Benznidazole Therapy Modulates Interferon-γ and M2 Muscarinic Receptor Autoantibody Responses in Trypanosoma cruzi-Infected Children

OBJECTIVE: The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benzonidazole (BZ) could modify both response patterns. METHODS: This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. RESULTS: At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs(+) patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7-88.1% decrease at T2. IFN-γ circulating levels also declined by T2. CONCLUSION: Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. Methods/design The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. Trial registration ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1929-0) contains supplementary material, which is available to authorized users

Trypanosoma cruzi Infection at the Maternal-Fetal Interface: Implications of Parasite Load in the Congenital Transmission and Challenges in the Diagnosis of Infected Newborns

Fil: Bustos, Patricia L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Milduberger, Natalia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Perrone, Alina E. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Laucella, Susana A. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Bua, Jacqueline. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Trypanosoma cruzi is the protozoan unicellular parasite that causes Chagas disease. It can be transmitted from infected mothers to their babies via the connatal route, thus being able to perpetuate even in the absence of Triatomine insect vectors. Chagas disease was originally endemic in Central and South America, but migration of infected women of childbearing age has spread the T. cruzi congenital infection to non-endemic areas like North America, Europe, Japan, and Australia. Currently, 7 million people are affected by this infection worldwide. This review focuses on the relevance of the T. cruzi parasite levels in different aspects of the congenital T. cruzi infection such as the mother-to-child transmission rate, the maternal and fetal immune response, and its impact on the diagnosis of infected newborns. Improvements in detection of this parasite, with tools that can be easily adapted to be used in remote rural areas, will make the early diagnosis of infected children possible, allowing a prompt trypanocidal treatment and avoiding the current loss of opportunities for the diagnosis of 100% of T. cruzi congenitally infected infants

Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification

Fil: Bua, Jacqueline. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Velázquez, Elsa B. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Ruiz, Andrés M. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Rissio, Ana María De. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.Fil: Cardoni, Rita L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.The relationship between parasite burden and vertical transmission of Trypanosoma cruzi was studied in pairs of chronically infected women and their children in a non-endemic area. Parasitemia was quantified by quantitative polymerase chain reaction (qPCR) in the peripheral blood amplifying a nuclear T. cruzi DNA and expressed as equivalent amounts of CL Brener parasites DNA per ml (eP/ml). Similar levels of parasitemia were found in non-transmitting pregnant women and in non-pregnant women: 1.8 ± 0.5 and 1.5 ± 0.7 eP/ml, respectively. In women pregnant with infected children parasitemia was 11.0 ± 2.7 eP/ml (n=20). In 12 of their neonates the infection was detected by microscopic observation of the parasites in peripheral blood in the 1(st) month of age. These children had variable levels of parasitemia (13,000 ± 7000 eP/ml), that were about 600-fold higher than that found in their mothers. To our knowledge, this is the first quantitative evaluation of parasitemia in these three groups of women and in their congenitally infected children. These parasite quantifications could be a basis to plan the control of mother-to-child transmission of T. cruzi

Benznidazole therapy modulates Interferon-γ and M2 Muscarinic receptor autoantibody responses in Trypanosoma cruzi-Infected children

Fil: Cutrullis, Romina A. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moscatelli, Guillermo F. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moroni, Samanta. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Cardoni, Rita L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Altcheh, Jaime. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Corral, Ricardo S. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Freilij, Héctor. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Petray, Patricia B. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Objective The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benznidazole (BZ) could modify both response patterns. Methods This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. Results At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7–88.1% decrease at T2. IFN-γ circulating levels also declined by T2. Conclusion Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Benznidazole therapy modulates Interferon-γ and M2 Muscarinic receptor autoantibody responses in Trypanosoma cruzi-Infected children

Fil: Cutrullis, Romina A. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moscatelli, Guillermo F. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Moroni, Samanta. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Volta, Bibiana J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Cardoni, Rita L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología Dr. Mario Fatala Chaben; Argentina.Fil: Altcheh, Jaime. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Corral, Ricardo S. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Freilij, Héctor. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Fil: Petray, Patricia B. Hospital de Niños Ricardo Gutiérrez. Servicio de Parasitología y Enfermedad de Chagas; Argentina.Objective The presence of autoantibodies with adrenergic and cholinergic activity, capable of triggering neurotransmitter receptor-mediated effects, has been associated with pathogenesis in T. cruzi-infected hosts. The goal of this study was to investigate the production of anti-M2 muscarinic receptor autoantibodies (Anti-M2R AAbs) as well as the IFN-γ profile in children at the early stage of Chagas disease, and to examine whether trypanocidal chemotherapy with benznidazole (BZ) could modify both response patterns. Methods This study comprised 30 T. cruzi-infected children (mean age: 13.8 years) and 19 uninfected controls (mean age: 12.7 years). Infected patients were treated with BZ and followed-up. Blood samples collected at diagnosis-T0, end of treatment-T1, and six months later-T2 were analysed by ELISA for detection of Anti-M2R AAbs and circulating levels of IFN-γ. Results At T0, anti-M2R AAbs were demonstrated in 56.7% of T. cruzi-infected patients, whereas uninfected controls were 100% negative. The average age of Anti-M2R AAbs+ patients was higher than that from negative population. Infected children also displayed significantly stronger serum IFN-γ responses than controls. Upon BZ treatment, a significant linear decreasing trend in Anti-M2R AAb reactivity was recorded throughout the follow-up, with 29.7–88.1% decrease at T2. IFN-γ circulating levels also declined by T2. Conclusion Anti-M2R AAbs and IFN-γ raise early during chagasic infection in children and are downmodulated by BZ therapy. These findings reinforce the usefulness of early BZ treatment not only to eliminate the parasite but also to reduce potentially pathogenic immune responses

Quantitative parasitemia in <i>T. cruzi</i> congenitally infected children.

<p>Parasite burden by qPCR was a retrospective work after all infected babies were referred for trypanocidal treatment. Median parasitemia (interquartile range), expressed as equivalent parasites per mL, of children diagnosed by parasitology at 1 or 6 months of age or by serology at around 12 months of age.</p

Flow diagram chart of the serological and parasitological studies in pregnant women and their infected children.

<p><i>T. cruzi</i> quantitative DNA amplification was retrospectively performed in three groups of congenitally infected children.</p