Global Morbidity and Mortality of Leptospirosis: A Systematic Review

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rabies 1 infectiousdiseases
visceral leishmaniasis 1 infectiousdiseases
cysticercosis 1 infectiousdiseases
echinococcosis 1 infectiousdiseases
leptospirosis 101 infectiousdiseases
malaria 3 infectiousdiseases

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cysticercosis 39044 including visceral leishmaniasis and severe dengue, and is similar to others, including echinococcosis and cysticercosis [[75]].The study provides decision makers with an evidence base to implement effective policy and responses
echinococcosis 39025 tropical diseases, including visceral leishmaniasis and severe dengue, and is similar to others, including echinococcosis and cysticercosis [[75]].The study provides decision makers with an evidence base to implement effective
leptospirosis 1419 affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis is a life-threatening disease and recognized as an important cause of pulmonary haemorrhage syndrome,
leptospirosis 2734 annually 1.03 million cases (95% CI 434,000–1,750,000) and 58,900 deaths (95% CI 23,800–95,900) due to leptospirosis worldwide. A large proportion of cases (48%, 95% CI 40–61%) and deaths (42%, 95% CI 34–53%) were
leptospirosis 3445 mortality were estimated to occur in resource-poor countries, which include regions where the burden of leptospirosis has been underappreciated.SummaryAuthor SummaryLeptospirosis is a zoonotic bacterial disease that affects
leptospirosis 3656 affects vulnerable populations such as rural subsistence farmers and urban slum dwellers. Although leptospirosis causes life-threatening clinical manifestations, such as pulmonary hemorrhage syndrome, and has a worldwide
leptospirosis 3959 insufficient data on its disease burden. We searched published literature and grey literature studies on leptospirosis and using information collected on disease incidence and case fatality, estimated leptospirosis incidence
leptospirosis 4055 on leptospirosis and using information collected on disease incidence and case fatality, estimated leptospirosis incidence and mortality at country, regional and global level. Overall leptospirosis was estimated to
leptospirosis 4140 fatality, estimated leptospirosis incidence and mortality at country, regional and global level. Overall leptospirosis was estimated to cause 1.03 million cases and 58,900 deaths each year. These estimates place leptospirosis
leptospirosis 4247 leptospirosis was estimated to cause 1.03 million cases and 58,900 deaths each year. These estimates place leptospirosis as a leading zoonotic cause of morbidity and mortality. In addition, morbidity and mortality was greatest
leptospirosis 5169 military personnel, and individuals partaking in water sports and recreation [[8]–[12]]. However, leptospirosis has a broader health impact as a disease of impoverished subsistence farmers [[13]–[15]], cash croppers,
leptospirosis 5349 subsistence farmers [[13]–[15]], cash croppers, and pastoralists [[16]] from tropical regions.Furthermore, leptospirosis has emerged as a health threat in new settings due the influence of globalization and climate. Disasters
leptospirosis 5563 Disasters and extreme weather events are now recognized to precipitate epidemics [[6]]. The emergence of leptospirosis in Thailand [[17]] and Sri Lanka [[18]] highlight the potential for the disease to rapidly spread and
leptospirosis 6053 the world’s slum population doubles to two billion by 2030 [[26]].The major burden attributed to leptospirosis has been its severe life-threatening manifestations. Leptospirosis has emerged as an important cause
leptospirosis 6447 haemorrhage syndrome and Weil’s disease is more than 10% and 70% respectively [[14]]. In addition, leptospirosis is increasingly recognized as an important cause of undifferentiated fever [[16],[32]–[38]]. The majority
leptospirosis 6572 increasingly recognized as an important cause of undifferentiated fever [[16],[32]–[38]]. The majority of leptospirosis patients are not recognized or misdiagnosed as malaria [[16]], dengue [[39]–[41]], and other causes
leptospirosis 6914 cases [[44],[45]], as well as deaths [[39]]. Underestimation of the morbidity and mortality due to leptospirosis is therefore common [[44]] and has directly contributed to its neglected disease status.The lack of
leptospirosis 7054 and has directly contributed to its neglected disease status.The lack of reliable estimates of the leptospirosis burden has hampered efforts to formulate the investment case to address key barriers, such as improved
leptospirosis 8135 present the findings of a study that aimed to perform a systematic literature review of the data on leptospirosis morbidity and mortality, estimate the annual burden of cases and deaths, and identify GBD and WHO regions
leptospirosis 8872 study.Data selection and extractionThe systematic review covered published reports and grey literature on leptospirosis morbidity and mortality from January 1970 to October 2008. We performed a systematic review of published
leptospirosis 9813 quality criteria (S3 Table), we applied LERG-approved definitions (S1 Protocol p. 5) for confirmed leptospirosis cases and deaths and extracted information on crude disease incidence and case fatality ratio. The systematic
leptospirosis 9975 crude disease incidence and case fatality ratio. The systematic review also identified case series of leptospirosis patients among the quality assured incidence studies, and extracted information on age and gender-stratified
leptospirosis 10206 proportions of cases and deaths (S1 Protocol pp. 4–5; S5 Table). Since standard serologic confirmation of leptospirosis requires evaluation of paired acute and convalescent-phase sera [[52]], we reviewed laboratory confirmation
leptospirosis 12179 Fig 3 and S1 Protocol pp. 5–6).10.1371/journal.pntd.0003898.g002Fig 2Estimated annual morbidity of leptospirosis by country or territory.Annual disease incidence is represented as an exponential colour gradient from
leptospirosis 12595 quality-assured studies, respectively.10.1371/journal.pntd.0003898.g003Fig 3Approach used to estimate global leptospirosis morbidity and mortality.We extracted information on leptospirosis disease incidence, case fatality,
leptospirosis 12661 3Approach used to estimate global leptospirosis morbidity and mortality.We extracted information on leptospirosis disease incidence, case fatality, age and gender distribution of cases and deaths, and the ratios of
leptospirosis 13131 were not available for every sub-region, a multivariable regression model was developed to estimate leptospirosis incidence and mortality for each country and territory. We estimated the age and gender-specific morbidity
leptospirosis 13765 gender-specific morbidity, we used a linear regression model approach to predict the log-transformation of leptospirosis morbidity based on country-specific indicator variables (S10 Table, equations 4 and 5, S9 Table and
leptospirosis 13976 and Fig 3). This model aimed to derive estimates based on the relationship between the mean reported leptospirosis incidence and country-level characteristics such climate, sociodemographic indicators and health indicators.
leptospirosis 14228 on plausibility, availability for all countries and territories, and univariable relationship with leptospirosis incidence. The final variables in the prediction model were selected to produce the highest adjusted
leptospirosis 14962 each country and territory as inputs, to obtain country, region, and global estimates and 95% CI of leptospirosis morbidity, mortality, cases and deaths (S10 Table equation 6, Fig 3 and S1 Protocol pp. 7–8). These
leptospirosis 16419 illustrate estimated morbidity using the rworldmap package for R [[57]]. Country-specific estimates of leptospirosis mortality and morbidity were shared with each country in compliance with WHO guidelines.ResultsThe search
leptospirosis 17136 10; 13%), and Oceania (n = 8; 10%). Among studies, 96% used hospital-based surveillance to identify leptospirosis cases, while 4% performed case ascertainment in community-based outpatient facilities.Reported disease
leptospirosis 17607 mortality based on study design and population (Table 1). Studies that used active surveillance to identify leptospirosis cases reported significantly higher morbidity than passive surveillance studies (12.09 vs. 2.13 per
leptospirosis 17919 populations and tropical regions compared to urban settings.10.1371/journal.pntd.0003898.t001Table 1Reported leptospirosis morbidity, mortality, and case fatality, according to study characteristic.CharacteristicMorbiditya
leptospirosis 19198 (74)3.02 (0.60–12.91)27 (78)0.34 (0.09–1.69)27 (78)8.00 (3.26–11.77)NA, not applicable.aAnnual leptospirosis morbidity and mortality rates are shown as cases or deaths, respectively, per 100 000 population, and
leptospirosis 19710 fatality ratio was 6.85% (95% CI 5.66–8.03). Ten studies reported age- and gender-stratified data for leptospirosis cases (listed in S5 Table). Adults and males had a greater risk for leptospirosis than children and
leptospirosis 19792 gender-stratified data for leptospirosis cases (listed in S5 Table). Adults and males had a greater risk for leptospirosis than children and females (S6 Table and Fig 4A), with highest risk (RR, 2.4, 95% CI 0.7–4.1) occurring
leptospirosis 20029 with 20–29 years of age. Among three studies with age- and gender-stratified data for deaths from leptospirosis (S5 Table), the age-specific risk for death was different from that for disease (S6 Table and Fig 4B),
leptospirosis 20588 reported data on both clinically-suspected and laboratory-confirmed cases and deaths, respectively, due to leptospirosis (S7 Table). Among these studies, the mean ratio of clinically-suspected to laboratory-confirmed cases
leptospirosis 20887 respectively.10.1371/journal.pntd.0003898.g004Fig 4Mean relative risk for membership in age and gender groups among leptospirosis cases (A) and deaths (B).Mean and standard deviation of the relative risks are presented for males (blue
leptospirosis 21145 selection process screened 147 candidate variables for entry in a multivariable regression model of leptospirosis morbidity (S1 Protocol pp. 6 and 7). Eight variables met statistical, plausibility, and availability
leptospirosis 21494 prediction model (Tables 2, S9 and S10, equation 4). This model predicted the natural logarithm of leptospirosis morbidity based on four country-specific variables related to geography and climate (distance from the
leptospirosis 22049 countries.10.1371/journal.pntd.0003898.t002Table 2Variables incorporated in the final multivariable linear regression prediction model for leptospirosis morbidity in 34 countries.VariableaR SquaredDistance from the equator0.105Percent urbanization of population0.243Life
leptospirosis 22785 incomplete diagnostic testing (Table 3, S11 and S12 Tables). The annual morbidity and mortality due to leptospirosis worldwide was estimated to be 14.77 cases per 100,000 population (95% CI 4.38–25.03) and 0.84 deaths
leptospirosis 23301 (25.65, 95% CI 9.29–43.31) (Fig 2 and Table 3). Small tropical islands had high estimated incidence of leptospirosis ; however, in several cases there was also significant uncertainty associated with those predictions.
leptospirosis 23628 (S13 Table) are detailed in the S1 Protocol.10.1371/journal.pntd.0003898.t003Table 3Estimated annual leptospirosis morbidity and mortality according to GBD region.GBD regionMorbidityaCasesMortalityaDeathsEstimate (95%
leptospirosis 25925 Sub–Saharan Africa9.67 (3.62–16.16)32,000 (12,000–53,500)0.85 (0.35–1.36)2,800 (1,200–4,500)aAnnual leptospirosis morbidity and mortality rates are shown as cases or deaths, respectively, per 100,000 population.The
leptospirosis 26178 are 1,030,000 cases (95% CI, 434,000–1,750,000) and 58,900 deaths (95% CI, 23,800–95,900) due to leptospirosis annually (Table 3). The majority of leptospirosis cases and deaths occur in tropical regions; 73% of
leptospirosis 26228 and 58,900 deaths (95% CI, 23,800–95,900) due to leptospirosis annually (Table 3). The majority of leptospirosis cases and deaths occur in tropical regions; 73% of the world’s leptospirosis cases and deaths occur
leptospirosis 26307 3). The majority of leptospirosis cases and deaths occur in tropical regions; 73% of the world’s leptospirosis cases and deaths occur in countries situated between the Tropics of Cancer and Capricorn. Highest morbidity
leptospirosis 26725 100,000, 95% CI 1.22–4.95). A significant proportion of global burden of cases and deaths due to leptospirosis occurred in the demographic group of males with 20–49 years of age (48% [95% CI 40–61%] and 42%
leptospirosis 26900 of age (48% [95% CI 40–61%] and 42% [95% CI 34–53%], respectively).DiscussionWe estimated that leptospirosis causes 1.03 (95% CI 0.43–1.75) million cases worldwide each year. These estimates place the disease
leptospirosis 27171 mortality. Furthermore, the number of estimated deaths (58,900; 95% CI 23.800–95,900) attributable to leptospirosis approaches or exceeds those for causes of haemorrhagic fever which were investigated in the Global Burden
leptospirosis 27558 countries. The systematic literature review also found that adult males were the principal risk group for leptospirosis . Based on model predictions, morbidity and mortality was estimated to be high in regions, such as South
leptospirosis 27702 morbidity and mortality was estimated to be high in regions, such as South and Southeast Asia, where leptospirosis is an under-recognized public health problem.Our approach had to address key challenges in the estimation
leptospirosis 27825 under-recognized public health problem.Our approach had to address key challenges in the estimation of leptospirosis burden. First, the available data was sparsely distributed and not representative of all world regions.
leptospirosis 29617 challenge related to incomplete laboratory testing of suspected cases. This is a widespread problem for leptospirosis since case confirmation relies primarily on identifying seroconversion of agglutinating antibodies between
leptospirosis 29885 Among studies with information on laboratory confirmation procedures, complete laboratory testing for leptospirosis was not performed in almost 50% of the suspected cases. In order to address this source of under-reporting,
leptospirosis 30261 reliance on antiquated serologic tests are shared among many of the neglected diseases [[59]], and as with leptospirosis , have directly contributed to their neglected disease status. Although our modelling approach has limitations,
leptospirosis 30539 estimating the disease burden for neglected diseases.Our estimates likely underestimate the morbidity of leptospirosis , since disease incidence data was obtained from hospital-based surveillance studies (S3 Table), the
leptospirosis 31497 model regional differences in case fatality ratio, or use ad-hoc adjustments. Our estimates of annual leptospirosis cases are higher than the approximately 500,000 cases estimated based on a survey of national surveillance
leptospirosis 31839 convenience sample of Ministries of Health.The study’s morbidity estimates reflect the incidence of severe leptospirosis , rather than rates for clinical or symptomatic illness, since selected studies used case definitions
leptospirosis 32019 selected studies used case definitions that relied on detection of severe manifestations [[60]]. Severe leptospirosis is generally believed to account for a small fraction (5–15%) of all clinical infections [[1],[14],[61]].
leptospirosis 32177 fraction (5–15%) of all clinical infections [[1],[14],[61]]. There is a growing recognition that leptospirosis is an important cause of an acute febrile illness: leptospirosis has been shown to be the cause of 5–69%
leptospirosis 32242 There is a growing recognition that leptospirosis is an important cause of an acute febrile illness: leptospirosis has been shown to be the cause of 5–69% of acute undifferentiated or non-malarial fever cases in different
leptospirosis 32684 findings highlight the contribution of geography, climate, and poverty in the worldwide distribution of leptospirosis . Countries situated in the tropics had the highest estimated disease incidence and accounted for 73%
leptospirosis 33127 exposures with these sources of infection [[3],[22],[23]]. Tropical climate also favours transmission of leptospirosis , which is often seasonal and increases during periods of heavy rainfall [[6],[19]]. The disease is well-recognized
leptospirosis 33652 2). Finally, although urban slum environments are an emerging and increasingly important setting for leptospirosis transmission [[19]–[22]], in our model, country percent urbanization was inversely associated with
leptospirosis 33767 transmission [[19]–[22]], in our model, country percent urbanization was inversely associated with leptospirosis incidence, reflecting in part the high burden of leptospirosis in rural settings, but also the well-recognized
leptospirosis 33830 urbanization was inversely associated with leptospirosis incidence, reflecting in part the high burden of leptospirosis in rural settings, but also the well-recognized association between lower aggregated country-level percent
leptospirosis 34053 urbanization and poverty.The study identified regions within the developing world where the burden of leptospirosis may be significantly under-recognized. The annual morbidity of leptospirosis was estimated to be high
leptospirosis 34130 world where the burden of leptospirosis may be significantly under-recognized. The annual morbidity of leptospirosis was estimated to be high in countries of South and Southeast Asia with large populations, such as India
leptospirosis 34511 endemic and large outbreaks have been reported in these countries [[15],[62],[64]], surveillance for leptospirosis has not been routinely performed.An important limitation of the study was the scarce data on disease
leptospirosis 35037 large spectrum of sylvatic and domestic animals are reservoirs for Leptospira in Africa [[65],[66]]; leptospirosis is a recognized animal health problem in the region [[4]]. A recent systematic review found high seroprevalence
leptospirosis 35292 different settings across the continent [[4]]. Furthermore, surveys of patient populations have found leptospirosis to be a prevalent cause of acute febrile illness [[32],[63]]. A recent population-based study reported
leptospirosis 35433 acute febrile illness [[32],[63]]. A recent population-based study reported an annual morbidity for leptospirosis of 75–102 cases per 100,000 population in northern Tanzania [[45]]. Additional locally representative
leptospirosis 36074 series of representative patient populations in order to estimate the age and gender-specific risk for leptospirosis , which in turn was incorporated as an input in our models (S1 Protocol pp. 5–8 and Fig 3). We found
leptospirosis 36217 incorporated as an input in our models (S1 Protocol pp. 5–8 and Fig 3). We found that the risk of acquiring leptospirosis was higher in adults than children and higher in males than females, and highest among adult males with
leptospirosis 36438 to 29 years of age (S6 Table and Fig 4A). Male gender preference is a well-recognized phenomenon in leptospirosis and due to the gender-specific occupational and peridomicilary risk activities [[22]–[24],[67]]. The
leptospirosis 38101 intensify in tropical regions [[71]], rural-based farming populations may be increasingly exposed to leptospirosis . A formal burden of disease calculation will need to be performed to provide estimates based disability-adjusted
leptospirosis 38284 provide estimates based disability-adjusted life years (DALYs). As a caveat, the health outcomes of leptospirosis have been traditionally associated with its acute disease. The disease causes sub-acute and chronic
leptospirosis 38640 rigorously quantified. Although the disease is life-threatening, the overall DALYs attributable to leptospirosis may be relatively low. Considering the annual number of deaths worldwide, the impact of leptospirosis
leptospirosis 38742 leptospirosis may be relatively low. Considering the annual number of deaths worldwide, the impact of leptospirosis equals that of canine rabies (59,000 annual deaths) [[74]]. The burden of leptospirosis, with respect
leptospirosis 38830 the impact of leptospirosis equals that of canine rabies (59,000 annual deaths) [[74]]. The burden of leptospirosis , with respect to morbidity, is higher than some other important neglected tropical diseases, including
leptospirosis 39169 study provides decision makers with an evidence base to implement effective policy and responses to leptospirosis . As identified in this study and cited in previous reviews [[42],[43]] the lack of an adequate diagnostic
leptospirosis 39474 than indicated by cases estimated in this study, since these estimates reflect the burden of severe leptospirosis and represent a lower boundary for the actual number. The distribution of the leptospirosis burden (Fig
leptospirosis 39566 severe leptospirosis and represent a lower boundary for the actual number. The distribution of the leptospirosis burden (Fig 2) overlaps significantly with that for malaria [[48]], dengue [[48],[58]], and enteric
leptospirosis 39778 enteric fever [[48]]. Misdiagnosis between these diseases is common [[16],[39]–[41]] and in the case of leptospirosis , leads to delayed treatment of severe complications and poor outcomes [[40]]. Development and roll-out
leptospirosis 40107 causes of acute fever in resource-poor, high-burden regions.Finally, the estimation of global burden of leptospirosis now provides the opportunity to evaluate One Health strategies for prevention and control. The lack
leptospirosis 40239 opportunity to evaluate One Health strategies for prevention and control. The lack of recognition of leptospirosis as an important zoonotic disease had previously hampered consideration of such approaches. Our estimates
leptospirosis 40385 had previously hampered consideration of such approaches. Our estimates support the assertion that leptospirosis is a leading zoonotic cause of morbidity and mortality in humans. The majority of the estimated morbidity
leptospirosis 40745 problem and cause of lost productivity. Additional work is needed to quantify the economic burden of leptospirosis , which incorporates an assessment of its impact on animal health. Vaccines for leptospirosis are routinely
leptospirosis 40838 burden of leptospirosis, which incorporates an assessment of its impact on animal health. Vaccines for leptospirosis are routinely used in livestock and domestic animals, although they do not appear to be transmission-blocking
leptospirosis 41256 sustainable practices considering ecosystems [[76],[77]] are needed for disease prevention. Finally, leptospirosis is a social-ecological problem, which often occurs in the context of social inequity. Therefore there
leptospirosis 42136 checklist.(DOCX)Click here for additional data file.S3 TableCharacteristics and findings of high and medium quality leptospirosis morbidity (N = 80) and mortality (N = 35) studies, according to GBD region.(DOCX)Click here for additional
leptospirosis 42525 file.S5 TableStudies that reported information on age and gender proportions of cases and deaths from leptospirosis .(DOCX)Click here for additional data file.S6 TableRelative risk of leptospirosis cases (N = 10 studies)
leptospirosis 42606 cases and deaths from leptospirosis.(DOCX)Click here for additional data file.S6 TableRelative risk of leptospirosis cases (N = 10 studies) and deaths (N = 3 studies) according to age and gender group.(DOCX)Click here
leptospirosis 42843 file.S7 TableStudies which reported information on both clinically-suspected and laboratory-confirmed leptospirosis cases and deaths.(DOCX)Click here for additional data file.S8 TableReported disease morbidity, mortality,
leptospirosis 43104 region (A) and WHO sub-region (B).(DOCX)Click here for additional data file.S9 TableModel parameters for leptospirosis morbidity and mortality estimation.(DOCX)Click here for additional data file.S10 TableEquations.(DOCX)Click
leptospirosis 43282 additional data file.S10 TableEquations.(DOCX)Click here for additional data file.S11 TableEstimated annual leptospirosis morbidity and mortality by WHO sub-region.(DOCX)Click here for additional data file.S12 TableEstimated
leptospirosis 43399 morbidity and mortality by WHO sub-region.(DOCX)Click here for additional data file.S12 TableEstimated leptospirosis morbidity and mortality by country, grouped according to WHO sub-region.(DOCX)Click here for additional
leptospirosis 43576 sub-region.(DOCX)Click here for additional data file.S13 TableEstimated age group and gender-specific leptospirosis morbidity and mortality, according to WHO sub-region.(DOCX)Click here for additional data file
malaria 6633 fever [[16],[32]–[38]]. The majority of leptospirosis patients are not recognized or misdiagnosed as malaria [[16]], dengue [[39]–[41]], and other causes of an acute febrile illness. The lack of an adequate
malaria 32331 febrile illness: leptospirosis has been shown to be the cause of 5–69% of acute undifferentiated or non- malaria l fever cases in different parts of the world [[16],[18],[32]–[38],[62]]. Leptospirosis, as in the
malaria 39632 actual number. The distribution of the leptospirosis burden (Fig 2) overlaps significantly with that for malaria [[48]], dengue [[48],[58]], and enteric fever [[48]]. Misdiagnosis between these diseases is common
rabies 38778 Considering the annual number of deaths worldwide, the impact of leptospirosis equals that of canine rabies (59,000 annual deaths) [[74]]. The burden of leptospirosis, with respect to morbidity, is higher than
visceral leishmaniasis 38947 with respect to morbidity, is higher than some other important neglected tropical diseases, including visceral leishmaniasis and severe dengue, and is similar to others, including echinococcosis and cysticercosis [[75]].The study

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