Laura Murcia

Risk Factors and Primary Prevention of Congenital Chagas Disease in a Nonendemic Country

BACKGROUND In this longitudinal cohort study we evaluated the congenital transmission of Chagas disease (CD) in a nonendemic area. The aim of this work was to analyze the predictive value of a Trypanosoma cruzi-positive polymerase chain reaction (PCR) result in pregnant women for the diagnosis of vertical transmission and to evaluate the use of PCR as a tool for early detection of infection. METHODS The offspring of 59 seropositive pregnant mothers were followed up. The parasitological status of mothers was studied by PCR in a total of 64 pregnancies; 10 of these women had received treatment before pregnancy. Sixty-five infants (including a pair of twins) were monitored at 0, 6, 9, and 12 months of age by PCR and serology. In cases of congenital transmission, hemoculture and parasite lineage typing were performed. RESULTS Nine infants had acquired CD congenitally. This represents a transmission rate of 13.8% among seropositive mothers (9 infected newborns of 65 total live births). All infants were infected with T. cruzi discrete typing unit V strain. A statistically significant correlation was found between T. cruzi vertical transmission and a positive PCR result during pregnancy (31%; 9 infected newborns in 29 live births). No infected infants were detected among 10 mothers who were treated before they became pregnant, compared with 16.4% (9 of 55 live births) among untreated mothers. CONCLUSIONS PCR is a useful tool for the detection of congenital CD, and the treatment of infected women of childbearing age seems to be useful for preventing vertical transmission.

The urgent need to develop new drugs and tools for the treatment of Chagas disease

Chagas disease Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi, which was discovered by the Brazilian Carlos Chagas in 1909, and affects people predominantly from poor rural areas of Latin America. Approximately 10–12 million people are infected in endemic areas and the disease kills more than 15,000 people each year [1]. T. cruzi is composed of hetero geneous strains that have been recently classified into six groups, TcI–VI, which have different geographical distributions and biological properties [2]. The parasite is transmitted in the feces of a triatomine insect after feeding on the blood of diverse mammals, including humans and other vertebrates. The parasite is able to penetrate the new host through broken skin or through the mucous membranes of the eyes and mouth. Vertical transmission is the second source of infection. In endemic countries, the vertical transmission rate is between less than 1 and 17% depending on geographic area [3]. Oral transmission to humans and animals has also been described after the ingestion of food and drink contaminated with the feces of an infected triatomine [4]. In nonendemic areas, vertical transmission and blood and organ donations from immigrants coming from an endemic area are the main pathways of Chagas disease transmission. In Europe (especially Spain and Portugal), the USA, Canada, Japan and Australia there are large numbers of South American immigrants who are often unaware of their infection, which has serious public health implications for the management of blood banks and healthcare provision [5]. Therefore, the compulsory screening of T. cruzi in hemoderivatives and solid organs donated by patients from Latin America should be considered. The infection goes through two clinical periods: an acute and a consecutive chronic phase [6]. The first symptoms of acute Chagas disease appear 1 week after entry of the parasite and include fever, discomfort and swelling of the lymph nodes and tissues. The most common manifestation of acute Chagas disease is Romaña’s sign, which is simply the bite mark of the vector when it is located in the eyelid. In most patients, acute Chagas disease symptoms resolve spontaneously. Nevertheless, without specific treatment during the acute phase, the infection progresses to a long asymptomatic period, which may last for years, and is known as indeterminate or asymptomatic chronic Chagas disease. It is estimated that in around one-third of those infected, clinical manifestations of different degrees of Maria J Muñoz

Diagnóstico y tratamiento de la enfermedad de Chagas

Resumen La infeccion por Tripanosoma cruzi o enfermedad de Chagas fue descubierta por Carlos Chagas hace mas de 100 anos. Esta considerada como una enfermedad tropical olvidada, aunque esta infeccion causa mas de 15.000 muertes anuales. Actualmente afecta a 8 millones de personas en 21 paises de America Latina. Sin embargo, debido a los movimientos migratorios, esta enfermedad tambien esta presente en zona no endemica. El numero de poblacion inmigrante con enfermedad de Chagas cronica ha aumentado en Espana en los ultimos anos. Ademas se han informado varios casos de transmision congenita. Algunos de los pacientes presentan manifestaciones clinicas graves y requieren tratamiento especializado, como la implantacion de marcapasos e incluso trasplante de corazon. Por tanto, esta infeccion tiene unos impactos clinico, social y economico considerables, principalmente en areas con una alta tasa de inmigracion. Benznidazol y nifurtimox son los unicos medicamentos disponibles para el tratamiento etiologico desde 1960. El tratamiento con ambos farmacos esta recomendado en la fase aguda y cronica de la enfermedad; no obstante, es urgente la busqueda de nuevos farmacos que presenten mayor eficacia y sean mejor tolerados por los pacientes. Recientemente se han desarrollado nuevas estrategias de diagnostico y control de la cura de la infeccion en fase cronica, permitiendo analizar la eficacia de los farmacos.Trypanosoma cruzi infection, or Chagas disease, was discovered more than 100 years ago by Carlos Chagas. Although the infection kills more than 15,000 people each year, it is still classified as a neglected tropical disease. Today, this disease affects eight million people in 21 Latin American countries and, due to immigration, is also present in non-endemic countries. In recent years, the size of the immigrant population with chronic imported forms of Chagas disease has increased in Spain. In addition, several cases of congenital transmission have been reported. Some patients have severe infection and require specialized treatment such as pacemaker implantation or even heart transplantation, representing a considerable clinical, social and economic burden, particularly in areas with a large immigrant population. Since the 1960s, the only drugs available for the etiological treatment of this infection have been benznidazole and nifurtimox. Although new, more effective and better tolerated compounds are urgently needed, treatment with these trypanocidal drugs is recommended in both the acute and chronic stages of Chagas disease. New strategies for diagnosis and infection control in chronically infected patients have recently been reported, allowing the effectiveness of treatments to be assessed.

Spatial distribution of human asymptomatic Leishmania infantum infection in southeast Spain: A study of environmental, demographic and social risk factors

Recent PCR studies indicate that asymptomatic L. infantum infection is common in people in southern Europe. Understanding its spatial distribution is a requisite to evaluate the public health implications and to design disease control schemes. We investigated infection in blood samples from 657 donors in southeast Spain using PCR and antibody ELISA. They came from 19 blood centers and were interviewed about their residence, occupation, dog ownership and Leishmaniosis awareness. The percentage of PCR and ELISA positives were 8% (49/618) and 2% (13/657). Donors residences were spatially clustered around blood donning centers and PCR prevalence was 18% in rural municipalities with 20-1330 inhabitants, 12% in those with 1467-5088 inhabitants and 3% in larger communities, and was associated with dog ownership (p<0.05). Further analysis of data from rural donors indicated that PCR status was strongly related to the climate, altitude and soil type in the donors residence area and not to other demographic or sociologic variables. Mixed logistic regression analysis predicted PCR prevalence to be greatest in the 200-300m altitude range with a mean spring-summer (time of highest vector activity) temperature of 18.4-19.0°C. A temperature and altitude risk map was generated that will provide the basis for elaborating evidence-based vector surveillance studies.

The innate immune response status correlates with a divergent clinical course in congenital Chagas disease of twins born in a non-endemic country.

The innate immune response from diamniotic and dichorionic twin brothers congenitally infected with Trypanosoma. cruzi (strain DTU-V) who displayed different clinical symptomatology was studied. While Brother I manifested severe cardiac and digestive disorders, the Brother II showed slight splenomegaly. The secretion level of IL-1β, TNF-α, IL-12, IL-10, IFN-α and IL-6 cytokines produced after stimulation of peripheral blood cells with TLR-2, TLR-4 and TLR-9 ligands was determined pre- and post-benznidazole treatment. Cells from 10 uninfected infants born to mothers seropositive for Chagas disease were included as control. The obtained data show that the cells of Brother I secreted lower levels of the pro-inflammatory cytokines IL-1β and TNF-α (upon TLR-2 and TLR-4 stimulation) relative to those secreted by cells from Brother II and uninfected controls. The cells from Brother II secreted high levels of the IL-1β cytokine following TLR-2 stimulation relative to uninfected controls. The cells from both brothers secreted a higher level of IL-6, following TLR-4 stimulation, than that secreted by uninfected infant cells. After treatments, the cytokine secretion levels were similar in both children and comparable to those of uninfected donors. Treatment success in Brother I and treatment interruption in Brother II was detected by the use of serological biomarkers (KMP11, HSP70, PFR2, Tgp63) as well as follow-up done by PCR. Therefore, the Brother II required a second treatment. The data presented suggest that benznidazol treatment allows the innate immune system to reach a fully functional status similar to that of uninfected subjects.

Components of a new gene family of ferroxidases involved in virulence are functionally specialized in fungal dimorphism

Mucormycosis is an emerging angio-invasive infection caused by Mucorales that presents unacceptable mortality rates. Iron uptake has been related to mucormycosis, since serum iron availability predisposes the host to suffer this infection. In addition, iron uptake has been described as a limiting factor that determines virulence in other fungal infections, becoming a promising field to study virulence in Mucorales. Here, we identified a gene family of three ferroxidases in Mucor circinelloides, fet3a, fet3b and fet3c, which are overexpressed during infection in a mouse model for mucormycosis, and their expression in vitro is regulated by the availability of iron in the culture media and the dimorphic state. Thus, only fet3a is specifically expressed during yeast growth under anaerobic conditions, whereas fet3b and fet3c are specifically expressed in mycelium during aerobic growth. A deep genetic analysis revealed partially redundant roles of the three genes, showing a predominant role of fet3c, which is required for virulence during in vivo infections, and shared functional roles with fet3b and fet3c during vegetative growth in media with low iron concentration. These results represent the first described functional specialization of an iron uptake system during fungal dimorphism.

Mucor circinelloides: Growth, Maintenance, and Genetic Manipulation

Mucor circinelloides is a fungus that belongs to the order Mucorales. It grows as mold in the environment and can cause mucormycosis, a potentially fatal infection in immunocompromised patients. M. circinelloides is a biodiesel producer and serves as a model organism for studying several biological processes, such as light responses and RNA interference–mediated gene silencing. Over the past decade, the increasing number of molecular tools has also allowed us to manipulate the genome of this fungus. This article outlines the fundamental protocols for the in vitro growth, maintenance, and genetic manipulation of M. circinelloides in the laboratory.

Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection: A systematic review and meta-analysis of individual participant data

Highlights • This is the first meta-analysis of individual data in chronic Trypanosoma cruzi infection after treatment.• The probability of seroreversion is variable along the course of follow-up.• An interaction was found between age at treatment and country setting.• The course of parasitological/molecular tests after treatment needs to be assessed.