T. cruzi Transmission: Vectorial & Nonvectorial

Vectorial Transmission

• T. cruzi infection is primarily a zoonosis transmitted by bloodsucking triatomine bugs to wild and domestic mammals.
• Sylvatic, peridomiciliary, and intradomiciliary vectorial cycles may overlap.
• Most human infections in the Americas occur intradomiciliary from triatomine bites during nighttime sleep.
• Infective metacyclic forms of T. cruzi are in triatomine feces and enter the human body through skin breaks, mucosae, or conjunctivae.
• Bedbugs are not proven to transmit T. cruzi to humans.

Nonvectorial Transmission

• T. cruzi can be transmitted congenitally, through blood transfusions, organ transplants, or contaminated food/drink in both endemic and nonendemic regions.
• Congenital infection occurs in 1–10% of newborns of infected mothers.
• Risk of infection from contaminated blood products is low: 1.7% overall, 13% for platelet recipients, and nearly 0 for red blood cells and plasma recipients.
• Organ and tissue transplants primarily affect heart, liver, and kidney recipients.
• Oral transmission through contaminated food (berries) or drinks (fruit/sugar cane juice) is increasingly reported and can cause outbreaks.

Epidemiology

• Approximately 6 million people are infected by T. cruzi, including >1 million with chronic cardiomyopathy.
• Highest numbers of infected individuals are in Argentina, Brazil, and Mexico.
• Prevalence is highest in Bolivia (6.1%), Argentina (3.6%), and Paraguay (2.1%).
• In highly endemic regions, prevalence may exceed 40%.
• Cases have extended to cities due to urbanization and rural migration.
• A recent history of migration from a rural area is the main risk factor in urban settings.
• Prevalence and incidence have decreased due to improved conditions and public health interventions like vector control and blood screening.
• Some countries are declared free of domiciliary transmission due to insecticide spraying.
• Progress is threatened by vector adaptation, resurgence, insecticide resistance, and peridomiciliary transmission.
• Localized outbreaks are increasing, especially in the Amazon basin.
• Chagas disease distribution has expanded to nonendemic countries: North America, Western Europe, Australia, and Japan.
• The United States has up to 300,000 cases, mostly among immigrants.
• Western Europe has 68,000–123,000 cases; Japan and Australia report a few thousand.
• Only a small proportion of cases have been identified and managed in non-endemic regions due to low awareness, access barriers, and social stigma.
• International tourists have a very low risk of infection.

Pathology

• Several T. cruzi strains exist with overlapping transmission cycles, but no clear association with specific clinical manifestations.
• Pathogenesis involves complex interactions between the parasite and host immune response.
• After penetration, parasites enter the bloodstream and infect nucleated cells, differentiating into amastigotes.
• Innate immune response leads to a T helper 1 response, reducing parasitemia within 4–8 weeks, marking the end of the acute phase.
• Immune evasion allows persistent proliferation of amastigotes and infection of various cells, including cardiac, skeletal, and smooth-muscle cells.
• Cardiomyopathy development is linked to parasite persistence, inability to downregulate the immune response, cell-mediated damage, and excessive proinflammatory cytokines.
• Secondary mechanisms like microcirculation abnormalities and dysautonomia can influence tissue damage.
• Chronic inflammation in the myocardium results in cellular destruction, fibrosis, and dilatation of chambers, increasing the risk of left ventricle apical aneurism.
• Focal hypoperfusion and tissue damage lead to ventricular arrhythmias, while scarring affects the conduction system.
• Autonomic cell destruction causes vagal and sympathetic denervation.
• T. cruzi has a direct toxic effect on digestive tract intramural autonomic ganglion cells, causing motility disorders and organ dilatation (megaviscera syndrome).
• Esophagus and colon are primarily affected, with inadequate relaxation of the lower esophageal sphincter (achalasia) and damage mimicking Hirschsprung’s disease.
• Factors reducing cellular immune response, such as HIV infection, posttransplantation therapies, or hematologic malignancies, may increase amastigote replication and parasitemia (reactivation).
• Lesions develop predominantly in the CNS, heart, and skin during reactivation.
• HIV-positive patients have ~20% risk of reactivation without antiretroviral therapies, occurring when CD4+ T cell count falls to <200/µL.

Drug Treatment

• Benznidazole and nifurtimox are drugs used for specific treatment.
• Treatment is recommended in the acute phase, for children <18 years of age, and in cases of reactivation.
• Treatment should be considered for adults >50 years old with no advanced cardiomyopathy.
• Treatment of women of childbearing age who have the chronic phase of the disease, but outside of pregnancy, is also recommended.
• Treatment depends on individual judgement for 18-50 year olds with the indeterminate form of the chronic phase.
• A negative pregnancy test required before treatment is initiated as drugs are unsafe in pregnancy.
• Efficacy of second-line treatment has not been evaluated.
• Limited regimens have fueled interest in novel therapeutic approaches (immunomodulatory interventions, drug combinations).
• Benznidazole was approved by the U.S. Food and Drug Administration for treatment of children 2–12 years of age in 2017.

Nonetiologic Treatment

• Management of Chagas cardiomyopathy follows guidelines for heart failure, conduction disturbances, or ventricular arrhythmia.
• Early initiation of treatment with amiodarone or cardioverter-defibrillator implantation should be considered in the presence of pathologic electrophysiologic abnormalities.
• Anticoagulation is recommended for primary and secondary prevention of cardioembolic events.
• Strict control of other cardiovascular risk factors is warranted.
• Chagas cardiomyopathy is an indication for heart transplantation in Latin America.
• Posttransplantation immunosuppression requires close monitoring due to the high risk of reactivation.
• Treatment of digestive dysmotility includes dietary counseling and medications.
• Surgery is indicated in patients with distressing symptoms that are refractory to medical treatment.

Prevention

• Preventive measures: primary (prevention of T. cruzitransmission), secondary (avoidance of complications), and tertiary (reduction of morbidity and mortality)
• Screening of blood/organ donations is being implemented in endemic areas and countries with migration.
• Vector control is an effective strategy to curb intradomiciliary transmission.
• Insecticide-impregnated bed nets provide individual protection against reduviid bug bites.
• Screening of child-bearing-age and pregnant Latin American migrant women has been highly cost-effective.
• Screening of child-bearing-age and pregnant Latin American migrant women has been highly cost-effective.
• Early identification of cases and treatment may reduce the risk of complications and congenital transmission.
• Identification and treatment of cardiac complications and prevention of cardioembolic events at an early stage positively influence the disease course.

Human African Trypanosomiasis (Sleeping Sickness) - Definition

• HAT is caused by infection with extracellular protozoan parasites transmitted by tsetse flies in sub-Saharan Africa.
• T. b. gambiense and T. b. rhodesiense are the two pathogenic subspecies; their epidemiologic and clinical features largely differ.

Human African Trypanosomiasis (Sleeping Sickness) - Epidemiology

• HAT is restricted to sub-Saharan Africa due to the distribution of the tsetse fly (Glossina species).
• HAT due to T. b. gambiense is endemic in 24 countries of western and central Africa.
• The number of reported cases fell by 97% between 1999 and 2018 due to control measures.
• The number of reported cases of HAT due to T. b. rhodesiense fell by 96% between 1999 and 2018.
• In 2018, DRC reported most cases of T. b. gambiense HAT, while Malawi and Uganda reported most cases of T. b. rhodesiense.
• The geographic distributions of T. b. gambiense and T. b. rhodesiense do not overlap, but the two species are present in distinct regions of Uganda.
• WHO has mapped out a roadmap for HAT elimination as a public health problem by 2020.

Pathology and Pathogenesis

• T. b. rhodesiense and T. b. gambiense can infect humans because they resist lytic factors in human serum—namely, apolipoprotein L-1 (APOL1).
• Human APOL1 variants are prevalent in individuals of African ancestry, conferring protection against livestock trypanosome species, but at the cost of increasing the likelihood of chronic kidney disease.
• Serum resistance–associated protein causes for resistance in T. b. rhodesiense, wherease T. b. gambiense uses other mechanisms.
• Trypanosomes are transmitted to humans by the tsetse bite, proliferate, and induce a local inflammatory reaction.
• Trypanosomes then disseminate into the hematolymphatic system, with lymph nodes becoming enlarged.
• The degree of enlargement of the liver and spleen is usually mild to moderate.
• Trypanosomes multiply in the blood, varying due to cyclic immune-evasion process.
• Each trypanosome genome encodes ~1000 variant surface glycoproteins between which the parasites can switch genetically.
• Trypanosomes multiply in extravascular tissues during the first stage of illness.
• The skin, skeletal muscles, serous membranes, and heart can be involved, with interstitial infiltration of mononuclear cells and vasculitis.
• Myocarditis and pericarditis with myocardial degeneration and interstitial hemorrhage are common features of T. b. rhodesiense infection.
• The CNS is invaded weeks to months or months to years after initial infection, which corresponds to the second stage of HAT.
• White matter is predominantly affected, with perivascular proliferation of astrocytes, microglial cells, and Mott’s (morular) cells, the location of which correlates with neurologic features.
• The cerebral cortex and neurons are spared until the terminal stages of illness.
• Neuropsychiatric symptoms and signs resolve during or after treatment due to reversible inflammatory lesions.

Human African Trypanosomiasis - Approach to the Patient

• HAT is usually lethal in the absence of treatment.
• Early diagnosis is crucial; physicians should include HAT in the differential diagnosis of several clinical syndromes when a patient has traveled or lived in at-risk sub-Saharan African countries
• In particular, HAT due to T. b. gambiense should be suspected in patients with persistent and intermittent fever or headaches, progressive neuropsychiatric disorders, and biological signs of systemic inflammation, even if the last exposure occurred several years previously.
• HAT due to T. b. rhodesiense should be suspected in patients with an acute febrile illness and a recent exposure to tsetse flies in an eastern African country, especially if diagnostic tests for malaria are negative.

Clinical Manifestations

• The clinical presentations of T. b. gambiense and T. b. rhodesiense HAT usually differ.
• T. b. gambiense HAT: a slowly evolving illness with a long incubation period (months to years) and a prolonged disease course
• T. b. rhodesiense HAT: an acute febrile illness with a short incubation period (