new cholera pandemics result from genetic changes leading to expression of new

surface antigens (O-group and capsule), permitting rapid spread of the disease through

populations that are immunologically naive to the new antigens.

From the standpoint of disease control, these findings underscore the need for rapid

vaccine development capabilities to permit the creation of new vaccines (for cholera as

well as for other possible emergent pathogens) to match whatever new antigenic

combination may appear. As a case study, based on our research, we were able to

develop a polysaccharide conjugate vaccine rapidly that was protective in animals



against the O139 cholera strain [16]. However, there was inadequate infrastructure and

funding to move on to human trials, leaving us, to date, with no available vaccine for

this new pandemic strain.

1.2. Endemic Cholera with Seasonal Epidemics

As noted above, after passage of a pandemic wave, cholera tends to shift to an endemic

pattern of seasonal epidemics. We undertook a series of studies in Lima, Peru, in the

mid-1990s [17] to try to gain a better understanding of why such epidemics occur. The

seventh pandemic had entered South America in 1991, appearing first in Peru and then

moving across South and Central America. In subsequent years, illness settled into an

endemic pattern, with epidemics occurring each summer (December–February). Over a

2-year period, we collected monthly samples from eight environmental sites in the

Lima area. Detection of CT-producing V. cholerae (i.e., strains capable of causing

epidemic disease) in the environment correlated significantly with occurrence of

disease in the community 2 and 3 months later; the increase in counts in the environment, in turn, correlated with increases in water temperature associated with the

beginning of summer. These data support a model of cholera seasonality in which

initial increases in number of V. cholerae in the environment (triggered by temperature)

are followed by “spillover” of illness into the human population, with these human

cases further amplifying the organism as the epidemic cycle proceeds (Fig. 3). Support

for the concept of temperature being an important element in triggering the epidemics

has come from other investigators working with data from Peru as well as Bangladesh,

with particular attention being given to the potential role of the El Nino-southern

oscillation as a driver of the process [18].



V. cholerae in





infections in


Figure 3. Model of cholera transmission.



In further studies in two rural communities in Bangladesh (Bakerganj and

Mathbaria), we used variable numbers of tandem repeats as a means of typing

V. cholerae strains from clinical and environmental sources [19]. As previously noted,

epidemic V. cholerae strains tend to be closely related phylogenetically, making it

difficult to separate strains by MLST (or other standard molecular epidemiologictyping methods). In contrast, we found that variable numbers of tandem repeats

provided us with excellent discrimination among strains. Using this technique, we

evaluated 68 environmental and 56 clinical isolates from the two communities. We

found that there was minimal crossover between environmental and clinical strains as

well as minimal crossover between strains in Bakerganj and Mathbaria. We also found

that “epidemics” in any one location, rather than being caused by a single strain,

appeared to reflect the sequential appearance of different strain subsets in the human

population. Although environmental V. cholerae may serve as a trigger for an epidemic,

these data suggest that subsequent transmission among humans is more likely to be

person-to-person. The data also suggest that distinct locales have their own strains and

strain subsets; that is, an epidemic is not due to a single strain sweeping across the

countryside but, rather, reflects the appearance of local strains in human populations.

To further explore questions relating to person-to-person transmission, we

developed a mathematic model of cholera transmission [20]. Interestingly, the best fit

for the model was obtained when we incorporated the concept of a “hyperinfectious

state.” This follows from laboratory experiments suggesting that passage of V. cholerae

through the intestinal tract results in a short-lived increase in infectivity that decays in a

matter of hours into a state of lower infectiousness.

These observations help to highlight possible control strategies. Although it is

unlikely that triggers for environmental proliferation of the microorganism (such as

temperature) can be blocked, an awareness of the role of environmental V. cholerae

in initiating epidemics may permit the focusing of resources on preventing such

transmission during high-risk time periods when temperatures are elevated. Given the

clear importance of person-to-person transmission, efforts also should be focused on

minimizing the risk of such transmission within households, with a particular emphasis

on minimizing risk of transmission of the short-lived, hyperinfectious form of the

microorganism present in recently passed fecal material.

2. Citrus Greening

Citrus greening is a recently emergent infectious disease that currently is estimated to

infect 30% of the citrus trees in Florida, and it is spreading rapidly. Although not a

human disease, it is causing major economic losses and provides some interesting, and

different, perspectives on disease emergence.

Citrus greening first was reported in the late 1800s in China, where it is known as

huanglongbing, or yellow dragon, reflecting the pattern of leaf-yellowing within affected

trees. It now has spread through citrus-growing areas in much of the world. There is no

effective control once a tree is infected. Infected trees produce less fruit, and the fruit

that is produced tends to be bitter and misshapen. The etiologic agent for the disease is

thought to be the bacterium Liberobacter asiaticum, transmitted by an insect, the Asian



psyllid. Although we have a basic understanding of the transmission pathways, a great

deal remains to be learned about both the bacterium and the vector [21].

The Asian psyllid first was identified in Florida in September 2005, and, as shown

in Fig. 4, it has spread rapidly across citrus-growing areas of the state. Efforts to control

the disease have focused on quarantining infected orchards and bulldozing and burning

Figure 4. Spread of citrus greening in Florida.



infected trees and on using insecticides to kill the psyllid vector. Neither approach has

been overwhelmingly successful, with the disease continuing to spread rapidly across

the state and with reports of psyllids being identified in Louisiana and, as of July 2008,

in California.

3. Conclusions

Emerging and epidemic pathogens have been an ongoing cause of human disease since

the dawn of recorded history. Factors that drive their emergence include genetic

changes, changes in opportunities for pathogen growth and spread, and changes in host

susceptibility. Prevention and/or control of emergent pathogens is possible but requires

early recognition and intervention; mathematic modeling that we have done [22]

underscores the fact that, by the time new diseases are recognized, they often have

spread to the point that control is difficult if not impossible. Citrus greening provides an

excellent example: traditional control strategies are, at this point, largely ineffective

owing in part to the high percentage of trees that already are infected. Prevention and

control also require a comprehensive understanding of pathogenesis and transmission.

Cholera provides an example of a pathogen for which better and better data are

becoming available, allowing focusing of control strategies. At the same time, cholera

demonstrates the complexity of these natural systems and the difficulties inherent in

designing interventions even with a reasonable knowledge base.



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Medical Book Company; 1992. p. 1–36.

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trends in emerging infectious diseases. Nature 451:990–993.

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cholerae NRT36S demonstrates the presence of pathogenic mechanisms that are distinct from O1

Vibrio cholerae. Infect. Immun. 75:2645–2647.

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14. Sozhamannan, S., Deng, Y.K., Li, M., Sulakvelidze, A., Kaper, J.B., Johnson, J.A., Nair, G.B., Morris,

J.G. 1999. Cloning and sequence of the genes downstream of the wbf gene cluster of Vibrio cholerae

serogroup O139 and analysis of the junction genes in other serogroups. Infect. Immun. 67:5033–5040.

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Stine, O.C. 2007. The capsule polysaccharide structure and biogenesis for non-O1 Vibrio cholerae

NRT36S: genes are embedded in the LPS region. BMC Microbiol. 7:20.

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has an early but important impact on antibiotic resistance in humans. Proc. Natl. Acad. Sci. USA


Section I


The Epidemiological Surveillance of

Highly Pathogenic Diseases in Kazakhstan

Alim M. AIKIMBAYEV1, Jumabek Y. BEKENOV2, Tatyana V.



M. Aikimbayev’s Kazakh Scientific Centre for Quarantine and Zoonotic Diseases,

Almaty, Kazakhstan


Aktobe Plague Control Station, Aktobe, Kazakhstan

Abstract. The Central Asian deserts’ plague focus occupies vast zones of desert

and semidesert in Central Asia and Kazakhstan. The differentiation of plague

strains on virulence from the plague foci of Kazakhstan testifies to its high

epidemic virulence. From 1990–2003, 23 cases of human plague were registered.

From 2004 to 2007, no cases human plague were registered. The growth of human

plague has been caused not only by an increase in epizootic activity of the natural

foci but also by the crises of social, economic, and health protection conditions in

the Republic of Kazakhstan during the period of Perestroika. The same conditions

challenged the increase in human anthrax, tularaemia, and brucellosis during the

same period. Annually, 70,000–100,000 people are vaccinated and revaccinated

with live vaccine strain tularemia. Kazakhstan is not endemic for cholera;

therefore, all initial cases of cholera were imported from places such as Pakistan,

Uzbekistan, Iran, Turkey, and Indonesia. For epidemiologic supervision of anthrax,

the cadastre of anthrax foci is transferred in electronic format using a Geographical

Information System (GIS). For Kazakh samples, 12 unique MLVA subtypes (KZ-1

through KZ-12) were used.

1. Geographical Epidemiology of Plague

A considerable portion of the Republic of Kazakhstan is located in the territory of one

of the biggest plague foci in the world: the Central Asian desert plague focus, which

occupies vast zones of desert and semidesert in Central Asia and Kazakhstan. In

Kazakhstan, the plague enzootic area covers 1,007,350 km2, that is 39% of Republic

territory or 70% of the Commonwealth of Independent States’ natural plague foci. The

M. Aikimbayev’s Kazakh Scientific Centre for Quarantine and Zoonotic Diseases (10

plague-control stations, 19 local plague branches, and 30 temporary antiepidemic

divisions) carries out plague surveillance. More than 1,500 people work in the plaguecontrol services of Kazakhstan, including 400 people with higher and middle specialized

education. All medical and biological employees are certified to do laboratory work

after 2–3 months of special training.

The main reservoir species of plague in the Central Asian desert plague focus are

gerbils, susliks, and marmots. Marmots and the yellow suslik are hunted, and people

usually are infected by fleas. For preventive measures and epidemiologic monitoring,

the most important plague flea vectors were determined. The initial stages of the flea’s

physiological development are the best period for using insecticides.

K.P. O’Connell et al. (eds.), Emerging and Endemic Pathogens,

DOI 10.1007/978-90-481-9637-1_2, © Springer Science + Business Media B.V. 2010




Veterinary surveillance of camels is an important prevention measure because

infection of these domestic animals could cause an epidemic [1]. Camels are only rarely

infected by plague; on average, a plague-infected camel is registered once every 10

years. However, the meat of a slaughtered camel can cause disease not only during the

slaughter, but human plague has been diagnosed in purchasers of infected meat long

distances from the location of slaughter. Wintertime human plague infections caused by

plague-infected camels have been connected to latent infection in the camels as a result

of poor feeding and a decrease in the animals’ resistance to infection.

Plague surveillance and prophylaxis consists of several synergistic elements: the

control of plague transmission, epidemiologic investigation, field disinfection, settlement disinfection and deracination, vaccination of humans, work with a medical network,

work with a veterinary service on camel plague prophylaxis, and sanitary and educational

work with the population. Those at risk for plague infection include cattle breeders and

members of their families, railway-communication workers, participants in expeditions,

workers at meteorologic stations, field workers, fur-trade workers, veterinary workers,

medical workers in the countryside, and inhabitants of small cities having cattle grazing

on the enzootic territories.

The natural factors of Aral Sea regression and Caspian Sea transgression were

considered when determining plague-focus epidemic potential. The expansion of

zone enzootics in the shoaled parts of the Aral Sea was revealed. The water level in the

Caspian Sea rose 2 m, changing the contours of the coastal site. Raised subsoil in the

waters has changed the microclimate in rodent holes, which has resulted in the dying

off of fleas and the sanitation of foci.

Use of landscape epidemiologic principles has allowed us to reduce epizootologic

inspection of plague foci tenfold and to concentrate our field work in areas where

the main part of the rodent population is located. Informative inspection in difficult

economic conditions was developed and used as the reconnaissance method for

inspections of gerbil foci. During a 10-day tour, the zoologist (parasitologist) collects

flea probes for testing in the central laboratory. The territory around the settlements was

subject to inspection; during this period, sparsely populated areas were not surveyed.

Positive results in the epizootics in any part of the autonomous focus were extrapolated

to the entire territory and were indications for prophylaxis. This has allowed us to

reduce the number of exposed antiepidemic groups [2].

2. Analysis of Plague Isolates

Differentiation of Yersinia pestis strains from the plague foci of Kazakhstan by genetic

analysis [3] suggests that the most of the strains are likely to be highly virulent in

humans. The high epidemic virulence of Central Asian plague-focus isolates is proved

by modern methods of genetic analyses [4] on the variability of the nucleotide

sequences of the genes of rha-locus Yersinia pestis strains of the basic and nonbasic

subspecies. The same research shows an evolutionary antiquity of Caucasian strains

and their similarity to Yersinia pseudotuberculosis, which explains the low epidemic

potential of Caucasian foci plague strains.



3. Incidence of Human Cases of Plague

As a result of the epizootologic investigations of the past two decades, new plague foci

or sites have been discovered in the Central Asian desert plague focus. From 1990 to

2003 in Kazakhstan, 23 cases of human plague were diagnosed in 17 geographical foci

of human plague. Morbidity increased fourfold in comparison with the foregoing period

(1977–1989), during which six cases of human plague were registered. Of the cases

diagnosed from 1990 to 2003, 11 cases of human plague were caused by flea bites. The

main causes of mortality in these cases were delayed medical attention, incorrect

primary diagnosis, and accompanying chronic disease [2]. The growth of human plague

has been caused not only by an increase in epizootic activity of the natural foci but also

by the crises of social and economic conditions in the Republic of Kazakhstan, which

did not allow adequate funds for preventive action.

The negative social effects during the period of Perestroika reduced the immune

status of the population and the resistance of the inhabitants of the Commonwealth

of Independent States not only to plague but also to other infectious diseases. The

decreasing immune status was caused by stressful living conditions, including unemployment and a falling standard of living. The stress accompanied by an increase in the

hormone level of corticosteroids resulted in an immune-depressive action and a

decrease in organisms’ resistance to infections. For example, earlier patients were

infected with bubonic plague by multiple flea bites; in 2003, one trace of flea bite was

found in a child who died of plague. Approximately 25,000 bacteria – the quantity of

plague microbe delivered by one flea bite – was enough for plague transmission.

From 2004 to 2007, no cases of human plague were registered. Since 2006, the

medical service has used a definition of cases of especially dangerous infection

regulated by the Order of the Ministry of Health RK #623 (15.12.2006), in which

stages of the diagnosis are subdivided into suspect, presumptive, and confirmed plague.

4. Treatment of Plague Infections

The first stage in the treatment plan for plague patients [1] is detoxification by

introduction a 0.5-L salt solution with diuretic. The use of bacteriostatic antibiotics then

is preferred. It allows avoiding the Jarisch-Herxher reaction. The daily dose of antibiotic should not exceed 2.0 g (3 g in combination). The antibiotics and the salt solution

should be administered in a 1:1 ratio (1.0 g of antibiotic to 1.0 L of solution). We prefer

gentamycin for replacement bacteriostatic antibiotics for bactericidal treatments on the

second day. This antibiotic penetrates well through the hematoencephalic barrier and

prevents infection with meningoencephalitis. Meningoencephalitis complicates 50% of

cases in children younger than 14 years [1]. This antibiotic also counteracts microbe

endotoxin. In cases of bubonic plague, 80.0 mg of gentamycin was injected three times

per day; in cases of pneumonic and septic plague, 80.0 mg of gentamycin was injected

three to four times per day.

The use of oxacillin is not recommended because it can cause necrosis at the point

of injection. Doxycycline in combination with ciprofloxacin has no expected synergistic

action. It is recommended to replace doxycycline with amikacin or rifampicin or, in

their absence, cefotaxim.

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