Chagas Disease and AfricanTrypanosomiasis¶
Chapter 234 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Parasitic · Chapter 234
Key Clinical Points¶
- Chagas disease is caused by T. cruzi; HAT is caused by T. b. gambiense or T. b. rhodesiense.
- Chronic Chagas diagnosis requires serology (two positive tests); acute phase uses microscopy/PCR.
- Benznidazole and nifurtimox are first-line treatments for Chagas, most effective in the acute phase and children.
- HAT has two clinical stages: early hemolymphatic (first stage) and late CNS (second stage; sleeping sickness).
- Chagas cardiomyopathy is a leading cause of heart failure in Latin America; ECG abnormalities like RBBB are common.
- Congenital transmission occurs in 1–10% of newborns; screening of pregnant women is cost-effective.
- HAT cases fell by 98% for T. b. gambiense (1999–2020); vector control is effective for T. cruzi.
- Reactivation of T. cruzi occurs in immunocompromised patients with CD4+ <100/μL.
- Leishmaniasis is distinct from Chagas/HAT despite shared geographic regions.
- T. b. rhodesiense is concentrated in East and Southern Africa; T. b. gambiense in West and Central Africa.
1. DEFINITION & OVERVIEW¶
• Chagas Disease (American trypanosomiasis): A zoonosis caused by the flagellated protozoan T. cruzi. • Human African Trypanosomiasis (HAT): A life-threatening illness caused by infection with extracellular protozoan parasites transmitted by tsetse flies in sub-Saharan Africa.
Definition (Harrison's 22e): First described in 1909 by Carlos Chagas, Chagas disease is a zoonosis caused by the flagellated protozoan T. cruzi.
Definition (Harrison's 22e): HAT is a life-threatening illness caused by infection with extracellular protozoan parasites transmitted by tsetse flies in sub-Saharan Africa.
• Relevant Species: ◦ T. cruzi (Chagas) ◦ T. b. gambiense (HAT) ◦ T. b. rhodesiense (HAT)
1.1 Chagas Disease Overview¶
• Clinical Progression: After an asymptomatic acute phase, 30–40% develop chronic cardiomyopathy or digestive dysfunction over decades. • Reactivation: Occurs in immunocompromised patients (e.g., HIV, transplant). • Public Health Impact: >6 million infected; 1 million with chronic cardiomyopathy; many cases remain undiagnosed.
1.2 Human African Trypanosomiasis Overview¶
• Pathogenic Subspecies: T. b. gambiense and T. b. rhodesiense. • Host Resistance: Both resist human serum lytic factors (APOL1). • Genetic Trade-off: APOL1 variants protect against livestock trypanosomes but increase chronic kidney disease risk.
2. EPIDEMIOLOGY¶
• Chagas Prevalence: 6–7 million T. cruzi infections globally; highest in Bolivia (6.1%), Argentina (3.6%), and Paraguay (2.1%). • Urban Impact: Urbanization/migration increased urban transmission; >300,000 cases in US; 68k–123k in Europe. • HAT Trends: Cases fell by 98% for T. b. gambiense (1999–2020); DRC reported 70% of cases. • Vector Control: Effective for T. cruzi but threatened by insecticide resistance and periurban resurgence.
2.1 Risk Factors¶
• Modifiable: Rural migration, lack of vector control, unscreened blood transfusion. • Non-modifiable: Geographic location (endemic areas), poverty.
2.2 HAT Epidemiology¶
• Geographic Restriction: Sub-Saharan Africa. • T. b. gambiense: 24 countries; 70% of cases in DRC. • T. b. rhodesiense: Uganda; 91% of cases in Malawi.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Strain Variation: T. cruzi strains have overlapping transmission cycles with no definitive link to specific clinical manifestations. • Pathogenesis Mechanism: Parasite dissemination → immune response (Th1) → chronic inflammation/fibrosis. • Reactivation Risk: Occurs in immunocompromised hosts with CD4+ <100/μL; HIV increases risk by ~20%.
3.1 Pathogenesis Cascade¶
• Step 1: Vectorial (triatomine bite) or non-vectorial transmission (congenital, transfusion, oral). • Step 2: Parasite penetration and bloodstream dissemination. • Step 3: Amastigote differentiation in nucleated cells. • Step 4: Th1 response with proinflammatory cytokines. • Step 5: Chronic inflammation/fibrosis (cardiac/digestive). • Step 6: Reactivation in immunocompromised hosts.
4. CLINICAL FEATURES¶
• Acute Phase: 2–8 weeks duration; asymptomatic or mild febrile illness, Romaña sign, myocarditis. • Chronic Indeterminate Form: No symptoms; normal ECG. • Chronic Determinate Form: Cardiomyopathy (dyspnea, syncope) or digestive issues (dysphagia, constipation). • Reactivation: Myocarditis, erythema nodosum, meningoencephalitis.
4.1 Acute Phase Manifestations¶
• Vector-borne: 1–2 weeks post-exposure; Romaña sign, splenomegaly. • Congenital: Asymptomatic in >90%; rare lymphadenopathy, jaundice. • Duration: 4–8 weeks (vector-borne); 2–8 weeks (congenital).
4.2 Chronic Phase Manifestations¶
• Indeterminate form: No symptoms; lifelong asymptomatic. • Determinate form: Cardiomyopathy (5-year mortality 2–63%); digestive disorders (megaviscera syndrome). • Mixed disorders: 5–10% of chronic complications.
4.3 Reactivation¶
• Risk Groups: HIV, posttransplantation, hematologic malignancies. • Trigger: CD4+ <100/μL; AIDS-defining opportunistic infection. • Symptoms: Myocarditis, panniculitis, meningoencephalitis.
5. DIFFERENTIAL DIAGNOSIS¶
• Chagas cardiomyopathy: Ischemic heart disease, other cardiomyopathies. • Digestive motility disorders: Achalasia, Hirschsprung’s disease, megacolon. • HAT: Encephalitis, sleep disturbances, lymphadenopathy.
5.1 Cardiac Differential¶
• Ischemic heart disease; other cardiomyopathies. • Clinical Note: Chagas cardiomyopathy is a prominent indication for heart transplantation in Latin America.
5.2 Digestive Differential¶
• Achalasia; Hirschsprung’s disease; other causes of megacolon.
6. INVESTIGATIONS & DIAGNOSIS¶
- Acute Phase Diagnosis: • Microscopy/PCR (blood, CSF) → Positivity in one test. • Congenital: PCR/cord blood testing within first weeks of life.
- Chronic Phase Diagnosis: • Serology → Requires two positive tests using different techniques and antigens.
- Reactivation Diagnosis: • Microscopy/PCR with evidence of increasing parasitemia.
- Ancillary Investigations: • ECG: Look for right bundle branch block (RBBB) and low QRS voltage. • Echocardiography/Holter: Assess for chamber dilation or apical aneurysm. • Barium Study: Identify megacolon (diameter ≥6.5 cm).
6.1 Diagnostic Criteria by Stage¶
• Acute: Microscopy/PCR; positivity in one test. • Chronic: Serology (two tests, different techniques). • Reactivation: Microscopy/PCR with increasing parasitemia.
6.2 Diagnostic Workup¶
• ECG: Right bundle branch block, low QRS voltage common in Chagas cardiomyopathy. • Echocardiography/Holter monitoring for chamber dilation/apical aneurysm. • Barium studies for megacolon (diameter ≥6.5 cm).
7. MANAGEMENT & TREATMENT¶
- Chagas Pharmacotherapy: • Benznidazole: First-line for adults; most effective in acute phase and children. • Nifurtimox: Alternative first-line; most effective in acute phase and children.
- HAT Treatment: • T. b. gambiense (First stage): Fexinidazole or Pentamidine. • T. b. gambiense (Severe second stage): Eflornithine + Nifurtimox OR Fexinidazole. • T. b. rhodesiense: Suramin (first stage) or Melarsoprol (second stage).
- Non-Pharmacologic Management: • Cardiac: Amiodarone/ICD for arrhythmias; anticoagulation for apical aneurysm. • Digestive: Dietary fiber, laxatives, pneumatic dilatation, surgery for refractory cases.
- Contraindications: • Pregnancy (Benznidazole/Nifurtimox). • Advanced renal or hepatic failure.
7.1 Pharmacologic Treatment¶
• Benznidazole (Table 3): ◦ Age <12 years: 5–7.5 mg/kg per day in 2 doses; Duration: 30–60 days. ◦ Age >12 years: 5 mg/kg per day in 2 doses; Duration: 30–60 days. ◦ Adverse Events (Adults): Allergic dermatitis (29–50%), anorexia/weight loss (5–40%), paresthesia (0–30%), peripheral neuropathy (0–30%). • Nifurtimox (Table 3): ◦ Dose: 25 mg/kg per day for 60 days. ◦ Adverse Events: Neurotoxicity, anorexia. • HAT Treatment (Table 4): ◦ T. b. gambiense First stage: Fexinidazole (≥35 kg: 1800 mg for 4 days, then 1200 mg for 6 days; 20–34 kg: 1200 mg for 4 days, then 600 mg for 6 days) OR Pentamidine (4 mg/kg per day for 7 days). ◦ T. b. gambiense Severe second stage (≥100 leukocytes/μL in CSF): Eflornithine (200 mg/kg bid for 7 days) + Nifurtimox (5 mg/kg tid for 10 days) OR Fexinidazole. ◦ T. b. rhodesiense: Suramin (4–5 mg/kg day 1, then 5 weekly injections of 20 mg/kg); Melarsoprol (2.2 mg/kg per day for 10 days).
7.2 Non-Pharmacologic Management¶
• Cardiac: Amiodarone/ICD for arrhythmias; anticoagulation for apical aneurysm. • Digestive: Dietary fiber, laxatives, pneumatic dilatation, surgery for refractory cases. • Prevention: Vector control (insecticide nets), blood donation screening.
8. PROGNOSIS & COMPLICATIONS¶
• Chagas cardiomyopathy: Leading cause of heart failure; 5-year mortality 2–63%. • HAT: Untreated, 100% fatal within 1 year of CNS stage. • Reactivation: Mortality ~50% without treatment.
8.1 Cardiac Complications¶
• Sudden death, heart failure, arrhythmias; worse prognosis than ischemic cardiomyopathy.
8.2 Digestive Complications¶
• Megaviscera syndrome (esophageal/colonic dilation); chronic constipation/fecaloma.
9. SPECIAL CONSIDERATIONS¶
• Pregnancy: ◦ Congenital transmission rate 1–10%. ◦ Screening of pregnant women is cost-effective. ◦ Benznidazole/Nifurtimox contraindicated; use contraception before treatment. • Immunocompromised Hosts: ◦ Reactivation risk ~20% in HIV without ART (CD4+ <100/μL). ◦ Treatment with Benznidazole or Nifurtimox. ◦ Posttransplantation: Monitor for reactivation; adjust immunosuppression.
9.1 Pregnancy¶
• Congenital transmission rate 1–10%; screening of pregnant women cost-effective. • Treatment contraindicated in pregnancy; use contraception before treatment.
9.2 Immunocompromised Hosts¶
• Reactivation risk ~20% in HIV without ART; treat with benznidazole/nifurtimox. • Posttransplantation: Monitor for reactivation; adjust immunosuppression.
10. KEY PEARLS & CLINICAL TRAPS¶
• Diagnostic clues: Romaña sign (eyelid swelling), RBBB on ECG, megacolon ≥6.5 cm. • Clinical traps: Chagas cardiomyopathy may mimic ischemic heart disease; HAT often misdiagnosed as encephalitis.
10.1 Diagnostic Clues¶
• Romaña sign (eyelid swelling), RBBB, low QRS voltage, megacolon ≥6.5 cm.
Reference Tables¶
TABLE 234-1 Characteristics of the Stages of Trypanosoma cruzi Infection¶
Harrison's 22e, p.1790
| PHASE OR SETTING |
CONTEXT | ONSET OF FIRST SYMPTOMS |
CLINICAL MANIFESTATIONS | DURATION | PROGNOSIS |
|---|---|---|---|---|---|
| Acute (congenital) |
~5% risk of maternal transmission to newborn |
At birth or weeks after delivery |
>90% asymptomatic; rare lymphadenopathy, hepatosplenomegaly, jaundice, respiratory distress, growth retardation |
2–8 weeks | Favorable when infant is born alive; unknown rate of in utero or neonatal death |
| Vector-borne transmission; oral transmission (ingestion of contaminated food/ drinks); blood product transfusion; tissue/organ transplantation |
1–2 weeks after vectorial transmission; may be sooner (days) after oral transmission or later (months) after transfusion/ transplantation |
>90% asymptomatic or mild febrile illness; local swelling at inoculation site (eyelid [Romaña sign] or skin [chagoma]); polyadenopathy; splenomegaly; myocarditis, hepatitis, and encephalitis more frequent with oral transmission |
4–8 weeks | ||
| Chronic (indeterminate form) |
Balanced immune response after acute phase subsides |
No symptoms | Normal clinical examination and ECG result |
Lifelong or until determinate phase |
No attributable mortality |
| Predominant inflammatory response (in cardiomyopathy only) |
Years to decades after initial infection |
Dyspnea, chest pain, palpitation, syncope, sudden death, stroke, dysphagia, regurgitation, constipation, fecaloma, volvulus, peripheral neuropathy |
Chronic | ||
| Acute (reactivation) |
Severe immunosuppression |
Variable | Myocarditis, erythema nodosum, panniculitis, Toxoplasma-like focal brain lesion, meningoencephalitis |
Variable | Mortality depends on rapidity of diagnosis and treatment and on underlying conditions |
TABLE 234-2 Diagnostic Procedures of Choice for Clinical Stages of T. cruzi Infection STAGE Acute¶
Harrison's 22e, p.1790
| STAGE | TECHNIQUE OF CHOICE |
SAMPLE | DIAGNOSTIC CRITERIA |
|---|---|---|---|
| Acute | Microscopy after concentration, PCR |
Peripheral blood, cerebrospinal or other body fluids |
Positivity in one test |
| Microscopy after concentration, PCR |
Cord or peripheral blood |
||
| Chronic (indeterminate and determinate forms) |
Serology | Peripheral blood | Positivity in two tests with different techniques and antigens |
| Microscopy after concentration, PCR |
Peripheral blood, cerebrospinal or other body fluids |
TABLE 234-3 Chagas Treatment Regimens and Adverse Reactions to Benznidazole and Nifurtimox DRUG Benznidazole Age <12…¶
Harrison's 22e, p.1791
| DRUG | REGIMEN | DURATION | ADVERSE EVENTS IN ADULTS (FREQUENCY) | PREMATURE DISCONTINUATION (RATE) |
|---|---|---|---|---|
| Benznidazole | Age <12 years: 5–7.5 mg/kg per day in 2 doses Age >12 years: 5 mg/kg per day in 2 doses |
30–60 days | Allergic dermatitis (29–50%), anorexia and weight loss (5–40%), paresthesia (0–30%), peripheral neuropathy (0–30%), nausea and vomiting (0–5%), leukopenia and thrombocytopenia (<1%) |
7–20% |
| Age <10 years: 15–20 mg/kg per day in 3 or 4 doses Age 11–16 years: 12.5–15 mg/kg per day in 3 or 4 doses Age >16 years: 8–10 mg/kg per day in 3 or 4 doses |
60–90 days | Anorexia and weight loss (50–81%), nausea and vomiting (15–50%), abdominal discomfort (12–40%), headaches (13–70%), dizziness and vertigo (12–33%), anxiety and depression (10–49%), insomnia (10–54%), myalgia (13–30%), peripheral neuropathy (2–5%), memory loss (6–14%), leukopenia (<1%) |
TABLE 234-4 Treatment of Human African Trypanosomiasis¶
Harrison's 22e, p.1796
| DISEASE AND STAGE | FIRST-LINE TREATMENT | ALTERNATIVE TREATMENT | |
|---|---|---|---|
| DRUG(S) AND ROUTE | DOSE AND DURATION | ||
| T. b. gambiense HAT | |||
| First stage | Fexinidazole PO | ≥35 kg: 1800 mg for 4 days, followed by 1200 mg for 6 days 20–34 kg: 1200 mg for 4 days, followed by 600 mg for 6 daysa |
Pentamidine isethionate IM or IVb: 4 mg/kg per day for 7 days |
| Fexinidazole PO | ≥35 kg: 1800 mg for 4 days, followed by 1200 mg for 6 days 20–34 kg: 1200 mg for 4 days, followed by 600 mg for 6 daysa |
||
| Severe second stage (≥100 leukocytes/μL in the CSF) |
Eflornithine IV + nifurtimox PO |
Eflornithine: 200 mg/kg bid for 7 days Nifurtimox: 5 mg/kg tid for 10 days |
Fexinidazole: ≥35 kg: 1800 mg for 4 days, followed by 1200 mg for 6 days 20–34 kg: 1200 mg for 4 days, followed by 600 mg for 6 daysa |
| T. b. rhodesiense HAT | |||
| Suramin IV | 4–5 mg/kg on day 1 followed by 5 weekly injections of 20 mg/kg (e.g., days 3, 10, 17, 24, 31)c |
||
| Second stage | Melarsoprol IV | 2.2 mg/kg per day for 10 days | — |