Jean Gaudart

Cytokine Regulation of Periportal Fibrosis in Humans Infected with Schistosoma mansoni: IFN-γ is Associated with Protection Against Fibrosis and TNF-α with Aggravation of Disease

Hepatic periportal fibrosis, which affects 5–10% of subjects infected by Schistosoma mansoni, is caused by the T cell-dependent granuloma that develop around schistosome eggs. Experimental models of infection have shown that granuloma and fibrosis are tightly regulated by cytokines. However, it is unknown why advanced periportal fibrosis occurs only in certain subjects. The goal of the present study was to evaluate the cytokine response of S. mansoni-infected subjects with advanced liver disease in an attempt to relate susceptibility to periportal fibrosis with an abnormal production of cytokines that regulate granuloma and fibrosis. Fibrosis was evaluated by ultrasound on 795 inhabitants of a Sudanese village in which S. mansoni is endemic: advanced periportal fibrosis was observed in 12% of the population; 35% of the affected subjects exhibited signs of portal hypertension. Age (odds ratio (OR), 11.5), gender (OR, 4.2), and infection levels (OR, 2.2) were significantly (p ≤ 0.01) associated with hepatic fibrosis. Cytokines produced by egg-stimulated blood mononuclear cells from 99 subjects were measured (75 with no or mild fibrosis; 24 subjects with advanced fibrosis). Multivariate analysis of cytokine levels showed that high IFN-γ levels were associated with a marked reduction of the risk of fibrosis (p = 0.01; OR, 0.1); in contrast, high TNF-α levels were associated with an increased risk (p = 0.05; OR, 4.6) of periportal fibrosis. Moreover, infection levels were negatively associated with IFN-γ production. These results with observations in experimental models strongly suggest that IFN-γ plays a key role in the protection of S. mansoni-infected patients against periportal fibrosis, whereas TNF-α may aggravate the disease.

Understanding the Cholera Epidemic, Haiti

After onset of a cholera epidemic in Haiti in mid-October 2010, a team of researchers from France and Haiti implemented field investigations and built a database of daily cases to facilitate identification of communes most affected. Several models were used to identify spatiotemporal clusters, assess relative risk associated with the epidemic’s spread, and investigate causes of its rapid expansion in Artibonite Department. Spatiotemporal analyses highlighted 5 significant clusters (p<0.001): 1 near Mirebalais (October 16–19) next to a United Nations camp with deficient sanitation, 1 along the Artibonite River (October 20–28), and 3 caused by the centrifugal epidemic spread during November. The regression model indicated that cholera more severely affected communes in the coastal plain (risk ratio 4.91) along the Artibonite River downstream of Mirebalais (risk ratio 4.60). Our findings strongly suggest that contamination of the Artibonite and 1 of its tributaries downstream from a military camp triggered the epidemic.

Multicenter EuroTravNet/GeoSentinel Study of Travel-related Infectious Diseases in Europe

We analyzed prospective data on 17,228 European patients who sought treatment at GeoSentinel sites from 1997 to 2007. Gastrointestinal illness (particularly in tourists), fever (those visiting friends and relatives [VFRs]), and skin disorders (in tourists) were the most common reasons for seeking medical care. Diagnoses varied by country of origin, region visited, or categories of travelers. VFRs who returned from sub-Saharan Africa and Indian Ocean islands were more likely to experience falciparum malaria than any other group. Multiple correspondence analysis identified Italian, French, and Swiss VFRs and expatriate travelers to sub-Saharan Africa and Indian Ocean Islands as most likely to exhibit febrile illnesses. German tourists to Southeast and south-central Asia were most likely to seek treatment for acute diarrhea. Non-European travelers (12,663 patients from other industrialized countries) were less likely to acquire certain travel-associated infectious diseases. These results should be considered in the practice of travel medicine and development of health recommendations for European travelers.

Space-time clustering of childhood malaria at the household level: a dynamic cohort in a Mali village.

BackgroundSpatial and temporal heterogeneities in the risk of malaria have led the WHO to recommend fine-scale stratification of the epidemiological situation, making it possible to set up actions and clinical or basic researches targeting high-risk zones. Before initiating such studies it is necessary to define local patterns of malaria transmission and infection (in time and in space) in order to facilitate selection of the appropriate study population and the intervention allocation. The aim of this study was to identify, spatially and temporally, high-risk zones of malaria, at the household level (resolution of 1 to 3 m).MethodsThis study took place in a Malian village with hyperendemic seasonal transmission as part of Mali-Tulane Tropical Medicine Research Center (NIAID/NIH). The study design was a dynamic cohort (22 surveys, from June 1996 to June 2001) on about 1300 children (<12 years) distributed between 173 households localized by GPS. We used the computed parasitological data to analyzed levels of Plasmodium falciparum, P. malariae and P. ovale infection and P. falciparum gametocyte carriage by means of time series and Kulldorffs scan statistic for space-time cluster detection.ResultsThe time series analysis determined that malaria parasitemia (primarily P. falciparum) was persistently present throughout the population with the expected seasonal variability pattern and a downward temporal trend. We identified six high-risk clusters of P. falciparum infection, some of which persisted despite an overall tendency towards a decrease in risk. The first high-risk cluster of P. falciparum infection (rate ratio = 14.161) was detected from September 1996 to October 1996, in the north of the village.ConclusionThis study showed that, although infection proportions tended to decrease, high-risk zones persisted in the village particularly near temporal backwaters. Analysis of this heterogeneity at the household scale by GIS methods lead to target preventive actions more accurately on the high-risk zones identified. This mapping of malaria risk makes it possible to orient control programs, treating the high-risk zones identified as a matter of priority, and to improve the planning of intervention trials or research studies on malaria.

Chikungunya Fever: A Clinical and Virological Investigation of Outpatients on Reunion Island, South-West Indian Ocean

Background Chikungunya virus (CHIKV) is responsible for acute febrile polyarthralgia and, in a proportion of cases, severe complications including chronic arthritis. CHIKV has spread recently in East Africa, South-West Indian Ocean, South-Asia and autochthonous cases have been reported in Europe. Although almost all patients are outpatients, medical investigations mainly focused on hospitalised patients. Methodology/Principal Findings Here, we detail clinico-biological characteristics of Chikungunya (CHIK) outpatients in Reunion Island (2006). 76 outpatients with febrile arthralgia diagnosed within less than 48 hours were included by general practitioners during the CuraChik clinical trial. CHIK was confirmed in 54 patients and excluded in 22. A detailed clinical and biological follow-up was organised, that included analysis of viral intrahost diversity and telephone survey until day 300. The evolution of acute CHIK included 2 stages: the ‘viral stage’ (day 1–day 4) was associated with rapid decrease of viraemia and improvement of clinical presentation; the ‘convalescent stage’ (day 5–day 14) was associated with no detectable viraemia but a slower clinical improvement. Women and elderly had a significantly higher number of arthralgia at inclusion and at day 300. Based on the study clinico-biological dataset, scores for CHIK diagnosis in patients with recent febrile acute polyarthralgia were elaborated using arthralgia on hands and wrists, a minor or absent myalgia and the presence of lymphopenia (<1G/L) as major orientation criteria. Finally, we observed that CHIKV intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with increased number of arthralgia and intensity of sequelae at day 300. Conclusions/Significance This study provided a detailed picture of clinico-biological CHIK evolution at the acute phase of the disease, allowed the elaboration of scores to assist CHIK diagnosis and investigated for the first time the impact of viral intra-host genetic diversity on the disease course.

IFN-gamma polymorphisms (IFN-gamma +2109 and IFN-gamma +3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni).

Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-γ. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN-γ gene are associated with PPF. The IFN-γ +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-γ +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN-γ mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the α-chain of the IFN-γ receptor, and low IFN-γ producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-γ expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).

Modelling malaria incidence with environmental dependency in a locality of Sudanese savannah area, Mali

BackgroundThe risk of Plasmodium falciparum infection is variable over space and time and this variability is related to environmental variability. Environmental factors affect the biological cycle of both vector and parasite. Despite this strong relationship, environmental effects have rarely been included in malaria transmission models.Remote sensing data on environment were incorporated into a temporal model of the transmission, to forecast the evolution of malaria epidemiology, in a locality of Sudanese savannah area.MethodsA dynamic cohort was constituted in June 1996 and followed up until June 2001 in the locality of Bancoumana, Mali. The 15-day composite vegetation index (NDVI), issued from satellite imagery series (NOAA) from July 1981 to December 2006, was used as remote sensing data.The statistical relationship between NDVI and incidence of P. falciparum infection was assessed by ARIMA analysis. ROC analysis provided an NDVI value for the prediction of an increase in incidence of parasitaemia.Malaria transmission was modelled using an SIRS-type model, adapted to Bancoumanas data. Environmental factors influenced vector mortality and aggressiveness, as well as length of the gonotrophic cycle. NDVI observations from 1981 to 2001 were used for the simulation of the extrinsic variable of a hidden Markov chain model. Observations from 2002 to 2006 served as external validation.ResultsThe seasonal pattern of P. falciparum incidence was significantly explained by NDVI, with a delay of 15 days (p = 0.001). An NDVI threshold of 0.361 (p = 0.007) provided a Diagnostic Odd Ratio (DOR) of 2.64 (CI95% [1.26;5.52]).The deterministic transmission model, with stochastic environmental factor, predicted an endemo-epidemic pattern of malaria infection. The incidences of parasitaemia were adequately modelled, using the observed NDVI as well as the NDVI simulations. Transmission pattern have been modelled and observed values were adequately predicted. The error parameters have shown the smallest values for a monthly model of environmental changes.ConclusionRemote-sensed data were coupled with field study data in order to drive a malaria transmission model. Several studies have shown that the NDVI presents significant correlations with climate variables, such as precipitations particularly in Sudanese savannah environments. Non-linear model combining environmental variables, predisposition factors and transmission pattern can be used for community level risk evaluation.

Characteristics of Arterial Stiffness in Very Low Birth Weight Premature Infants

Premature birth is a factor of increased blood pressure in adulthood. Little is known about the physiologic characteristics of the arterial bed in neonates. The aim of this study was to characterize in vivo the arterial compliance in neonates and its maturation profile in very low birth weight (VLBW) premature infants. A group of stable, VLBW premature infants was compared with a control group of near term neonates. The abdominal aortic wall distensibility coefficient (DC) and whole-body arterial compliance (WBAC) were determined using specifically designed noninvasive methods, based on ultrasonic measurements in combination with synchronous, beat-to-beat recording of aortic pulse pressure (PP). On the fifth day of life, WBAC and the CD were lower in VLBW premature infants than in controls. Furthermore, WBAC and the DC remained unchanged in VLBW premature infants 7 wk after birth. In conclusion, VLBW premature infants are characterized as early as the fifth day of life by high arterial stiffness, which persists when they reach their theoretical term. It can be speculated that early alteration of arterial elastic properties may pave the way for long-term elevation of arterial pressure in VLBW premature infants.

Using Mobile Phone Data to Predict the Spatial Spread of Cholera

Effective response to infectious disease epidemics requires focused control measures in areas predicted to be at high risk of new outbreaks. We aimed to test whether mobile operator data could predict the early spatial evolution of the 2010 Haiti cholera epidemic. Daily case data were analysed for 78 study areas from October 16 to December 16, 2010. Movements of 2.9 million anonymous mobile phone SIM cards were used to create a national mobility network. Two gravity models of population mobility were implemented for comparison. Both were optimized based on the complete retrospective epidemic data, available only after the end of the epidemic spread. Risk of an area experiencing an outbreak within seven days showed strong dose-response relationship with the mobile phone-based infectious pressure estimates. The mobile phone-based model performed better (AUC 0.79) than the retrospectively optimized gravity models (AUC 0.66 and 0.74, respectively). Infectious pressure at outbreak onset was significantly correlated with reported cholera cases during the first ten days of the epidemic (p < 0.05). Mobile operator data is a highly promising data source for improving preparedness and response efforts during cholera outbreaks. Findings may be particularly important for containment efforts of emerging infectious diseases, including high-mortality influenza strains.

Spatio-temporal dynamics of cholera during the first year of the epidemic in Haiti.

Background In October 2010, cholera importation in Haiti triggered an epidemic that rapidly proved to be the worlds largest epidemic of the seventh cholera pandemic. To establish effective control and elimination policies, strategies rely on the analysis of cholera dynamics. In this report, we describe the spatio-temporal dynamics of cholera and the associated environmental factors. Methodology/Principal findings Cholera-associated morbidity and mortality data were prospectively collected at the commune level according to the World Health Organization standard definition. Attack and mortality rates were estimated and mapped to assess epidemic clusters and trends. The relationships between environmental factors were assessed at the commune level using multivariate analysis. The global attack and mortality rates were 488.9 cases/10,000 inhabitants and 6.24 deaths/10,000 inhabitants, respectively. Attack rates displayed a significantly high level of spatial heterogeneity (varying from 64.7 to 3070.9 per 10,000 inhabitants), thereby suggesting disparate outbreak processes. The epidemic course exhibited two principal outbreaks. The first outbreak (October 16, 2010–January 30, 2011) displayed a centrifugal spread of a damping wave that suddenly emerged from Mirebalais. The second outbreak began at the end of May 2011, concomitant with the onset of the rainy season, and displayed a highly fragmented epidemic pattern. Environmental factors (river and rice fields: p<0.003) played a role in disease dynamics exclusively during the early phases of the epidemic. Conclusion Our findings demonstrate that the epidemic is still evolving, with a changing transmission pattern as time passes. Such an evolution could have hardly been anticipated, especially in a country struck by cholera for the first time. These results argue for the need for control measures involving intense efforts in rapid and exhaustive case tracking.