Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis.

BACKGROUND: Chagas disease is caused by the parasite Trypanosoma cruzi and is endemic in much of Latin America. With increased globalisation and immigration, it is a risk in any country, partly through congenital transmission. The frequency of congenital transmission is unclear. OBJECTIVE: To assess the frequency of congenital transmission of T. cruzi. SEARCH STRATEGY: PubMed, Journals@Ovid Full Text, EMBASE, CINAHL, Fuente Academica and BIREME databases were searched using seven search terms related to Chagas disease or T. cruzi and congenital transmission. SELECTION CRITERIA: The inclusion criteria were the following: Dutch, English, French, Portuguese or Spanish language; case report, case series or observational study; original data on congenital T. cruzi infection in humans; congenital infection rate reported or it could be derived. This systematic review included 13 case reports/series and 51 observational studies. DATA COLLECTION AND ANALYSIS: Two investigators independently collected data on study characteristics, diagnosis and congenital infection rate. The principal summary measure--the congenital transmission rate--is defined as the number of congenitally infected infants divided by the number of infants born to infected mothers. A random effects model was used. MAIN RESULTS: The pooled congenital transmission rate was 4.7% (95% confidence interval: 3.9-5.6%). Countries where T. cruzi is endemic had a higher rate of congenital transmission compared with countries where it is not endemic (5.0% versus 2.7%). CONCLUSIONS: Congenital transmission of Chagas disease is a global problem. Overall risk of congenital infection in infants born to infected mothers is about 5%. The congenital mode of transmission requires targeted screening to prevent future cases of Chagas disease.

Differential IFN-γ production by adult and neonatal blood CD56+ natural killer (NK) and NK-like-T cells in response to Trypanosoma cruzi and IL-15.

Early interferon-gamma (IFN-γ) release by innate cells is critical to direct type 1 immune response able to control intracellular pathogens like Trypanosoma cruzi. Although CD56(bright) natural killer (NK) cells are reported to be potent early IFN-γ producers, other CD56(+) cells like CD56(dim) NK cells and NK-like T cells have recently been shown to also release IFN-γ. We have here studied the contribution of each CD56(+) lymphocyte populations in early IFN-γ production in both adults and neonates. On this purpose, we analysed the kinetics of IFN-γ production by RT-PCR, ELISA and flow cytometry from 2 h onwards after T. cruzi and IL-15 stimulation and sought for the responding CD56(+) cells. CD56(bright) and CD56(dim) CD16(-) NK cells were the more potent IFN-γ early producers in response to IL-15 and parasites in adults and neonates. In both age groups, the majority of IFN-γ producing cells were NK cells. However, on the contrary to neonates, CD3(+) CD56(+) NK-like T cells and CD3(+) CD56(-) 'classical' T cells also contributed to early IFN-γ production in adults. Altogether, our results support that whereas NK cells responded almost similarly in neonates and adults, cord blood innate CD56(+) and CD56(-) T cells displayed major quantitative and qualitative defects that could contribute to the well-known neonatal immune immaturity.

Chagas disease in European countries: the challenge of a surveillance system.

A study of aggregate data collected from the literature and official sources was undertaken to estimate expected and observed prevalence of Trypanosoma cruzi infection, annual incidence of congenital transmission and rate of underdiagnosis of Chagas disease among Latin American migrants in the nine European countries with the highest prevalence of Chagas disease. Formal and informal data sources were used to estimate the population from endemic countries resident in Europe in 2009, diagnosed cases of Chagas disease and births from mothers originating from endemic countries. By 2009, 4,290 cases had been diagnosed in Europe, compared with an estimated 68,000 to 122,000 expected cases. The expected prevalence was very high in undocumented migrants (on average 45% of total expected cases) while the observed prevalence rate was 1.3 cases per 1,000 resident migrants from endemic countries. An estimated 20 to 183 babies with congenital Chagas disease are born annually in the study countries. The annual incidence rate of congenital transmission per 1,000 pregnancies in women from endemic countries was between none and three cases. The index of under diagnosis of T. cruzi infection was between 94% and 96%. Chagas disease is a public health challenge in the studied European countries. Urgent measures need to be taken to detect new cases of congenital transmission and take care of the existing cases with a focus on migrants without legal residency permit and potential difficulty accessing care.

Globalization of Chagas disease (American trypanosomiasis): the situation in Europe and Belgium.

Trypanosoma cruzi, the protozoan agent of Chagas disease infects ten million people in Latin America where it is the main cause of cardiac failure. It is transmitted by insect vectors in endemic areas, and also congenitally, by transfusion of infected blood, transplantation of infected organs and oral route in both endemic and non-endemic areas. Since the 1990s, a constant decrease of incidence of infection is observed in Latin America, where vector control programmes and improvement of blood banks have been implemented. However, the important migration flows in the last decades for economic reasons have brought considerable numbers of Latin American subjects infected with T. cruzi, in US, Europe, Japan and Australia. Such globalization of T. cruzi infection/Chagas disease has been confirmed in an WHO historical meeting in 2007, emphasizing the importance of a wise management of such patients and the need of implementing control measures in blood banks, transplantation centres and maternities of involved countries in non-endemic areas. This paper considers these elements and the present situation of Chagas disease in Europe and Belgium.

Trichinellosis acquired in Nunavut, Canada in September 2009: meat from grizzly bear suspected.

Five cases of trichinellosis with onset of symptoms in September 2009, were reported in France, and were probably linked to the consumption of meat from a grizzly bear in Cambridge Bay in Nunavut, Canada. Travellers should be aware of the risks of eating raw or rare meat products in arctic regions, particularly game meat such as bear or walrus meat.

[Congenital Chagas disease: from the laboratory to public health]. / Maladie de chagas congénitale: du laboratoire a la santé publique.

Trypanosoma cruzi, the protozoan agent of Chagas disease can be transmitted from mother to foetus. The incidence of congenital infection is estimated to be at least 15,000 cases per year in Latin-America. Its incidence in the non endemic countries (U.S.A., Europe, Japan) is not known. Thanks to multidisciplinary studies performed in Bolivia, it has been possible to specify the epidemiologic and clinical features of congenital Chagas disease. The transplacental route, as well as the role of some parasitic (genotype and parasitic charge) or host factors (capacity of maternal and fetal/neonatal immune responses, particularly the generation of CD8T cells with cytotoxic and IFN-gamma-producing capacities) in mother-to-fetus transmission of infection and/or development of congenital Chagas disease, have been also studied. Altogether, these data have allowed the development of a strategy to control T. cruzi congenital infection, which has been validated by WHO and is applied in various Latin American countries.

Diffuse unilateral subacute neuroretinitis in Africa.

PURPOSE: Diffuse unilateral subacute neuroretinitis (DUSN) is well known in endemic areas of the southeastern United States, South America, and the northern Midwestern United States. Two different categories of nematodes, according to their length, are related to endemic areas. We report the first case of DUSN caused by a small nematode in Africa. METHODS: We describe the case of a 12-year-old Senegalese girl who presented a long-standing diffuse unilateral subacute neuroretinitis and in whom the worm could be localized. RESULTS: The length of the unidentified worm measured using the software of the fundus camera was approximately 600 microm. This measurement corresponds to the smaller nematode usually found in patients from the southeastern United States and South America. CONCLUSION: Diffuse unilateral subacute neuroretinitis can also be observed in patients living in Africa.

Estudio de costo/beneficio de un programa de control de Enfermedad de Chagas Congénita en Bolivia / Cost effectiveness study of a control program of congenital Chagas disease in Bolivia

Cost effectiveness analysis of Chagas' vertical transmission control program in Bolivia: Today, Bolivia is the most concerned country in America by Chagas disease: Trypanosoma cruzi infection affects 20% of whole population, around 1800000 inhabitants, and mother-to-child transmission is around 5%, from 1.6 to 9.8%. Direct and indirect costs derived from disease complications and death, from birth to adulthood, add up around US$ 21 millions per year for 2,718 infected new-borns. This cost falls on individual, family and society, when the nation is struggling in a depressed economy. On the other side, an effective control program could detect and treat all cases with an investment of US$ 123 per infected new-born, or US$ 1.2 per new-born in Bolivia. Indirect benefits, apart of suffering relieve and improving of life quality, are related with Chagas vector control program, increasing the demand thanks to increasing risk awareness and also induced demand testing all pregnant women in endemic areas. So the conclusion is that such investment is profitable.

Factores y mecanismos involucrados en la transmissión y el desarollo de la infección congénita por Trypanosoma cruzi / Factors and mechanisms involved in the transmission and development of congenital infection with Trypanosoma cruzi

This paper synthesizes the results obtained from multidisciplinary studies of Bolivian cases of congenital infection with T. cruzi. Congenital infection and congenital Chagas disease do not result from transmission of a particular strain of parasite, but from an equilibrium between complex phenomena, such as a weak maternal type 1 adaptative immune response associated with high maternal parasitemia, an invasion of placental chorion and umbilical cord by parasites, in front of a fetal T. cruzi-specific immune response characterized by an activation of cytotoxic CD8 T cells producing IFN-gamma and able to limit parasite multiplication and morbi-mortality of congenital Chagas disease.

Estatus inmunológico de las madres infectadas por T. cruzi / Immunological status of mothers infected with Trypanosoma cruzi

The mechanisms of congenital transmission of Chagas disease remain largely unknown. To better understand the role of maternal immunology during pregnancy in congenital Chagas transmission, we studied the cytokine production and the parasitic load in three groups of mothers: infected mothers who transmitted the disease to their babies (M+B+-), infected mothers who did not transmit the disease to their babies (M+B-) and not infected mothers as a control group (M-B-). M+B+ mothers produced less IFNgamma and more IL-10 than the M+B- mothers, and they are not able to produce IL-2. M+B+ mothers showed a higher parasitic load. These results, indicated that the congenital Chagas transmission is associated with an immunological imbalance and a high parasitic load in the M+B+ mothers.

Respuesta inmune en neonatos no infectados nacidos de madres infectadas por Trypanosoma cruzi / Immune responses of non-infected neonates of mothers infected with Trypanosoma cruzi

We have investigated if maternal T. cruzi infection could induce in utero innate and/or adaptive immune responses in uninfected neonates by measuring specific IgM and IgA antibodies in cord blood plasma, and by performing phenotypic and functional studies of umbilical cord blood cells of their newborns (M+B- group). We detected T. cruzi-specific IgM and IgA antibodies in M+B- cord blood, indicating they had mounted in utero a strong B cell response, although they are not infected. On the other hand, circulating T cells of such uninfected neonates displayed a low level of activation, as seen bya slightly increased expression of the activation markers CD45RO on CD4+ T cells and HLA-DR on CD8+ T cells, although the proportion of CD4+ and CD8+ T cells was unmodified as compared to newborns from uninfected mothers (MB- group). This activation did not give rise to a proliferative response upon stimulation by T. cruzi antigens in vitro. However, M+B- cells produced low levels of lymphokines (IFN-gamma and IL-13) upon mitogenic stimulation, which was not the case of M-B- newborn cells. Beside this, M+B- blood cells produced higher levels of inflammatory cytokines (IL-1b, IL-6, TNF-alpha) than M-B- cells when stimulated with the T. cruzi lysate or LPS, suggesting the over-activation of the innate response in M+B- newborns. Monocytes participated in such inflammatory response since M+B- purified cord blood monocytes produced higher levels of TNF- when incubated with LPS or a T. cruzi lysate than M-B- cells. Altogether, these results show that, even in the absence of congenital infection, maternal T. cruzi infection triggers in utero both adaptive and innate immune responses in their babies. This indicates that parasite circulating antigens have been transferred from mothers to their fetuses.

Las lesiones placentarias en la infección humana por Trypanosoma cruzi / Placental lesions in human Trypanosoma cruzi infection

This histopathological study analyzes placentas of babies congenitally infected with T. cruzi (M+B+), or babies not infected but born from infected- (M+B-), or non infected-mothers (M-B-). Placentas M+B+ showed lesions of chorionitis, chorioamnionitis and cord edema with lymphocyte infiltration, whereas such lesions were infiltrated only with polymorphonuclear cells in M+B- and M-B- placentas. Parasites were found in M+B+ placentas, in fibroblasts and macrophages of chorion, membranes, chorionic plate, mainly in the area of membrane insertion, as well as in cells of Wharton jelly and myocytes of umbilical cord vessels. These results suggest that the materno-fetal transmission of parasites occurs mainly through the marginal sinus, spreading into the chorionic plate infecting fibroblasts and macrophages so far as to found a fetal vessel, inducing a fetal infection by hematogenous route.

Detección de la heterogeneidad molecular de Trypanosoma cruzi / Detection of molecular heterogeneity of Trypanosoma cruzi

Congenital transmission of T. cruzi in Cochabamba affects 6% of newborns from infected mothers. Only limited information is available on the type of transmitted parasites. However, it is well established that T. cruzi isolated from various vectors as well from host animals are highly heterogeneous. In our presentation we analyse aspects of molecular heterogeneity of T. cruzi and we review methods used for the molecular typing of T. cruzi lineages. Experimentally, we performed the PCR amplification of [quot ]Sequence-characterised region Markers[quot ] for typing T. cruzi isolated from umbilical blood of newborns in Cochabamba. We compared these results with those we obtained from general infected population. All 16 analysed, congenitally infected samples were of lineage IId. Our data also indicated that this lineage was found in about 80% of samples originated from general infected population in Cochabamba.

Efectos de la infección materna por Trypanosoma cruzi en el desarrollo del embarazo y del recien nacido / Effects of maternal infection with Trypanosoma cruzi in pregnancy development and in the newborn infant

In the endemic regions of Bolivia the infection of the feminine population in fertile age by T. cruzi is frequent (20 to 50 % of the women in fertile age) and the rate of fetal maternal transmission is of approximately 5%. A great percentage of infected women do not transmit the infection to the fetus. The intention of the present study carried out at the Maternal-Infantile Hospital Germán Urquidi of Cochabamba (Bolivia) is to contribute to the knowledge regarding the pregnancy and birth of a newborn of Chagas infected women who do not transmit the infection to the fetus. 2124 mothers and 2,155 newborns were studied. The prevalence of infection by T. cruzi among these pregnant women is of 26,3%. Two groups of mothers were studied: 554 that presented infection by T. cruzi (group M+B-) and 1520 not infected (group control M-B-). Both groups of mothers are comparable in their anthropometric and obstetrical antecedents. The mothers (M+B+) are in average older than those not infected (p<0.05), which will probably have an influence on the number of gestations and abortion antecedents, which were of p<0.05 and p=0.01 respectively. Among the different anthropometric and biological parameters studied in newborns of groups M+B- and M-B -, no statistically significant differences between both groups were found. It can be inferred that the chronic maternal infection by T. cruzi seems to have no clinical influence, neither on the course of the pregnancy nor during birth, if a group of T. cruzi infected mothers is compared to a non infected group.

Efectos de la infección aguda y crónica por Trypanosoma cruzi en la gestación de los ratones / Effects of acute and chronic Trypanosoma cruzi infection in pregnant mice

Pathogens may impair reproduction in association or not with congenital infections. We have investigated the effect of acute infection with Trypanosoma cruzi, the protozoan agent of Chagas disease, on reproduction of female mice. In the acute, parasitemic, phase of the infection, female mice were totally unable to reproduce. Most of them (80%) were infertiles and did not develop any gestation. In the few gravid infected mice, implantation numbers were as in uninfected control mice. However, their fetuses presented a weight meanly reduced by 40% as compared to those of uninfected females, and all of them died during the gestation or whithin 48 h after birth. Such massive mortality did not result from congenital infection, which did not occur. The infertility and the fetal mortality occuring early in gestation (resorptions) were significantly correlated with a high maternal parasitemia, whereas later fetal mortality was associated with the presence of intracellular parasites in the utero-placental unit. The decidua was particularly receptive to T. cruzi multiplication, since this tissue harboured 125 fold more amastigotes than the maternal heart or other placental tissues. In addition, placentas of dead fetuses presented histopathological lesions (inflammatory infiltrates, fibrine deposits and ischemic necrosis). Such harmfull effects of acute infection were not observed when female mice were in the chronic phase of the infection, since these reproduce normally. Their fetuses only suffered from moderate and reversible growth retardation. These results indicate that, following the maternal parasite burden, T. cruzi infection may induce very deleterious effects on gestation.

Comparación de métodos de PCR para el diagnóstico de la infección congenita por Trypanosoma cruzi / Comparison of PCR methods for the diagnosis of congenital Trypanosoma cruzi infection

PCR is a potentially interesting diagnostic tool to detect congenital T. cruzi infection. We have compared the sensitivity and capacity of a battery of T. cruzi PCR primers to detect the complete spectrum of known T. cruzi lineages, in order to improve and simplify the detection of infection in neonatal blood. We found that the primers Tcz1/Tcz2, targeting the 195 bp satellite repeat, detected all the parasitic lineages with the same sensitivity For all other tested primers (nDNA primers: BP1/BP2, 01/02, Pon1/ Pon2 and Tca1/Tca2; kDNA primers: S35VS36, 121/122), either, the intensity of amplicons varied according to T. cruzi lineages, or the assess were less sensitive. In order to better assess such PCR protocol, we assayed 311 samples of neonatal blood previously tested with parasitological methods. Reliability of our PCR test was demonstrated since all the 18 blood samples from newborns with congenital T. cruzi infection were positive, whereas the remaining samples (30 from control newborns of uninfected mothers and 262 out of 263 from babies, parasitologically negative, born from infected mothers) were negative. As our PCR method is simple, reliable, robust and cheap, it appears suitable for the detection of T. cruzi infection in neonatal blood.

Dosificación de anticuerpos IgM e IgA anti-trypanosoma cruzi en sangre de recién nacidos de madres con serología positiva para Chagas / Serum levels for IgM and IgA antibodies to anti-trypanosoma cruzi in samples of blood from newborns from mothers with positive serology for Chagas disease

This study compares the levels of specific antibodies IgM and IgA for Chagas in samples of blood from newborns. Three groups of cord blood samples have been analysed: a group of 42 samples from newborns, displaying positive parasitemia, of seropositive mothers (M+B+), 68 samples from newborns with negative parasitemia whose mothers were seropositive (M+B-) and a group of 45 control newborns coming from mothers with negative serology for Chagas. From the 42 M+B+ samples with congenital Chagas disease, 81 and 82.9% displayed detectable levels of IgM and IgA antibodies, respectively In the M+B- group, 70.6 and 33.8% presented antibodies of IgM and IgA classes, respectively, whereas in the control group M-B-, we detected 6% and 11.1% of IgM and IgA antibodies, respectively. The calculated sensitivity of detection of congenital cases using IgM or IgA antibodies was of 82.9% and 80.9% respectively, whereas the specificity of detection was of 29.4% for IgM antibodies and of 66.1% for IgA antibodies.

Estimación de la parasitemia en la infección humana por Trypanosoma cruzi: las altas parasitemias están asociadas con la severa y fatal enfermedad de Chagas congenita / Estimation of the parasitemia in Trypanosoma cruzi human infection: high parasitemias are associated with severe and fatal congenital Chagas disease

The aim of this study was to validate the method of microhematocrit tube, as a rapid method to estimate the parasitemia in blood and to associate the parasites concentration with the morbidity and mortality of new born children with congenital Chagas diseases. Our results were determined experimentally and shown that the detection limit of the microhematocrit tube method is 40 parasites/ml when at least one of the four observed tubes is positive. Besides, it was also established that when the four examined tubes are positive the parasitemia in blood reaches more than 100 parasites/ml. It is important to highlight the modification made by our laboratory in the microscopic observation of the microhematocrit tubes with respect to the methodology used by previous investigators. A positive association exists between a high number of parasites in blood and the morbi-mortality of the newly born children with congenital chagas. The results of positive association between the parasitic load and the morbility and mortality could constitute an argument to understand the possible role of the parasite in the pathology of the disease.