Trypanosoma Species (Trypanosomiasis)

Description of the Pathogen

African trypanosomes are extracellular hemoflagellate parasites belonging to the Trypanosomatidae family, Trypanosoma genus , and Trypanozoon subgenus . T. b. gambiense and T. b. rhodesiensei share a common morphology, biochemistry, and life cycle. However, molecular markers have been identified in both species for differentiation, which includes the serum resistance-associated gene found in T. b. rhodesiense and the T. b. gambiense– specific glycoprotein gene found in T. b. gambiense . ^, The life cycle includes both insect vector and mammalian host. After inoculation of infective metacyclic trypomastigotes into subcutaneous tissue by an infected tsetse fly, trypanosomes are converted to pleomorphic bloodstream trypomastigotes, which are infective for the tsetse fly ( Fig. 275.1 ). In the vertebrate host, African Trypanosoma organisms always occur in the trypomastigote form, where they live and multiply in blood, cerebrospinal fluid (CSF), interstitial space of the lymph nodes, spleen, and brain. The tsetse fly ingests bloodstream forms when taking a blood meal from an infected animal. Procyclic trypomastigotes eventually migrate through the fly’s esophagus toward the hypopharynx in the proboscis and into the salivary glands. In the salivary glands, the procyclic trypomastigotes transform into epimastigotes, attach to the epithelium, and finally become infective metacyclic trypomastigotes that are inoculated into the vertebrate host during a new blood meal ( Fig. 275.2 ). ^,

Epidemiology

T. b. gambiense is found in West and Central Africa and accounts for more than 98% of all cases of human African trypanosomiasis. T. b. rhodesiense is found in East and south-central Africa. ^, The majority of recent cases (>70%) have occurred in the Democratic Republic of the Congo (DRC). ^, The geographic gap between the 2 subspecies has been decreasing in Tanzania, the DRC, and Uganda. ^{, ,} This finding is of clinical significance, as laboratory differentiation between the 2 species is difficult, and treatment varies by species. Estimates have shown that approximately 65 million people living in 36 sub-Saharan African countries are at risk of infection and that underreporting of cases likely is substantial. Historically, several epidemics have occurred, most recently from 1970 through the 1990s. Significant control efforts, including improvements in surveillance, vector and reservoir control, and wider accessibility to diagnostic methods and treatment have resulted in a significant decline in the number of cases, with reported incident cases dropping from nearly 40,000 in 1998 to a record low of 977 in 2018.

Tsetse flies flourish at temperatures from between 20°C and 30°C, in high humidity, and at an altitude <1800 m. The development period of the parasite in the tsetse fly takes approximately 3 weeks; infection is lifelong (≤11 months) but is not passed to the fly’s progeny. Glossina palpalis and G. tachinoides , which inhabit dense vegetation along riverbanks, are the most common vectors of T. b. gambiense . T. b. rhodesiense is transmitted to humans by G. morsitans and less frequently by G. swynnertoni and G. pallidipes, which inhabit savannas and lake shores. The primary reservoir for T. b. gambiense is humans; however, animal reservoirs play important roles in human transmission of T. b. rhodesiense , with natural infections occurring in domestic animals, including cattle, sheep, and goats, and in some wild animals such as lions, hyenas, and several species of antelope. The incubation period ranges from 5 days to a few weeks in T. b. rhodesiense infection and up to years in T. b. gambiense infection. Humans primarily acquire T. brucei infections through the bite of infected tsetse flies while engaging in activities such as farming, fishing, and hunting. Rarely, humans can be infected transplacentally or by blood transfusion. The disease attacks all age groups and is equally frequent in female and male patients; however, children are infected rarely, mainly because of a decreased risk of exposure. The disease is invariably fatal if untreated.

Pathogenesis and Pathology

After organisms are injected into the mammalian host with the saliva of the tsetse fly, they enter the lymphatics and then the bloodstream ( Fig. 275.2 ). Protective factors isolated from normal human plasma include trypanosome lytic factors 1 and 2, which destroy trypanosomes that are pathogenic in animals, but not T. b. gambiense and T. b. rhodesiense, as a result of acquired resistance mechanisms. The trypanosome lytic factors have 2 components: (1) apolipoprotein A1 (APOL1), which can form pores in lysosomes and elicit apoptotic pathways, and (2) haptoglobin-related protein. Together, APOL1 and haptoglobin-related protein assemble into a single high-density lipoprotein to attack the parasite.

Each subspecies has evolved and developed mechanisms to evade these protective responses. T. b. rhodesiense expresses a serum resistance-associated gene that confers resistance to APOL1 by preventing its membrane insertion and enabling its degradation by proteases. ^, T. b. gambiense expresses a T. b. gambiense– specific glycoprotein that prevents APOL1 insertion into endolysosomal membranes. ^{, ,} Inhibition of the T. brucei receptor for haptoglobin-hemoglobin also reduces the uptake of APOL1, thereby allowing for protease-mediated digestion of APOL1 in T. b. gambiense. Both subspecies also use antigenic variation of the cell surface glycoproteins (variant surface glycoproteins) to avoid antibody-mediated clearance. ^{, ,}

Once these trypanosomes are able to avoid destruction by the immune system, they infect mammalian hosts and enter the lymphatic system where they cause lymph node enlargement with lymphocyte and mononuclear cell population expansion. Subsequently, the trypanosomes enter the bloodstream where they can disseminate to any organ ( Fig. 275.2 ). After a variable period, depending on the species, the organism enters the central nervous system (CNS) where it causes meningoencephalitis. The severity of symptoms is related directly to parasite burden. Histopathologic examination of the CNS reveals infiltration of plasma cells, macrophages, and lymphocytes, with perivascular proliferation of endothelial and neuroglia cells, severe cerebral edema, and punctate hemorrhage. Demyelination and neuronal damage have been observed and can extend deeply into white matter. Chronic meningoencephalitis also can occur. Vasculitis associated with increased permeability of the capillary vessels is considered to be the essential factor in pathogenesis and is suspected to be of immunopathogenic origin. ^{, ,}

Clinical Manifestations

Human African trypanosomiasis presents in 2 stages: the hemolymphatic stage and the meningoencephalitis stage. Infection with T. b. rhodesiense causes acute, severe disease with few CNS symptoms and often results in death within weeks or months. T. b. gambiense infection is characterized by a milder, chronic, progressive course with involvement of the lymph nodes, CNS invasion, and a fatal outcome after several years. ^,

Within a few days, but up to 2 weeks after infection, an indurated, erythematous, painful, warm, circumscribed, rubbery lesion (trypanosomal chancre) may develop at the site of the tsetse fly bite. This lesion is seen in up to 20% of patients infected with T. b. rhodesiense but is less common in T. b. gambiense infection . The lesion usually resolves within 3 weeks but with residual scarring and depigmentation. ^, The differential diagnosis includes cutaneous anthrax, syphilis, and African tick bite fever, caused by Rickettsia africae and R. conorii .

The hemolymphatic stage is characterized by parasitemia with high fever, headache, and general malaise interspersed with relatively asymptomatic periods. As infection progresses, fever is intermittent, and a papular rash and generalized enlargement of lymph nodes occur, especially in the posterior cervical triangle (Winterbottom sign) and in the submaxillary, inguinal, and femoral regions. The nodes are discrete, soft, and nontender and contain abundant parasites. The spleen and liver can be mildly enlarged. Over time, the patient develops dyspnea, chest pain, and loss of strength, and becomes emaciated. Endocrine abnormalities include increased or decreased thyroid function, decreased sexual function, and, in women, amenorrhea. Arthralgia, weakness, and painful local edema of the hands, feet, and joints can be present. Deep hyperesthesia (Kerandel sign) often is reported in non-Africans; delayed, intense pain occurs when soft tissue is compressed. ^,

The most common laboratory abnormalities include hemolytic anemia, elevation of serum hepatic enzymes, coagulation abnormalities, thrombocytopenia, and hypocomplementemia. The sedimentation rate is markedly elevated. The differential diagnosis during the first stage of the disease includes other etiologies of febrile illness occurring in the same geographic areas, such as malaria, typhoid fever, tuberculosis, brucellosis, syphilis, leptospirosis, hepatitis, borrelial relapsing fever, viral hemorrhagic fevers, and acute human immunodeficiency virus (HIV) infection.

In the second stage (i.e., CNS disease), sleep disturbance and neuropsychiatric disorders become more apparent. Meningoencephalitis can involve the spinal cord as well as the brain. The white matter of the brain shows pathognomonic cells called morula or Mott cells, which are plasma cells containing large concentrations of immunoglobulin M (IgM). With CNS invasion, the chronic or sleeping sickness stage of infection is initiated. Headache is severe, and irritability, personality and behavior changes, and gradual loss of cognitive function are common. Muscle spasms, ataxia, incoordination, tremor, alteration of reflexes, stiffness in the neck, papilledema, and flaccid paralysis occur. Psychiatric manifestations include hallucinations, delusional states, and overt psychoses. Choreiform or oscillatory movements of the arms, head, neck, and trunk are frequent. ^{, ,} Sleep disorders with diurnal somnolence, inappropriate episodes of sleeping, and nocturnal insomnia are prominent symptoms of the second stage. ^{, ,} Progressive somnolence and convulsions develop and lead to deep coma and death. Cardiac involvement can lead to congestive heart failure, pericardial effusion, and electrocardiographic changes. Death results from meningitis, heart failure, or complications such as bacterial pneumonia. The differential diagnosis during the second stage of the disease includes other causes of chronic meningoencephalitis, especially tuberculosis, cryptococcal infection, and syphilis.

Congenital African trypanosomiasis, defined as disease onset within the first 5 days of life, has been described in a few case series. In this form, progression to the second stage of the disease is faster. Transmission risk remains unknown. ^,

Diagnosis

The initial symptoms of human African trypanosomiasis are nonspecific. Therefore, a combination of clinical signs in the correct epidemiologic setting should raise suspicion for the disease. Diagnosis typically begins with a screening test to detect anti-trypanosome antibodies followed by a confirmatory test to directly visualize parasites. Finally, a lumbar puncture is performed to examine CSF for trypanosomes for staging purposes.