1753CHAPTER 227 Chagas Disease and African Trypanosomiasis

passive and active screening of the population at risk, along with provision of treatment, may reduce the risk of complications and secondary

transmission, particularly congenital transmission. Finally, identification and treatment of cardiac complications and prevention of cardioembolic events at an early stage positively influence the disease

course.

■ GLOBAL CONSIDERATIONS

With its geographic expansion, Chagas disease has become a global

health issue, predominantly affecting vulnerable people on four continents. Yet, as with other neglected tropical diseases, progress against

Chagas is limited by a lack of research and development and a lack

of financial and political commitment. For example, the production

and registration of existing drugs, and access to them, are still problematic in many countries, including the United States. Difficulties in

research on and development of new drugs are compounded by the

lack of financial incentives. The future of Chagas disease is likely to be

influenced by global phenomena. Climatic changes, population aging,

increasing prevalence of noncommunicable comorbidities (e.g.,

diabetes, hypertension) in low- and middle-income countries, and

increasing use of immunosuppressive drugs are likely to impact the

epidemiology, clinical course, and burden of Chagas disease. To tackle

these challenges, clinical, public health, and policy interventions need

to be scaled up and improved in areas of high or hidden prevalence

(e.g., in the Chaco Region of Argentina, Bolivia, and Paraguay and in

Mexico, Western Europe, and the United States, respectively).

HUMAN AFRICAN TRYPANOSOMIASIS

(SLEEPING SICKNESS)

■ DEFINITION

HAT is a life-threatening illness caused by infection with extracellular

protozoan parasites that are transmitted by tsetse flies in sub-Saharan

Africa. T. b. gambiense and T. b. rhodesiense are the two pathogenic

subspecies affecting humans; their epidemiologic and clinical features

largely differ.

■ EPIDEMIOLOGY

The geographic range of HAT is restricted to sub-Saharan Africa in

line with the distribution of its vector, the tsetse fly (Glossina species;

Fig. 227-3). HAT due to T. b. gambiense is endemic in 24 countries of

western and central Africa. Between 1999 and 2018, the number of

reported cases fell by 97% (from 27,862 to 953) as a result of successful control measures based on systematic screening of populations at

risk, diagnostic confirmation, and treatment of infected individuals.

During the same period, the number of reported cases of HAT due

to T. b. rhodesiense fell by 96% (from 619 to 24) in the 10 diseaseendemic countries of eastern and southeastern Africa. However, the

ratio of reported to unreported cases remains uncertain for disease

caused by both species. In 2018, most cases of T. b. gambiense HAT

were reported by the Democratic Republic of the Congo (DRC; 69%),

whereas Malawi and Uganda reported most of the cases caused by T. b.

rhodesiense (63 and 17%, respectively). 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. A roadmap for HAT elimination as a public health problem by 2020 has been mapped out by the

World Health Organization (WHO) with two primary indicators: the

number of cases reported annually (target: <2000; reached since 2018)

and the area at risk reporting ≥1 case/10,000 people/year (target: reduction of 90% by 2016−2020 compared to the 2000−2004 baseline). The

next goal set by WHO is the global elimination of transmission by 2030.

Humans are the predominant or exclusive reservoir of T. b. gambiense. Rare cases of vertical (in utero) or transfusional transmission

have been reported, but almost all patients are infected by the bite of

tsetse flies during their daily activities along or near rivers, where the

flies live and reproduce. In contrast, T. b. rhodesiense causes zoonosis

in a variety of wild and domesticated animals (e.g., antelopes and cattle, respectively), which act as reservoirs. Humans are infected by T. b.

rhodesiense via tsetse bites in woodland savannah. Honey gatherers,

game park rangers, poachers, and firewood collectors are particularly

at risk. Imported cases of HAT are occasionally diagnosed among

African immigrants and other travelers. While long-term travelers

(>30 days) are at increased risk of T. b. gambiense HAT, most imported

FIGURE 227-3 Areas at risk for human African trypanosomiasis, 2014–2018. (Reproduced with permission from JR Franco et al: Monitoring the elimination of human African

trypanosomiasis at continental and country level: Update to 2018. PLoS Negl Trop Dis 14:e0008261, 2020. © World Health Organization and Food and Agriculture Organization

of the United Nations.)

1754 PART 5 Infectious Diseases

cases of T. b. rhodesiense HAT are seen in short-term travelers, typically

following visits to game parks.

■ PATHOLOGY AND PATHOGENESIS

T. b. rhodesiense and T. b. gambiense, unlike other trypanosome species, 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. The serum resistance–associated

protein is responsible for resistance in T. b. rhodesiense, whereas other

mechanisms, notably involving the T. b. gambiense–specific glycoprotein (TgsGP) gene, are used by T. b. gambiense.

Trypanosomes are transmitted to humans by the tsetse bite, proliferate, and induce a local inflammatory reaction that is sometimes

clinically apparent as a chancre. Trypanosomes then disseminate into

the hematolymphatic system, with lymph nodes becoming enlarged

after infiltration by mononuclear cells and lymphocytes. The degree of

enlargement of the liver and spleen is usually mild to moderate, with

infiltration by mononuclear cells as a prominent feature. Trypanosomes multiply in the blood, but their presence and density vary. This

variation is mainly due to a cyclic immune-evasion process, whereby

the parasite population can be decimated by the host’s immune

response until the reemergence of offspring parasites that express a

different variant surface glycoprotein to which the immune system is

temporarily blind. Each trypanosome genome encodes a repertoire of

~1000 variant surface glycoproteins between which the parasites can

switch genetically. Trypanosomes also multiply in extravascular tissues during the first stage of illness. The skin, skeletal muscles, serous

membranes (peritoneum, pleurae, and pericardium), and heart can be

involved, with interstitial infiltration of mononuclear cells and vasculitis evident on microscopic examination. Myocarditis and pericarditis

with myocardial degeneration and interstitial hemorrhage are common

features of T. b. rhodesiense infection.

The CNS is invaded weeks to months (T. b. rhodesiense) or months

to years (T. b. gambiense) after initial infection. This invasion corresponds to the second stage of HAT, which is defined by the presence of

trypanosomes or mononuclear cells in the cerebrospinal fluid (CSF).

The white matter is predominantly affected, with perivascular proliferation of astrocytes, microglial cells, and Mott’s (morular) cells that

contain IgM in intracellular vacuoles. The location of white-matter

lesions in the brain correlates with the main neurologic clinical features. The cerebral cortex and neurons are spared until the terminal

stages of illness. Because reversible inflammatory lesions predominate

over the irreversible destruction of tissue, neuropsychiatric symptoms

and signs resolve partially or completely during or after treatment of

second-stage HAT.

APPROACH TO THE PATIENT

Human African Trypanosomiasis

HAT is usually lethal in the absence of treatment. Therefore, 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, and

obtaining a thorough recent and remote travel history from the

patient is a prerequisite for diagnosis. 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 is a slowly evolving illness with

a long incubation period (months to years) and a prolonged disease

course. In contrast, T. b. rhodesiense HAT is an acute febrile illness

with a short (<3-week) incubation period and a shorter (weeks to

months) disease course. There are exceptions to this classical pattern.

Acute forms of T. b. gambiense HAT have been reported, especially

among travelers, and chronic forms of T. b. rhodesiense HAT occur

in the southern range of its geographic distribution (e.g., Zambia and

Malawi). Trypano-resistance (i.e., self-resolving first-stage infections)

and trypano-tolerance (i.e., the long-term persistence of parasites [e.g.,

in the skin] without clinical features of disease) have been reported for

T. b. gambiense. Concomitant HIV co-infection does not seem to predispose individuals to an increased risk of HAT, and the impact of the

virus on the clinical presentation of HAT is not known.

T. b. gambiense The occurrence of trypanosomal chancre is reported

in a sizeable proportion of travelers, but very rarely in patients living

in endemic areas, where the nonpurulent, painful, and itchy nodule

can easily be confused with the bite of another arthropod. The chancre

spontaneously disappears in 1–3 weeks.

SYSTEMIC FEATURES After an asymptomatic incubation period that

usually lasts for weeks or months but occasionally lasts for years,

patients may present with irregular and remittent fever, sometimes

accompanied by fatigue, malaise, and myalgia. Fever is more frequent

among travelers than among natives, but the absence of fever in no

way rules out the disease. Circinate or serpiginous rashes, commonly

called trypanids, can occur on the trunk and on proximal parts of the

extremities. Trypanids are almost impossible to detect on dark skin and

have been reported only in Caucasians. Pruritus is a common but nonspecific symptom that affects up to half of patients during the second

stage. Painless edema of the face and extremities occasionally occurs

during the first phase.

Enlarged lymph nodes—a classical sign of HAT—are detected

in 38–85% of patients at both disease stages. Cervical palpation is

essential in patients with suspected HAT. The lateroposterior cervical

group (Winterbottom sign) and the supraclavicular group are most

commonly affected. Lymph nodes are movable, soft initially, harder

later, and painless. A variable proportion of patients present with mild

to moderate hepatomegaly and splenomegaly. Signs of myocarditis and

pericarditis are occasionally detected by ECG and echocardiography

but are usually clinically silent. Symptoms of HAT may mimic hypothyroidism or adrenal insufficiency, but thyroid and adrenal function

tests yield normal results. Loss of libido, impotence, and amenorrhea,

with decreased levels of testosterone and estradiol, are common in

second-stage patients and are most likely caused by dysfunction of the

hypothalamic–pituitary axis.

NEUROPSYCHIATRIC FEATURES Most patients with second-stage illness have no or only mild specific neuropsychiatric symptoms and

signs, which, when they develop, tend to do so late in the disease course.

In contrast, some nonspecific features, such as headaches and mood

and behavioral changes, are present in both disease stages but become

more permanent and severe during the second stage. As mentioned

earlier, HAT is commonly called “sleeping sickness” because of various

sleep disturbances (daytime somnolence, nocturnal insomnia) that are

more pronounced late in the second stage. Dysregulation of the daily

sleep/wake cycle and fragmentation of sleeping patterns are characteristic. Depending on the area of the brain affected, various neurologic

syndromes can also develop, including disorders that are pyramidalrelated (e.g., motor weakness, rare instances of hemiplegia), extrapyramidal-related (e.g., rigidity, paratonia), and cerebellar-related (e.g.,

ataxia, abnormal gait). Fine tremor, resting myoclonus, and abnormal

(athetoid or choreic) movements have also been reported. Mental disorder is a key feature of HAT and can easily be misdiagnosed as primary

psychiatric illness. Common presentations are antisocial or aggressive

behavior, mood disorders (e.g., irritability, indifference), apathy or

hyperactivity, and depression or psychosis (e.g., delirium, hallucinations). In the final stage of illness, decreased consciousness, dementia,

and sometimes epilepsy are present, leading to coma, bed sores, aspiration pneumonia, or other bacterial infections and ultimately to death.

1755CHAPTER 227 Chagas Disease and African Trypanosomiasis

T. b. rhodesiense The clinical presentation of T. b. rhodesiense HAT

can be similar to that of T. b. gambiense HAT in areas (e.g., Zambia,

Malawi) that characteristically harbor specific parasite genotypes

and host factors. The typical acute form with an incubation period of

<3 weeks occurs in the northern range of the disease’s distribution (e.g.,

Tanzania, Uganda) and in travelers. The initial trypanosomal chancre

is clinically similar to that seen in T. b. gambiense HAT but is more

common, especially among travelers.

SYSTEMIC FEATURES Fever can be high and occurs in both first- and

second-stage patients, often in association with headaches and with

diffuse myalgia and arthralgia. Pruritus and edema of the face and legs

can be present. Lymphadenopathies have been reported in variable proportions in both disease stages and predominately affect the submandibular, axillary, and inguinal regions. Mild to moderate hepatomegaly and

splenomegaly are documented in a minority of patients. Myocarditis and

pericarditis appear to influence clinical course and outcome, even though

clinical features of cardiac failure or arrhythmia have not been prominent

findings in large case series. In contrast, conduction abnormalities, with

various degrees of atrioventricular block, have been reported in travelers.

Sepsis-like features, with disseminated intravascular coagulation and

multiple-organ failure, can occur in the terminal stage.

NEUROPSYCHIATRIC FEATURES Neuropsychiatric symptoms and

signs in T. b. rhodesiense HAT are reported with varying frequency but

overall are similar to those described above for T. b. gambiense HAT.

The notable exception in T. b. rhodesiense disease is a more rapid evolution toward coma and death.

■ DIAGNOSIS

The clinical and biological features of T. b. gambiense and T. b. rhodesiense HAT—anemia, thrombocytopenia, elevated levels of C-reactive

protein and IgM—are not sufficiently specific, and current drug regimens are not sufficiently practical to allow the initiation of treatment

solely on the basis of suspicion. Diagnostic confirmation is therefore

mandatory in all patients.

T. b. gambiense The diagnosis of T. b. gambiense HAT is based on a

three-step approach: screening, diagnostic confirmation, and staging.

SCREENING Immunologic (serologic) methods constitute the preferred screening tool. The card agglutination test for trypanosomiasis

(CATT) has been used in most endemic areas for several decades. The

test reagent contains stained, freeze-dried trypanosomes of selected

variable-antigen types. If specific antibodies are present in the patient’s

blood or serum, agglutination can be seen with the naked eye. The

sensitivity of the CATT on undiluted blood or serum is 69–100%

(>90% in most studies), with some regional variation; its specificity

is 84–99%. The CATT and associated equipment (e.g., a rotator) are

manufactured and distributed by the Institute of Tropical Medicine in

Antwerp, Belgium, but are not widely available outside endemic areas.

In recent years, lateral flow tests have been developed and commercialized, first based on whole parasites and later on recombinant antigens.

Their diagnostic performance appears similar to that of the CATT.

Other serologic test formats (ELISA, immunofluorescence, indirect

hemagglutination) are available in some reference laboratories in both

endemic and nonendemic countries.

DIAGNOSTIC CONFIRMATION The microscopic observation of trypanosomes in the lymph, blood, or CSF confirms the diagnosis. Direct

observation of motile trypanosomes on a wet preparation of lymph

obtained by cervical lymph node puncture is simple and cheap but has

limited sensitivity (50–65% in most studies). Trypanosomes can be

found in the blood but often occur at low densities. Therefore, stained

thin and thick blood smears have very low sensitivity. Sensitivity is

improved (to 40–60% in most studies) with the microhematocrit centrifugation technique, which is based on microscopic examination of

the buffy coat after centrifugation of four to six microhematocrit tubes.

The most sensitive method (~90%) is the miniature anion-exchange

centrifugation technique, which is based on the visualization of trypanosomes in eluate after the passage of a large volume (500 μL) of blood

through an anion-exchange column and subsequent centrifugation.

STAGING Staging is based on the examination of CSF obtained by

lumbar puncture. Second-stage HAT is defined by the presence in

CSF of a raised leukocyte count (>5/μL) and/or of trypanosomes. The

latter can be detected in the cell-counting chamber or, preferably, after

centrifugation of the CSF. Staging is no longer an obligatory step in

settings where fexinidazole is used as first-line treatment for both firstand second-stage HAT patients, except for young children (<6 years

or weighing <20 kg) and for patients with neuropsychiatric symptoms

and signs consistent with severe HAT, i.e., mental confusion, abnormal

behavior, logorrhea, anxiety, ataxia, tremor, motor weakness, speech

impairment, abnormal gait or movements, or seizures (see “Treatment,” below).

Several molecular methods based on PCR or loop-mediated isothermal amplification have been developed, mostly based on the detection

of multiple-copy DNA targets of the Trypanozoon group (to which

T. brucei belongs) or the single-copy TgsGP gene of T. b. gambiense.

None of these methods have been fully validated for diagnostic purposes, and a positive result of their application to blood should be

interpreted as suspected rather than confirmed HAT. Molecular methods applied to CSF (to detect biomarkers) have not proven more accurate than classical methods for staging and have yielded false-positive

results in a substantial proportion of cases.

T. b. rhodesiense The diagnosis of T. b. rhodesiense HAT is usually

simpler because parasites are more numerous in body fluids. They can

occasionally be visualized in a chancre aspirate. In light of the lack of

available serologic tests and the high sensitivity of parasite detection

methods in blood, wet mounts, and thin/thick smears (Fig. 227-4),

the microhematocrit or other concentration techniques are used for

both screening and confirmation. Because the modalities of treatment

of T. b. rhodesiense are stage dependent, staging remains an obligatory

step, and the definition and methods used are the same as for T. b.

gambiense HAT.

TREATMENT

Human African Trypanosomiasis

The management of HAT is based on general supportive therapy

(e.g., rehydration, pain management), treatment of concomitant

infections (e.g., malaria, pneumonia), and antiparasitic treatment.

The modalities of antitrypanosomal treatment depend on the Trypanosoma species, the stage of illness, and the presence of contraindications (Table 227-4).

T. B. GAMBIENSE

Fexinidazole, a nitroimidazole compound, is the first effective oral

treatment against HAT. It is administered with food for 10 days,

FIGURE 227-4 Trypanosoma brucei rhodesiense in blood (thin smear, Giemsa stain).

(Credit to the DPDx team, U.S. Centers for Disease Control and Prevention, Atlanta.)

1756 PART 5 Infectious Diseases

TABLE 227-4 Treatment of Human African Trypanosomiasis (HAT)

FIRST-LINE TREATMENT

DISEASE AND STAGE DRUG(S) AND ROUTE DOSE AND DURATION ALTERNATIVE TREATMENT

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

Nonsevere second

stage (6–99 leukocytes/

μL in the cerebrospinal

fluid [CSF])

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

Eflornithine: 200 mg/kg bid for 7 days

plus

Nifurtimox: 5 mg/kg tid for 10 days

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

First stage 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

Pentamidine isethionate IM or IVb

: 4 mg/kg per day

for 7 days

Second stage Melarsoprol IV 2.2 mg/kg per day for 10 days —

a

 Fexinidazole should not be administered in children <6 years and weighing <20 kg. b

For IV administration, slow infusion (60–120 min) should be used. c

The maximal dose is

1 g per injection; the drug should be diluted in distilled water.

Sources: Control and surveillance of human African trypanosomiasis: Report of a WHO Expert Committee. WHO Technical Report Series 984, 2013; WHO interim guidelines

for the treatment of gambiense human African trypanosomiasis. August 2019; www.who.int/trypanosomiasis_african/resources/9789241550567/en/.

FIGURE 227-5 Intramuscular injection of pentamidine by a nurse in a village health

center, Province Orientale, Democratic Republic of the Congo.

divided into a 4-day loading phase and a 6-day maintenance phase.

It is highly effective (>95% cure rate) in patients with first-stage

and nonsevere second-stage HAT, the latter being defined as <100

leukocytes/μL in the CSF. Fexinidazole is associated with a lower cure

rate (87%) in patients with severe second-stage (≥100 leukocytes/μL

in the CSF) HAT. The most relevant adverse reactions reported in

clinical trials are vomiting, headache, and neuropsychiatric disorders (e.g., insomnia, anxiety, agitation). Fexinidazole is contraindicated in patients with hepatic insufficiency or at increased risk

of QT interval prolongation. In the absence of safety and efficacy

data, it remains contraindicated in small children (<6 years and/or

weighing <20 kg).

Pentamidine isethionate is highly effective (>95%) against firststage T. b. gambiense HAT and is an excellent alternative to fexinidazole when the latter is contraindicated or not available. It

is generally well tolerated and can therefore be administered in

peripheral health care centers in endemic countries (Fig. 227-5).

Hypotension after injection is common but generally mild. Hypoglycemia or hyperglycemia occasionally occurs, but permanent diabetes is very rare. Severe adverse events, such as acute pancreatitis

and anaphylaxis, occur extremely rarely.

Nifurtimox-eflornithine combination therapy is very effective

(>95% cure rate) and safe in patients with second-stage HAT,

including patients with severe (≥100 leukocytes/μL in the CSF)

illness. Common adverse reactions include gastrointestinal disturbances (nausea, vomiting, abdominal pain), headache, anorexia,

and reversible bone marrow toxicity (anemia, leukopenia). Convulsions and psychosis are reported in <5% of patients.

T. B. RHODESIENSE

Suramin has been used for >90 years and remains the first-line

treatment for first-stage T. b. rhodesiense HAT. Common adverse

events are pyrexia and nephrotoxicity, which is usually mild and

reversible but necessitates surveillance of albuminuria and renal

function before each dose.

Because eflornithine is ineffective against T. b. rhodesiense,

melarsoprol, an arsenic-based derivative, remains the only existing

treatment for second-stage T. b. rhodesiense HAT. Reactive encephalopathy is a life-threatening adverse event that occurs in 5–18% of

patients, with an associated mortality rate of 10–70%. The efficacy

of concomitant high-dose prednisolone to prevent reactive encephalopathy in patients with T. b. rhodesiense HAT is not known. Other

severe but less frequent adverse reactions to melarsoprol include

exfoliative dermatitis, bloody diarrhea, peripheral neuropathy, renal

dysfunction, and liver toxicity. Phlebitis is common, as is soft tissue

necrosis if the drug is accidentally given paravenously.

■ PROGNOSIS

Provided that treatment guidelines are properly followed, >95% of

patients with first-stage and second-stage T. b. gambiense HAT are

definitively cured with fexinidazole, pentamidine, and nifurtimox–

eflornithine combination therapy. The overall case–fatality rate is <1%

except in very advanced cases. Because relapses can occur long after

completion of treatment, follow-up visits are advised every 6 months

for at least 2 years. If clinical features of HAT are present, both blood

and CSF examinations are indicated. Patients with second-stage T. b.

rhodesiense HAT are at a 5–10% risk of dying during or after melarsoprol treatment, but relapses are very rare.

1757CHAPTER 228 Toxoplasma Infections

■ DEFINITION

Toxoplasmosis is caused by infection with the obligate intracellular

parasite Toxoplasma gondii. Acute infection acquired after birth is

typically asymptomatic, but some immunocompetent individuals can

present with systemic or ocular disease. Acute infection is thought to

result in the lifelong chronic persistence

of cysts in the host’s tissues. The classic

presentation of toxoplasmosis is encephalitis in immunocompromised individuals (especially HIV-positive individuals)

in whom latent infection has reactivated.

Among the clinical manifestations of

disease are lymphadenopathy, encephalitis, myocarditis, pneumonitis, and

retinitis. Congenital toxoplasmosis is an

infection of newborns that results from

the transplacental passage of parasites

from an infected mother to the fetus.

These infants may be asymptomatic at

birth, but many children later manifest

signs and symptoms, including chorioretinitis, strabismus, epilepsy, and psychomotor retardation. Toxoplasmosis can

also present as acute disease (typically

chorioretinitis) associated with food- or

waterborne sources.

■ ETIOLOGY

T. gondii is an intracellular coccidian

that infects both birds and mammals.

Up to a third of the world’s population

is thought to be infected latently with

this organism. There are two distinct

stages in the life cycle that are transmissible to humans (Fig. 228-1). Tissue

cysts that contain bradyzoites are transmitted in undercooked meat. After an

228 Toxoplasma Infections

Kami Kim

Definitive host

Bradyzoites encyst

within the CNS

and muscle of the

infected host.

Oocysts are excreted

in cat feces.

Contaminated soil is

ingested by birds,

mammals, and humans.

Intermediate host:

birds, mammals, humans

Toxoplasmic

encephalitis

Tachyzoites infect

all nucleated cells in

the host, replicate,

and cause tissue

damage.

FIGURE 228-1 Life cycle of Toxoplasma gondii. The cat is the definitive host in which the sexual phase of the cycle is

completed. Oocysts shed in cat feces can infect a wide range of animals, including birds, rodents, grazing domestic

animals, and humans. The bradyzoites found in the muscle of food animals may infect humans who eat insufficiently

cooked meat products, particularly lamb and pork. Although human disease can take many forms, congenital infection

and encephalitis from reactivation of latent infection in the brains of immunosuppressed persons are the most important

manifestations. CNS, central nervous system. (Courtesy of Dominique Buzoni-Gatel, Institut Pasteur, Paris.)

■ GLOBAL CONSIDERATIONS

The elimination of sleeping sickness as a public health problem

has been achieved, thanks to increased control activities run by

national control programs and nongovernmental medical organizations, improved funding, and the end of several civil wars (e.g., in

Angola) in the past 20 years. Funding for research, development, and

implementation of improved diagnostic (e.g., rapid diagnostic tests),

therapeutic (e.g., oral drugs), and vector control tools remains crucial

to sustain recent achievements and to move on to the next objective,

i.e., the global elimination of transmission by 2030.

■ FURTHER READING

Bern C et al: Chagas disease in the United States: A public health

approach. Clin Microbiol Rev 33:e00023-19, 2019.

Büscher P et al: Human African trypanosomiasis. Lancet 390:2397,

2017.

Lindner AK et al: New WHO guidelines for treatment of gambiense

human African trypanosomiasis including fexinidazole: Substantial

changes for clinical practice. Lancet Infect Dis 20:e38, 2020.

Pérez-Molina JA, Molina I: Chagas disease. Lancet 391:82, 2018.

Urech K et al: Sleeping sickness in travelers—Do they really sleep?

PLoS Negl Trop Dis 5:e1358, 2011.

intermediate host (e.g., a human, mouse, sheep, pig) ingests the cyst,

it is rapidly digested by the acidic-pH gastric secretions. Sporulated

oocysts that contain sporozoites are products of the sexual cycle in

feline intestines and acquired by ingestion of food or water contaminated with infected cat feces. Bradyzoites or sporozoites are released,

enter the intestinal epithelium, and transform into rapidly dividing

tachyzoites. The tachyzoites can infect and replicate in all mammalian

cells except red blood cells. The parasite actively penetrates the cell and

forms a parasitophorous vacuole. Parasite replication continues within

the vacuole. After the parasites reach a critical mass, intracellular signaling within the host and the parasite result in parasite egress from the

vacuole. The host cell is destroyed, and the released tachyzoites infect

adjoining cells. Parasites can disseminate throughout the body as free

tachyzoites or within phagocytic cells in the bloodstream or via lymphatics. Tachyzoites actively invade host cells and can cross epithelial

and endothelial barriers.

The tachyzoite replication cycle within an infected organ causes

cytopathology and clinical symptoms. Most tachyzoites are eliminated by the host’s humoral and cell-mediated immune responses.

Tissue cysts containing bradyzoites develop 7–10 days after systemic

tachyzoite infection. These tissue cysts occur in various host organs

but persist principally within the central nervous system (CNS) and

muscle. The development of this chronic stage completes the asexual

portion of the life cycle. Active infection in the immunocompromised

host is usually due to the spontaneous release of encysted parasites that

undergo rapid transformation into tachyzoites within the CNS that

cannot be contained by the immune system.

The sexual stage in the life cycle takes place in the cat (the definitive host) and is defined by the formation of oocysts within the feline

host intestine. This enteroepithelial cycle begins with the ingestion

of the bradyzoite tissue cysts and, after several intermediate stages,

culminates in the production of gametes. Gamete fusion produces

a zygote, which envelops itself in a rigid wall and is secreted in the

feces as an unsporulated oocyst. After 2–3 days of exposure to air at

ambient temperature, the noninfectious oocyst sporulates to produce

eight sporozoite progeny. The sporulated oocyst can be ingested by an

intermediate host, such as a person emptying a cat’s litter box or a pig