J. Glenn Morris, Jr.
Cholera has affected humans for at least a millennium We are currently in the throes of the seventh pandemic and persists as a major cause of illness and death worldwide, (caused by V. cholerae of the El Tor biotype), which with recent epidemics in Zimbabwe (2008–2009) and Haiti originated almost 50 years ago in the Celebes. In contrast (2010). Clinically, evidence exists of increasing severity of to the earlier 6 pandemics, at no time in these past 50 years disease linked with emergence of atypical Vibrio cholerae has cholera retreated to its southern Asian home. It has organisms that have incorporated genetic material from instead established endemicity at multiple sites around the classical biotype strains into an El Tor biotype background. A key element in transmission may be a recently recognized globe and continues to trigger major localized epidemics, hyperinfectious phase, which persists for hours after passage including the epidemics in Zimbabwe during 2008–2009 in diarrheal feces. We propose a model of transmission in (3) and Haiti during 2010.
which environmental triggers (such as temperature) lead In 2009, the most recent year for which data are to increases in V. cholerae in environmental reservoirs, available, 221,226 cholera cases were reported to the with spillover into human populations. However, once the World Health Organization (WHO) from 45 countries microorganism is introduced into a human population, (4). This number includes 4,946 deaths, for a case-fatality transmission occurs primary by “fast” transmission from rate of 2.24%. Although the disease was reported from all person to person (taking advantage of the hyperinfectious continents, 98% of cases reported during 2009 were from state), without returning to the aquatic environment.
Africa, driven in part by large numbers from the latter part of the 2008–2009 Zimbabwe epidemic. However, Cholera has been an unwanted companion among human these numbers should be interpreted with caution because civilizations for at least a millennium, with suggestions of well-recognized problems with underreporting in the that it has existed in India “since immemorial times” (1). WHO system, particularly because cholera is no longer Its impact in Bengal society was suffi cient to have resulted a notifi able disease and countries can choose whether to in recognition of a goddess of cholera, Oladevi (or Oola report cases. In 2 examples, no cholera cases were included Beebee), who required propitiation to protect villages in the annual WHO cholera summary report for 2009 (4) from the disease (2). Global pandemic spread of cholera from India or Bangladesh, despite anecdotal evidence to from its ancestral home in Bengal was fi rst documented in the contrary.
1817 (1), the beginning of what has been designated as the Cholera today takes advantage of breakdowns in fi rst pandemic. In the intervening 2 centuries, cholera has sanitation and health infrastructure, often in the setting continued to ebb and fl ow from southern Asia to other parts of natural and complex disasters. More notably, cholera of the known world, with 6 additional pandemics identifi ed. has survived the transition from ancient to modern world, During the third pandemic, which ravaged London in with the establishment of endemic foci in virtually every 1854, John Snow conducted his pioneering epidemiologic continent. We have learned a great deal about cholera during studies (and gained fame for removal of a pump handle). the past few decades. Major advances have been made in therapy, which has decreased expected case-fatality rates Author affi liation: University of Florida, Gainesville, Florida, USA to <0.5%. However, we are just coming to appreciate the DOI: evolutionary capabilities of the microorganism and the Emerging Infectious Diseases • • Vol. 17, No. 11, November 2011 complexity of transmission pathways, an understanding of body weight) intravenous rehydration is almost always which is essential to ultimate control of the disease.
necessary; limited anecdotal reports suggest that use of intravenous therapy is becoming more frequent in areas Clinical Features and Management
where cholera is endemic and epidemic, consistent with Clinically, cholera is a simple disease. Its concerns about increasing severity of illness. In early manifestations result almost entirely from action of cholera placebo-controlled studies, tetracycline reduced duration toxin, a protein enterotoxin excreted by the bacterial cell. of diarrhea, total volume of diarrhea, and days of excretion The A subunit of cholera toxin activates adenylate cyclase, of V. cholerae by >50%; more recent studies demonstrated causing increased Cl– secretion by intestinal crypt cells equivalent or better results with ciprofl oxacin and and decreased NaCl-coupled absorption by villus cells and azithromycin. However, antimicrobial drug use is also resulting in a net movement of electrolytes (and water) clearly associated with development of resistance, leading into the lumen of the intestine (5). All manifestations of to current WHO recommendations that antimicrobial the disease can be reproduced by administration of cholera agents be limited to use in patients with severe dehydration. toxin: in studies conducted in the 1970s at the University As recently suggested by Nelson et al. (12), extending use of Maryland (Baltimore, MD, USA), volunteers given 25 of antimicrobial drugs to a larger patient group may be μg of pure cholera toxin had >20 L of rice-water feces; reasonable, particularly in light of increasing awareness ingestion of as little as 5 μg of purifi ed toxin resulted in of direct transmission of the microorganism from person 1–6 L of diarrhea in 5 of 6 volunteers (6).
to person, as discussed below. Zinc supplementation also Severity of illness varies widely. In the most severe has been recognized as a potentially useful adjunct to form of the disease, cholera gravis, patients can pass >1 L therapy; recent studies among children in Bangladesh have
of diarrheal feces per hour. Feces are passed effortlessly, shown that its administration resulted in a 12% reduction in
with the diarrhea assuming a rice-water appearance. If duration of diarrhea and 11% reduction in fecal volume in
volumes are not repleted, this diarrhea can result, in as patients compared with controls (13).
little as 6–8 hours, in circulatory collapse, shock, and
death. Shock, even if adequately treated, may precipitate Genetics/Microbiology
acute renal failure. Severe acidosis results from fecal loss
V. cholerae is a diverse species and a natural (and of bicarbonate, exacerbated by hypotension-related lactic common) inhabitant of estuarine environments around the acidosis and renal failure.
world. Distribution depends on water temperature (optimal Although cholera gravis is a devastating disease, growth at water temperatures >20°C) and salinity (14). In studies in the early 1970s suggested that such severe cases contrast to most other Vibrio species, it is able to grow in accounted for only 11% of total infections among persons fresh water and is often present in inland rivers and lakes infected with strains of the classical biotype (responsible in regions where it is endemic. In areas with seasonal for the sixth cholera pandemic); 59% of infections were variations in water temperatures, the microorganism shows asymptomatic or inapparent, and the remainder represented clear seasonality: environmental counts increase during illness of mild to moderate severity. In studies during that warmer periods and decline (or become nondetectable) same period, only 2% infected with seventh pandemic during cold weather. In studies in Peru (15), V. cholerae biotype El Tor strains had severe disease, and 75% of counts in the Rimac River (at a site above Lima where infected persons were asymptomatic (7). Although the El sewage contamination was minimal) spiked ≈2 months Tor biotype has persisted, its relative lack of virulence has after an initial summer rise in water temperature but then not; recent studies have noted substantial increases in the returned to a nondetectable level within 1–2 months (online percentage of patients with severe dehydration (8), and Technical Appendix, percentage of asymptomatic infected patients appears Techapp.pdf). The reason for the sharp drop in counts to be much smaller (<50%, in a recent study by Harris et after the initial spike (a pattern also seen in some ponds al. [9]). As described below, these observations coincide in Bangladesh [16]) is not clear. One hypothesis is with the appearance of new atypical V. cholerae strains that that it is related to rapid increases in the number of V. include classical biotype genetic material within an El Tor cholerae–specifi c lytic bacteriophages in the local aquatic background (10,11).
environment (17,18), providing natural predation as a The cornerstone of therapy is replacement of lost fl uid. countermeasure to the initial rapid increase in numbers of With an infrastructure able to provide adequate rehydration the microorganism.
therapy, case-fatality rates should be <1%, ideally <0.5%. V. cholerae can assume a variety of survival forms, In mild to moderate cases, rehydration can generally be including a shift to what has been termed a viable but successfully accomplished with oral rehydration solution. nonculturable form, which is often associated with biofi lms. In patients who are severely dehydrated (loss of 10% of Strains can also assume a rugose phenotype (identifi able Emerging Infectious Diseases • • Vol. 17, No. 11, November 2011 on culture by a characteristic rough/wrinkled appearance), O1 and O139. These serotypes include O141 and O75 in in which the microorganism produces large quantities of the United States and O37, O10, O12, O6, and O14 in other an amorphous exopolysaccharide, leading to formation of parts of the world (23,26). Changes in serotype, in turn, a biofi lm that is resistant to chlorine, UV light, and other appear to result from lateral transfer of the gene cassettes standard disinfectants (19). V. cholerae has been closely responsible for O-antigen biosynthesis (23,26).
linked with copepods (binding to chitin through the action Recent changes or recombinational events also have of a specifi c chitinase) and with zooplankton (14). It has been seen in the ctx gene cluster, with introduction of the also been found in association with chironomid egg masses classical biotype ctx gene into an El Tor background and the and water hyacinth and can be carried by gulls, other birds, appearance of strains containing multiple recombinational and mammals.
events that have modifi cations in ctx as well as other Although V. cholerae as a species is ubiquitous changes that result in loss of traditional El Tor biotype in the environment, strains responsible for the disease characteristics (10,11,27). Although nomenclature remains cholera are restricted to a fairly tight subset of strains, as in fl ux (11), these new atypical strains have, at this point, refl ected in clustering seen by multilocus sequence typing entirely supplanted traditional seventh pandemic El Tor and sequence analysis. The key gene clusters responsible strains at a global level (including, most recently, the strain for the manifestations of cholera are associated with responsible for the Haiti epidemic [28]). As discussed production of cholera toxin located within the ctx element above, these strains also appear to have major increases (which is part of a fi liamentous phage capable of movement in virulence (potentially because of increased levels of among strains [20]) and the vibrio pathogenicity island, cholera toxin production [29]), comparable with (or in which includes the TCP (toxin-coregulated pilus) gene, excess of) clinical characteristics of the sixth pandemic essential for binding of the microorganism to the intestinal classical biotype strains.
mucosa. Other genes common to strains with an epidemic V. cholerae strains associated with epidemic disease phenotype also have been identifi ed; however, the role of can respond to changes in their immediate environment many of these genes in the pathogenesis of cholera remains as they move from environmental reservoirs to humans to be determined (21,22). Even though virtually all strains and back. Of particular relevance, it has been shown that cause cholera produce cholera toxin and have the vibrio that V. cholerae passed in human rice-water feces are pathogenicity island, not all V. cholerae that carry 1 or both in a “hyperinfectious” state (17,30); in animal studies, of these gene complexes cause cholera; several studies infectious dose is 1–2 orders of magnitude lower than that have noted the isolation of 1 or both from environmental for strains grown by using traditional in vitro methods. The strains that appear to lack other components of the genetic hyperinfectious state lasts at least 5 hours after passage of background essential for virulence in humans and epidemic the microorganism from patients. The physiologic basis spread (22,23).
for this effect is unclear but appears to be associated, at The V. cholerae genome readily undergoes change, least in part, with changes that include down-regulation with extensive genetic recombination through lateral gene of chemotaxis genes (31). V. cholerae as it is passed from
transfer, resulting in what have been termed shifts and drifts the body also up-regulates a series of genes that are not
in the genome sequence (21). This genetic plasticity is required for infection but are needed for survival in the
refl ected in the observation that feces from a single infected environment. Twenty-four hours after the microorganism
patient in an area where cholera is endemic almost always reaches the aquatic environment, these shifts, potentially
show evidence of infection with multiple genetically combined with lytic phage, result in a dramatic decrease in
distinct V. cholerae strains, as defi ned by variable-number the ability of V. cholerae to cause infection (18).
tandem-repeat analysis (24). Variability also can be seen in
serotype. Traditionally, epidemic disease was thought to be Epidemiology/Transmission
confi ned to cholera toxin-producing strains in V. cholerae
During the 1960s, the scientifi c consensus was that O group 1. However, in 1992, a new serotype, O139, was cholera was transmitted from person to person; a great recognized as the cause of a major cholera epidemic on deal of attention was given to the role of convalescent and the Indian subcontinent (25); emergence was linked to chronic carriage in transmission. During the following replacement of the O group 1 biosynthesis cassette with decades, attention shifted sharply from human carriage a biosynthesis cassette for the O139 antigen (which also to environmental reservoirs, with a focus on the role encoded material for formation of a capsule). O group 1 of environmental factors in persistence of the disease strains continue to predominate among epidemic isolates, and triggering of epidemics. However, with the advent but serotype clearly does not directly predict virulence; of increasingly sensitive molecular techniques—and cholera-like illness (albeit without epidemic spread) is now mathematical modeling approaches—there has been associated with several different serotypes in addition to movement back toward a transmission model that Emerging Infectious Diseases • • Vol. 17, No. 11, November 2011 recognizes the role of environmental reservoirs and direct The picture changes once the microorganism is (human-to-human) transmission. In this context, we introduced into human populations. Rice-water feces propose the transmission model shown in the Figure.
contain 107–109 V. cholerae microorganisms per mL. The aquatic environmental reservoir is critical to Immediately after passage, these microorganisms are in long-term maintenance of epidemic V. cholerae. These a hyperinfectious state (further dropping the infectious reservoirs constitute complex biological systems, with dose by 1 or 2 logs), generating the opportunity for “fast” modulation of V. cholerae populations by environmental transmission of V. cholerae to other persons either by conditions (the local microenvironment [15,16] as well as direct contact with feces or direct contamination of food global macroenvironmental factors, such as the El Niño/ or water within the immediate household environment. Southern Oscillation [32]); by predatory bacteriophage Microorganisms from feces can also reenter environmental populations (18); and by fl uctuations in populations of reservoirs by fecal contamination. However, one then has to copepods and zooplankton (which can, in turn, be driven deal with dilutional effects within the environment and the by predation by fi sh), binding to chironomid egg masses, striking drop in infectivity (noted above) that can occur as water hyacinth, carriage by birds and mammals, and a host the microorganism adjusts to an environmental habitat (18). of other variables. At the same time, our data from Lima In our studies in Lima at the peak of a cholera epidemic, (online Technical Appendix) and from Bangladesh show a we found environmental counts of toxigenic V. cholerae of signifi cant association between a spike in numbers of ctx- ≈105/mL in areas with heavy sewage contamination, so the positive V. cholerae in the environment and subsequent potential for infection from environmental sources clearly occurrence of cholera in the community (15,16), consistent increases in settings of poor sanitation during epidemics. with the concept of spillover of the microorganism from the Nonetheless, looking at the relative counts from different environment to human populations.
sources of exposure, these observations are consistent On the basis of our studies in Lima and Bangladesh, with the hypothesis that a major transmission pathway peak environmental counts of ctx-positive V. cholerae from for V. cholerae during an epidemic (particularly at the pristine areas range from 101 to 102 CFU/mL (15,16). The beginning of an epidemic) is through a “fast” pathway, infectious dose for V. cholerae (classical biotype) ingested taking advantage of the short-lived hyperinfectious state to by healthy North American volunteers is in the range of 108 move from person to person, without an intervening “slow” to 1011 CFU/mL, which drops to 104–108 when the inoculum transmission step through the environment.
is given with bicarbonate or food (5,33). Assuming Data from a variety of sources support this hypothesis. consumption of a large enough volume of contaminated In studies in Bangladesh that used variable-number material; mixing with food (with the potential for further tandem-repeat analysis (36), we found minimal overlap growth in food before consumption (34,35]); and possible between clinical strain populations circulating in human underlying host factors, such as mild hypochlorhydria populations and the ctx-positive V. cholerae strains that (which can be associated with Helicobacter pylori infection, were circulating concurrently in environmental reservoirs. endemic to many developing countries) and malnutrition, If the environmental reservoir was playing a major role transmission from environmental sources that are not in the ongoing epidemic, one would have expected to heavily fecally contaminated becomes plausible. However, see the same genetic types appearing in strains from the this infectious dose still would be at the low end of the environment and strains from patients. In mathematical curve, and the percentage of exposed persons becoming models, inclusion of a fast (presumed person-to-person or infected at these low levels is likely to be relatively small.
person-to–household environment–to-person) transmission pathway that incorporates the short-lived hyperinfectious state results in a much better match with outbreak data than models that rely solely on a “slow” human-to–aquatic environment–to-human pathway (37). In subsequent work we have applied our models to data from the 2008–2009 Zimbabwe epidemic (3). When calculated by province, the reproductive number (R ) for the epidemic ranged from 1.1 to 2.7; our calculations suggest that 47%–94% of this value, dependent on province, was accounted for by fast (hyperinfectious/presumed person-to-person) transmission.
These observations underscore the need to focus prevention efforts on the short window of time after passage of feces when strains are in a hyperinfectious state. This observation translates into the need for an emphasis on Vibrio cholerae transmission.
Emerging Infectious Diseases • • Vol. 17, No. 11, November 2011 households (and, in particular, an emphasis on households 5. Kaper JB, Morris JG Jr, Levine MM. Cholera. Microbiol Rev with index cases), where exposure to recently excreted microorganisms is most likely. This fi nding fi ts with those 6. Levine MM, Kaper JB, Black RE, Clements ML. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine from earlier epidemiologic studies from Bangladesh, where development [erratum in: Clin Microbiol Rev 1995;8:316]. Clin Mi- risk for illness was linked with the presence of an infected person in the household, not with whether the household 7. Gangarosa EJ, Mosley WH. Epidemiology and surveillance of chol-used clean tube well water versus potentially contaminated era. In: Barua D, Burrows W, editors. Cholera. Philadelphia: W.B. Saunders; 1974. p. 381–403.
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Edited by Nancy Männikkö; DOI: Emerging Infectious Diseases • • Vol. 17, No. 11, November 2011


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