Trypanosomiasis

Etiology

African trypanosomiasis is caused by the parasite species Trypanosoma brucei with subspecies Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense transmitted by the tsetse fly.[3] Trypanosoma is a multicellular parasitic protozoan with a complex life cycle. Collectively, Trypanosoma brucei is transmitted by arthropod vectors and to mammalian hosts. When it presents with clinical disease in animals, it is referred to as “nagana” with significant agricultural implications.[3][4] American trypanosomiasis referred to as Chagas disease is caused by the protozoa Trypanosoma cruzi and is transmitted by the Triatoma species of the Reduviidae family.[2]

Epidemiology

African trypanosomiasis is seen in up to 30 countries across sub-Saharan Africa, and over 7000 cases of the disease were reported in 2012.[5] The parasite and subsequent disease are classically broken up into west and east African variants. The west/central African form is caused by T. brucei gambiense. It is often chronic and deadly if untreated. The east/southern African infection caused by T. brucei rhodesiense and in addition to humans is often found in cattle.[6][1] The vast majority of reported infections are caused by T. brucei gambiense. Geographical distribution has demonstrated progressive overlap as T. brucei rhodesiense has moved northwest.[3]

Historically, T. brucei have been responsible for epidemics in the late 1800s and early 1900s, killing near a million people. Colonial countries started early vector control and disease surveillance, and the disease was nearly eradicated in the 1960s. Governmental independence and ceased surveillance led to recurrence with a peak incidence in the late 1990s.

African trypanosomiasis is mainly seen in rural communities and impoverished areas. This distribution is underreported, and although the World Health Organization (WHO) has attempted to re-institute control programs, not all countries report disease or implement these measures.

The chronic form of African trypanosomiasis from T. brucei gambiense is rare in short-term tourists and visitors but is seen in refugees and immigrants. In contrast T. brucei rhodesiense has been seen in tourists to East Africa, mainly in Tanzania.[3]

Longitudinally, the WHO's goal is to eliminate African trypanosomiasis by 2020. Multiple screening methods, therapeutic delivery plans, and disease reporting programs are being implemented in an attempt to make this a reality.

Chagas disease, although originally discovered in 1909, is still a major cause of morbidity and mortality in endemic Central and South America, and up to 10 million individuals are thought to be infected worldwide. While the United States is not an endemic area, the disease has been seen in the southern states such as Texas and Arizona.[2][7] The majority of these cases are thought to be secondary to the recent large-scale immigration of Latin Americans into non-endemic areas. The disease in Europe and Australia may reflect this pattern as well.[2]

Pathophysiology

The vector tsetse fly, Glossina, carries the trypanosome within the midgut after a blood meal. These protozoa then migrate to the salivary glands of the fly whereby they can be transmitted during the next feeding. After inoculation within the host, the parasite can live freely within the bloodstream and evade mammalian host defenses through variable surface glycoproteins (VSG). The slender form secretes bloodstream stage-specific VSG to evade the host immune system, and it is in this form that the organism proliferates. As the parasite population increases, a morphologic stumpy form with division arrest occurs. It is in this stage it may be transmitted to another tsetse fly from the mammalian host. Within the new tsetse vector and, after this stumpy stage, the organism progresses to a procyclic form whereby VSG is lost, and the organism is established again in the fly midgut. Cell division is again arrested, and they migrate to the salivary glands as epimastigote forms. These transition from another proliferative stage to a non-proliferative form where they again re-acquire VSG and are now capable to re-infect a new mammal at the next blood meal.[4]

The vector, the Reduviid bug, also called the kissing bug, is primarily a nocturnal insect. At the time of feeding the insect deposits feces through breaks in the skin that contain T. cruzi. Less common modes of transmission include the ingestion of contaminated food, congenital transmission, or transmission through contaminated blood or tissue.[7] As blood transfusions historically have been a major route of infection in endemic areas, blood donated is often routinely screened.

History and Physical

The clinical disease has 2 stages. These are characterized by an early/first hemolymphatic stage and late /second meningoencephalitis stage with an invasion of the central nervous system (CNS).

The earliest manifestation of the disease is a cutaneous chancre at the site of inoculation. This however only occurs rarely in patients with T. brucei gambiense and infrequently (19%) with those infected by T. brucei rhodesiense. Systemic symptoms develop after that with intermittent fever, headache, pruritus, and lymphadenopathy.[3] The lymphadenopathy may be particularly conspicuous in the posterior triangle of the neck and has received the eponym “Winterbottom’s sign.”[8] Fevers often persist from a day to a week and are separated by afebrile intervals of days to months. Undulating fevers reflect parasites multiplying within the blood. Less frequently hepatosplenomegaly may occur in the early stage. In the late/second stage, CNS symptoms manifest as sleep disturbances or neuropsychiatric disorders. A sleep disorder is the most common symptom of the second stage, and it is from this that the term “African sleeping sickness” was ascribed. Sleep problems are further described as dysregulation of sleep/wake cycles and fragmentation of sleep. Previously inversion of sleep patterns was reported. Additional symptoms include tremor, weakness, paralysis, dyskinesia, or chorea-athetosis. Parkinsonian hypertonia and abnormal reflexes may be seen. Psychiatric changes such as aggression, apathy, psychosis, or irritability may present.

Other organ systems can be involved. Similar to the trypanosome disease of T. cruzi the heart may be affected, albeit less frequently, with African trypanosomiasis. T. brucei gambiense presents as a prolonged QTc, repolarization abnormalities, or low voltage. These are usually not of clinical significance. T. brucei rhodesiense may cause severe pericarditis or myopericarditis.

The thyroid and adrenal cortex may be involved with either hyperfunction or hypofunction. Both are more pronounced with infections caused by T. brucei rhodesiense.

Notably, the disease in non-native individuals (i.e., travelers or tourists) may be different with a cutaneous chancre and the trypanosomal rash much more frequently observed. Additionally, internal involvement is much more pronounced as well.

The clinical endpoint from either subgroup of T. brucei results in coma and death if untreated. Death occurs more rapidly with infections from T. brucei rhodesiense often occurring within weeks to months, and later with T. brucei gambiense at an average time of 3 years from inoculation.[3][8]

Chagas disease has acute, indeterminate, and chronic stages. Acutely infected patients often are asymptomatic or have a mild non-specific febrile illness. Symptoms may include fever, chills, gastrointestinal manifestations, lymphadenopathy, hepatosplenomegaly, or a mixture of cutaneous manifestations. A chagoma is an indurated, erythematous, papule or nodule that occurs at the site of inoculation. This may occur weeks after initial infection. Romana’s sign is classically associated with acute Chagas disease and is characterized by eyelid and periocular edema secondary to parasite deposition into the conjunctiva. Schizotrypanides is a term used to describe a diffuse morbilliform eruption during acute infection and is seen in a minority of infected patients.[2]

The indeterminate stage of Chagas disease reflects a host immune response and a decrease in parasite burden. This occurs over months after infection. At this time antibodies to T. cruzi are present and clinical disease is absent.

The most devastating stage of the disease is the chronic stage. Up to a third of patients with Chagas disease progress to this stage which exhibits cardiac conduction abnormalities, dilated congestive heart failure, or thromboembolic events. Heart failure often shows aneurysmal dilation of the left ventricle, and the most common conduction defect is a right bundle branch block with or without an anterior fascicular block. Gastrointestinal (GI) involvement occurs in a minority of infected patients, however, of those, the most common manifestation is megaesophagus from damage to autonomic ganglia with subsequent achalasia, dysphagia, weight loss, or recurrent aspiration. Finally, patients with the disease who become immunocompromised may experience reactivation. This may present as recurrence of fever and cutaneous erythematous nodules or plaques along with meningoencephalitis.[2]

Evaluation

Before disease onset, screening tests using a card agglutination test have can be implemented. The card agglutination test is a serologic test that utilizes capillary blood, plasma, or serum dilutions. The latter is more specific. This test employs antigens from T. brucei gambiense and has a variable sensitivity of near 90%. While some sources boast a negative predictive value of equal to 99%,[9] the low prevalence in even endemic areas (less than 5%) causes the positive predictive value to remain low, and thus, the test cannot be used for confirmation of disease.[3] Other sensitive serologic tests such as immunofluorescence or enzyme-linked immunosorbent assays are used in non-endemic areas as a screening tool among those in whom it is clinically warranted.

Diagnosis of active disease relies on the constellation of clinical history, exposure to endemic areas, direct visualization of organisms, and adjunctive serologic tests. Microscopic examination of blood, lymph node aspirate, or cerebrospinal fluid (CSF) may yield parasites. Thin and thick blood films have low sensitivity, and miniature anion-exchange centrifugation technique and/or capillary tube centrifugation should be used to increase yield.[3][9] Other than as clinically determined, differentiation between the 2 stages of the disease occurs through an examination of the CSF. The number of parasites may be low regardless of stage, and therefore, the WHO criteria allow a white blood cell count (WBC) of greater than 5 cells per microliter or the presence of trypanosomes to be supportive of late disease.[9]

Diagnosis of T. cruzi is usually established by a history of exposure to an endemic area and direct observation of trypomastigotes in Giemsa-stained wet mounts of blood or CSF. Organisms may be seen in pericardial fluid, bone marrow, brain, skin, or other infected tissues. Polymerase chain reaction (PCR) is the most sensitive mode of detection, but often serologic assays are used to confirm the disease.[2]

Treatment / Management

Treatment for Trypanosoma brucei gambiense and T. brucei rhodesiense are different, and additionally, treatment is dependent on the stage of infection.

For the first-stage of the disease caused by T. brucei gambiense pentamidine is the first-line therapy. Route of administration is intramuscular for one week or intravenous with normal saline over 2 hours. Three injections versus prolonged therapy may be equally effective. Once an involvement of CSF is detected pentamidine is no longer effective. Side effects of pentamidine include injection site reactions, abdominal pain, and hypoglycemia. More serious adverse events seen with pentamidine in the treatment of other diseases include leukopenia, thrombocytopenia, hyperkalemia, and QT-prolongation.

Second stage disease caused by T. brucei gambiense includes eflornithine or melarsoprol. Eflornithine has been shown to be superior in reducing mortality as compared to melarsoprol and is, therefore, the preferred medication for the second-stage of disease. Combination of nifurtimox and eflornithine reduces dosage and cost of therapy.[10] Adverse reactions are similar to eflornithine and include pancytopenia, GI distress, and convulsions.(B3)

The first stage of disease caused by T. brucei rhodesiense is treated with suramin. Although also effective for disease caused by T. brucei gambiense the high prevalence of Onchocerca in those areas, and the risk of severe allergic reaction with suramin prohibits use in west and central Africa. For T. brucei rhodesiense, first-stage disease suramin is used for up to 30 days. Notably, this medication is rapidly degraded in the air and needs to be injected immediately after dilution with distilled water. Adverse reactions with suramin include hypersensitivity reactions, nephrotoxicity, peripheral neuropathy, bone marrow toxicity, and subsequent agranulocytosis and/or thrombocytopenia.[3](B3)

T. brucei rhodesiense second-stage disease can be treated with melarsoprol. Adverse reactions may be severe including an encephalopathic syndrome in up to 8% of patients. Dexamethasone and diazepam are used for this. Skin reactions including pruritus and maculopapular rashes are common with bullous lesions occurring rarely. Motor and sensorial neuropathies may occur.[3][10](B3)

Treatment for Chagas disease is unique in that 2 nitroheterocyclic compounds are used. These are benznidazole and nifurtimox, and the former is preferred secondary to its favorable side effect profile. Dosing of benznidazole is 5 mg/kg per day for 60 days, and nifurtimox is given 8 to 10 mg/kg per day in adults, 12.5 mg/kg per day in adolescents, and 15 to 20 mg/kg per day in children, all with a duration of 90 to 120 days. Side effects of benznidazole include photosensitivity, severe exfoliative dermatitis, peripheral neuropathy, and bone marrow suppression. This necessitates a complete metabolic panel, hepatic function panel, and complete blood count with the latter repeated every two weeks while therapy is given. Side effects with nifurtimox include gastrointestinal distress, peripheral neuropathy, and mood disturbances. Complete blood count, hepatic function panel, and a complete metabolic panel (CMP) should be obtained with peripheral neuropathy assessment every 2 weeks while on treatment.[11]

Differential Diagnosis

Relapsing fevers may be seen in multiple diseases and is often characteristic of an intracellular parasite. A non-exhaustive list is provided below. The known endemic areas, exposure, lack of bleeding diathesis, and encephalopathic late stages make a diagnosis of African trypanosomiasis distinct from these diseases:

• Malaria
• Typhoid fever
• Viral hepatitis
• Ehrlichiosis
• Dengue
• Brucellosis
• Babesiosis
• Yellow fever

Chagas disease with its ocular manifestations may mimic or incur secondary:

• Preeseptal cellulitis
• Conjunctivitis

The other cutaneous manifestations may appear non-specific and be confused with:

• Drug rash
• Arthropod assault

Prognosis

Prognosis of untreated disease is dismal with death being invariable.[9] Early treatment has dramatically reduced mortality rates but a delay in diagnosis may be fatal. When melarsoprol was the only therapeutic option mortality was higher with 4 % to 12% of deaths occurring from treatment alone.[8]

Among patients with Chagas disease, cardiomyopathy may occur in up to a third of infected patients and be devastating. Megaesophagus occurs less frequently, but when present, contributes tremendous morbidity. Treatment of the acute disease may result in a cure rate up to 80% and treatment with benznidazole may reduce the occurrence of ECG abnormalities and serological titers. The success of treating patients with chronic stage Chagas disease is uncertain.[2][11]