Clinical and Immunopathological Aspects of Heart Damage in Dogs Infected with Trypanosoma brucei

In an attempt to increase the understanding of the mechanisms of cardiac damage in African trypanosomiasis, a group of beagle dogs were infected with Trypanosoma brucei. Cardiac involvement during the course of the disease was monitored using various non-invasive techniques, including auscultation, palpation, echocardiography and electrocardiography (ECG). Parasitological, haematological, endocrinological and biochemical studies were carried out. Two dogs per time point were euthanised at mid-infection on days 10 and 15, and in the terminal stages on days 21, 22 and 26, and tissue samples taken from the heart for histological, histochemical, transmission electron microscopical and immunofluorescence investigations. The dogs developed an acute disease syndrome, characterised by high parasitaemia, persistent fever, increased plasma levels of acute phase proteins, severe anaemia, lymph node and splenic enlargement, wasting and weight loss. If the dogs were not treated or the experiments terminated by humane euthanasia, death would have invariably occurred during week 4 of infection. Clinical evidence of cardiac damage was demonstrated from the end of week 1 by echocardiography and ECG. The clinical signs included tachycardia, incompetence of all the cardiac valves, and first degree heart block. With progress of the disease, second degree and in some cases complete heart block developed. Towards the end of week 3 and beginning of week 4, cardiac performance deteriorated, as demonstrated by a reduction in left ventricular function, bradycardia, and accumulation of pericardial effusion. Histological and ultrastructural studies confirmed a severe pancarditis involving the myocardium, the cardiac valves, and the vasculature. Deposition of fibrinogen and sparse quantities of IgG, IgM and C3 was demonstrated in perivascular and interstitial spaces. A terminal fall in plasma levels of the cardiac hormone atrial natriuretic factor (ANF) occurred, and was associated with decreased numbers, sizes and electron density of the atrial storage granules. The low plasma levels of ANF were accompanied by an inverse increase in plasma renin activity, an indication that the dogs at that time were incapable of controlling blood volume. From the end of week 2 of infection, a gradually developing hyperlipidaemia and intense deposition of lipids in the myocardium and infiltrating macrophages was demonstrated for the first time. It is possible that cachectin/tumour necrosis factor (TNF) was contributing to the hyperlipidaemic state, following the detection of increased cachectin/TNF activity in monocytes from infected dogs. The presence of large numbers of trypanosomes, infiltrating cells that consisted mainly of macrophages, neutrophils, plasma cells and a few lymphocytes, in areas of extensive myocardial damage indicated that tissue damage was initiated by excessive immunological responses by the host to this highly antigenic parasite. Tissue damage was probably exacerbated by accumulation of toxic and biologically active substances released from dead trypanosomes and autolysing inflammatory cells, following obstruction of the lymphatic vessels draining the heart. Anaemia, vascular damage and interstitial oedema reduced tissue perfusion and increased the incidence of myocardial ischaemia. The presence of lipid deposits in ischaemic myocardium indicated that they too could be playing a major role in the pathogenesis of tissue damage. Further, the presence of mesangial deposits of immune complexes in the kidneys confirmed their presence in the circulation, indicating that immune complexes played a role in the pathogenesis of general tissue damage. Intravenous treatment of terminally ill dogs with the trypanocidal drug suramin at 10 to 20 mg/kg was usually unsuccessful. In most cases, a post-treatment reaction, with increased severity of heart damage, was observed. Nevertheless, the survival period of the dogs was prolonged, precipitating a condition of chronic cardiac failure. The dogs that survived longest were those that were best able to control anaemia after treatment. When a group of infected dogs were treated with the non-steroidal anti-inflammatory drugs (NSAIDs) cyclosporin A and azathioprine, or a combination of azathioprine and prednisolone, the severity of cardiac damage was reduced, despite intense trypanosome infiltration in the myocardium. These results confirmed the immunological and inflammatory nature of the cardiac disease induced by T. brucei. It would appear that if such drugs were used as an adjunct to trypanocidal drug treatment, the severity of post-treatment myocardial damage, and possibly general tissue damage, might have been reduced. The present work has conclusively demonstrated that cardiac damage in canine trypanosomiasis caused by T. brucei is mainly immunologically mediated. The similarity of the disease to human African trypanosomiasis indicated that cardiac damage in humans could be mediated through similar mechanisms. The future of the dog as large monogastric animal model for studying cardiac damage in African trypanosomiasis is promising

The burden of congenital Chagas disease and implementation of molecular diagnostic tools in Latin America

It is estimated that between 8000 and 15 000 Trypanosoma cruzi infected babies are born every year to infected mothers in Chagas disease endemic countries. Currently, poor access to and performance of the current diagnostic algorithm, based on microscopy at birth and serology at 8-12 months after delivery, is one of the barriers to congenital Chagas disease (CCD) control. Detection of parasite DNA using molecular diagnostic tools could be an alternative or complement to current diagnostic methods, but its implementation in endemic regions remains limited. Prompt diagnosis and treatment of CCD cases would have a positive clinical and epidemiological impact. In this paper, we analysed the burden of CCD in Latin America, and the potential use of molecular tests to improve access to early diagnosis and treatment of T. cruzi infected newborns.Fil: Picado, Albert. Foundation for Innovative New Diagnostics; SuizaFil: Cruz, Israel. Foundation for Innovative New Diagnostics; SuizaFil: Redard Jacot, Maël. Foundation for Innovative New Diagnostics; SuizaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Torrico, Faustino. Universidad Mayor de San Simón; Bolivia. Fundación CEADES; BoliviaFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Drugs for Neglected Diseases initiative; BrasilFil: Katz, Zachary. Foundation for Innovative New Diagnostics; SuizaFil: Ndung'u, Joseph Mathu. Foundation for Innovative New Diagnostics; Suiz

Access to prompt diagnosis: The missing link in preventing mental health disorders associated with neglected tropical diseases

Globally, there are an estimated 1 billion people suffering from at least one of the 20 neglected tropical diseases (NTDs) prioritized by the World Health Organization (WHO). Prevalent in tropical and subtropical regions, this group of NTDs comprises diverse diseases, including vector-borne parasitic diseases (such as human African trypanosomiasis [HAT], Chagas disease, and leishmaniasis), skin diseases caused by environmental bacteria (such as Buruli ulcer [BU]), foodborne parasitic diseases (such as taeniasis/cysticercosis) or snake bite envenoming, which—together with scabies and other ectoparasites, mycetoma, and deep mycoses—were recently added to the list [1]. Despite their differences, NTDs are synonymous with poverty, life-long disability, stigma, and discrimination, not to mention the lack of effective control tools such as vaccines, diagnostics, and drugs.S

Trypanosome diversity in wildlife species from the Serengeti and Luangwa Valley ecosystems

<p>Background: The importance of wildlife as reservoirs of African trypanosomes pathogenic to man and livestock is well recognised. While new species of trypanosomes and their variants have been identified in tsetse populations, our knowledge of trypanosome species that are circulating in wildlife populations and their genetic diversity is limited.</p> <p>Methodology/Principal Findings: Molecular phylogenetic methods were used to examine the genetic diversity and species composition of trypanosomes circulating in wildlife from two ecosystems that exhibit high host species diversity: the Serengeti in Tanzania and the Luangwa Valley in Zambia. Phylogenetic relationships were assessed by alignment of partial 18S, 5.8S and 28S trypanosomal nuclear ribosomal DNA array sequences within the Trypanosomatidae and using ITS1, 5.8S and ITS2 for more detailed analysis of the T. vivax clade. In addition to Trypanosoma brucei, T. congolense, T. simiae, T. simiae (Tsavo), T. godfreyi and T. theileri, three variants of T. vivax were identified from three different wildlife species within one ecosystem, including sequences from trypanosomes from a giraffe and a waterbuck that differed from all published sequences and from each other, and did not amplify with conventional primers for T. vivax.</p> <p>Conclusions/Significance: Wildlife carries a wide range of trypanosome species. The failure of the diverse T. vivax in this study to amplify with conventional primers suggests that T. vivax may have been under-diagnosed in Tanzania. Since conventional species-specific primers may not amplify all trypanosomes of interest, the use of ITS PCR primers followed by sequencing is a valuable approach to investigate diversity of trypanosome infections in wildlife; amplification of sequences outside the T. brucei clade raises concerns regarding ITS primer specificity for wildlife samples if sequence confirmation is not also undertaken.</p&gt

In-hospital safety in field conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. B. Gambiense Sleeping Sickness

Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use

Stakeholder narratives on trypanosomiasis, their effect on policy and the scope for One Health

Background This paper explores the framings of trypanosomiasis, a widespread and potentially fatal zoonotic disease transmitted by tsetse flies (Glossina species) affecting both humans and livestock. This is a country case study focusing on the political economy of knowledge in Zambia. It is a pertinent time to examine this issue as human population growth and other factors have led to migration into tsetse-inhabited areas with little historical influence from livestock. Disease transmission in new human-wildlife interfaces such as these is a greater risk, and opinions on the best way to manage this are deeply divided. Methods A qualitative case study method was used to examine the narratives on trypanosomiasis in the Zambian policy context through a series of key informant interviews. Interviewees included key actors from international organisations, research organisations and local activists from a variety of perspectives acknowledging the need to explore the relationships between the human, animal and environmental sectors. Principal Findings Diverse framings are held by key actors looking from, variously, the perspectives of wildlife and environmental protection, agricultural development, poverty alleviation, and veterinary and public health. From these viewpoints, four narratives about trypanosomiasis policy were identified, focused around four different beliefs: that trypanosomiasis is protecting the environment, is causing poverty, is not a major problem, and finally, that it is a Zambian rather than international issue to contend with. Within these narratives there are also conflicting views on the best control methods to use and different reasoning behind the pathways of response. These are based on apparently incompatible priorities of people, land, animals, the economy and the environment. The extent to which a One Health approach has been embraced and the potential usefulness of this as a way of reconciling the aims of these framings and narratives is considered throughout the paper. Conclusions/Significance While there has historically been a lack of One Health working in this context, the complex, interacting factors that impact the disease show the need for cross-sector, interdisciplinary decision making to stop rival narratives leading to competing actions. Additional recommendations include implementing: surveillance to assess under-reporting of disease and consequential under-estimation of disease risk; evidence-based decision making; increased and structurally managed funding across countries; and focus on interactions between disease drivers, disease incidence at the community level, and poverty and equity impacts

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Quantifying the burden of rhodesiense sleeping sickness in Urambo district, Tanzania

Sleeping sickness (human African trypanosomiasis - HAT) is a disease transmitted by tsetse flies and is always fatal if left untreated. The disease occurs in foci affecting poor communities with limited access to health service provision and as such the disease is often left undiagnosed, mistaken for more common afflictions. Even if diagnosed, sleeping sickness is costly to treat, both for health services and patients and their families in terms of costs of diagnosis, transport, hospital care, and the prolonged period of convalescence. Here we estimate the health burden of the acute form T. b. rhodesiense sleeping sickness in Urambo District, Tanzania in terms of Disability Adjusted Life Years (DALYs), the yardstick commonly used by policy makers to prioritize disease management practices, representing a year of healthy life lost to disease. In this single district, the burden of the disease over one year was estimated at 979 DALYs and the estimated monetary costs to health services for the 143 treated patients at US$11,841 and to the patients themselves at US$ 3,673 for direct medical costs and US$ 9,781 for indirect non-medical costs. Sleeping sickness thus places a considerable burden on the affected rural communities and health services