CHAPTER 127: CHAGAS DISEASE AND AFRICAN TRYPANOSOMIASIS

Although the genus Trypanosoma contains many species of protozoans, only T. cruzi, T. brucei gambiense, and T. brucei rhodesiense cause disease in humans. T. cruzi is the etiologic agent of Chagas disease in the Americas; T. b. gambiense and T. b. rhodesiense cause African trypanosomiasis.

DEFINITION

Chagas disease, or American trypanosomiasis, is a zoonosis caused by the protozoan parasite T. cruzi. Acute Chagas disease is usually a mild febrile illness that results from initial infection with the organism. After spontaneous resolution of the acute illness, most infected persons remain for life in the indeterminate phase of chronic Chagas disease, which is characterized by subpatent parasitemia, easily detectable IgG antibodies to T. cruzi, and an absence of associated signs and symptoms. In 10–30% of chronically infected patients, cardiac and/or gastrointestinal symptoms develop that can lead to serious morbidity and even death.

LIFE CYCLE AND TRANSMISSION

T. cruzi is transmitted among its mammalian hosts by hematophagous triatomine insects, often called reduviid bugs. The insects become infected by sucking blood from animals or humans with circulating parasites. Ingested organisms multiply in the gut of the triatomines, and infective forms are discharged with the feces at the time of subsequent blood meals. Transmission to a second vertebrate host occurs when breaks in the skin, mucous membranes, or conjunctivae become contaminated with bug feces that contain infective parasites. T. cruzi can also be transmitted by transfusion of blood donated by infected persons, by organ transplantation, from mother to unborn child, by ingestion of contaminated food or drink, and in laboratory accidents.

PATHOLOGY

Initial infection at the site of parasite entry is characterized by local histologic changes that include the presence of parasites within leukocytes and cells of subcutaneous tissues and the development of interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes. After dissemination of the organisms through the lymphatics and the bloodstream, primarily muscles (including the myocardium) (Fig. 127-1) and ganglion cells may become heavily parasitized. The characteristic pseudocysts present in sections of infected tissues are intracellular aggregates of multiplying parasites.

In persons with chronic T. cruzi infections who develop related clinical manifestations, the heart is the organ most commonly affected. Changes include thinning of the ventricular walls, biventricular enlargement, apical aneurysms, and mural thrombi. Widespread lymphocytic infiltration, diffuse interstitial fibrosis, and atrophy of myocardial cells are often apparent. Although parasites are difficult to find in myocardial tissue by conventional histologic methods, more sensitive techniques of parasite detection, such as immunohistochemistry and polymerase chain reaction (PCR), have more frequently demonstrated T. cruzi antigens and parasite DNA in chronic lesions. Conduction-system abnormalities often affect the right branch and the left anterior branch of the bundle of His. In chronic Chagas disease of the gastrointestinal tract (megadisease), the esophagus and colon may exhibit varying degrees of dilation. On microscopic examination, focal inflammatory lesions with lymphocytic infiltration are seen, and the number of neurons in the myenteric plexus may be markedly reduced. Accumulating evidence implicates the persistence of parasites and the accompanying chronic inflammation—rather than autoimmune mechanisms—as the basis for the pathology in patients with chronic T. cruzi infection.

EPIDEMIOLOGY

T. cruzi is found only in the Americas. Wild and domestic mammals harboring T. cruzi and infected triatomines are found in spotty distributions from the southern United States to southern Argentina. Humans become involved in the cycle of transmission when infected vectors take up residence in the primitive wood, adobe, and stone houses common in much of Latin America. Thus human T. cruzi infection is a health problem primarily among the poor in rural areas of Mexico and Central and South America. Most new T. cruzi infections in rural settings occur in children, but the incidence is unknown because most cases go undiagnosed. Historically, transfusion-associated transmission of T. cruzi was a serious public health problem in many endemic countries. Transmission by this route has been largely eliminated, however, as effective programs for serologic screening of donated blood have been implemented. Several dozen patients with HIV and chronic T. cruzi infections who underwent acute recrudescence of the latter have been described. These patients generally presented with T. cruzi brain abscesses, a manifestation of the illness that does not occur in immunocompetent persons. Currently, it is estimated that 8 million people are chronically infected with T. cruzi and that 14,000 deaths due to the illness occur each year. The resulting morbidity and mortality make Chagas disease the most important parasitic disease burden in Latin America.

In recent years, the rate of T. cruzi transmission has decreased markedly in several endemic countries as a result of successful programs involving vector control, screening of donated blood, and education of at-risk populations. A major program, which began in 1991 in the “southern cone” nations of South America (Uruguay, Paraguay, Bolivia, Brazil, Chile, and Argentina), has provided the framework for much of this progress. Uruguay and Chile were certified free of transmission by the main domiciliary vector species (Triatoma infestans) in the late 1990s, and Brazil was declared transmission-free in 2006. Transmission has been reduced markedly in Argentina as well. Similar control programs have been initiated in the countries of northern South America and in the Central American nations.

Acute Chagas disease is rare in the United States, where 22 cases of autochthonous transmission and seven instances of transmission by blood transfusion have been reported. Moreover, T. cruzi was transmitted to five recipients of organs from three T. cruzi–infected donors, two of whom became infected through cardiac transplants. Acute Chagas disease has been reported in only one tourist returning to the United States from Latin America, although three such instances have been reported in Europe as well as one in Canada. In contrast, the prevalence of chronic T. cruzi infections in the United States has increased considerably in recent years. An estimated 23 million immigrants from Chagas-endemic countries currently live in the United States, ~17 million of whom are Mexicans. The total number of T. cruzi–infected persons living in the United States is estimated to be 300,000. Screening of the U.S. blood supply for T. cruzi infection began in January 2007. The overall prevalence of T. cruzi infection among donors is ~1 in 13,300, and to date nearly 3000 infected donors have been identified and deferred permanently (see “Diagnosis,” below).

CLINICAL COURSE

The first signs of acute Chagas disease develop at least 1 week after invasion by the parasites. When the organisms enter through a break in the skin, an indurated area of erythema and swelling (the chagoma), accompanied by local lymphadenopathy, may appear. Romaña sign—the classic finding in acute Chagas disease, which consists of unilateral painless edema of the palpebrae and periocular tissues—can result when the conjunctiva is the portal of entry. These initial local signs may be followed by malaise, fever, anorexia, and edema of the face and lower extremities. Generalized lymphadenopathy and hepatosplenomegaly may develop. Severe myocarditis develops rarely; most deaths in acute Chagas disease are due to heart failure. Neurologic signs are not common, but meningoencephalitis occurs occasionally, especially in children <2 years old. Usually within 4–8 weeks, acute signs and symptoms resolve spontaneously in virtually all patients, with commencement of the asymptomatic or indeterminate form of chronic T. cruzi infection.

Symptomatic chronic Chagas disease becomes apparent years or even decades after the initial infection. The heart is commonly involved, and symptoms are caused by rhythm disturbances, segmental or dilated cardiomyopathy, and thromboembolism. Right bundle branch block is a common electrocardiographic abnormality, but other types of intraventricular and atrioventricular blocks, premature ventricular contractions, and tachy- and bradyarrhythmias occur frequently. Cardiomyopathy often results in biventricular heart failure, with a predominance of right-sided failure at advanced stages. Embolization of mural thrombi to the brain or other areas may take place. Sudden death is the main cause of death in Chagas heart disease; congestive heart failure and stroke are next most common. Patients with megaesophagus suffer from dysphagia, odynophagia, chest pain, and regurgitation. Aspiration can occur (especially during sleep) in patients with severe esophageal dysfunction, and repeated episodes of aspiration pneumonitis are common. Weight loss, cachexia, and pulmonary infection can result in death. Patients with megacolon are plagued by abdominal pain and chronic constipation, which predisposes to fecaloma formation. Advanced megacolon can cause obstruction, volvulus, septicemia, and death.

DIAGNOSIS

The diagnosis of acute Chagas disease requires the detection of parasites. Microscopic examination of fresh anticoagulated blood or the buffy coat is the simplest way to see the motile organisms. Parasites also can be seen in Giemsa-stained thin and thick blood smears. Microhematocrit tubes containing acridine orange as a stain can be used for the same purpose. When used repeatedly by experienced personnel, all of these methods yield positive results in a high proportion of cases of acute Chagas disease. Serologic testing does not play a major role in diagnosing acute Chagas disease. PCR assays often give positive results in infected patients in whom traditional parasitologic tests are negative, including infants with congenital Chagas disease.

Chronic Chagas disease is diagnosed by the detection of specific IgG antibodies that bind to T. cruzi antigens. Demonstration of the parasite is not of primary importance. In Latin America, ~30 assays are commercially available, including several based on recombinant antigens. Although these tests usually show good sensitivity and reasonable specificity, false-positive reactions may occur—typically with samples from patients who have other infectious and parasitic diseases or autoimmune disorders. In addition, confirmatory testing has presented a persistent challenge. For these reasons, the World Health Organization recommends that specimens be tested in at least two assays and that well-characterized positive and negative comparison samples be included in each run. The Chagas radioimmune precipitation assay (RIPA), a highly sensitive and specific confirmatory method for detecting antibodies to T. cruzi, is approved under the Clinical Laboratory Improvement Amendment and available in the laboratory of one of the authors (L.V.K.). In 2006, the U.S. Food and Drug Administration (FDA) approved a test to screen blood and organ donors for T. cruzi infection (Ortho T. cruzi ELISA Test System; Ortho-Clinical Diagnostics, Raritan, NJ). Since January 2007, the vast majority of U.S. blood donors have been screened, and positive units have undergone confirmatory testing with the Chagas RIPA. A second test for donor screening was approved by the FDA in 2010 (Abbott PRISM® Chagas Assay; Abbott Laboratories, Abbott Park, IL), as was an enzyme strip assay (Abbott ESA Chagas) in 2011. The use of PCR assays to detect T. cruzi DNA in chronically infected persons has been studied extensively; unfortunately, the sensitivity of this approach has not been shown to be reliably greater than that of serology.

TREATMENT

PREVENTION

Because drug therapy has limitations and vaccines are not available, the control of T. cruzi transmission in endemic countries depends on the reduction of domiciliary vector populations by spraying of insecticides, improvements in housing, and education of at-risk persons. As noted above, these measures, coupled with serologic screening of blood donors, have markedly reduced transmission of the parasite in many endemic countries. Tourists would be wise to avoid sleeping in dilapidated houses in rural areas of endemic countries. Mosquito nets and insect repellent can provide additional protection.

In view of the possibly serious consequences of chronic T. cruzi infection, it would be prudent for all immigrants from endemic regions who are living in the United States to be tested for evidence of infection. Identification of persons harboring the parasite would permit periodic electrocardiographic monitoring, which is important to detect incipient heart disease and guide further diagnostic studies and treatment. The possibility of congenital transmission is yet another justification for screening. T. cruzi is classified as a Risk Group 2 agent in the United States and a Risk Group 3 agent in some European countries. Laboratory staff should work with the parasite or infected vectors and mammals at containment levels consistent with the risk group designation in their areas.

DEFINITION

Sleeping sickness, or human African trypanosomiasis (HAT), is caused by flagellated protozoan parasites that belong to the T. brucei complex and are transmitted to humans by tsetse flies. In untreated patients, the trypanosomes first cause a febrile illness that is followed months or years later by progressive neurologic impairment and death.

THE PARASITES AND THEIR TRANSMISSION

The East African (rhodesiense) and the West African (gambiense) forms of sleeping sickness are caused, respectively, by two trypanosome subspecies: T. b. rhodesiense and T. b. gambiense. These subspecies are morphologically indistinguishable but cause illnesses that are epidemiologically and clinically distinct (Table 127-1). The parasites are transmitted by blood-sucking tsetse flies of the genus Glossina. The insects acquire the infection when they ingest blood from infected mammalian hosts. After many cycles of multiplication in the midgut of the vector, the parasites migrate to the salivary glands. Their transmission takes place when they are inoculated into a mammalian host during a subsequent blood meal. The injected trypanosomes multiply in the blood (Fig. 127-2) and other extracellular spaces and evade immune destruction for long periods by undergoing antigenic variation, a process driven by gene switching in which the antigenic structure of the organisms’ surface coat of glycoproteins changes periodically.

PATHOGENESIS AND PATHOLOGY

A self-limited inflammatory lesion (trypanosomal chancre) may appear a week or so after the bite of an infected tsetse fly. A systemic febrile illness then evolves as the parasites are disseminated through the lymphatics and bloodstream. Systemic HAT without central nervous system (CNS) involvement is generally referred to as stage 1 disease. In this stage, widespread lymphadenopathy and splenomegaly reflect marked lymphocytic and histiocytic proliferation and invasion of morular cells, which are plasmacytes that may be involved in the production of IgM. Endarteritis, with perivascular infiltration of both parasites and lymphocytes, may develop in lymph nodes and the spleen. Myocarditis develops frequently in patients with stage 1 disease and is especially common in T. b. rhodesiense infections.

Hematologic manifestations that accompany stage 1 HAT include moderate leukocytosis, thrombocytopenia, and anemia. High levels of immunoglobulins, consisting primarily of polyclonal IgM, are a constant feature, and heterophile antibodies, antibodies to DNA, and rheumatoid factor are often detected. High levels of antigen–antibody complexes may play a role in the tissue damage and increased vascular permeability that facilitate dissemination of the parasites.

Stage 2 disease involves invasion of the CNS. The presence of trypanosomes in perivascular areas is accompanied by intense infiltration of mononuclear cells. Abnormalities in cerebrospinal fluid (CSF) include increased pressure, elevated total protein concentration, and pleocytosis. In addition, trypanosomes are frequently found in CSF.

EPIDEMIOLOGY

The trypanosomes that cause sleeping sickness are found only in sub-Saharan Africa. After its near-eradication in the mid-1960s, sleeping sickness underwent a resurgence in the 1990s, primarily in Uganda, Sudan, the Central African Republic, the Democratic Republic of the Congo, and Angola. A subsequent increase in control activities reduced the incidence in many endemic areas, however, and in 2009 fewer than 10,000 cases were reported to the World Health Organization. Although underreporting is a persistent problem, the level of control achieved to date was the basis for convening a panel of experts in 2009 to develop a vision for eradication of HAT.

Humans are the only reservoir of T. b. gambiense, which occurs in widely distributed foci in tropical rain forests of Central and West Africa. Gambiense trypanosomiasis is primarily a problem in rural populations; tourists rarely become infected. Trypanotolerant antelope species in savanna and woodland areas of Central and East Africa are the principal reservoir of T. b. rhodesiense. Cattle can also be infected with this and other trypanosome species but generally succumb to the infection. Because risk results from contact with tsetse flies that feed on wild animals, humans acquire T. b. rhodesiense infection only incidentally, usually while visiting or working in areas where infected game and vectors are present. Roughly one or two imported cases of HAT acquired in East African parks are reported to the CDC each year.

CLINICAL COURSE

A painful trypanosomal chancre appears in some patients at the site of inoculation of the parasite. Hematogenous and lymphatic dissemination (stage 1 disease) is marked by the onset of fever. Typically, bouts of high temperatures lasting several days are separated by afebrile periods. Lymphadenopathy is prominent in T. b. gambiense trypanosomiasis. The nodes are discrete, movable, rubbery, and nontender. Cervical nodes are often visible, and enlargement of the nodes of the posterior cervical triangle, or Winterbottom’s sign, is a classic finding. Pruritus and maculopapular rashes are common. Inconstant findings include malaise, headache, arthralgias, weight loss, edema, hepatosplenomegaly, and tachycardia. The differential diagnosis of stage 1 HAT includes many diseases that are common in the tropics and are associated with fevers. HIV infection, malaria, and typhoid fever are common in populations at risk for HAT and need to be considered.

CNS invasion (stage 2 disease) is characterized by the insidious development of protean neurologic manifestations that are accompanied by progressive abnormalities in the CSF. A picture of progressive indifference and daytime somnolence develops (hence the designation “sleeping sickness”), sometimes alternating with restlessness and insomnia at night. A listless gaze accompanies a loss of spontaneity, and speech may become halting and indistinct. Extrapyramidal signs may include choreiform movements, tremors, and fasciculations. Ataxia is frequent, and the patient may appear to have Parkinson’s disease, with a shuffling gait, hypertonia, and tremors. In the final phase, progressive neurologic impairment ends in coma and death.

The most striking difference between the gambiense and rhodesiense forms of HAT is that the latter illness tends to follow a more acute course. Typically, in tourists with T. b. rhodesiense disease, systemic signs of infection, such as fever, malaise, and headache, appear before the end of the trip or shortly after the return home. Persistent tachycardia unrelated to fever is common early in the course of T. b. rhodesiense trypanosomiasis, and death may result from arrhythmias and congestive heart failure before CNS disease develops. In general, untreated T. b. rhodesiense trypanosomiasis leads to death in a matter of weeks to months, often without a clear distinction between the hemolymphatic and CNS stages. In contrast, T. b. gambiense disease can smolder for many months or even for years.

DIAGNOSIS

A definitive diagnosis of HAT requires detection of the parasite. If a chancre is present, fluid should be expressed and examined directly by light microscopy for the highly motile trypanosomes. The fluid also should be fixed and stained with Giemsa. Material obtained by needle aspiration of lymph nodes early in the illness should be examined similarly. Examination of wet preparations and Giemsa-stained thin and thick films of serial blood samples is also useful. If parasites are not seen initially in blood, efforts should be made to concentrate the organisms, which can be done in microhematocrit tubes containing acridine orange. Alternatively, the buffy coat from 10–15 mL of anticoagulated blood can be examined directly under a microscope. The likelihood of finding parasites in blood is higher in stage 1 than in stage 2 disease and in patients infected with T. b. rhodesiense rather than T. b. gambiense. Trypanosomes may also be seen in material aspirated from the bone marrow; the aspirate can be inoculated into liquid culture medium, as can blood, buffy coat, lymph node aspirates, and CSF. It is essential to examine CSF from all patients in whom HAT is suspected. Abnormalities in the CSF that may be associated with stage 2 disease include an increase in the CSF cell count as well as increases in opening pressure and in levels of total protein and IgM. Trypanosomes may be seen in the sediment of centrifuged CSF. Any CSF abnormality in a patient in whom trypanosomes have been found at other sites must be viewed as pathognomonic for CNS involvement and thus must prompt specific treatment for CNS disease. In patients with CSF pleocytosis in whom parasites are not found, tuberculous meningitis and HIV-associated CNS infections such as cryptococcosis should be considered in the differential diagnosis.

A number of serologic assays, such as the card agglutination test for trypanosomes (CATT) for T. b. gambiense, are available to aid in the diagnosis of HAT. Their ease of use makes them valuable for epidemiologic surveys, but their variable sensitivity and specificity mandate that decisions about treatment be based on demonstration of the parasite. Accurate PCR assays for detecting African trypanosomes in humans have been developed, but the lack of the necessary technical and human resources in most endemic areas stands in the way of their widespread use.

TREATMENT

PREVENTION

HAT poses complex public-health and epizootic problems in Africa. Considerable progress has been made in many areas through control programs that focus on eradication of vectors and drug treatment of infected humans. People can reduce their risk of acquiring trypanosomiasis by avoiding areas known to harbor infected insects, by wearing protective clothing, and by using insect repellent. Chemoprophylaxis is not recommended, and no vaccine is available to prevent transmission of the parasites.