High-resolution spatial analysis of cholera patients reported in Artibonite department, Haiti in 2010-2011.

BACKGROUND: Cholera is caused by Vibrio cholerae, and is transmitted through fecal-oral contact. Infection occurs after the ingestion of the bacteria and is usually asymptomatic. In a minority of cases, it causes acute diarrhea and vomiting, which can lead to potentially fatal severe dehydration, especially in the absence of appropriate medical care. Immunity occurs after infection and typically lasts 6-36 months. Cholera is responsible for outbreaks in many African and Asian developing countries, and caused localised and episodic epidemics in South America until the early 1990s. Haiti, despite its low socioeconomic status and poor sanitation, had never reported cholera before the recent outbreak that started in October 2010, with over 720,000 cases and over 8700 deaths (Case fatality rate: 1.2%) through 8 december 2014. So far, this outbreak has seen 3 epidemic peaks, and it is expected that cholera will remain in Haiti for some time. METHODOLOGY/FINDINGS: To trace the path of the early epidemic and to identify hot spots and potential transmission hubs during peaks, we examined the spatial distribution of cholera patients during the first two peaks in Artibonite, the second-most populous department of Haiti. We extracted the geographic origin of 84,000 patients treated in local health facilities between October 2010 and December 2011 and mapped these addresses to 63 rural communal sections and 9 urban cities. Spatial and cluster analysis showed that during the first peak, cholera spread along the Artibonite River and the main roads, and sub-communal attack rates ranged from 0.1% to 10.7%. During the second peak, remote mountain areas were most affected, although sometimes to very different degrees even in closely neighboring locations. Sub-communal attack rates during the second peak ranged from 0.2% to 13.7%. The relative risks at the sub-communal level during the second phase showed an inverse pattern compared to the first phase. CONCLUSION/SIGNIFICANCE: These findings demonstrate the value of high-resolution mapping for pinpointing locations most affected by cholera, and in the future could help prioritize the places in need of interventions such as improvement of sanitation and vaccination. The findings also describe spatio-temporal transmission patterns of the epidemic in a cholera-naïve country such as Haiti. By identifying transmission hubs, it is possible to target prevention strategies that, over time, could reduce transmission of the disease and eventually eliminate cholera in Haiti.

Mortality Rates during Cholera Epidemic, Haiti, 2010-2011.

The 2010 cholera epidemic in Haiti was one of the largest cholera epidemics ever recorded. To estimate the magnitude of the death toll during the first wave of the epidemic, we retrospectively conducted surveys at 4 sites in the northern part of Haiti. Overall, 70,903 participants were included; at all sites, the crude mortality rates (19.1-35.4 deaths/1,000 person-years) were higher than the expected baseline mortality rate for Haiti (9 deaths/1,000 person-years). This finding represents an excess of 3,406 deaths (2.9-fold increase) for the 4.4% of the Haiti population covered by these surveys, suggesting a substantially higher cholera mortality rate than previously reported.

Normal and premature rupture of fetal membranes at term delivery differ in regional chemotactic activity and related chemokine/cytokine production.

A gradient of immunological mediators exists in the fetal membranes from the periplacental zone (PZ) to the rupture zone (RZ) at term delivery (rupture of fetal membranes [ROM]). However, it is unknown if this gradient is different in premature rupture of these tissues (premature rupture of fetal membranes [PROM]). We therefore analyzed leukocyte chemotactic activity and chemokine/cytokine production in fetal membrane zones in ROM and PROM. In ROM, leukocyte chemotactic activity increased from the PZ to the RZ; however, this did not occur in PROM. This was due to consistently elevated leukocyte chemotactic activity in PROM compared to ROM tissues. In the RZ, ROM was characterized by increased T-cell attraction and high levels of chemokine (C-X-C motif) ligand 8 (CXCL-8)/interleukin 8, and PROM by increased granulocyte attraction and high levels of granulocyte-macrophage colony-stimulating factor and CXCL-10/interferon gamma-induced protein 10. We conclude that normal and premature rupture of fetal membranes differ in regional chemotactic activity and related chemokine/cytokine production, which may represent evidence for differential mechanisms of rupture at term delivery.

Specific inflammatory microenvironments in the zones of the fetal membranes at term delivery.

OBJECTIVE: The purpose of this study was to examine the histologic and immunologic differences between fetal membrane zones after membrane rupture at term delivery. STUDY DESIGN: Fetal membrane explants from postrupture zones (periplacental, middle, rupture) were obtained from women following spontaneous vaginal delivery at term (n = 5). Tissues for histology, protein extracts, and RNA were isolated. RESULTS: The collagen distribution decreased and the leukocyte density increased from the periplacental zone to the rupture zone. T cells were mainly present in the rupture zone and granulocytes in the middle zone. CXCL10, CXCR1, ICAM-1, -2, PSEL, tumor necrosis factor alpha, and matrix metalloproteinase-9 levels were higher in the middle zone than in the rupture zone and periplacental zone (P < .021). Interleukin-1beta and CXCL8 levels were higher in the rupture zone than in the middle zone and periplacental zone (P = .018 and P < .0001). CONCLUSION: During labor specific immunologic microenvironments are created in the zones of the fetal membrane that may be involved in their rupture at the end of gestation.

Choriodecidua and amnion exhibit selective leukocyte chemotaxis during term human labor.

OBJECTIVE: The purpose of this study was to compare the chemotactic activity of the choriodecidua and amnion, and to identify the phenotype of the leukocytes chemoattracted by each tissue. STUDY DESIGN: Amnion, choriodecidua and whole fetal membranes extracts were obtained from women at term (>37 weeks of gestation) with or without labor (n = 5 each). Extracts were assayed for leukocyte chemotactic activity, and the number and phenotype of the chemoattracted leukocytes were characterized by flow cytometry. RESULTS: Although all of the extracts exhibited chemotactic activity, more leukocytes were chemoattracted by the choriodecidua and the whole fetal membranes during labor compared with no labor (P = .010, .008). During labor the choriodecidua is responsible for granulocyte, T-lymphocyte, monocyte, and natural killer-cell chemoattraction, and the amnion is responsible for B-lymphocyte chemoattraction. CONCLUSION: Choriodecidua and amnion exhibit chemotactic activity for selective leukocytes and thus, each fetal membrane differentially regulates leukocyte chemotactic activity during labor.

Interaction between pathogenic bacteria and intrauterine leukocytes triggers alternative molecular signaling cascades leading to labor in women.

Increased risk of preterm labor has been linked to cervicovaginal infection with Ureaplasma urealyticum and group B streptococci. Although various experimental models have been developed to study the role of amniochorion infection in preterm labor, they typically exclude the initial interaction between intrauterine leukocytes (recruited from decidual vessels into the avascular fetal membranes) and infecting bacteria. In this work, we ascertained whether inflammatory molecules secreted by bacterium-activated intrauterine leukocytes stimulate the amniochorion production of mediators involved in human labor. Using a two-step process beginning with placental circulating leukocytes as a proxy for intrauterine leukocytes, we found that coincubation of amniochorion explants with plasma from placental whole blood preincubated with group B streptococci resulted in a significant increase in tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 9 (MMP-9) levels in tissue. Extensive changes in the connective tissue arrangement and a decrease in collagen content demonstrated the degradation of the extracellular matrix following this treatment. In contrast, plasma from blood preconditioned with U. urealyticum induced a highly significant secretion of interleukin-1ß (IL-1ß) and prostaglandin E(2) (PGE(2)) by the amniochorion without changes in the extracellular matrix organization or content. These data demonstrate that group B streptococci induce degradation of the amniochorion as a result of MMP-9 production, probably via TNF-α, whereas U. urealyticum stimulates the secretion of PGE(2), probably via IL-1ß, potentially stimulating myometrial contraction. Our study provides novel evidence that the immunological cells circulating within the uterine microenvironment respond differentially to an infectious agent, triggering alternative molecular signaling pathways leading to human labor.

An immunological insight into the origins of pre-eclampsia.

BACKGROUND: Pre-eclampsia is a syndrome of heterogeneous origin characterized by deficient placentation due to the inability of the cytotrophoblast to acquire an invasive phenotype and to remodel the uterine spiral arteries. One of the main problems observed early in pre-eclampsia is an altered regulation of the immune system, where the shift toward a Th2 cytokine profile observed in normal pregnancies, does not occur. In pre-eclampsia, high interferon (IFN)-gamma concentrations are present, along with transforming growth factor-beta cytokines, which retard migration of cytotrophoblasts. METHODS: A review of the scientific literature was performed on the immunological factors associated with the origins of pre-eclampsia. The various components of the immune system that may be participating in the aberrant immune activation that pathologically affect early pregnancy events and inhibit cytotrophoblast invasion were identified. RESULTS AND CONCLUSIONS: Cells and their signaling and regulatory molecules have been implicated in the immunological alterations found in the placental microenvironment of patients who develop pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th1 responses and the production of IFN-gamma. The origin of IFN-gamma is not clearly identified and could be the uterine natural killer cells, the placental dendritic cells modulating Th responses, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. Understanding the immunological basis for pre-eclampsia will expand knowledge regarding other adverse pregnancy outcomes.

The role of chemokines in term and premature rupture of the fetal membranes: a review.

Several studies indicate that at the choriodecidual interface, where maternal and fetal tissues make contact, a network of signals is established during labor that includes infiltration of leukocytes and secretion of pro-inflammatory cytokines. In this review, we provide an overview of the inflammatory milieu present in the choriodecidua during membrane rupture, describe the recruitment and homing of leukocytes to the reproductive tissues, and detail specific actions of the key chemokines released by the choriodecidual cells. These data lend further support to the hypothesis that labor is an inflammatory response, wherein the infiltrated leukocytes in the choriodecidua interface could be contributing to the creation of a microenvironment leading to collagenolysis, which would promote the rupture of these tissues during labor. In addition to the available information describing biological actions of chemokines during various pathological conditions such as infection, preterm labor and preterm rupture of membranes suggest that these compounds play important roles in other gestational events such as cervical dilation and myometrial contractions. Even though we do not know the totality of biochemical signals that integrate the molecular dialogue between leukocytes and the various gestational tissues, it is becoming increasingly evident that this microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the fetal membranes. Therefore, chemokines should be considered as important regulatory molecules with the ability to initiate the events that characterize normal and pathological labor.