A Prospective cohort study of zoonotic cutaneous leishmaniasis in tunisia: Clinical and Immunological features and immune correlates of protection.

BACKGROUND: This study aimed to define immunological markers of exposure to L. major parasites and identify correlates of protection against infection. METHODS: We analyzed a cohort of 790 individuals at risk of developing ZCL living in endemic areas with varying L. major infection prevalence. One area had a high infection prevalence indicated by high proportions of leishmanin skin test (LST) positive subjects, while the other areas were recent foci with lower infection prevalence. Blood samples were collected before the transmission season to measure Interferon gamma (IFN-γ), Interleukin 10 (IL-10), and Granzyme B (GrB) levels in response to parasite stimulation in peripheral blood mononuclear cells. A one-year follow-up period involved active detection of new ZCL cases to estimate disease incidence after a transmission season and identify immune correlates of protection. RESULTS: The study population showed heterogeneity in parasite contact, evident from specific scars and/or positive LST results, significantly higher in the old focus compared to recent foci. IFN-γ and GrB were markers of parasite exposure and reliable indicators of immunity to L. major. Positive correlations were observed between IFN-γ/IL-10 and GrB/IL-10 ratios and LST results. Unexpectedly, only 29 new ZCL cases (4%) appeared after a transmission season, with 27 cases reported in recent foci and 2 in the oldest focus. Our findings indicate that individuals in L. major endemic areas are likely to develop ZCL regardless of their LST status. We showed that high pre-transmission season levels of IFN-γ and GrB produced by PBMC, along with a high IFN-γ/IL-10 ratio, were associated with protection. CONCLUSION: This study on a large cohort at risk of ZCL confirmed IFN-γ and GrB as protective factors against the disease. A high IFN-γ/IL-10 ratio, but not GrB/IL-10 ratio was associated with resistance. These results are valuable for developing and evaluating of a vaccine against human leishmaniasis.

Core health indicators in countries with high proportion of expatriates: Case study of Qatar.

Background: Population size and structure have a huge impact on health indicators. In countries with a high proportion of expatriates, there are some limitations in estimating, aggregating and reporting of the health indicators, and corrections may be required in the established estimation methodologies. We review the case of Qatar to see how its specific population characteristics affect its health indicators. Methods: We used routinely collected data and reviewed and calculated a selected list of health indicators for Qatari and non-Qatari populations residing in Qatar. Mortality and cancer incidence rates, stratified by nationality, were used for this purpose. Also, a direct method was used to estimate completeness of the death registry, compared to the mortuary data. Results: Age and sex distribution of Qatari and non-Qatari populations are completely different. Compared to the mortuary data, completeness of death registration for the total population was estimated at 98.9 and 94.3%, with and without considering overseas deaths, respectively. Both estimates were considerably higher than estimates from the indirect methods. Mortality patterns were different even after standardization of age and stratification of sex groups; male age-standardized mortality rates were 502.7 and 242.3 per 100,000 individuals, respectively for Qataris and non-Qataris. The rates were closer in female populations (315.6 and 291.5, respectively). The leading types of cancer incidents were different in Qataris and non-Qataris. Conclusions: Expatriates are a dynamic population with high-turnover, different from Qatari population in their age-sex structure and health status. They are more likely to be young or middle-aged and are less affected by age related diseases and cancers. Also, they might be at higher risks for specific diseases or injuries. Aggregating indicators of Qatari and non-Qatari populations might be mis-leading for policy making purposes, and common estimation correction approaches cannot alleviate the limitations. High-proportion of expatriate population also imposes significant errors to some of the key demographic estimates (such as completeness of death registry). We recommend a standardized approach to consider nationality in addition to age and sex distributions for analysis of health data in countries with a high proportion of expatriates.

Type 2 diabetes epidemic and key risk factors in Qatar: a mathematical modeling analysis.

INTRODUCTION: We aimed to characterize and forecast type 2 diabetes mellitus (T2DM) disease burden between 2021 and 2050 in Qatar where 89% of the population comprises expatriates from over 150 countries. RESEARCH DESIGN AND METHODS: An age-structured mathematical model was used to forecast T2DM burden and the impact of key risk factors (obesity, smoking, and physical inactivity). The model was parametrized using data from T2DM natural history studies, Qatar's 2012 STEPwise survey, the Global Health Observatory, and the International Diabetes Federation Diabetes Atlas, among other data sources. RESULTS: Between 2021 and 2050, T2DM prevalence increased from 7.0% to 14.0%, the number of people living with T2DM increased from 170 057 to 596 862, and the annual number of new T2DM cases increased from 25 007 to 45 155 among those 20-79 years of age living in Qatar. Obesity prevalence increased from 8.2% to 12.5%, smoking declined from 28.3% to 26.9%, and physical inactivity increased from 23.1% to 26.8%. The proportion of incident T2DM cases attributed to obesity increased from 21.9% to 29.9%, while the contribution of smoking and physical inactivity decreased from 7.1% to 6.0% and from 7.3% to 7.2%, respectively. The results showed substantial variability across various nationality groups residing in Qatar-for example, in Qataris and Egyptians, the T2DM burden was mainly due to obesity, while in other nationality groups, it appeared to be multifactorial. CONCLUSIONS: T2DM prevalence and incidence in Qatar were forecasted to increase sharply by 2050, highlighting the rapidly growing need of healthcare resources to address the disease burden. T2DM epidemiology varied between nationality groups, stressing the need for prevention and treatment intervention strategies tailored to each nationality.

Characterizing epidemiology of prediabetes, diabetes, and hypertension in Qataris: A cross-sectional study.

OBJECTIVES: To characterize the epidemiologic profiles of prediabetes mellitus (preDM), diabetes mellitus (DM), and hypertension (HTN) in Qataris using the nationally representative 2012 Qatar STEPwise Survey. METHODS: A secondary data analysis of a cross-sectional survey that included 2,497 Qatari nationals aged 18-64 years. Descriptive and analytical statistical analyses were conducted. RESULTS: Prevalence of preDM, DM, and HTN in Qataris aged 18-64 years was 11.9% (95% confidence interval [CI] 9.6%-14.7%), 10.4% (95% CI 8.4%-12.9%), and 32.9% (95% CI 30.4%-35.6%), respectively. Age was the common factor associated with the three conditions. Adjusted analyses showed that unhealthy diet (adjusted odds ratio (aOR) = 1.84, 95% CI 1.01-3.36) was significantly associated with preDM; that physical inactivity (aOR = 1.66, 95% CI 1.12-2.46), central obesity (aOR = 2.08, 95% CI 1.02-4.26), and HTN (aOR = 2.18, 95% CI 1.40-3.38) were significantly associated with DM; and that DM (aOR = 2.07, 95% CI 1.34-3.22) was significantly associated with HTN. Population attributable fraction of preDM associated with unhealthy diet was 7.7%; of DM associated with physical inactivity, central obesity, and HTN, respectively, was 14.9%, 39.8%, and 17.5%; and of HTN associated with DM was 3.0%. CONCLUSIONS: One in five Qataris is living with either preDM or DM, and one in three is living with HTN, conditions that were found to be primarily driven by lifestyle factors. Prevention, control, and management of these conditions should be a national priority to reduce their disease burden and associated disease sequelae.

A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes.

We developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.

A prospective cohort study of Cutaneous Leishmaniasis due to Leishmania major: Dynamics of the Leishmanin skin test and its predictive value for protection against infection and disease.

BACKGROUND: Leishmanin Skin Test (LST) is considered as a useful indicator of past infection by Leishmania parasites. However, the temporal dynamics of a positive LST under different epidemiologic scenarios and whether it relates to the protection against the recurrence of an overt disease are not fully documented. METHODOLOGY/PRINCIPAL FINDINGS: We report here on a population based prospective study conducted on 2686 individuals living in two foci located in Central Tunisia, to assess over a one-year epidemiologic season, the incidence of Leishmania (L.) major infection and disease and changes in LST reactivity. The two foci were both endemic for Cutaneous Leishmaniasis (CL) due to L. major, but contrasted in their history for this disease (ie: an old focus versus a recent focus). We found that most infections occurred in the new focus (290/1000; 95% CI: 265-315 person-years) with an incidence rate of CL lesions 2.4 times higher than in the old focus. Likewise, the rates of LST reactivity reversion and loss, in the new focus, were 99/1000[38-116] person-years and 14/1000[8-21] person-years, respectively. Loss of LST reactivity was not noticed in the old focus. Interestingly, the incidence rates of symptomatic infection did not differ significantly according to the LST status at enrolment (negative versus positive) between the combined foci and the new one. CONCLUSIONS/SIGNIFICANCE: Our findings confirm LST as a good tool for assessing L. major cryptic infection. However, the instability of the LST positivity in new foci should be considered as an important confounder of the outcome of this infection when developing a research protocol for vaccine trial.

Trends in the leading causes of childhood mortality from 2004 to 2016 in Qatar.

INTRODUCTION: Childhood mortality is an important health indicator that reflects the overall health status of a population. Despite the decrease in global childhood mortality rates over the past decades, it still remains an important public health issue in Qatar. METHODS: The data from 2004-2016 were extracted from the Qatar Ministry of Public Health Birth and Death Database. International Classification of Diseases (ICD-10) was used for coding the causes of death. The childhood mortality rate was defined as the probability of a child dying between the first and the fifth birthday, expressed as the number of deaths per 1,000 children surviving to 12 months of age. The sex ratio was calculated by dividing the mortality rate of males by that of females. Mann-Kendall trend test was performed to examine time trends. Relative risks were calculated to examine differences by nationality (Qatari and non-Qatari) and sex. RESULTS: A significant decrease in mortality rate of children aged one to five was observed from 1.76 to 1.05 per 1000 children between 2004 and 2016 (Kendall tau=-0.6, p=0.004). Three prominent causes of mortality were motor vehicle accidents, congenital malformations of the circulatory system, and accidental drowning/submersion. A statistically non-significant decrease in childhood mortality from motor vehicle accidents was oberved for all nationalities (total (Kendall tau=-0.03), Qatari (Kendall tau=-0.14), and non-Qatari (Kendall tau=-0.12)). A significant decrease was seen for total accidental drowning and submersion (Kendall tau=-0.54, p=0.012), while no statistically significant decrease was seen for total congenital malformations of the circulatory system (Kendall tau=-0.36, NS). The Qatari population did have a significant decrease in childhood mortality due to congenital malformations of the circulatory system (Kendall tau=-0.67, p=0.003) and accidental drowning and submersion (Kendall tau=-0.55, p=0.016). CONCLUSION: The study is a first attempt to evaluate childhood mortality statistics from Qatar and could be useful in supporting Qatar's ongoing national health strategy programs.

An Overview of Infant Mortality Trends in Qatar from 2004 to 2014.

Background Infant mortality is an important health indicator that estimates population well-being. Infant mortality has declined globally but is still a major public health challenge. This article provides the characteristics, causes, burden, and trends of infant mortality in Qatar. Methods Frequencies, percentages, and rates were calculated using data from birth-death registries over 2004-2014 to describe infant mortality by nationality, gender, and age group. We calculated the relative risks of the top causes of infant mortality among subgroups according to the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10, Version 2016). Results During 2004-2014, 204,224 live births and 1,505 infant deaths were recorded. The infant mortality rate (IMR) averaged 7.4/1000 live births (males 8.1, females 6.6, non-Qataris 7.7, and Qataris 6.8). IMR declined 20% from 2004 to 2014. The decline in IMR was significant for the overall population of infants (p=0.006), male infants (p=0.04), females (p=0.006), and for non-Qatari males (p=0.007) and non-Qatari females (p=0.007). The leading causes of infant mortality were congenital malformations (all types) (34.5%), low birth weight (LBW) (27%), and respiratory distress of newborns (2.8%). Male infants had a higher risk of mortality than female infants due to a congenital malformation of lungs (p=0.02), other congenital malformations, not elsewhere classified (p=0.01), and cardiovascular disorders (p=0.05). Conclusion The study shows that infant mortality among male infants is high due to the top infant mortality-related disorders, and male infants have a higher risk of mortality than female infants.

Human cellular and humoral immune responses to Phlebotomus papatasi salivary gland antigens in endemic areas differing in prevalence of Leishmania major infection.

BACKGROUND: Sand fly saliva compounds are able to elicit specific immune responses that have a significant role in Leishmania parasite establishment and disease outcome. Characterizing anti-saliva immune responses in individuals living in well defined leishmaniasis endemic areas would provide valuable insights regarding their effect on parasite transmission and establishment in humans. METHODOLOGY/PRINCIPAL FINDINGS: We explored the cellular and humoral immune responses to Phlebotomus (P.) papatasi salivary gland extracts (SGE) in individuals living in cutaneous leishmaniasis (CL) old or emerging foci (OF, EF). OF was characterized by a higher infection prevalence as assessed by higher proportions of leishmanin skin test (LST) positive individuals compared to EF. Subjects were further subdivided into healed, asymptomatic or naïve groups. We showed anti-SGE proliferation in less than 30% of the individuals, regardless of the immune status, in both foci. IFN-γ production was higher in OF and only observed in immune individuals from OF and naïve subjects from EF. Although IL-10 was not detected, addition of anti-human IL-10 antibodies revealed an increase in proliferation and IFN-γ production only in individuals from OF. The percentage of seropositive individuals was similar in immune and naïves groups but was significantly higher in OF. No correlation was observed between anti-saliva immune responses and LST response. High anti-SGE-IgG responses were associated with an increased risk of developing ZCL. No differences were observed for anti-SGE humoral or cellular responses among naïve individuals who converted or not their LST response or developed or not ZCL after the transmission season. CONCLUSIONS/SIGNIFICANCE: These data suggest that individuals living in an old focus characterized by a frequent exposure to sand fly bites and a high prevalence of infection, develop higher anti-saliva IgG responses and IFN-γ levels and a skew towards a Th2-type cellular response, probably in favor of parasite establishment, compared to those living in an emerging focus.

Spatio-temporal Genetic Structuring of Leishmania major in Tunisia by Microsatellite Analysis.

In Tunisia, cases of zoonotic cutaneous leishmaniasis caused by Leishmania major are increasing and spreading from the south-west to new areas in the center. To improve the current knowledge on L. major evolution and population dynamics, we performed multi-locus microsatellite typing of human isolates from Tunisian governorates where the disease is endemic (Gafsa, Kairouan and Sidi Bouzid governorates) and collected during two periods: 1991-1992 and 2008-2012. Analysis (F-statistics and Bayesian model-based approach) of the genotyping results of isolates collected in Sidi Bouzid in 1991-1992 and 2008-2012 shows that, over two decades, in the same area, Leishmania parasites evolved by generating genetically differentiated populations. The genetic patterns of 2008-2012 isolates from the three governorates indicate that L. major populations did not spread gradually from the south to the center of Tunisia, according to a geographical gradient, suggesting that human activities might be the source of the disease expansion. The genotype analysis also suggests previous (Bayesian model-based approach) and current (F-statistics) flows of genotypes between governorates and districts. Human activities as well as reservoir dynamics and the effects of environmental changes could explain how the disease progresses. This study provides new insights into the evolution and spread of L. major in Tunisia that might improve our understanding of the parasite flow between geographically and temporally distinct populations.

Prevalence and determinants of Leishmania major infection in emerging and old foci in Tunisia.

BACKGROUND: Zoonotic Cutaneous Leishmaniasis (ZCL) due to Leishmania major (L. major) is still a serious public health problem in Tunisia. This study aimed to compare the prevalence and risk factors associated with L. major infection in old and new foci using leishmanin skin test (LST) in central Tunisia. METHODS: A cross sectional household survey was carried out between January and May 2009 on a sample of 2686 healthy individuals aged between 5 and 65 years. We determined the prevalence of L. major infection using the LST. Risk factors of LST positivity were assessed using a logistic regression model. RESULTS: The overall prevalence of LST positivity was 57% (95% CI: 53-59). The prevalence of L. major infection was significantly higher in the old focus (99%; 95% CI: 98-100) than in the emerging foci (43%; 95% CI: 39-46) (p = <0.001). Multivariate analysis of LST positivity risk factors showed that age, the nature of the foci (old/emerging), personal and family history of ZCL are determinants of positive LST results. CONCLUSION: The results updated the current epidemiologic profile of ZLC in central Tunisia. Past history of transmission in a population should be considered as a potential confounder in future clinical trials for drugs and vaccines against L. major cutaneous leishmaniasis.

Temporal dynamics and impact of climate factors on the incidence of zoonotic cutaneous leishmaniasis in central Tunisia.

BACKGROUND: Old world Zoonotic Cutaneous Leishmaniasis (ZCL) is a vector-borne human disease caused by Leishmania major, a unicellular eukaryotic parasite transmitted by pool blood-feeding sand flies mainly to wild rodents, such as Psammomys obesus. The human beings who share the rodent and sand fly habitats can be subverted as both sand fly blood resource. ZCL is endemic in the Middle East, Central Asia, Subsaharan and North Africa. Like other vector-borne diseases, the incidence of ZCL displayed by humans varies with environmental and climate factors. However, so far no study has addressed the temporal dynamics or the impact of climate factors on the ZCL risk. PRINCIPAL FINDINGS: Seasonality during the same epidemiologic year and interval between ZCL epidemics ranging from 4 to 7 years were demonstrated. Models showed that ZCL incidence is raising i) by 1.8% (95% confidence intervals CI:0.0-3.6%) when there is 1 mm increase in the rainfall lagged by 12 to 14 months ii) by 5.0% (95% CI: 0.8-9.4%) when there is a 1% increase in humidity from July to September in the same epidemiologic year. CONCLUSION/SIGNIFICANCE: Higher rainfall is expected to result in increased density of chenopods, a halophytic plant that constitutes the exclusive food of Psammomys obesus. Consequently, following a high density of Psammomys obesus, the pool of Leishmania major transmissible from the rodents to blood-feeding female sand flies could lead to a higher probability of transmission to humans over the next season. These findings provide the evidence that ZCL is highly influenced by climate factors that could affect both Psammomys obesus and the sand fly population densities.

Leishmania major infection among Psammomys obesus and Meriones shawi: reservoirs of zoonotic cutaneous leishmaniasis in Sidi Bouzid(central Tunisia).

A study was undertaken between November 2008 and March 2010, in the focus of cutaneous leishmaniasis of Central Tunisia, to evaluate the role of Psammomys obesus (n=472) and Meriones shawi (n=167) as reservoir hosts for Leishmania major infection. Prevalence of L. major infection was 7% versus 5% for culture (p=not signifiant [NS]), 19% versus 16% for direct examination of smears (p=NS), and 20% versus 33% (p=NS) for Indirect Fluorescent Antibody Test among P. obesus and M. shawi, respectively. The peak of this infection was in winter and autumn and increased steadily with age for the both species of rodents. The clinical examination showed that depilation, hyper-pigmentation, ignition, and severe edema of the higher edge of the ears were the most frequent signs observed in the study sample (all signs combined: 47% for P. obesus versus 43% for M. shawi; p=NS). However, the lesions were bilateral and seem to be more destructive among M. shawi compared with P. obesus. Asymptomatic infection was ~40% for both rodents. This study demonstrated that M. shawi plays an important role in the transmission and the emergence of Leishmania major cutaneous leishmaniasis in Tunisia.

Heterogeneity of hepatitis B transmission in Tunisia: risk factors for infection and chronic carriage before the introduction of a universal vaccine program.

UNLABELLED: A population-based sero-epidemiological study enrolled 9486 volunteers in two governorates, Béja in the north and Tataouine in the south of Tunisia, in order to assess the magnitude of HBV transmission heterogeneity between the north and the south and within the same governorate, as well as the risk factors associated with infection and chronic carriage. RESULTS: The overall prevalence of anti-HBc, HBsAg and chronic carriage was 28.5, 5.3 and 2.9%, respectively. Significant differences were observed between the two governorates according to anti-HBc (32.1% in Béja and 27.8% in Tataouine; p=0.005) and HBsAg prevalence (4.2% in Béja and 5.6% in Tataouine; p=0.001). Significant differences were noticed between districts revealing important heterogeneity in HBV transmission within the same governorate (HBsAg ranged from 12 to <2% within the same governorate). At the individual level, the presence of a family member infected with HBV, scarification practices, needle practices in the Primary Care Center and gender (male) significantly increased the risk of anti-Hbc, HBsAg positivity and chronic carriage of infection while existence of sanitation in the house was found to be protective. The basic reproductive number and the force of infection confirmed the heterogeneity of transmission. Horizontal transmission within the family explains hyperendemic clusters in Tunisia.