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1.  Determining Risk for Severe Leptospirosis by Molecular Analysis of Environmental Surface Waters for Pathogenic Leptospira 
PLoS Medicine  2006;3(8):e308.
Background
Although previous data indicate that the overall incidence of human leptospirosis in the Peruvian Amazon is similar in urban and rural sites, severe leptospirosis has been observed only in the urban context. As a potential explanation for this epidemiological observation, we tested the hypothesis that concentrations of more virulent Leptospira would be higher in urban than in rural environmental surface waters.
Methods and Findings
A quantitative real-time PCR assay was used to compare levels of Leptospira in urban and rural environmental surface waters in sites in the Peruvian Amazon region of Iquitos. Molecular taxonomic analysis of a 1,200-bp segment of the leptospiral 16S ribosomal RNA gene was used to identify Leptospira to the species level. Pathogenic Leptospira species were found only in urban slum water sources (Fisher's exact test; p = 0.013). The concentration of pathogen-related Leptospira was higher in urban than rural water sources (~103 leptospires/ml versus 0.5 × 102 leptospires/ml; F = 8.406, p < 0.05). Identical 16S rRNA gene sequences from Leptospira interrogans serovar Icterohaemorrhagiae were found in urban slum market area gutter water and in human isolates, suggesting a specific mode of transmission from rats to humans. In a prospective, population-based study of patients presenting with acute febrile illness, isolation of L. interrogans-related leptospires from humans was significantly associated with urban acquisition (75% of urban isolates); human isolates of other leptospiral species were associated with rural acquisition (78% of rural isolates) (chi-square analysis; p < 0.01). This distribution of human leptospiral isolates mirrored the distribution of leptospiral 16S ribosomal gene sequences in urban and rural water sources.
Conclusions
Our findings data support the hypothesis that urban severe leptospirosis in the Peruvian Amazon is associated with higher concentrations of more pathogenic leptospires at sites of exposure and transmission. This combined quantitative and molecular taxonomical risk assessment of environmental surface waters is globally applicable for assessing risk for leptospiral infection and severe disease in leptospirosis-endemic regions.
Vinetz and colleagues used a quantitative real time PCR assay combined with molecular taxonomic analysis to quantify Leptospira in environmental surface waters in the Peruvian Amazon region of Iquitos.
Editors' Summary
Background.
Humans catch many diseases from animals—so-called zoonotic infections. Often, these occur in limited regions of the world. However, one—leptospirosis—occurs in temperate and tropical climates, and in urban and rural settings, making it the most widespread zoonotic disease. Leptospirosis is caused by Leptospira, a large group of closely related spiral-shaped bacteria that live in both domestic animals (for example, cattle) and wild animals (particularly rats). Millions of humans become infected each year with leptospires through close contact with water, food, or soil contaminated with the urine of infected animals—swimming or wading in contaminated water is particularly hazardous. Some infected people have no symptoms; others develop a flu-like disease that clears up within a few days. However, in 5%–10% of infected people, the disease progresses to a second, sometimes fatal phase. This is usually characterized by jaundice, kidney problems, and an enlarged spleen (it's then called Weil disease) but can also involve the lungs (pulmonary leptospirosis). Leptospirosis can be successfully treated with antibiotics if treatment is started soon after infection.
Why Was This Study Done?
In a recent study in the Peruvian Amazon, half of the people visiting urban hospitals and rural health posts with acute fever had antibodies in their blood to Leptospira, suggesting that they had acute leptospirosis. However, only patients living in urban areas developed pulmonary leptospirosis. In this study, the researchers tested the hypothesis that this pattern arose because more virulent types of Leptospira were present at higher levels in urban environmental surface water than in rural water sources.
What Did the Researchers Do and Find?
Between June 2003 and March 2004, the researchers isolated strains of Leptospira from patients with acute fever who visited a hospital in the town of Iquitos or clinics in nearby villages. Early in 2004, they also collected a large number of different water samples from an urban slum in Iquitos and from a nearby rural community. They measured the concentrations of Leptospira in these samples by using a molecular technique called real-time PCR (polymerase chain reaction) to detect and quantify a type of RNA found only in disease-causing Leptospira. They also identified which specific Leptospira were present in the water samples and the patient samples by sequencing this RNA. The researchers found that leptospires were present in both urban and rural water samples (particularly in samples from gutters and puddles in the urban slum's market area) but that their concentration in the positive water samples from the urban sites was 20 times that in the positive samples from the rural sites. Furthermore, the distribution of different Leptospira types isolated from the patients mirrored that of the bacteria in the local environment. So, one particular type of Leptospira interrogans known as icterohaemorrhagiae—the leptospire most commonly associated with severe leptospirosis in the patients—was found more often in the urban water samples than in the rural ones. Finally, the researchers discovered a new group of Leptospira in the rural environment. This group may contain one or several new species of Leptospira but whether any of them causes human disease is unknown.
What Do These Findings Mean?
These results support the researchers' hypothesis that pulmonary leptospirosis in urban areas of the Peruvian Amazon is associated with high environmental levels of specific disease-causing leptospires. The researchers were able to discover this link only by using molecular techniques—this sort of study is impossible with traditional bacteriological techniques because Leptospira are hard to grow in the laboratory and cannot be isolated efficiently from environmental water sources. Different types can't be identified using a microscope. The researchers' findings need to be validated in other settings, but they suggest that environmental interventions such as reducing sources of standing water and clearing away garbage in urban areas might reduce the number of cases of severe leptospirosis. The distribution of different Leptospira types also suggests that whereas rats may be the main disease reservoir in towns, cattle, pigs, and bats may be more important in rural settings in Peru and presumably elsewhere. Overall, this new information, together with the availability of molecular methods for rapid clinical diagnosis and environmental risk assessment, should aid attempts to control leptospirosis around the world.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030308.
US Centers for Disease Control and Prevention, information for patients and professionals on leptospirosis
The Leptospirosis Information Center, information and advice on human leptospirosis for the public and medical professionals
MedlinePlus encyclopedia entry on leptospirosis
NHS Direct Online, patient information on leptospirosis from the UK National Health Service online encyclopedia
Wikipedia pages on leptospirosis (note: Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030308
PMCID: PMC1551915  PMID: 16933963
2.  Human leptospirosis in The Federated States of Micronesia: a hospital-based febrile illness survey 
BMC Infectious Diseases  2014;14:186.
Background
Human leptospirosis is an emerging infectious disease of global significance, and is endemic to several countries in the Pacific. Zoonotic transmission dynamics combined with diagnostic challenges lead to difficulties in prevention and identification of cases. The Federated States of Micronesia (FSM) lacks surveillance data for human leptospirosis. This hospital-based serologic survey sought to estimate the burden of leptospirosis, collect information relating to associated factors, and assess the leptospirosis point-of-care rapid diagnostic test (RDT) commonly used in FSM.
Methods
A four-month hospital-based survey was conducted in Pohnpei State, FSM in 2011. Patients with undifferentiated fevers presenting to hospital were referred for enrolment by physicians. Consenting participants provided paired blood specimens 10–30 days apart, and responded to interview questions regarding demographics, clinical symptoms, exposure to animals, and environmental exposure. Blood samples were subjected to immunochromatographic RDT and confirmed by microscopic agglutination test (MAT).
Results
Of 54 participants tested by MAT, 20.4% (95% confidence interval [CI] 10.1–30.6%) showed serologic evidence of acute infection. Occupation student (odds ratio [OR], 17.5; 95% CI: 1.9–161.1) and recreational gardening (OR, 8.6; 95% CI: 1.0-73.8), identified by univariate logistic regression, were associated with infection. The local rapid diagnostic test (RDT) performed with a sensitivity of 69.2 (42.3-89.3 CI) and specificity of 90.0 (81.6-95.6 CI) compared to MAT.
Conclusions
This study demonstrated a high burden of leptospirosis in Pohnpei. Further work is warranted to identify additional risk factors and opportunities to control leptospirosis in Pohnpei and other Pacific settings.
doi:10.1186/1471-2334-14-186
PMCID: PMC3985585  PMID: 24708723
Leptospirosis; Pohnpei; Federated States of Micronesia; Serosurvey
3.  Estimating Leptospirosis Incidence Using Hospital-Based Surveillance and a Population-Based Health Care Utilization Survey in Tanzania 
Background
The incidence of leptospirosis, a neglected zoonotic disease, is uncertain in Tanzania and much of sub-Saharan Africa, resulting in scarce data on which to prioritize resources for public health interventions and disease control. In this study, we estimate the incidence of leptospirosis in two districts in the Kilimanjaro Region of Tanzania.
Methodology/Principal Findings
We conducted a population-based household health care utilization survey in two districts in the Kilimanjaro Region of Tanzania and identified leptospirosis cases at two hospital-based fever sentinel surveillance sites in the Kilimanjaro Region. We used multipliers derived from the health care utilization survey and case numbers from hospital-based surveillance to calculate the incidence of leptospirosis. A total of 810 households were enrolled in the health care utilization survey and multipliers were derived based on responses to questions about health care seeking in the event of febrile illness. Of patients enrolled in fever surveillance over a 1 year period and residing in the 2 districts, 42 (7.14%) of 588 met the case definition for confirmed or probable leptospirosis. After applying multipliers to account for hospital selection, test sensitivity, and study enrollment, we estimated the overall incidence of leptospirosis ranges from 75–102 cases per 100,000 persons annually.
Conclusions/Significance
We calculated a high incidence of leptospirosis in two districts in the Kilimanjaro Region of Tanzania, where leptospirosis incidence was previously unknown. Multiplier methods, such as used in this study, may be a feasible method of improving availability of incidence estimates for neglected diseases, such as leptospirosis, in resource constrained settings.
Author Summary
Leptospirosis is a zoonotic infection that occurs worldwide and is caused by a spirochete, Leptospira spp. The incidence of leptospirosis is unknown in most of sub-Saharan Africa, including Tanzania. Incidence estimates are important in prioritizing resources for disease prevention and control. In this study, we calculated leptospirosis incidence in 2 districts in the Kilimanjaro Region of Tanzania using a multiplier method. We used responses from a population-based survey that asked where participants and their household members would seek health care in the event of fever along with the number of leptospirosis cases found at 2 hospitals under surveillance to calculate estimated incidence. We calculated a high incidence of leptospirosis in the study area that was previously unrecognized. This has important implications for prioritizing further research and consideration of public health control measures for leptospirosis in Tanzania.
doi:10.1371/journal.pntd.0002589
PMCID: PMC3855074  PMID: 24340122
4.  Leptospirosis in American Samoa – Estimating and Mapping Risk Using Environmental Data 
Background
The recent emergence of leptospirosis has been linked to many environmental drivers of disease transmission. Accurate epidemiological data are lacking because of under-diagnosis, poor laboratory capacity, and inadequate surveillance. Predictive risk maps have been produced for many diseases to identify high-risk areas for infection and guide allocation of public health resources, and are particularly useful where disease surveillance is poor. To date, no predictive risk maps have been produced for leptospirosis. The objectives of this study were to estimate leptospirosis seroprevalence at geographic locations based on environmental factors, produce a predictive disease risk map for American Samoa, and assess the accuracy of the maps in predicting infection risk.
Methodology and Principal Findings
Data on seroprevalence and risk factors were obtained from a recent study of leptospirosis in American Samoa. Data on environmental variables were obtained from local sources, and included rainfall, altitude, vegetation, soil type, and location of backyard piggeries. Multivariable logistic regression was performed to investigate associations between seropositivity and risk factors. Using the multivariable models, seroprevalence at geographic locations was predicted based on environmental variables. Goodness of fit of models was measured using area under the curve of the receiver operating characteristic, and the percentage of cases correctly classified as seropositive. Environmental predictors of seroprevalence included living below median altitude of a village, in agricultural areas, on clay soil, and higher density of piggeries above the house. Models had acceptable goodness of fit, and correctly classified ∼84% of cases.
Conclusions and Significance
Environmental variables could be used to identify high-risk areas for leptospirosis. Environmental monitoring could potentially be a valuable strategy for leptospirosis control, and allow us to move from disease surveillance to environmental health hazard surveillance as a more cost-effective tool for directing public health interventions.
Author Summary
Leptospirosis is the most common bacterial infection transmitted from animals to humans. Infected animals excrete the bacteria in their urine, and humans can become infected through contact with animals or a contaminated environment such as water and soil. Environmental factors are important in determining the risk of human infection, and differ between ecological settings. The wide range of risk factors include high rainfall and flooding; poor sanitation and hygiene; urbanisation and overcrowding; contact with animals (including rodents, livestock, pets, and wildlife); outdoor recreation and ecotourism; and environmental degradation. Predictive risk maps have been produced for many infectious diseases to identify high-risk areas for transmission and guide allocation of public health resources. Maps are particularly useful where disease surveillance and epidemiological data are poor. The objectives of this study were to estimate leptospirosis seroprevalence at geographic locations based on environmental factors, produce a predictive disease risk map for American Samoa, and assess the accuracy of the maps in predicting infection risk. This study demonstrated the value of geographic information systems and disease mapping for identifying environmental risk factors for leptospirosis, and enhancing our understanding of disease transmission. Similar principles could be used to investigate the epidemiology of leptospirosis in other areas.
doi:10.1371/journal.pntd.0001669
PMCID: PMC3362644  PMID: 22666516
5.  Surveillance for leptospirosis in the Americas, 1996–2005: a review of data from ministries of health 
Objective
To characterize current leptospirosis reporting practices in the Americas.
Methods
Information was collected from the official websites of national ministries of health from the Americas region and two international organizations; personal communications; and three international morbidity databases. For all sources other than the morbidity databases, the review was limited to official reports citing clinically suspected and laboratory confirmed leptospirosis cases or deaths during the period 1996–2005.
Results
A total of 73 out of 1 644 reports met the selection criteria and were included in the analysis. Published leptospirosis data were available from half of the countries/sovereign territories (24 out of 48), and 18 of them had mandatory notification policies for leptospirosis. The sum of the median number of leptospirosis cases notified annually by the 24 countries/territories was 4 713.5, but just three countries (Brazil, Costa Rica, and Cuba) accounted for 83.1% (3 920 cases) of the notifications. Eight (16.7%) countries reported deaths due to leptospirosis. The sum of the median number of deaths reported annually for the eight countries was 380, but 349 (91.8%) were reported by Brazil.
Conclusions
Notification practices in the Americas for leptospirosis are limited. Therefore, the numbers of cases and deaths reported are not representative for the region. The lack of leptospirosis data for many countries/territories may reflect weaknesses in certain aspects of national surveillance systems, including mandatory reporting policies, clinical laboratory infrastructure for performing case confirmation, and capacity to collect reported cases. Improved surveillance of leptospirosis cases and deaths in the Americas is needed to allow monitoring of regional epidemiological patterns and to estimate the burden of this important disease.
PMCID: PMC3970205  PMID: 23183556
Leptospirosis; epidemiologic surveillance; disease notification; review; Americas
6.  El Niño Southern Oscillation and Leptospirosis Outbreaks in New Caledonia 
Leptospirosis is an important cause of seasonal outbreaks in New Caledonia and the tropics. Using time series derived from high-quality laboratory-based surveillance from 2000–2012, we evaluated whether climatic factors, including El Niño Southern Oscillation (ENSO) and meteorological conditions allow for the prediction of leptospirosis outbreaks in New Caledonia. We found that La Niña periods are associated with high rainfall, and both of these factors were in turn, temporally associated with outbreaks of leptospirosis. The sea surface temperature in El Niño Box 4 allowed forecasting of leptospirosis outbreaks four months into the future, a time lag allowing public health authorities to increase preparedness. To our knowledge, our observations in New Caledonia are the first demonstration that ENSO has a strong association with leptospirosis. This association should be tested in other regions in the South Pacific, Asia or Latin America where ENSO may drive climate variability and the risk for leptospirosis outbreaks.
Author Summary
The El Niño Southern Oscillation is a major ocean – atmosphere phenomenon that strongly contributes to the timing and intensity of rainfall in the tropical Pacific islands and beyond. As a consequence, it also has a major effect on the number of cases of leptospirosis. By incorporating oceanographic parameters in models, we have been able to predict leptospirosis outbreaks in New Caledonia 4 months in advance. We discuss that this forecasting delay might be used to implement timely interventions prior to the occurrence of outbreaks. Possible interventions include controlling rodent reservoir populations before population growth and maintaining sewage networks or river banks. The major impact of El Niño on the climate of Pacific Islands Countries and Territories suggests that other countries might be able to build similar predictive models.
doi:10.1371/journal.pntd.0002798
PMCID: PMC3990495  PMID: 24743322
7.  Human Leptospirosis on Reunion Island: Past and Current Burden 
Since 1953, leptospirosis has been recognized as a public health problem on Reunion Island. In 2004, was implemented a specific surveillance system that included systematic reporting and the realization of environmental investigations around hospitalized cases. Here, we present the synthesis of historical data and the assessment of 9 years of leptospirosis surveillance. From 2004 to 2012, 414 hospitalized cases were reported. Cases of leptospirosis occurred mostly during the rainy season from December to May. Approximately 41% of infections occurred at home, 12% of infections occurred during aquatic leisure and 5% of cases were linked to professional activities. Furthermore, for 41% of cases, the place of infection could not be determined due to the accumulation of residential and non-residential exposure. Most of the cases of leptospirosis were linked to rural areas or traditional, rural occupations. We did not observe a shift to recreational leptospirosis as described in some developed countries. According to the new surveillance system, the number of reported cases has regularly increased since 2004. This situation is in part due to the improvement of the system in the first years but also to a real increase in the number of detected cases due to the introduction of molecular methods and to increased biological investigation into the Dengue-like syndrome by medical practitioners on the island since the Chikungunya crisis in 2006. This increase is probably due to surveillance and diagnosis biases but need to be carefully monitored. Nevertheless, the possibility of an outbreak is always present due to climatic events, such as after the “hyacinth” hurricane in 1980.
doi:10.3390/ijerph110100968
PMCID: PMC3924485  PMID: 24434593
leptospirosis; epidemiology; surveillance; human; Reunion Island; Indian Ocean
8.  Accuracy of a Dual Path Platform (DPP) Assay for the Rapid Point-of-Care Diagnosis of Human Leptospirosis 
Background
Diagnosis of leptospirosis by the gold standard serologic assay, the microscopic agglutination test (MAT), requires paired sera and is not widely available. We developed a rapid assay using immunodominant Leptospira immunoglobulin-like (Lig) proteins in a Dual Path Platform (DPP). This study aimed to evaluate the assay's diagnostic performance in the setting of urban transmission.
Methodology
We determined test sensitivity using 446 acute and convalescent sera from MAT-confirmed case-patients with severe or mild leptospirosis in Brazil. We assessed test specificity using 677 sera from the following groups: healthy residents of a Brazilian slum with endemic transmission, febrile outpatients from the same slum, healthy blood donors, and patients with dengue, hepatitis A, and syphilis. Three operators independently interpreted visual results without knowing specimen status.
Results
The overall sensitivity for paired sera was 100% and 73% for severe and mild disease, respectively. In the acute phase, the assay achieved a sensitivity of 85% and 64% for severe and mild leptospirosis, respectively. Within seven days of illness onset, the assay achieved a sensitivity of 77% for severe disease and 60% for mild leptospirosis. Sensitivity of the DPP assay was similar to that for IgM-ELISA and increased with both duration of symptoms (chi-square regression P = 0.002) and agglutinating titer (Spearman ρ = 0.24, P<0.001). Specificity was ≥93% for dengue, hepatitis A, syphilis, febrile outpatients, and blood donors, while it was 86% for healthy slum residents. Inter-operator agreement ranged from very good to excellent (kappa: 0.82–0.94) and test-to-test reproducibility was also high (kappa: 0.89).
Conclusions
The DPP assay performed acceptably well for diagnosis of severe acute clinical leptospirosis and can be easily implemented in hospitals and health posts where leptospirosis is a major public health problem. However, test accuracy may need improvement for mild disease and early stage leptospirosis, particularly in regions with high transmission.
Author Summary
Leptospirosis is an important cause of acute fever in the tropics and the mortality rate may exceed 15% in patients with severe disease manifestations. The gold standard serological test for diagnosing leptospirosis, the microagglutination test or MAT, requires significant laboratory resources and results are not timely. Improved diagnostics are therefore critically needed to identify patients and outbreaks earlier and to thereby prevent unnecessary deaths. The need for a rapid diagnostic test is particularly acute in resource-poor settings where leptospirosis is a major public health problem and sophisticated laboratories are unavailable. In this study, we measured the diagnostic accuracy of the novel Dual Path Platform (DPP) for leptospirosis using serum from patients with mild and severe disease. The DPP assay detected up to 85% of severe leptospirosis and 64% of mild leptospirosis patients using the initial clinical specimen collected at hospital presentation and its diagnostic performance was comparable to a commonly used IgM-ELISA. Furthermore, the DPP assay produces a result in 20 minutes and can be more easily implemented in field settings than existing diagnostic technologies. The commercially available DPP kit offers the simple, accurate, and quick diagnosis of leptospirosis and, consequently, more timely clinical and public health decision-making.
doi:10.1371/journal.pntd.0001878
PMCID: PMC3486890  PMID: 23133686
9.  Globalization of leptospirosis through travel and migration 
Leptospirosis remains the most widespread zoonotic disease in the world, commonly found in tropical or temperate climates. While previous studies have offered insight into intra-national and intra-regional transmission, few have analyzed transmission across international borders. Our review aimed at examining the impact of human travel and migration on the re-emergence of Leptospirosis. Results suggest that alongside regional environmental and occupational exposure, international travel now constitute a major independent risk factor for disease acquisition. Contribution of travel associated leptospirosis to total caseload is as high as 41.7% in some countries. In countries where longitudinal data is available, a clear increase of proportion of travel-associated leptospirosis over the time is noted. Reporting patterns is clearly showing a gross underestimation of this disease due to lack of diagnostic facilities. The rise in global travel and eco-tourism has led to dramatic changes in the epidemiology of Leptospirosis. We explore the obstacles to prevention, screening and diagnosis of Leptopirosis in health systems of endemic countries and of the returning migrant or traveler. We highlight the need for developing guidelines and preventive strategies of Leptospirosis related to travel and migration, including enhancing awareness of the disease among health professionals in high-income countries.
doi:10.1186/s12992-014-0061-0
PMCID: PMC4131158  PMID: 25112368
Leptospirosis; Travel; Migration
10.  Impact of Environment and Social Gradient on Leptospira Infection in Urban Slums 
Background
Leptospirosis has become an urban health problem as slum settlements have expanded worldwide. Efforts to identify interventions for urban leptospirosis have been hampered by the lack of population-based information on Leptospira transmission determinants. The aim of the study was to estimate the prevalence of Leptospira infection and identify risk factors for infection in the urban slum setting.
Methods and Findings
We performed a community-based survey of 3,171 slum residents from Salvador, Brazil. Leptospira agglutinating antibodies were measured as a marker for prior infection. Poisson regression models evaluated the association between the presence of Leptospira antibodies and environmental attributes obtained from Geographical Information System surveys and indicators of socioeconomic status and exposures for individuals. Overall prevalence of Leptospira antibodies was 15.4% (95% confidence interval [CI], 14.0–16.8). Households of subjects with Leptospira antibodies clustered in squatter areas at the bottom of valleys. The risk of acquiring Leptospira antibodies was associated with household environmental factors such as residence in flood-risk regions with open sewers (prevalence ratio [PR] 1.42, 95% CI 1.14–1.75) and proximity to accumulated refuse (1.43, 1.04–1.88), sighting rats (1.32, 1.10–1.58), and the presence of chickens (1.26, 1.05–1.51). Furthermore, low income and black race (1.25, 1.03–1.50) were independent risk factors. An increase of US$1 per day in per capita household income was associated with an 11% (95% CI 5%–18%) decrease in infection risk.
Conclusions
Deficiencies in the sanitation infrastructure where slum inhabitants reside were found to be environmental sources of Leptospira transmission. Even after controlling for environmental factors, differences in socioeconomic status contributed to the risk of Leptospira infection, indicating that effective prevention of leptospirosis may need to address the social factors that produce unequal health outcomes among slum residents, in addition to improving sanitation.
Author Summary
Leptospirosis, a life-threatening zoonotic disease, has become an important urban slum health problem. Epidemics of leptospirosis now occur in cities throughout the developing world, as the growth of slum settlements has produced conditions for rat-borne transmission of this disease. In this prevalence survey of more than 3,000 residents from a favela slum community in Brazil, Geographical Information System (GIS) and modeling approaches identified specific deficiencies in the sanitation infrastructure of slum environments—open sewers, refuse, and inadequate floodwater drainage—that serve as sources for Leptospira transmission. In addition to the environmental attributes of the slum environment, low socioeconomic status was found to independently contribute to the risk of infection. These findings indicate that effective prevention of leptospirosis will need to address the social factors that produce unequal health outcomes among slum residents, in addition to improving sanitation.
doi:10.1371/journal.pntd.0000228
PMCID: PMC2292260  PMID: 18431445
11.  Risk Factors and Predictors of Severe Leptospirosis in New Caledonia 
Background
Leptospirosis is a major public health concern in New Caledonia (NC) and in other tropical countries. Severe manifestations of the disease are estimated to occur in 5–15% of all human infections worldwide and factors associated with these forms are poorly understood. Our objectives were to identify risk factors and predictors of severe forms of leptospirosis in adults.
Methods and Findings
We conducted a retrospective case-control study of inpatients with laboratory-confirmed leptospirosis who were admitted to two public hospitals in NC in 2008–2011. Cases were patients with fatal or severe leptospirosis, as determined by clinical criteria. This approach was meant to be pragmatic and to reflect the routine medical management of patients. Controls were defined as patients hospitalized for milder leptospirosis. Risk and prognostic factors were identified by multivariate logistic regression. Among the 176 patients enrolled in the study, 71 had criteria of severity including 10 deaths (Case Fatality Rate = 14.1%). Three risk factors were independently associated with severe leptospirosis: current cigarette smoking (OR = 2.94 [CI 1.45–5.96]); delays >2 days between the onset of symptoms and the initiation of antibiotherapy (OR = 2.78 [CI 1.31–5.91]); and Leptospira interrogans serogroup Icterohaemorrhagiae as the infecting strain (OR = 2.79 [CI 1.26–6.18]). The following post-admission laboratory results correlated with poor prognoses: platelet count ≤50,000/µL (OR = 6.36 [CI 1.79–22.62]), serum creatinine >200 mM (OR = 5.86 [CI 1.61–21.27]), serum lactate >2.5 mM (OR = 5.14 [CI 1.57–16.87]), serum amylase >250 UI/L (OR = 4.66 [CI 1.39–15.69]) and leptospiremia >1000 leptospires/mL (OR = 4.31 [CI 1.17–15.92]).
Conclusions
To assess the risk of developing severe leptospirosis, our study illustrates the benefit for clinicians to have: i) the identification of the infective strain, ii) a critical threshold of qPCR-determined leptospiremia and iii) early laboratory results. In New Caledonia, preventative measures should focus on early presumptive antibacterial therapy and on rodent (reservoir of Icterohaemorrhagiae serogroup) control.
Author Summary
Leptospirosis is a neglected tropical disease and a public health concern worldwide. Factors responsible for the progression towards severe forms have not been clearly established. However, pathogen- as well as host-related factors are both believed to play a role in the development of severe leptospirosis. This study aimed to determine risk and prognostic factors independently associated with severe leptospirosis in laboratory-confirmed cases in adults in New Caledonia. Our study provides important results on these factors. One major finding was the independent association between the serogroup Icterohaemorrhagiae and severe leptospirosis in the multivariate analysis. Though empirically recognized, we think that this association between this highly prevalent serogroup and most severe forms of the disease was seldom (if ever) clearly demonstrated. Our data also illustrate the benefit of using a critical threshold of qPCR-determined leptospiremia to assess the risk of developing severe leptospirosis in patients after their admission to hospital.
doi:10.1371/journal.pntd.0001991
PMCID: PMC3542117  PMID: 23326614
12.  Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study 
PLoS Medicine  2010;7(1):e1000221.
By combining data from the Malaria Atlas Project with country-specific data, Feiko ter Kuile and colleagues provide the first contemporary global estimates of the annual number of pregnancies at risk of malaria.
Background
Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission.
Methods and Findings
A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only.
Conclusions
In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, is a major global public-health problem. About half of the world's population is at risk of malaria, which kills about one million people every year. Most of these deaths are caused by Plasmodium falciparum, which thrives in tropical and subtropical regions. However, the most widely distributed type of malaria is P. vivax malaria, which also occurs in temperate regions. Most malaria deaths are among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also very vulnerable to malaria. About 10,000 women and 200,000 babies die annually because of malaria in pregnancy, which can cause miscarriages, preterm births, and low-birth-weight births. Over the past decade, a three-pronged approach has been developed to prevent and control malaria in pregnancy. This approach consists of intermittent preventative treatment of pregnant women with antimalarial drugs, the use of insecticide-treated bed nets to protect pregnant women from the bites of infected mosquitoes, and management of malarial illness among pregnant women.
Why Was This Study Done?
This strategy has begun to reduce the burden of malaria among pregnant women and their babies but the resources available for its introduction are very limited in many of the developing countries where malaria is endemic (always present). Policy makers in these countries need to know the number of pregnancies at risk of malaria so that they can use their resources wisely. However, although the World Health Organization recently estimated that more than 30 million African women living in malaria endemic areas become pregnant and are at risk for malaria each year, there are no comprehensive and contemporary estimates of the number of pregnancies at risk of malaria for endemic areas outside Africa. In this study, the researchers derive global estimates of the number of women who became pregnant in 2007 in areas with P. falciparum and P. vivax transmission.
What Did the Researchers Do and Find?
The researchers estimated the sizes of populations at risk of malaria in 2007 by combining maps of the global limits of P. vivax and P. falciparum transmission with data on population densities. They used data from various sources to calculate the annual number of pregnancies (the sum of live births, induced abortions, miscarriages, and still births) in each country. Finally, they calculated the annual number of pregnancies at risk of malaria in each country by multiplying the number of pregnancies in the entire country by the fraction of the population living within the spatial limits of malaria transmission in that country. In 2007, they calculate, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission. These pregnancies—60% of all pregnancies globally—resulted in 82.6 million live births. 77.4 million at-risk pregnancies occurred in Southeast Asia and the Western Pacific (India had the most pregnancies at risk of both P. falciparum and P. vivax malaria), 30.3 million in Africa, 13.1 million in Europe and the Eastern Mediterranean, and 4.3 million in the Americas. 54.7 million at-risk pregnancies occurred in regions with stable P. falciparum transmission (more than one case of malaria per 10,000 people per year), whereas 70.5 million occurred in areas with low malaria transmission or P. vivax transmission only.
What Do These Findings Mean?
These findings are the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria. They do not provide any information on the actual incidence of malaria during pregnancy or the health burden on mothers and unborn babies. They simply represent “any risk” of exposure. So, for example, the researchers calculate that only about 5,000 actual malaria infections may occur annually among the 70.5 million at-risk pregnancies in areas with very low malaria transmission or with P. vivax transmission only. Furthermore, these findings do not allow for the seasonality of malaria—pregnancies that occur outside of the transmission season may be at no or very low risk of malaria. Nevertheless, the estimates reported in this study are an important first step towards a spatial map of the burden of malaria in pregnancy and should help policy makers allocate resources for research into and control of this important public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000221.
Information is available from the World Health Organization on malaria and on malaria in pregnancy (in several languages)
The US Centers for Disease Control and Prevention also provides information on malaria and on malaria in pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy and also provides a comprehensive bibliographic database of published and unpublished literature relating to malaria in pregnancy
The Malaria Atlas Project provides maps of malaria transmission around the world
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000221
PMCID: PMC2811150  PMID: 20126256
13.  Household Transmission of Leptospira Infection in Urban Slum Communities 
Background
Leptospirosis, a spirochaetal zoonotic disease, is the cause of epidemics associated with high mortality in urban slum communities. Infection with pathogenic Leptospira occurs during environmental exposures and is traditionally associated with occupational risk activities. However, slum inhabitants reside in close proximity to environmental sources of contamination, suggesting that transmission during urban epidemics occurs in the household environment.
Methods and Findings
A survey was performed to determine whether Leptospira infection clustered within households located in slum communities in the city of Salvador, Brazil. Hospital-based surveillance identified 89 confirmed cases of leptospirosis during an outbreak. Serum samples were obtained from members of 22 households with index cases of leptospirosis and 52 control households located in the same slum communities. The presence of anti-Leptospira agglutinating antibodies was used as a marker for previous infection. In households with index cases, 22 (30%) of 74 members had anti-Leptospira antibodies, whereas 16 (8%) of 195 members from control households had anti-Leptospira antibodies. Highest titres were directed against L. interrogans serovars of the Icterohaemorrhagiae serogroup in 95% and 100% of the subjects with agglutinating antibodies from case and control households, respectively. Residence in a household with an index case of leptospirosis was associated with increased risk (OR 5.29, 95% CI 2.13–13.12) of having had a Leptospira infection. Increased infection risk was found for all age groups who resided in a household with an index case, including children <15 years of age (P = 0.008).
Conclusions
This study identified significant household clustering of Leptospira infection in slum communities where recurrent epidemics of leptospirosis occur. The findings support the hypothesis that the household environment is an important transmission determinant in the urban slum setting. Prevention therefore needs to target sources of contamination and risk activities which occur in the places where slum inhabitants reside.
Author Summary
Leptospirosis has emerged to become an urban slum health problem. Epidemics of severe leptospirosis, characterized by jaundice, acute renal failure and haemorrhage, are now reported in cities throughout the developing world due to rapid expansion of slum settlements, which in turn has produced the ecological conditions for rodent-borne transmission of the spirochete pathogen. A survey was performed in the city of Salvador, Brazil, to determine whether the risk of Leptospira infection clustered in households within slum communities in which a member had developed severe leptospirosis. We found that members of households with an index case of leptospirosis had more than five times the risk of having serologic evidence for a prior infection than members of neighbourhood households in the same communities. Increased risk of infection was found among all age groups who resided in these households. The finding that Leptospira infection clusters in specific slum households indicates that the factors associated with this environment are important determinants for transmission. Further research is needed to identify the sources of contamination and risk exposures which occur in the places where slum inhabitants reside such that effective community-based prevention of urban leptospirosis can be implemented.
doi:10.1371/journal.pntd.0000154
PMCID: PMC2270796  PMID: 18357340
14.  A Multicentre Study of Shigella Diarrhoea in Six Asian Countries: Disease Burden, Clinical Manifestations, and Microbiology 
PLoS Medicine  2006;3(9):e353.
Background
The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia.
Methods and Findings
Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]).
Conclusions
Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.
A prospective, population-based study in six Asian countries showed thatShigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains have emerged.
Editors' Summary
Background.
Infections that cause diarrhea are a major public health problem in developing countries and other places where resources are scarce, particularly in young children. Although deaths from diarrhea have decreased considerably in recent decades, diarrheal illnesses continue to cause some 2.5 million deaths each year. Shigella, a group of rod-shaped bacteria closely related to those that normally live in the human intestine, is known to cause severe diarrhea in both developed and developing countries, but the global impact of Shigella infection (shigellosis) has not been well characterized. Shigella exists in more than 40 different varieties, an increasing number of cases have been found to be resistant to available antibiotics, and no vaccine is licensed except one oral vaccine in China.
Why Was This Study Done?
The best information available on the impact of shigellosis has been based on historical estimates, which are subject to inaccuracy. More recent studies suggest that the older reports may have underestimated the impact of shigellosis. The authors of this study wanted to obtain more accurate, current estimates of the impact of shigellosis in developing countries.
In addition, immunity to one type of Shigella does not necessarily provide protection against other types. Therefore, in order to develop an effective vaccine, researchers would need to know which types of Shigella are causing illness in affected parts of the world. Accordingly, the authors of this study also wanted to investigate the specific types of Shigella (called “serotypes” because they can be distinguished using serum from immune individuals) involved in cases of diarrhea.
What Did the Researchers Do and Find?
The researchers set up surveillance projects for diarrhea in six developing countries throughout Asia: at three rural or semirural sites (in China, Vietnam, and Thailand) and three urban slum sites (in Bangladesh, Pakistan, and Indonesia). They conducted information campaigns in each area to encourage residents to visit a participating clinic if they or their children developed diarrhea. Patients presenting with diarrhea were enrolled in the study and their medical findings were documented on standardized report forms. Stool or rectal swab specimens were obtained (with patient consent) and sent to laboratories to test for Shigella. When Shigella was identified, the bacteria was serotyped and tested for resistance to antibiotics. Because standard culture methods do not always detect Shigella when it is present, as a double-check, the researchers also tested some of the specimens for a type of DNA (called the ipaH gene) that serves as a molecular “footprint” of Shigella. Patients received treatment according to national guidelines.
The study involved approximately 600,000 participants over 1–3 years, and detected approximately 60,000 cases of diarrhea. Shigella was found in 5% of diarrhea episodes, meaning that two new cases of shigellosis occurred per 1,000 people (of all ages) per year. Rates were higher in children and in people over age 40. Among children less than 5 years old, there were 13 new cases per 1,000 children per year. Rates of shigellosis were higher in the Bangladesh site than in the China, Pakistan, and Indonesia sites, which in turn had higher rates than the Vietnam and Thailand sites.
In contrast to prior studies, no deaths were detected following episodes of shigellosis, and less than one-third of cases of shigellosis were associated with bloody diarrhea (dysentery).
The distribution of serotypes was found to differ from one site to another and within a given site over time. A high percentage of Shigella detected at all sites were resistant to two or more antibiotics. Testing for the ipaH gene was able to identify Shigella in half of patients with bloody diarrhea whose routine stool cultures did not reveal Shigella.
What Do These Findings Mean?
This study found that shigellosis occurs in these Asian sites at a rate approximately 100 times higher than in industrialized countries. The finding that shigellosis frequently occurs in the absence of bloody stool means that government data collections using dysentery as part of the case definition can be expected to miss the majority of shigellosis cases. Also, the increased rate of shigellosis above age 40 shows that older people share significantly in the burden (and most likely the transmission) of shigellosis.
The generally benign clinical course of Shigella-associated diarrhea calls into question the priority that this disease should receive in global vaccine development efforts, especially given the technological challenges posed by the complex and variable distribution of serotypes. Nonetheless, the emergence of multidrug-resistant strains clearly remains a threat, and raises the perennial issue of improved sanitation, rather than new antibiotics, as a long-term solution to the plethora of water-borne illnesses that disproportionately affect developing countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030353.
World Health Organization topic page on diarrhea
Centers for Disease Control and Prevention: Shigellosis
Wikipedia entry on Shigella (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030353
PMCID: PMC1564174  PMID: 16968124
15.  Geographical Scale Effects on the Analysis of Leptospirosis Determinants 
Leptospirosis displays a great diversity of routes of exposure, reservoirs, etiologic agents, and clinical symptoms. It occurs almost worldwide but its pattern of transmission varies depending where it happens. Climate change may increase the number of cases, especially in developing countries, like Brazil. Spatial analysis studies of leptospirosis have highlighted the importance of socioeconomic and environmental context. Hence, the choice of the geographical scale and unit of analysis used in the studies is pivotal, because it restricts the indicators available for the analysis and may bias the results. In this study, we evaluated which environmental and socioeconomic factors, typically used to characterize the risks of leptospirosis transmission, are more relevant at different geographical scales (i.e., regional, municipal, and local). Geographic Information Systems were used for data analysis. Correlations between leptospirosis incidence and several socioeconomic and environmental indicators were calculated at different geographical scales. At the regional scale, the strongest correlations were observed between leptospirosis incidence and the amount of people living in slums, or the percent of the area densely urbanized. At the municipal scale, there were no significant correlations. At the local level, the percent of the area prone to flooding best correlated with leptospirosis incidence.
doi:10.3390/ijerph111010366
PMCID: PMC4210984  PMID: 25310536
leptospirosis; geographical scale; unit of analysis; socioeconomic indicators; environmental indicators
16.  Leptospira species and serovars identified by MALDI-TOF mass spectrometry after database implementation 
BMC Research Notes  2014;7:330.
Background
Leptospirosis, a spirochaetal zoonotic disease of worldwide distribution, endemic in Europe, has been recognized as an important emerging infectious disease, though yet it is mostly a neglected disease which imparts its greatest burden on impoverished populations from developing countries. Leptospirosis is caused by the infection with any of the more than 230 serovars of pathogenic Leptospira sp. In this study we aimed to implement the MALDI-TOF mass spectrometry (MS) database currently available in our laboratory with Leptospira reference pathogenic (L. interrogans, L. borgpetersenii, L. kirschneri, L. noguchii), intermediate (L. fainei) and saprophytic (L. biflexa) strains of our collection in order to evaluate its possible application to the diagnosis of leptospirosis and to the typing of strains. This was done with the goal of understanding whether this methodology could be used as a tool for the identification of Leptospira strains, not only at species level for diagnostic purposes, but also at serovar level for epidemiological purposes, overcoming the limits of serological and molecular conventional methods. Twenty Leptospira reference strains were analysed by MALDI-TOF MS. Statistical analysis of the protein spectra was performed by ClinProTools software.
Results
The spectra obtained by the analysis of the reference strains tested were grouped into 6 main classes corresponding to the species analysed, highlighting species-specific protein profiles. Moreover, the statistical analysis of the spectra identified discriminatory peaks to recognize Leptospira strains also at serovar level extending previously published data.
Conclusions
In conclusion, we confirmed that MALDI-TOF MS could be a powerful tool for research and diagnostic in the field of leptospirosis with broad applications ranging from the detection and identification of pathogenic leptospires for diagnostic purposes to the typing of pathogenic and non-pathogenic leptospires for epidemiological purposes in order to enrich our knowledge about the epidemiology of the infection in different areas and generate control strategies.
doi:10.1186/1756-0500-7-330
PMCID: PMC4048046  PMID: 24890024
Leptospira sp.; MALDI-TOF MS; Identification; Database implementation
17.  Leptospirosis in Germany, 1962–2003 
Emerging Infectious Diseases  2005;11(7):1048-1054.
Epidemiologic trends of human leptospirosis in Germany were investigated by analyzing national surveillance data from 1962 to 2003 and by conducting a questionnaire-based survey from 1997 to 2000. After a steady decrease of leptospirosis incidence from 1962 to 1997, surveillance data indicate an increase in disease incidence to 0.06 per 100,000 (1998–2003). Of 102 laboratory-confirmed cases in humans from 1997 to 2000, 30% were related to occupational exposures. Recreational exposures were reported in 30% (including traveling abroad in 16%), whereas residential exposure accounted for 37% of the cases. Direct contact with animals, mostly rats and dogs, was observed in 31% of the cases. We conclude that recent changes in transmission patterns of leptospirosis, partially caused by an expanding rat population and the resurgence of canine leptospirosis, may facilitate the spread of the disease in temperate countries like Germany. Preventive measures should be adapted to the changing epidemiology of leptospirosis.
doi:10.3201/eid1107.041172
PMCID: PMC3371786  PMID: 16022779
leptospirosis; Leptospira interrogans; vector-borne diseases; epidemiology; developed countries; Germany
18.  Current immunological and molecular tools for leptospirosis: diagnostics, vaccine design, and biomarkers for predicting severity 
Leptospirosis is a zoonotic spirochaetal illness that is endemic in many tropical countries. The research base on leptospirosis is not as strong as other tropical infections such as malaria. However, it is a lethal infection that can attack many vital organs in its severe form, leading to multi-organ dysfunction syndrome and death. There are many gaps in knowledge regarding the pathophysiology of leptospirosis and the role of host immunity in causing symptoms. This hinders essential steps in combating disease, such as developing a potential vaccine. Another major problem with leptospirosis is the lack of an easy to perform, accurate diagnostic tests. Many clinicians in resource limited settings resort to clinical judgment in diagnosing leptospirosis. This is unfortunate, as many other diseases such as dengue, hanta virus, rickettsial infections, and even severe bacterial sepsis, can mimic leptospirosis. Another interesting problem is the prediction of disease severity at the onset of the illness. The majority of patients recover from leptospirosis with only a mild febrile illness, while a few others have severe illness with multi-organ failure. Clinical features are poor predictors of potential severity of infection, and therefore the search is on for potential biomarkers that can serve as early warnings for severe disease. This review concentrates on these three important aspects of this neglected tropical disease: diagnostics, developing a vaccine, and potential biomarkers to predict disease severity.
doi:10.1186/s12941-014-0060-2
PMCID: PMC4299796  PMID: 25591623
Leptospirosis; Vaccine; Biomarkers; Diagnosis
19.  Isolation and Characterization of New Leptospira Genotypes from Patients in Mayotte (Indian Ocean) 
Background
Leptospirosis has been implicated as a severe and fatal form of disease in Mayotte, a French-administrated territory located in the Comoros archipelago (southwestern Indian Ocean). To date, Leptospira isolates have never been isolated in this endemic region.
Methods and Findings
Leptospires were isolated from blood samples from 22 patients with febrile illness during a 17-month period after a PCR-based screening test was positive. Strains were typed using hyper-immune antisera raised against the major Leptospira serogroups: 20 of 22 clinical isolates were assigned to serogroup Mini; the other two strains belonged to serogroups Grippotyphosa and Pyrogenes, respectively. These isolates were further characterized using partial sequencing of 16S rRNA and ligB gene, Multi Locus VNTR Analysis (MLVA), and pulsed field gel electrophoresis (PFGE). Of the 22 isolates, 14 were L. borgpetersenii strains, 7 L. kirschneri strains, and 1, belonging to serogoup Pyrogenes, was L. interrogans. Results of the genotyping methods were consistent. MLVA defined five genotypes, whereas PFGE allowed the recognition of additional subgroups within the genotypes. PFGE fingerprint patterns of clinical strains did not match any of the patterns in the reference strains belonging to the same serogroup, suggesting that the strains were novel serovars.
Conclusions
Preliminary PCR screening of blood specimen allowed a high isolation frequency of leptospires among patients with febrile illness. Typing of leptospiral isolates showed that causative agents of leptospirosis in Mayotte have unique molecular features.
Author Summary
Leptospirosis has been recognized as an increasing public health problem affecting poor people from developing countries and tropical regions. However, the epidemiology of leptospirosis remains poorly understood in remote parts of the world. In this study of patients from the island of Mayotte, we isolated 22 strains from the blood of patients during the acute phase of illness. The pathogenic Leptospira strains were characterized by serology and various molecular typing methods. Based on serological data, serogroup Mini appears to be the dominant cause of leptospirosis in Mayotte. Further molecular characterization of these isolates allowed the identification of 10 pathogenic Leptospira genotypes that could correspond to previously unknown serovars. Further progress in our understanding of the epidemiology of Leptospira circulating genotypes in highly endemic regions should contribute to the development of novel strategies for the diagnosis and prevention of this neglected emerging disease.
doi:10.1371/journal.pntd.0000724
PMCID: PMC2889827  PMID: 20582311
20.  Travel-Related Leptospirosis in Israel: A Nationwide Study 
Leptospirosis is re-emerging in developed countries as a travel-related infection. In this nationwide study of travel-related leptospirosis in Israel, all cases diagnosed at the Central Reference Laboratory for Leptospirosis, during 2002–2008 were retrospectively reviewed and only travel-related cases were included. During the study years, 20 (42%) of 48 leptospirosis cases in Israel were travel-related. Exposure occurred in Southeast Asia in 15 (75%) of 20 cases. The estimated yearly incidence of travel-related leptospirosis was 1.78/100,000 travelers compared with an incidence of endemic cases of 0.06/100,000 inhabitants (risk ratio = 29.6, 95% confidence interval = 16.7–52.4). Most patients (89%) were infected during water-related activities. Severe disease was present in 10 (55%) of 18 patients; 7 of them were presumptively infected with the Icterohaemorrhagiae serogroup. Thus, travel-related leptospirosis is becoming increasingly important in the epidemiology of leptospirosis in Israel. Leptospirosis should be suspected in any traveler with undifferentiated febrile illness, especially when water exposure is reported.
doi:10.4269/ajtmh.2010.09-0239
PMCID: PMC2829909  PMID: 20207873
21.  Serovar Diversity of Pathogenic Leptospira Circulating in the French West Indies 
Background
Leptospirosis is one of the most important neglected tropical bacterial diseases in Latin America and the Caribbean. However, very little is known about the circulating etiological agents of leptospirosis in this region. In this study, we describe the serological and molecular features of leptospires isolated from 104 leptospirosis patients in Guadeloupe (n = 85) and Martinique (n = 19) and six rats captured in Guadeloupe, between 2004 and 2012.
Methods and Findings
Strains were studied by serogrouping, PFGE, MLVA, and sequencing 16SrRNA and secY. DNA extracts from blood samples collected from 36 patients in Martinique were also used for molecular typing of leptospires via PCR. Phylogenetic analyses revealed thirteen different genotypes clustered into five main clades that corresponded to the species: L. interrogans, L. kirschneri, L. borgpetersenii, L. noguchi, and L. santarosai. We also identified L. kmetyi in at least two patients with acute leptospirosis. This is the first time, to our knowledge, that this species has been identified in humans. The most prevalent genotypes were associated with L. interrogans serovars Icterohaemorrhagiae and Copenhageni, L. kirschneri serovar Bogvere, and L. borgpetersenii serovar Arborea. We were unable to identify nine strains at the serovar level and comparison of genotyping results to the MLST database revealed new secY alleles.
Conclusions
The overall serovar distribution in the French West Indies was unique compared to the neighboring islands. Typing of leptospiral isolates also suggested the existence of previously undescribed serovars.
Author Summary
Leptospirosis is an emerging zoonotic disease caused by infection with pathogenic strains of Leptospira. Isolation of Leptospira strains is rare, making it difficult to assess their distribution worldwide. In this study, we characterized cultures of Leptospira obtained from more than one hundred leptospirosis patients from the French West Indies by serology and various molecular typing methods to identify the strains circulating in this endemic region. Typing of leptospiral isolates showed that causative agents of leptospirosis in the French West Indies are mainly from the serogroups Icterohaemorrhagiae and Ballum, but we also identified new genotypes. We also found that the distribution of the predominant pathogenic leptospiral serovars differed between the Caribbean islands. A better understanding of the epidemiology of leptospirosis will improve our knowledge in the distribution of this emerging neglected tropical disease worldwide. The identification of the circulating etiological agents of leptospirosis in the French West Indies will also help establish appropriate control and prevention measures in this area where the disease is endemic.
doi:10.1371/journal.pntd.0002114
PMCID: PMC3597474  PMID: 23516654
22.  A Global Research Agenda for Leptospirosis 
Journal of postgraduate medicine  2005;51(3):174-178.
Leptospirosis is a zoonotic spirochetal disease of global importance. This disease continues to have a major impact on people living in urban and rural areas of developing countries with inestimable morbidity and mortality. Funding for research and control efforts is currently haphazard, not organized and not effective for public health efforts, primarily because there are no concerted, ongoing international efforts to assess the impact of leptospirosis on human health. Major issues in the field need to be addressed to develop strategies of control, amelioration and treatment. These include the following: mechanisms of naturally acquired and vaccine-induced protective immunity against clinical leptospirosis; mechanisms of severe leptospirosis pathogenesis; standardized, precise and simplified taxonomy of Leptospira relevant to disease manifestations, transmission and control; effective adjunct treatments in addition to antimicrobials; and environmental assessment for risk of leptospirosis transmission and relevant mammalian reservoirs. Once effective ongoing, collaborative international efforts to assess the impact of leptospirosis on human and veterinary health are underway, appropriate mobilization of clinical and public health research funding will follow.
PMCID: PMC2270399  PMID: 16333188
Epidemiology; Disease burden; Vaccine; Taxonomy; Pathogenesis
23.  Determinants of leptospirosis in Sri Lanka: Study Protocol 
BMC Infectious Diseases  2010;10:332.
Background
Leptospirosis is becoming a major public health threat in Sri Lanka as well as in other countries. We designed a case control study to determine the factors associated with local transmission of leptospirosis in Sri Lanka, in order to identify major modifiable determinants of leptospirosis. The purpose of this paper is to describe the study protocol in detail prior to the publishing of the study results, so that the readership will be able to understand and interpret the study results effectively.
Methods
A hospital based partially matched case control design is proposed. The study will be conducted in three selected leptospirosis endemic districts in central Sri Lanka. Case selection will include screening all acute fever patients admitted to selected wards to select probable cases of leptospirosis and case confirmation using an array of standard laboratory criteria. Age and sex matched group of acute fever patients with other confirmed diagnosis will be used as controls. Case to control ratio will be 1:2. A minimum sample of 144 cases is required to detect 20% exposure with 95% two sided confidence level and 80% power. A pre tested interviewer administered structured questionnaire will be used to collect data from participants. Variables included in the proposed study will be evaluated using conceptual hierarch of variables in three levels; Exposure variables as proximal; reservoir and environmental variables as intermediate; socio-demographic variables as distal. This conceptual hierarch hypothesised that the distal and intermediate variables are mediated through the proximal variables but not directly. A logistic regression model will be used to analyse the probable determinants of leptospirosis. This model will evaluate the effect of same level and upper level variables on the outcome leptospirosis, using three blocks.
Discussion
The present national control programme of leptospirosis is hampered by lack of baseline data on leptospirosis disease transmission. The present study will be able to provide these essential information for formulation of better control strategies.
doi:10.1186/1471-2334-10-332
PMCID: PMC2994874  PMID: 21087520
24.  Worldwide Incidence of Malaria in 2009: Estimates, Time Trends, and a Critique of Methods 
PLoS Medicine  2011;8(12):e1001142.
Richard Cibulskis and colleagues present estimates of the worldwide incidence of malaria in 2009, together with a critique of different estimation methods, including those based on risk maps constructed from surveys of parasite prevalence, and those based on routine case reports compiled by health ministries.
Background
Measuring progress towards Millennium Development Goal 6, including estimates of, and time trends in, the number of malaria cases, has relied on risk maps constructed from surveys of parasite prevalence, and on routine case reports compiled by health ministries. Here we present a critique of both methods, illustrated with national incidence estimates for 2009.
Methods and Findings
We compiled information on the number of cases reported by National Malaria Control Programs in 99 countries with ongoing malaria transmission. For 71 countries we estimated the total incidence of Plasmodium falciparum and P. vivax by adjusting the number of reported cases using data on reporting completeness, the proportion of suspects that are parasite-positive, the proportion of confirmed cases due to each Plasmodium species, and the extent to which patients use public sector health facilities. All four factors varied markedly among countries and regions. For 28 African countries with less reliable routine surveillance data, we estimated the number of cases from model-based methods that link measures of malaria transmission with case incidence. In 2009, 98% of cases were due to P. falciparum in Africa and 65% in other regions. There were an estimated 225 million malaria cases (5th–95th centiles, 146–316 million) worldwide, 176 (110–248) million in the African region, and 49 (36–68) million elsewhere. Our estimates are lower than other published figures, especially survey-based estimates for non-African countries.
Conclusions
Estimates of malaria incidence derived from routine surveillance data were typically lower than those derived from surveys of parasite prevalence. Carefully interpreted surveillance data can be used to monitor malaria trends in response to control efforts, and to highlight areas where malaria programs and health information systems need to be strengthened. As malaria incidence declines around the world, evaluation of control efforts will increasingly rely on robust systems of routine surveillance.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a life-threatening disease caused by the Plasmodium parasite, which is transmitted to people through the bites of infected mosquitoes. According to latest estimates from the World Health Organization (WHO), in 2009, there were 225 million cases of malaria and an estimated 781,000 deaths worldwide—most deaths occurring among children living in the WHO African Region (mainly sub-Saharan Africa). Knowing the burden of malaria in any country is an essential component of public health planning and accurately estimating the global burden is essential to monitor progress towards the United Nations' Millennium Development Goals.
Currently, there are generally two approaches used to estimate malaria incidence:
One method uses routine surveillance reports of malaria cases compiled by national health ministries, which are analyzed to take into account some deficincies in data collection, such as incomplete reporting by health facilities, the potential for overdiagnosis of malaria among patients with fever, and the use of private health facilities or none at all. The second method uses population-based surveys of Plasmodium prevalence and case incidence from selected locations in malaria endemic areas and then uses this information to generate risk maps and to estimate the case incidence of malaria per 1,000 population, for all of the world's malaria endemic regions. The Malaria Atlas Project—a database of malaria epidemiology based on medical intelligence and satellite-derived climate data—uses this second method.
Why Was This Study Done?
In order for malaria epidemiology to be as accurate as possible, an evaluation of the strengths and weaknesses of both methods is necessary. In this study, the researchers analyzed the merits of the estimates calculated by using the different approaches, to highlight areas in which both methods need to be improved to provide better assessments of malaria control.
What Did the Researchers Do and Find?
The researchers estimated the number of malaria cases in 2009, for each of the 99 countries with ongoing malaria transmission using a combination of the two methods. The researchers used the first method for 56 malaria endemic countries outside the WHO African Region, and for nine African countries which had the quality of data necessary to calculate estimates using the researchers statistical model—which the researchers devised to take the upper and lower limits of case detection into account. The researchers used the second method for 34 countries in the African Region to classify malaria risk into low-transmission and high-transmission categories, and then to derive incidence rates for populations from observational studies conducted in populations in which there were no malaria control activities. For both methods, the researchers conducted a statistical analysis to determine the range of uncertainty.
The researchers found that using a combination of methods there was a combined total of 225 million malaria cases, in the 99 countries malaria endemic countries—the majority of cases (78%) were in the WHO African region, followed by the Southeast Asian (15%) and Eastern Mediterranean regions. In Africa, there were 214 cases per 1,000 population, compared with 23 per 1,000 in the Eastern Mediterranean region, and 19 per 1,000 in the Southeast Asia region. Sixteen countries accounted for 80% of all estimated cases globally—all but two countries were in the African region. The researchers found that despite the differences between methods 1 and 2, the ratio of the upper and lower limit for country estimates was approximately the same.
What Do These Findings Mean?
Using the combined methods, the incidence of malaria was estimated to be lower than previous estimates, particularly outside of Africa. Nevertheless the methods suggest that malaria surveillance systems currently miss the majority of cases, detecting less than 10% of those estimated to occur globally. Although the best assessment of malaria burden and trends should rely on a combination of surveillance and survey data, accurate surveillance is the ultimate goal for malaria control programs, especially as routine surveillance has advantages for estimating case incidence, spatially and through time. However, as the researchers have identified in this study, strengthening surveillance requires a critical evaluation of inherent errors and these errors must be adequately addressed in order to have confidence in estimates of malaria burden and trends, and therefore, the return on investments for malaria control programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001142.
This study is further discussed in a PLoS Medicine Perspective by Ivo Mueller and colleagues
The WHO provides information on malaria and produces the World Malaria Report each year, summarizing global progress in malaria control
More information is available on The Malaria Atlas Project
doi:10.1371/journal.pmed.1001142
PMCID: PMC3243721  PMID: 22205883
25.  Regional Differences of Leptospirosis in Sri Lanka: Observations from a Flood-Associated Outbreak in 2011 
Leptospirosis is known to be an important cause of weather disaster-related infectious disease epidemics. In 2011, an outbreak of leptospirosis occurred in the relatively dry district of Anuradhapura, Sri Lanka where diagnosis was resisted by local practitioners because leptospirosis was not known in the area and the clinical presentation was considered atypical. To identify the causative Leptospira associated with this outbreak, we carried out a cross-sectional study. Consecutive clinically suspected cases in this district were studied during a two-and-a-half-month period. Of 96 clinically suspected cases, 32 (33.3%) were confirmed by qPCR, of which the etiological cause in 26 cases was identified using 16S rDNA sequencing to the species level. Median bacterial load was 4.1×102/mL (inter-quartile range 3.1–6.1×102/mL). In contrast to a 2008 Sri Lankan leptospirosis outbreak in the districts of Kegalle, Kandy, and Matale, in which a predominance of Leptospira interrogans serovars Lai and Geyaweera was found, most cases in the 2011 outbreak were caused by Leptospira kirschneri. Seven (21.9%) confirmed cases had acute renal failure; five (15.6%) had myocarditis; severe thrombocytopenia (<20,000/uL) was seen in five (15.6%) cases. This outbreak of leptospirosis in the relatively dry zone of Sri Lanka due primarily to L. kirschneri was characterized by markedly different clinical presentations and low leptospiremia. These observations and data demonstrate the public health relevance of molecular diagnostics in such settings, possibly related to the microgeographic variations of different Leptospira species, but of particular value to public health intervention in what appears to have been a regionally neglected tropical disease.
Author Summary
Leptospirosis outbreaks occur predictably in Sri Lanka after seasonal rains and flooding in the endemic wet zone. Molecular investigations with quantification of a post-flood leptospirosis outbreak in the non-endemic dry zone of Sri Lanka in 2011 suggest variation of biological, clinical, and molecular characteristics compared to previous reported leptospirosis outbreaks in the endemic areas, probably showing a micro-geographic variation of leptospirosis. This work demonstrates the direct clinical and public health relevance of modern molecular diagnostic technologies to identifying an endemic neglected tropical disease where previously not suspected, especially in the resource-poor setting.
doi:10.1371/journal.pntd.0002626
PMCID: PMC3894175  PMID: 24454971

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