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Vibrio cholerae and Vibrio parahaemolyticus are the major human pathogens among Vibrio species. Despite their distinctive biologic and ecologic features, both pathogens show some parallelisms in their epidemic dynamics and are currently involved in 2 pandemic spreads.
The seventh cholera pandemic began in Indonesia in 1961 and was confined to Asia until 1970 when it reached Africa and Europe. It re-emerged in northern Peru in 1991, causing more than 1 million cases of cholera and 10,000 deaths in Latin America in just 3 years.1V. cholerae was the unique case of pandemic spread among Vibrio pathogens until 1996, when a dramatic increase in the number of V. parahaemolyticus illnesses was detected in India.2
Before 1996, V. parahaemolyticus infections were sporadically detected in various geographic areas associated with diverse serotypes.3 However, the emergence of V. parahaemolyticus infections in Calcutta in February 1996 was distinctively linked to isolates belonging to the O3:K6 serotype, with identical genotypes (tdh positive and trh negative) and profiles indistinguishable by molecular typing techniques.2 The first reported isolate belonging to the new O3:K6 clone was previously detected in a patient from Indonesia in 1995.2 In 1996 and 1997, diseases caused by this clone spread throughout most Southeast Asian countries (Fig. 1). The epidemiology of the O3:K6 infections changed abruptly in November 1997, when infections caused by this clone were first detected outside of Asia at a single location on the northern coast of Chile,4 triggering the first pandemic expansion of this organism. The factors that endow the O3:K6 clone with this pandemic potential are not well understood because no specific advantages in virulence or enhanced survival of these isolates have yet been established.5
Until the appearance of Vibrio epidemics in South America, the infection had spread mostly westward, consistent with the prevailing westward movement of water associated with the Indonesian throughflow (a system of currents flowing from the Pacific Ocean to the Indian Ocean through the Indonesian Sea).6,7 The emergence of V.cholerae in 1991 and V. parahaemolyticus in 1997 on the west coast of South America was evidence of an eastward drift of Asian endemic infections, concurrent with the arrival of warm equatorial waters displaced from Asia to America by the last 2 El Niño episodes.
The origin of the 1991 cholera epidemic in America remains uncertain. An oceanic theory for the transPacific transport of cholera from Asia to America was proposed,8 in which the exchange of water masses throughout the Strait of Makassar near Indonesia was suggested as the route of entry of V. cholerae to the Pacific, and from there transporting bacteria to Peru by eastward equatorial displacement of waters of El Niño.8 However, this hypothesis could not be consistently contrasted because of the rapid dissemination of infections that spread over 2000 km of the west coast of Peru in just 2 weeks and reached the tropical forests 1 month later.9,10,10a Furthermore, the scarcity of oceanic records and satellite data available in 1991 constrained reliable analysis of the role of El Niño in the origin of the American cholera epidemic.
The emergence of the V. parahaemolyticus epidemic in America concurrently with the 1997 El Niño episode provided an opportunity to test the hypothesis of the oceanic spread of Vibrio infections from Asia. Unlike V. cholerae, V. parahaemolyticus is a strictly halophilic organism with a habitat restricted to the marine environment. This ecologic feature limits its distribution to coastal areas, thereby enabling accurate tracking of the disease spread. Moreover, the pandemic clone of V. parahaemolyticus emerged in 1996 and was restricted to Asia until its detection in America. Finally, the 1997 El Niño was the best-documented episode of El Niño, and numerous studies were undertaken to assess the oceanographic and biologic changes coupled with this event.
To evaluate the hypothesis of oceanic dispersion of Vibrio infections, we focused our study on Peru, a country greatly affected historically by El Niño episodes, and also the place of emergence of the cholera epidemic in 1991.
Epidemiologic Information and Strains of V. parahaemolyticus
V. parahaemolyticus is not routinely investigated in hospitals in Peru, and related infections are not reported to the infectious diseases surveillance system. However, mandatory investigation of V. cholera in clinical laboratories after the emergence of cholera epidemic in 1991 enabled parallel identification of other pathogenic Vibrio.
Vibrio strains isolated from clinical sources in hospitals and public health laboratories in Peru are shipped to the Instituto Nacional de Salud (Lima, Peru) for final identification and characterization. Information concerning isolates received by this Institute is registered weekly. We conducted an extensive survey of their records to establish the number of V. parahaemolyticus strains received from clinical laboratories between 1994 and 2005. We inferred the rate of V. parahaemolyticus infections from the number of strains received by the Institute in that period. As each strain shipped was associated with a patient who received medical assistance, we assumed that the number of isolates shipped was indicative of the dynamics of V. parahaemolyticus infections over the period of study. However, considering that V. parahaemolyticus infections often cause mild illnesses that rarely need medical care, these values probably represent only a small fraction of the actual number of infections.
Additionally, 63 V. parahaemolyticus isolates from the National Culture Strain Collection, deposited in the Instituto Nacional de Salud, were subjected to serologic and genetic characterization. Two environmental strains of V. parahaemolyticus obtained from previous studies were also characterized.
Identification of the isolates was confirmed by the presence of the species-specific Vp-toxR and tlh genes. The presence of the Vp-toxR gene was investigated by PCR as described previously.11 Presence of tlh and the virulence-related genes tdh and trh was determined by multiplex PCR according to the procedure of Bej et al12 Virulence attributes were also investigated by single PCR protocols for identifying tdh and trh genes, according to Tada et al13 The pandemic nature of isolates was investigated by use of the Group-Specific PCR assay as described previously14; this procedure allows specific detection of the pandemic clone-specific nucleotides in the toxRS operon of V. parahaemolyticus. Serotyping of isolates was performed according to the manufacturer's instructions (Denka-Seiken Ltd., Tokyo, Japan). Lipopolysaccharide (O) and capsular (K) serotypes were determined by agglutination tests in which specific antisera were used.
Pulsed-Field Gel Elecrophoresis
Peruvian V. parahaemolyticus isolates were compared with a panel of isolates from Asia representing prepandemic, pandemic spread, and pandemic serovar transition periods. Isolates from the first emergence of pandemic V. parahaemolyticus in Antofagasta (Chile) in 1997 were also included. Asian and Chilean isolates were provided by Mitsuaki Nishibuchi (Kyoto University, Japan) and Romilio Espejo (University of Chile, Chile), respectively. Pulsed-field gel electrophoresis was performed according to “One-Day (24–28 hours) Standardized Laboratory Protocol for Molecular Subtyping of Nontyphoidal Salmonella by PFGE”15 following a previously described method.16 Restriction patterns were compared by use of BioNumerics software (Applied Maths, Sint-Martens-Latem, Belgium).
Association between El Niño waters and the arrival and dissemination of V.parahaemolyticus epidemic was evaluated by selecting oceanographic factors distinctive of El Niño phenomena. In addition to surface seawater temperature, which varied seasonally independently of the El Niño episodes, we also considered sea height anomaly and the heat content above 20°C as consistent indicators of the advance of warm waters displaced by the Kelvin waves.
The thermal structure of ocean impacts on sea surface topography and the variations of this parameter are detected by radar altimeters, which allow inference of sea height anomaly values at an accuracy of 1–2 cm rms.17 This parameter is the deviation of the sea height from a climatologic annual mean. We use the gridded sea height anomaly fields computed by AVISO (http://www.jason.oceanobs.com/).
The heat content above 20°C is defined as the integrated heat content from the surface to the depth of the 20°C isotherm, estimated by a 2-layer reduced gravity model.18 This isotherm represents the depth of the thermocline in the equatorial region19 and serves as a proxy for monitoring the evolution of El Niño and the propagation of Kelvin waves. Other variables in this parameter are the monthly relationships among the depth of the isotherms above 20°C and values of sea surface temperature obtained from ∼9 km NOAA/NASA AVHRR Oceans Pathfinder Best-surface seawater temperature data product20 and the Tropical Rainfall Measuring Mission Microwave Imager by Remote Sensing Systems and sponsored by the NASA Earth Science REASoN DISCOVER Project (www.remss.com).
Time series of these 3 parameters show the evolution of El Niño in 1997–1998. Fields were averaged and resampled weekly into 1° × 1° grids.
The relationships between V. parahaemolyticus strains isolated in Peru during the study and the environmental explanatory variables were analyzed by generalized additive models (GAMs)21 applied to time-series data.22–24 The variable response was defined as the number of strains isolated per week in the area, and the explanatory variables considered were surface seawater temperature, sea height anomaly, and heat content above 20°C. We also used a smooth function of time as an independent variable when autocorrelation was detected in the residuals. Because the isolations of strains throughout 1 week were not independent events, a variance of the response variable higher than the mean (overdispersion) may have resulted. We, therefore, used negative binomial models rather than Poisson response models to obtain standard errors corrected for overdispersed parameters. The logarithm “log” link function was used to achieve interpretable epidemiologic measures of the effect. We used thin-plate regression splines as trend smoothers, according to Wood,25 and automatically selected the optimal degrees of freedom by using generalized cross validation criterion.26 The use of log link in our model and the high proportion of zeros encountered in the response variable may cause problems of convergence in the algorithm for fitting GAMs (because of a fundamental lack of identifiability of the models). We, therefore, applied a ridge regression with penalties to impose identifiability in the GAMs. Models were estimated by use of the mgcv package version 1.3–13, in the R environment, version 2.5.0 (R Development Core Team, 2003).
Cases of V. parahaemolyticus infections in Lima were analyzed during 3 periods: pre–El Niño (1994–1996), El Niño (1997 and 1998), and post–El Niño (1999–2004) to evaluate whether similar oceanographic conditions were related to infections associated with the different serotype-dominance periods (1994–1996, 1997–1998, and 1999–2004), or whether the propagation of O3:K6 infections in Peru was associated with distinctive oceanographic factors linked to the movement of El Niño waters.
To elaborate the models, we identified lagged periods (weeks) for each independent variable that showed lower values of the Akaike's Information Criterion. For this, we constructed a model for each explanatory variable and each lag, with lags ranging from 1–5 weeks. For each period, we developed 2 models: the first included surface seawater temperature and sea height anomaly as covariates, and the second included surface seawater temperature and heat content above 20°C. As the sea height anomaly and heat content above 20°C variables were used as indicators of the same phenomenon, they were not simultaneously included in the same model to prevent potential collinearity. To check nonlinear relationships, all 3 variables were included in the models as a smooth function of continuous covariates through thin-regression splines. A linear relationship was assumed when the estimated degrees of freedom was 1 or close to 1, whereas when they were different from 1, a Bayesian approach to smooth modeling was used to derive standard errors on predictions and obtain credible confidence bands for the effects, assuming linearity if a straight line could be delineated between the boundaries of the 95% confidence bands. When this did not occur, we categorized the variable by using the change points observed. We then assessed the simple autocorrelation function of Pearson residuals. If an elevated autocorrelation was observed, a smooth function of the time was included in the model. In those cases still supporting residual autocorrelation, we included autoregressive terms of the dependent variables for lags with autocorrelation.
Results were expressed as rate ratios (RRs) with 95% confidence intervals (CIs), indicating an increase or decrease in the probability of obtaining a response for an increase of 1 unit in the independent variable. We also included the interquartile RR (IqRR) to take into account the distributions of dependent variables24 and to allow for comparing the magnitudes of the effects of independent variables measured in different units.
Distribution of V. parahaemolyticus infections in Peru between 1994 and 2005 showed a pronounced seasonal pattern (Fig. 2) during the entire period. Case records from 1994–1996 were associated with occasional scattered infections restricted to the warmest months. This pattern of infections was suddenly disrupted in 1997 with the presence of an anomalous increase in the number of V. parahaemolyticus cases in the course of the austral winter dispersed from north to south along coastal regions. The onset of infections was initially detected in July and lasted for 10 months, with 2 peaks occurring in September and February (Fig. 2). Infections were observed along the entire coastline of the country, and spread more than 1500 km in just 4 months (Fig. 3A). The first record was detected in Chiclayo, Department of Lambayeque, in the north of the country, in July. From there, infections spread in a constant southward direction, affecting the Department of Cajamarca in August, La Libertad in September, Huaraz in October, and finally reaching the southern Peruvian border in November—the same time as the emergence of V. parahaemolyticus illnesses in the northern Chilean city of Antofagasta.4
Laboratory investigations of 64 strains recovered from the Instituto Nacional de Salud strain collections representative of the 1994–2005 period showed an extraordinary shift in pathogenic V. parahaemolyticus populations associated with the rise of infections in July 1997 (eFigures 1 and 2 and eTable; available with the online version of this article). Serotypes O4:K8, O4:K55, and O4:K28 were identified as the prevailing serovars among pathogenic strains from environmental and clinical sources in a previous study conducted in Peru in 1983–1984.27 Serotype O4:K8 was also identified in strains isolated before 1997 in the present study, whereas O5:KUntypable (UT) was associated with the large outbreak of disease in Lima in 1995. The onset of infections in 1997 was associated with a complete change in serotype dominance. All the isolates obtained in the 1997–1998 period belonged exclusively to the O3:K6 serotype, which remained the dominant serotype until its total disappearance in 2004. The O3:K6 isolates showed typical molecular characteristics of the pandemic clone and were positive for the specific PCR pandemic test. Molecular typing procedures revealed high clonal uniformity among O3:K6 specimens. Pandemic isolates obtained in 1997 and 1998 presented highly uniform DNA restriction patterns, as revealed by pulsed-field gel electrophoresis analysis with NotI and SfI enzymes, and shared serotype and indistinguishable genetic properties with the pandemic O3:K6 strains obtained from India, Bangladesh, Thailand, and Taiwan, for the initial spread of V. parahaemolyticus epidemic in 1996. Peruvian O3:K6 isolates were also identical to the pandemic isolates subsequently detected on the north coast of Chile in November 1997 (eFigs. 1 and 2). Conversely, whereas O3:K6 populations from Asia evolved rapidly in 1997 and showed a dynamic serovar transition with the generation of new serotypes (O4:K68, O1:KUT),14 Peruvian pandemic strains maintained a unique serotype and homogeneous genetic characteristics until their disappearance in 2004.
The emergence and pattern of dissemination of V. parahaemolyticus infections along coastal cities associated with O3:K6 strains showed a close correspondence with the arrival and propagation of 1997 El Niño along the coast of South America. This El Niño episode reached northern Peru by April 1997 and exhibited 2 periods of peak intensity in June and November 1997 (Fig. 3B). The 2 peaks of maximum intensity were linked to the arrival of the 2 major sets of equatorial Kelvin waves, which were observed along the coast of Peru with different degrees of intensity.28,29 The first set of Kelvin waves reached Chiclayo (7° S latitude) by the end of May and showed a strong effect in the northern area. The intensity of this first anomaly decreased gradually during its poleward displacement, to become almost imperceptible south of 12° S latitude (Fig. 3B). This dynamic matched with the first epidemic spread of V.parahaemolyticus infections, which emerged in Chiclayo in July and was restricted to the north and central areas of Peru, whereas no infections were detected in southern Lima. The second and stronger set of Kelvin waves was first observed at the equator in August 1997 and subsequently detected in northern Peru in November. This additional anomaly had a more severe and extended effect on the entire coastline of Peru and was observed in the north of Chile (23° S latitude). The propagation pattern was similar to that observed for the second spread of infections that were detected in Moquegua in November and subsequently reached the Antofagasta area. The 1997 El Niño first began to decline in northern Chile in May 1998 and, from this point, anomalies entered in a constant northward recession until its total disappearance from the north of Peru by June 1998, coinciding with the decline of V. parahaemolyticus infections.
Interactions between V. parahaemolyticus cases and the environmental variables confirmed the earlier observations linking the emergence of pandemic cases with the arrival of El Niño to Peru (Table 1). For the pre–El Niño period, surface seawater temperature was the dominant factor affecting the disease dynamics in the zone. The rise of temperature with the warmer months was the prevalent factor that affected the appearance of infections associated with nonpandemic V. parahaemolyticus populations. An increment in surface seawater temperature from 18.4°C–23.4°C accounted for an increase of more than 600-fold in the risk of infections (IqRR = 601; 95% CI = 128–2811).
By contrast, the dominant effect of surface seawater temperature disappeared entirely from the model with the arrival of the 1997 El Niño episode, and the appearance of pandemic cases in Peru could then be linked only to the incoming of El Niño waters. The heat content over 20°C for this period was associated with an IqRR of 4.7 (2.2–9.8).
Finally, disease dynamic during the post–El Niño period could not be consistently explained by the models constructed with the considered parameters, possibly because of the complex environmental situation that prevailed during the long period of ecologic restoration of the Peruvian coastal areas after the El Niño event.
The pattern of spreading of pandemic V. parahaemolyticus in Peru showed characteristics similar to those observed for the 1991 cholera epidemic. The first cholera case was detected in Trujillo on 23 October 1990; new cases were then diagnosed in Chimbote on 11 December, Chancay on 26 December, and in Lima on 13 January (Fig. 3A). This gradual southward dissemination of cases was similar in sequence and speed to that observed for the fist spreading of pandemic V. parahaemolyticus in 1997, which was linked to the weakest set of Kelvin waves with southern boundary in Lima. Both epidemics were initially detected in the same area, Chiclayo and Trujillo, and shared their southward rate progression, covering 600 km of distance in just 3 months. Furthermore, although the dimensions of the 2 diseases were not comparable, the 2 epidemics also showed similarities in the dynamics of infection (Fig. 4). Both epidemics showed a characteristic explosive emergence, a rapid fall in the number of cases, and a final cyclic seasonal pattern under the influence of increases in surface seawater temperature, before disappearing almost totally. Surface seawater temperature failed to account for the extraordinary dimension of emergence of cases in both epidemics, which were linked with the arrival of specific El Niño episodes.
The cause of the dramatic emergence of the cholera epidemic in Peru in 1991 has not previously been understood. The appearance of a new Vibrio disease in the same area has yielded novel information that allows a better understanding of the spreading mechanisms and the dynamics of these waterborne diseases. The absence of environmental information about the impact of the arrival of El Niño waters on the native Vibrio community severely constrains a comprehensive overview of the role of El Niño episodes in the introduction of new Vibrio pathogens in these remote regions. However, the abundant information about the major biologic and oceanographic impacts of El Niño in this area, obtained from oceanographic studies conducted in the Pacific coasts of South America throughout the El Niño event, could potentially provide new insight into the possible mechanisms involved in these processes.
One of the main manifestations of the El Niño episodes in America is the inflow of foreign zooplankton populations trapped in the El Niño waters,29–32 as has been reported for different areas of Peru and Chile for the 1997 El Niño.28–31,33,34 The arrival of warm tropical waters produced a drastic reduction in upwelling and primary production,30,35 which in turn caused a dramatic decrease in the abundance of phytoplankton and the subsequent collapse in zooplankton production. Conversely, this decline in native zooplankton species did not have a direct effect on the overall abundance of zooplankton, which was maintained throughout the El Niño episode by the massive input of equatorial species of zooplankton—mainly small copepods.28–31,33,34
The survival and growth of V. parahaemolyticus in the marine environment have been strongly associated with its ability to attach to planktonic organisms, predominantly copepods.36–39 A close correlation between the zooplankton blooms and cholera infections in endemic areas has been suggested.40,41 The chitin present in copepods represents an important food source for vibrios and provides protection under unfavorable environmental conditions, thereby allowing these organisms enhanced survival in the marine environment.42–45 The interaction between Vibrio and chitin has also been found to provide a selective advantage for the survival in the host.46–48 The biologic association of bacterium and copepod may provide a stable platform for the displacement and gathering of Vibrio specimens in the open ocean which, under certain extraordinary oceanographic circumstances, may allow for the long-distance displacement of Vibrio specimens. This could have been the mechanism for the extraordinary migration of Asian pathogens to America coupled with El Niño. The arrival of the invasive exogenous zooplankton populations to the coasts of Peru associated with the El Niño waters may have been the vehicle of entry and distribution of foreign Vibrio populations along the coast of Peru and the subsequent contamination of fish and shellfish in the coastal zones. The consumption of the contaminated seafood may have finally been responsible for the emergence of infections in phase with the evolution of the El Niño episode described in this study. Due to the dose-response dependence of both pathogens,49–52 the explosive emergence of Vibrio infections in the first stages of the epidemics may be explained by the ingestion of seafood contaminated with large amounts of Vibrio. From this point, the 2 diseases acquired separate dimensions due to their distinctive abilities to spread among the population. The acquisition of a hyperinfectious state by V. cholerae resulting from its passage through humans may have stimulated the rapid progression of the cholera disease in interior regions associated with the human-to-human transmission,51 whereas V.parahaemolyticus infections remained restricted to coastal areas because of their dependence on environment-to-human transmission.
The manifestation of an El Niño episode may imply the generation of a temporary eastward corridor for the sporadic displacement of marine organisms to America. This process may additionally provide a periodic and unique source of new pathogens in America, with serious implications for the future spreading of waterborne infections on a global scale.
The authors thank Juan Tarazona for helpful information on the impact of El Niño in Peru; Mitsuaki Nishibuchi and Romilio Espejo for providing some of the strains included in this study; Douglas Bartlett, Tomas G. Villa, and Oscar Garcia for critical advice. The authors are grateful for the financial support and assistance contributed by the Xunta de Galicia and the NOAA CoastWatch Program.
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