1741CHAPTER 226 Leishmaniasis

RCE cannot be based solely on parasitemia at admission and should

take the clinical status of the patient into consideration, particularly

end-organ dysfunction such as renal compromise.

Severely Immunocompromised Patients Asplenia and use of rituximab for B-cell lymphoma or autoimmune disorder predispose

to persistent or relapsing babesiosis. Other predisposing conditions

include HIV/AIDS and immunosuppressive regimens for transplantation or malignancy. Antimicrobial therapy should be administered to patients with these conditions for at least 6 consecutive

weeks, including 2 final weeks during which parasites are no longer

seen on blood smear. Given the duration of treatment, atovaquone

plus azithromycin is the preferred regimen. Azithromycin should

be administered IV and should be initiated at a dosage of 500 mg/d.

Laboratory parameters should be monitored daily until symptoms

abate and parasitemia is reduced to <4%. Thereafter, azithromycin

can be administered orally, but the dosage should not be <500 mg/d

because lower dosages may promote antibiotic resistance. Once the

patient is no longer severely ill, blood smears should be obtained

at least weekly until treatment is completed. If the patient remains

symptomatic but parasites are no longer observed on blood smear,

real-time PCR should be used to monitor the infection. Once treatment is completed, close follow-up is recommended. If symptoms

recur, blood smears and/or real-time PCR should be ordered.

Resistance to Antimicrobial Therapy Failure to respond to atovaquone plus azithromycin has been documented in highly immunocompromised patients infected with B. microti. Such resistance to

atovaquone and azithromycin is explained by missense mutations

in the parasite’s mitochondrial cytochrome b gene (cob) and the

apicoplast-encoded ribosomal protein subunit L4 gene (rpl4), respectively. Patients who are unresponsive to atovaquone plus azithromycin can be managed with clindamycin plus quinine (Table 225-1,

footnote e). If quinine toxicity is a concern and the molecular basis

of drug resistance unknown, clindamycin can be added to atovaquone plus azithromycin. An alternative approach is to substitute

atovaquone-proguanil for atovaquone (Table 225-1, footnote f).

Splenic Rupture As a complication of babesiosis, splenic rupture

typically occurs in young, healthy immunocompetent patients

with low-grade parasitemia. If the patient is hemodymanically

unstable or rapidly deteriorates, emergent splenectomy should be

performed. If the patient is hemodynamically stable but bleeding

persists, splenic arterial embolization should be considered. In

the absence of hemoperitoneum, splenic rupture should be managed without surgery but with careful hemodynamic monitoring.

Removal of the spleen leaves patients at risk for relapsing babesiosis

or severe disease caused by other microorganisms.

OTHER BABESIA INFECTIONS

B. duncani and B. divergens–like infections typically have been

treated with IV clindamycin (600 mg three or four times daily or

1200 mg twice daily) plus oral quinine (600–650 mg three times

daily) for 7–10 days. If symptoms persist, antimicrobial therapy

should be extended.

GLOBAL CONSIDERATIONS

In Europe, B. divergens infection is considered a medical emergency. The recommended approach is immediate, complete RCE

combined with administration of clindamycin plus oral quinine

(Table 225-1). Some cases have been cured with RCE and clindamycin monotherapy. Anemia may persist for >1 month and require

blood transfusion. A severe case of B. divergens infection resolved

during therapy with atovaquone plus azithromycin. A relapse in

a spleen-intact individual was treated with atovaquone-proguanil

plus azithromycin. The first-line therapy for B. venatorum infection

in Europe has been IV or oral clindamycin plus quinine. In a patient

intolerant to quinine, infection was cured after administration of

atovaquone plus azithromycin. A pediatric case of mild B. venatorum infection in China was successfully treated by a standard

course of atovaquone plus azithromycin.

■ PREVENTION

Given the increasing incidence and high mortality rate of transfusion-transmitted babesiosis, the U.S. Food and Drug Administration

(FDA) has recommended that blood donated in 14 endemic states

and the District of Columbia be screened for B. microti DNA with a

nucleic acid test. In January 2019, the FDA approved the use of an

ultrasensitive nucleic acid test that detects transcripts of the parasite’s

18S rRNA gene. Screening of the blood supply, once implemented,

likely will reduce if not prevent transfusion-transmitted babesiosis. At

present, individuals with a history of babesiosis or asymptomatic Babesia infection confirmed by laboratory testing are indefinitely deferred

from donating blood.

Given the lack of vaccine and prophylaxis, individuals who reside in

endemic areas, especially those at risk of severe babesiosis, should wear

protective clothing, apply tick repellents to the skin and permethrin to

clothing, and limit outdoor activities where ticks abound from May

through October. The skin should be thoroughly examined after outdoor activities and ticks carefully removed with tweezers. As babesiosis

continues to spread into new areas and because climate change likely

will shift the boundaries of these endemic areas, individuals at risk and

physicians should remain aware of this once neglected disease.

■ FURTHER READING

Gray EB, Herwaldt BL: Babesiosis surveillance—United States,

2011–2015. MMWR Surveill Summ 68:1, 2019.

Kletsova EA et al: Babesiosis in Long Island: Review of 62 cases

focusing on treatment with azithromycin and atovaquone. Ann Clin

Microbiol Antimicrob 16:26, 2017.

Krause PJ et al: Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 46:370, 2008.

Krause PJ et al: Clinical practice guidelines by the Infectious Diseases

Society of America (IDSA): 2020 guideline on diagnosis and management of babesiosis. Clin Infect Dis 72:185, 2021.

Nixon CP et al: Adjunctive treatment of clinically severe babesiosis

with red blood cell exchange: A case series of nineteen patients.

Transfusion 59:2629, 2019.

Vannier E, Krause PJ: Human babesiosis. N Engl J Med 366:2397,

2012.

Encompassing a complex group of disorders, leishmaniasis is caused

by unicellular eukaryotic obligatory intracellular protozoa of the genus

Leishmania and primarily affects the host’s reticuloendothelial system.

Leishmania species produce widely varying clinical syndromes ranging from self-healing cutaneous ulcers to fatal visceral disease. These

syndromes fall into three broad categories: visceral leishmaniasis (VL),

cutaneous leishmaniasis (CL), and mucosal leishmaniasis (ML).

■ ETIOLOGY AND LIFE CYCLE

Leishmaniasis is caused by ~20 species of the genus Leishmania in the

order Kinetoplastida and the family Trypanosomatidae (Table 226-1).

Several clinically important species are of the subspecies Viannia. The

organisms are transmitted by phlebotomine sandflies of the genus Phlebotomus in the “Old World” (Asia, Africa, and Europe) and the genus

Lutzomyia in the “New World” (the Americas). Transmission may be

anthroponotic (i.e., the vector transmits the infection from infected

humans to healthy humans) or zoonotic (i.e., the vector transmits the

infection from an animal reservoir to humans). Human-to-human

transmission via shared infected needles has been documented in IV

drug users in the Mediterranean region. In utero transmission to the

fetus occurs rarely.

226 Leishmaniasis

Shyam Sundar

1742 PART 5 Infectious Diseases

TABLE 226-1 Geographic Distribution and Characteristic Epidemiology of Leishmaniases

ORGANISM, ENDEMIC REGION

CLINICAL

SYNDROME SPECIES VECTOR RESERVOIR TRANSMISSION SETTING

Leishmania donovani Complex

South Asia VL, PKDL L. donovani Phlebotomus

argentipes

Humans Anthroponotic Rural, domestic

South Sudan, Sudan, South Sudan,

Somalia, Ethiopia, Kenya, Uganda

VL, PKDL L. donovani P. orientalis,

P. martini

Humans,

rodents in

Sudan, canines

Anthroponotic,

occasionally

zoonotic

Majority peridomestic,

occasionally sylvatic

Mediterranean basin, Middle East, Central

Asia, China

VL, CL L. infantum P. perniciosus,

P. ariasi

Dogs, foxes,

jackals

Zoonotic Domestic, peridomestic

Middle East, Saudi Arabia, Yemen VL L. donovani P. perniciosus,

P. ariasi

Dogs, foxes,

jackals

Zoonotic Domestic, peridomestic

Central and South America VL, CL L. infantuma Lutzomyia

longipalpis

Foxes, dogs,

opossums

Zoonotic Domestic, peridomestic,

periurban

Azerbaijan, Armenia, Georgia,

Kazakhstan, Kyrgyzstan, Tajikistan,

Turkmenistan, Uzbekistan

VL L. infantum P. turanicus Humans, dogs,

foxes

Anthroponotic,

zoonotic

Domestic

L. tropica

Western India to Turkey, parts of

North and East Africa

CL,

leishmaniasis

recidivans

L. tropica P. sergenti Humans Anthroponotic Urban domestic,

peridomestic

L. major

Western and Central Asia, North and

sub-Saharan Africa

CL L. major P. papatasi,

P. duboscqi

Nile rats,

rodents

Zoonotic Sylvatic, peridomestic

Kazakhstan, Turkmenistan, Uzbekistan CL L. major P. papatasi,

P. duboscqi

Gerbils Zoonotic Rural

L. aethiopica

Ethiopia, Uganda, Kenya CL, DCL L. aethiopica P. longipes,

P. pedifer

Hyraxes Zoonotic Sylvatic, peridomestic

Subspecies Viannia

Peru, Ecuador CL, ML L. (V.) peruviana Lutzomyia

verrucarum,

L. peruensis

Wild rodents Zoonotic Andean Valleys

Guyana, Surinam, French Guyana,

Ecuador, Brazil, Colombia, Bolivia

CL, ML L. (V.) guyanensis L. umbratilis Sloths, arboreal

anteaters,

opossums

Zoonotic Tropical forest

Central America, Ecuador, Colombia CL, ML L. (V.) panamensis L. trapidoi Sloths Zoonotic Tropical forest and

deforested areas

South and Central America CL, ML L. (V.) braziliensis Lutzomyia spp.,

L. umbratilis,

Psychodopygus

wellcomei

Forest rodents,

peridomestic

animals

Zoonotic Tropical forest and

deforested areas

L. mexicana Complex

Central America and northern parts of

South America

CL, ML, DCL L. amazonensis L. flaviscutellata Forest rodents Zoonotic Tropical forest and

deforested areas

CL, ML, DCL L. mexicana L. olmeca Variety of forest

rodents and

marsupials

Zoonotic Tropical forest and

deforested areas

CL, DCL L. pifanoi L. olmeca Variety of forest

rodents and

marsupials

Zoonotic Tropical forest and

deforested areas

a

L. infantum is designated L. chagasi in the New World.

Abbreviations: CL, cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; ML, mucosal leishmaniasis; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral

leishmaniasis.

Leishmania organisms occur in two forms: extracellular, flagellate

promastigotes (length, 10–20 μm) in the sandfly vector and intracellular, nonflagellate amastigotes (length, 2–4 μm; Fig. 226-1) in vertebrate

hosts, including humans. Promastigotes are introduced through the

proboscis of the female sandfly into the skin of the vertebrate host.

Neutrophils predominate among the host cells that first encounter

and take up promastigotes at the site of parasite delivery. The infected

neutrophils may undergo apoptosis and release viable parasites that

are taken up by macrophages, or the apoptotic cells may themselves be

taken up by macrophages and dendritic cells. The parasites multiply as

amastigotes inside macrophages, causing cell rupture with subsequent

invasion of other macrophages. While feeding on infected hosts, sandflies pick up amastigotes, which transform into the flagellate form in

the flies’ posterior midgut and multiply by binary fission; the promastigotes then migrate to the anterior midgut and can infect a new host

when flies take another blood meal.

■ EPIDEMIOLOGY

Leishmaniasis occurs in 98 countries—most of them developing—in

tropical and temperate regions (Fig. 226-2). More than 1.5 million

cases occur annually, of which 0.7–1.2 million are CL (and its variations) and 200,000–400,000 are VL. More than 350 million people are

1743CHAPTER 226 Leishmaniasis

FIGURE 226-1 A macrophage with numerous intracellular amastigotes (2–4 μm)

in a Giemsa-stained splenic smear from a patient with visceral leishmaniasis.

Each amastigote contains a nucleus and a characteristic kinetoplast consisting of

multiple copies of mitochondrial DNA. A few extracellular parasites are also visible.

Visceral Leishmaniasis Cutaneous Leishmaniasis CL and VL

FIGURE 226-2 Worldwide distribution of human leishmaniasis. CL, cutaneous leishmaniasis; VL, visceral leishmaniasis.

at risk, with an overall prevalence of 12 million. The distribution of

Leishmania is limited by the distribution of sandfly vectors.

■ VISCERAL LEISHMANIASIS

VL (also known as kala-azar, a Hindi term meaning “black fever”)

is caused by the Leishmania donovani complex, which includes

L. donovani and Leishmania infantum (the latter designated Leishmania chagasi in the New World); these species are responsible for anthroponotic and zoonotic transmission, respectively. India and neighboring

Bangladesh, Sudan and neighboring South Sudan, Ethiopia, and Brazil

are the four largest foci of VL and account for 90% of the world’s VL

burden. Human leishmaniasis is on the increase worldwide except

on the Indian subcontinent (India, Nepal, and Bangladesh), where a

VL elimination program has been implemented, and VL incidence

is markedly declining. More than 90% of the program sites in these

three countries have reached the elimination target of the incidence

of <1 in 10,000 persons. East Africa now has the distinction of being

the largest focus of VL. Zoonotic VL is reported from all countries in

the Middle East, Pakistan, and other countries from western Asia to

China. Endemic foci also exist in the independent states of the former

Soviet Union, mainly Georgia and Azerbaijan. In the Horn of Africa,

Sudan, South Sudan, Ethiopia, Kenya, Uganda, and Somalia report VL.

In Sudan and South Sudan, large outbreaks are thought to be anthroponotic, although zoonotic transmission also occurs. VL is rare in West

and sub-Saharan Africa.

Mediterranean VL, long an established endemic disease due to

L. infantum, has a large canine reservoir and was seen primarily in

infants before the advent of HIV infection. In Mediterranean Europe,

70% of adult VL cases are associated with HIV co-infection. The

combination is deadly because of the combined impact of the two

infections on the immune system. IV drug users are at particular risk.

Other forms of immunosuppression (e.g., that associated with organ

transplantation) also predispose to VL. In the Americas, disease caused

by L. infantum is endemic from Mexico to Argentina, but 90% of cases

in the New World are reported from northeastern Brazil. After the

introduction of highly active antiretroviral therapy, the incidence of

HIV–VL co-infection declined significantly in Europe; however, ~30

and 5% of VL patients are co-infected with HIV in Ethiopia and India,

respectively.

Immunopathogenesis The majority of individuals infected by

L. donovani or L. infantum mount a successful immune response

and control the infection, never developing symptomatic disease.

Forty-eight hours after intradermal injection of killed promastigotes,

these individuals exhibit delayed-type hypersensitivity (DTH) to leishmanial antigens in the leishmanin skin test (also called the Montenegro

skin test). Results in mouse models indicate that the development of

acquired resistance to leishmanial infection is controlled by the production of interleukin (IL) 12 by antigen-presenting cells and the subsequent secretion of interferon (IFN) γ, tumor necrosis factor (TNF)

α, and other proinflammatory cytokines by the T helper 1 (TH1) subset

of T lymphocytes. The immune response in patients developing active

VL is complex; in addition to increased production of multiple proinflammatory cytokines and chemokines, patients with active disease

have markedly elevated levels of IL-10 in serum as well as enhanced

IL-10 mRNA expression in lesional tissues. A direct role for IL-10 in

the pathology of VL in humans is supported by studies demonstrating

that IL-10 blockade can enhance IFN-γ responses in whole blood from

VL patients. The main disease-promoting activity of IL-10 in VL may

be to condition host macrophages for enhanced survival and growth

of the parasite. IL-10 can render macrophages unresponsive to activation signals and inhibit killing of amastigotes by downregulating the

production of TNF-α and nitric oxide. Multiple antigen-presentation

1744 PART 5 Infectious Diseases

functions of dendritic cells and macrophages are also suppressed by

IL-10. Patients with such suppression do not have positive leishmanin

skin tests, nor do their peripheral-blood mononuclear cells respond to

leishmanial antigens in vitro. Organs of the reticuloendothelial system

are predominantly affected, with remarkable enlargement of the spleen,

liver, and lymph nodes in some regions. The tonsils and intestinal

submucosa are also heavily infiltrated with parasites. Bone marrow

dysfunction results in pancytopenia.

Clinical Features On the Indian subcontinent and in the Horn of

Africa, persons of all ages are affected by VL. In endemic areas of the

Americas and the Mediterranean basin, immunocompetent infants

and small children as well as immunodeficient adults are affected

especially often. The most common presentation of VL is an abrupt

onset of moderate- to high-grade fever associated with rigor and chills.

Fever may continue for several weeks with decreasing intensity, and

the patient may become afebrile for a short period before experiencing another bout of fever. The spleen may be palpable by the second

week of illness and, depending on the duration of illness, may become

hugely enlarged (Fig. 226-3). Hepatomegaly (usually moderate in

degree) soon follows. Lymphadenopathy is common in most endemic

regions of the world except the Indian subcontinent, where it is rare.

Patients lose weight and feel weak, and the skin gradually develops

dark discoloration due to hyperpigmentation that is most easily seen

in brown-skinned individuals. In advanced illness, hypoalbuminemia

may manifest as pedal edema and ascites. Anemia appears early and

may become severe enough to cause congestive heart failure. Epistaxis,

retinal hemorrhages, and gastrointestinal bleeding are associated with

thrombocytopenia. Secondary infections such as measles, pneumonia,

tuberculosis, bacillary or amebic dysentery, and gastroenteritis are

common. Herpes zoster, chickenpox, boils in the skin, and scabies may

also occur. Untreated, the disease is fatal in most patients, including

100% of those with HIV co-infection.

Leukopenia and anemia occur early and are followed by thrombocytopenia. There is a marked polyclonal increase in serum immunoglobulins. Serum levels of hepatic aminotransferases are raised in

a significant proportion of patients, and serum bilirubin levels are

elevated occasionally. Renal dysfunction is uncommon.

Laboratory Diagnosis Demonstration of amastigotes in smears

of tissue aspirates is the gold standard for the diagnosis of VL (Fig. 226-1).

The sensitivity of splenic smears is >95%, whereas smears of bone

marrow (60–85%) and lymph node aspirates (50%) are less sensitive.

Culture of tissue aspirates increases sensitivity. Splenic aspiration is

invasive and may be dangerous in untrained hands. Several serologic

techniques are currently used to detect antibodies to Leishmania.

An enzyme-linked immunosorbent assay (ELISA) and the indirect

immunofluorescent antibody test (IFAT) are used in sophisticated

laboratories.

In the field, however, a rapid immunochromatographic test based on

the detection of antibodies to a recombinant antigen (rK39) consisting

of 39 amino acids conserved in the kinesin region of L. infantum is

used worldwide. The test requires only a drop of fingerprick blood or

serum, and the result can be read within 15 min. Except in East Africa

(where both its sensitivity and its specificity are lower), the sensitivity

of the rK39 rapid diagnostic test (RDT) in immunocompetent individuals is ~98% and its specificity is ~90%. In Sudan, an RDT based

on a new synthetic polyprotein, rK28, was more sensitive (96.8%) and

specific (96.2%) than rK39-based RDTs. Since these antibody detection tests remain positive for years after cure, they cannot be used for

measurement of cure or detection of relapse. Qualitative detection

of leishmanial nucleic acid by polymerase chain reaction (PCR) or

by loop-mediated isothermal amplification (LAMP) and quantitative

detection by real-time PCR are highly sensitive; however, because the

capacity to perform these tests is confined to specialized laboratories,

they have yet to be used for routine diagnosis of VL in endemic areas.

PCR can distinguish among the major species of Leishmania infecting

humans.

Differential Diagnosis VL is easily mistaken for malaria. Other

febrile illnesses that may mimic VL include typhoid fever, tuberculosis,

brucellosis, schistosomiasis, and histoplasmosis. Splenomegaly due to

portal hypertension, chronic myeloid leukemia, tropical splenomegaly syndrome, and (in Africa) schistosomiasis may also be confused

with VL. Fever with neutropenia or pancytopenia in patients from an

endemic region strongly suggests a diagnosis of VL; hypergammaglobulinemia in patients with long-standing illness strengthens the diagnosis. In nonendemic countries, a careful travel history is essential when

any patient presents with fever.

TREATMENT

Visceral Leishmaniasis

GENERAL CONSIDERATIONS

Severe anemia should be corrected by blood transfusion, and other

comorbid conditions should be managed promptly. Treatment of

VL is complex because the optimal drug, dosage, and duration

vary with the endemic region. Despite completing recommended

treatment, some patients experience relapse (most often within

6−12 months), and prolonged follow-up is recommended. A pentavalent antimonial is the drug of choice in most endemic regions

of the world, but there is widespread resistance to antimony in

the Indian state of Bihar, where either amphotericin B (AmB)—

deoxycholate or liposomal—or miltefosine is preferred. Dose requirements for AmB are lower in India than in the Americas, Africa, or

the Mediterranean region. In Mediterranean countries, where cost

is seldom an issue, liposomal AmB (LAmB) is the drug of choice.

In immunocompetent patients, relapses are uncommon with AmB

in its deoxycholate and lipid formulations. Antileishmanial therapy

FIGURE 226-3 A patient with visceral leishmaniasis has a hugely enlarged spleen

visible through the surface of the abdomen. Splenomegaly is the most important

feature of visceral leishmaniasis.

1745CHAPTER 226 Leishmaniasis

has recently evolved as new drugs and delivery systems have become

available and resistance to antimonial compounds has emerged.

Except for AmB (deoxycholate and lipid formulations), antileishmanial drugs are available in the United States only from the Centers

for Disease Control and Prevention Drug Service (telephone: 404-

639-3670; email: drugservice@ cdc.gov; www.cdc.gov/ncpdcid/dsr/).

PENTAVALENT ANTIMONIAL COMPOUNDS

Two pentavalent antimonial (SbV) preparations are available:

sodium stibogluconate (100 mg of SbV/mL) and meglumine antimoniate (85 mg of SbV/mL). The daily dose is 20 mg/kg by IV

infusion or IM injection, and therapy continues for 28–30 days.

Cure rates exceed 90% in Africa, the Americas, and most of the Old

World but are <50% in Bihar, India, as a result of resistance. Adverse

reactions to SbV treatment are common and include arthralgia,

myalgia, and elevated serum levels of aminotransferases. Electrocardiographic changes are common. Concave ST-segment elevation

is not significant, but prolongation of QTc to >0.5 s may herald

ventricular arrhythmia and sudden death. Chemical pancreatitis is

common but usually does not require discontinuation of treatment;

severe clinical pancreatitis occurs in immunosuppressed patients.

AMPHOTERICIN B

AmB is currently used as a first-line drug in Bihar, India. In other

parts of the world, it is used when initial antimonial treatment fails.

Conventional AmB deoxycholate is administered in doses of 0.75–1.0

mg/kg on alternate days for a total of 15 infusions. Fever with chills

is an almost universal adverse reaction to AmB infusions. Nausea

and vomiting are also common, as is thrombophlebitis in the infused

veins. Acute toxicities can be minimized by administration of antihistamines like chlorpheniramine and antipyretic agents like acetaminophen before each infusion. AmB can cause renal dysfunction and

hypokalemia and, in rare instances, elicits hypersensitivity reactions,

bone marrow suppression, and myocarditis, all of which can be fatal.

Several lipid formulations of AmB, developed to replace the

deoxycholate formulation, are preferentially taken up by reticuloendothelial tissues. Because very little free drug is available to cause

toxicity, a large amount of drug can be delivered over a short period.

LAmB has been used extensively to treat VL in all parts of the

world. With a terminal half-life of ~150 h, LAmB can be detected in

the liver and spleen of animals for several weeks after a single dose.

In addition to oral miltefosine (see below), this is the only drug

approved by the U.S. Food and Drug Administration (FDA) for the

treatment of VL; the regimen is 3 mg/kg daily on days 1–5, 14, and 21

(total dose, 21 mg/kg). However, the total-dose requirement for different

regions of the world varies widely. In Asia, it is 10–15 mg/kg; in Africa,

~18 mg/kg; and in Mediterranean/American regions, ≥20 mg/kg.

The daily dose is flexible (1–10 mg/kg). In a study in India, a single

dose of 10 mg/kg cured infection in 96% of patients. This singledose regimen is the preferred treatment in India, Bangladesh, and

Nepal. Adverse effects of LAmB are usually mild and include infusion reactions, backache, and occasional reversible nephrotoxicity.

PAROMOMYCIN

Paromomycin (aminosidine) is an aminocyclitol-aminoglycoside

antibiotic with antileishmanial activity. Its mechanism of action

against Leishmania has yet to be established. Paromomycin is

approved in India for the treatment of VL at an IM dose of 11 mg

of base/kg daily for 21 days; this regimen produces a cure rate of

94.6%. However, the optimal dose has not been established in other

endemic regions. Paromomycin is a relatively safe drug, but some

patients develop hepatotoxicity, reversible ototoxicity, and (in rare

instances) nephrotoxicity and tetany. Paromomycin, in combination with SbV

, is used in sub-Saharan Africa.

MILTEFOSINE

Miltefosine, an alkylphosphocholine, is the first oral compound

approved for the treatment of leishmaniasis in several endemic

countries including the United States. This drug has a long half-life

(150–200 h); its mechanism of action is not clearly understood.

The recommended therapeutic regimens for patients on the Indian

subcontinent are a daily dose of 50 mg for 28 days for patients

weighing <25 kg, a twice-daily dose of 50 mg for 28 days for patients

weighing ≥25 kg, and 2.5 mg/kg for 28 days for children 2–11 years

of age. These regimens have resulted in a cure rate of 94% in India.

However, recent studies from the Indian subcontinent indicate a

decline in the cure rate. Doses in other regions remain to be established. Because of its long half-life, miltefosine is prone to induce

resistance in Leishmania. Its adverse effects include mild to moderate vomiting and diarrhea in 40 and 20% of patients, respectively;

these reactions usually clear spontaneously after a few days. Rare

cases of severe allergic dermatitis, hepatotoxicity, and nephrotoxicity have been reported. Because miltefosine is expensive and is

associated with significant adverse events, it is best administered

as directly observed therapy to ensure completion of treatment and

to minimize the risk of resistance induction. Because miltefosine is

teratogenic in rats, its use is contraindicated during pregnancy and

(unless contraceptive measures are strictly adhered to for at least

3 months after treatment) in women of childbearing age.

MULTIDRUG THERAPY

Multidrug therapy for leishmaniasis is likely to be preferred in the

future. Its potential advantages in VL include (1) better compliance

and lower costs associated with shorter treatment courses and

decreased hospitalization, (2) less toxicity due to lower drug doses

and/or shorter duration of treatment, and (3) a reduced likelihood

that resistance to either agent will develop. In a study from India,

one dose of LAmB (5 mg/kg) followed by miltefosine for 7 days,

paromomycin for 10 days, or both miltefosine and paromomycin

simultaneously for 10 days (in their usual daily doses) produced a

cure rate of >97% (all three combinations). In Africa, a combination

of SbV and paromomycin given for 17 days was as effective and safe

as SbV given for 30 days. Studies are being conducted in East Africa

to test combination chemotherapy with recently approved drugs

such as miltefosine and LAmB.

Prognosis of Treated VL Patients Recovery from VL is quick.

Within a week after the start of treatment, defervescence, regression of

splenomegaly, weight gain, and recovery of hematologic parameters are

evident. With effective treatment, no parasites are recovered from tissue

aspirates at the posttreatment evaluation. Continued clinical improvement

over 12 months is suggestive of cure. A small percentage of patients (with

the exact figure depending on the regimen used) relapse but respond well

to retreatment with AmB deoxycholate or lipid formulations.

VL in the Immunocompromised Host HIV/VL co-infection

has been reported from 35 countries. Where both infections are

endemic, VL behaves as an opportunistic infection in HIV-1-infected

patients. HIV infection can increase the risk of VL development by

several-fold in endemic areas. Co-infected patients usually show the

classic signs of VL, but they may present with atypical features due

to loss of immunity and involvement of unusual anatomic locations,

e.g., infiltration of the skin, oral mucosa, gastrointestinal tract, lungs,

and other organs. Serodiagnostic tests may be negative in up to 50% of

patients. Parasites can be recovered from unusual sites such as bronchoalveolar lavage fluid and buffy coat. LAmB is the drug of choice for

HIV/VL co-infection—both for primary treatment and for treatment

of relapses. A total dose of 40 mg/kg, administered as 4 mg/kg on days

1–5, 10, 17, 24, 31, and 38, is considered optimal and is approved by the

FDA, but most patients experience a relapse within 1 year. Pentavalent

antimonials and AmB deoxycholate can also be used where LAmB is

not accessible. Reconstitution of patients’ immunity by antiretroviral

therapy has led to a dramatic decline in the incidence of co-infection

in the Mediterranean basin. In contrast, HIV/VL co-infection is on

the rise in African and Asian countries. Ethiopia is worst affected: up

to 30% of VL patients are also infected with HIV. Because restoration

of the CD4+ T-cell count to >200/μL does decrease the frequency of

relapse, antiretroviral therapy (in addition to antileishmanial therapy) is a cornerstone of the management of HIV/VL co-infection.

1746 PART 5 Infectious Diseases

Secondary prophylaxis with pentamidine or lipid AmB has been shown

to delay relapses, but no regimen has been established as optimal.

Post–Kala-Azar Dermal Leishmaniasis On the Indian subcontinent and in Sudan and other East African countries, 2–50% of

patients develop skin lesions concurrent with or after the cure of VL.

Most common are hypopigmented macules, papules, and/or nodules

or diffuse infiltration of the skin and sometimes of the oral mucosa.

The African and Indian diseases differ in several respects; important

features of post–kala-azar dermal leishmaniasis (PKDL) in these two

regions are listed in Table 226-2, and disease in an Indian patient is

depicted in Fig. 226-4.

In PKDL, parasites are scanty in hypopigmented macules but may

be seen and cultured more easily from nodular lesions. Cellular infiltrates are heavier in nodules than in macules. Lymphocytes are the

dominant cells; next most common are histiocytes and plasma cells. In

about half of cases, epithelioid cells—scattered individually or forming

compact granulomas—are seen. The diagnosis is based on history and

clinical findings, but rK39 and other serologic tests are positive in

most cases. Indian PKDL was treated with prolonged courses (up to

120 days) of pentavalent antimonials. This prolonged course frequently

led to noncompliance. The alternative—several courses of AmB spread

over several months—is expensive and unacceptable for most patients.

Except for cosmetic reasons, these patients do not have any physical

limitation, and thus motivation for such long and arduous treatment is

very low. This leads to either no or incomplete treatment. In the Indian

subcontinent, the currently recommended regimen is oral miltefosine

for 12 weeks, in the usual daily doses. This regimen cures most patients;

however, its lower efficacy is now being reported in some studies. The

efficacy of LAmB in combination with miltefosine in PKDL is being

tested on the Indian subcontinent. In East Africa, a majority of patients

experience spontaneous healing. In those with persistent lesions, the

response to 60 days of treatment with a pentavalent antimonial is good.

■ CUTANEOUS LEISHMANIASIS

CL can be broadly divided into Old World and New World forms. Old

World CL caused by Leishmania tropica is anthroponotic and is confined to urban or suburban areas throughout its range. Zoonotic CL is

most commonly due to Leishmania major, which naturally parasitizes

several species of desert rodents that act as reservoirs over wide areas

of the Middle East, Africa, and central Asia. Local outbreaks of human

disease are common. Major outbreaks currently affect Afghanistan,

Syria, Iraq, Lebanon, and Turkey in association with refugees and

population movement. CL is increasingly seen in tourists and military personnel on mission in CL-endemic regions of countries and

as a co-infection in HIV-infected patients. Leishmania aethiopica is

restricted to the highlands of Ethiopia, Kenya, and Uganda, where it

is a natural parasite of hyraxes. New World CL is mainly zoonotic and

is most often caused by Leishmania mexicana, Leishmania (Viannia)

panamensis, and Leishmania amazonensis. A wide range of forest

animals act as reservoirs, and human infections with these species

are predominantly rural. As a result of extensive urbanization and

deforestation, Leishmania (Viannia) braziliensis has adapted to peridomestic and urban animals, and CL due to this organism is increasingly

becoming an urban disease. In the United States, a few cases of CL have

been acquired indigenously in Texas.

Immunopathogenesis As in VL, the proinflammatory (TH1)

response in CL may result in either asymptomatic or subclinical infection. However, in some individuals, the immune response causes ulcerative skin lesions, the majority of which heal spontaneously, leaving a

scar. Healing is usually followed by immunity to reinfection with that

species of parasite.

Clinical Features A few days or weeks after the bite of a sandfly,

a papule develops and grows into a nodule that ulcerates over weeks

or months. The base of the ulcer, which is usually painless, consists of

necrotic tissue and crusted serum, but secondary bacterial infection

sometimes occurs. The margins of the ulcer are raised and indurated.

Lesions may be single or multiple and vary in size from 0.5 to >3 cm

(Fig. 226-5). Lymphatic spread and lymph gland involvement may be

palpable and may precede the appearance of the skin lesion. There may

be satellite lesions, especially in L. major and L. tropica infections. The

lesions usually heal spontaneously after 2–15 months. Lesions due to

L. major and L. mexicana tend to heal rapidly, whereas those due to

L. tropica and parasites of subspecies Viannia heal more slowly. In CL

caused by L. tropica, new lesions—usually scaly, erythematous papules

and nodules—develop in the center or periphery of a healed sore, a

condition known as leishmaniasis recidivans. Lesions of L. mexicana

and Leishmania (Viannia) peruviana closely resemble those seen in

the Old World; however, lesions on the pinna of the ear are common, chronic, and destructive in the former infections. L. mexicana

TABLE 226-2 Clinical, Epidemiologic, and Therapeutic Features of

Post–Kala-Azar Dermal Leishmaniasis: East Africa and the Indian

Subcontinent

FEATURE EAST AFRICA INDIAN SUBCONTINENT

Most affected country Sudan and South Sudan Bangladesh

Incidence among

patients with VL

~50% 5–15%

Interval between VL and

PKDL

During VL to 6 months 6 months to 3 years

Age distribution Mainly children Any age

History of prior VL Yes Not necessarily

Rashes of PKDL in

presence of active VL

Yes No

Treatment with sodium

stibogluconate

2–3 months 2–4 months

Natural course Spontaneous cure in

majority of patients

Spontaneous cure in

minority of patients

Abbreviations: PKDL, post–kala-azar dermal leishmaniasis; VL, visceral

leishmaniasis.

FIGURE 226-4 Post–kala-azar dermal leishmaniasis in an Indian patient. Note

nodules of varying size involving the entire face. The face is erythematous, and the

surface of some of the large nodules is discolored.

1747CHAPTER 226 Leishmaniasis

FIGURE 226-5 Cutaneous leishmaniasis in a Bolivian child. There are multiple

ulcers resulting from several sandfly bites. The edges of the ulcers are raised.

(Courtesy of P. Desjeux, Retired Medical Officer, World Health Organization, Geneva,

Switzerland.)

is responsible for chiclero’s ulcer, the so-called self-healing sore of

Mexico. CL lesions on exposed body parts (e.g., the face and hands),

permanent scar formation, and social stigmatization may cause anxiety

and depression and may affect the quality of life of CL patients.

Differential Diagnosis A typical history (an insect bite followed

by the events leading to ulceration) in a resident of or a traveler to an

endemic focus strongly suggests CL. Cutaneous tuberculosis, fungal

infections, leprosy, sarcoidosis, and malignant ulcers are sometimes

mistaken for CL.

Laboratory Diagnosis Demonstration of amastigotes in material

obtained from a lesion remains the diagnostic gold standard. Microscopic examination of slit skin smears, aspirates, or biopsies of the

lesion is used for detection of parasites. Culture of smear or biopsy

material may yield Leishmania. PCR is more sensitive than microscopy

and culture and allows identification of Leishmania to the species level.

This information is important in decisions about therapy because

responses to treatment can vary with the species. Isoenzyme profiling

is used to determine species for research purposes.

TREATMENT

Cutaneous Leishmaniasis

Although lesions heal spontaneously in the majority of cases, their

spread or persistence indicates that treatment may be needed. One

or a few small lesions due to “self-healing species” can be treated

with topical agents. Systemic treatment is required for lesions over

the face, hands, or joints; multiple lesions; large ulcers; lymphatic

spread; New World CL with the potential for development of ML;

and CL in HIV-co-infected patients.

A pentavalent antimonial is the first-line drug for all forms of CL

and is used in a dose of 20 mg/kg for 20 days. The exceptions to this

rule are CL caused by Leishmania (Viannia) guyanensis, for which

pentamidine isethionate is the drug of choice (two injections of

4 mg of salt/kg separated by a 48-h interval), and CL due to L.

aethiopica, which responds to paromomycin (16 mg/kg daily)

but not to antimonials. Relapses usually respond to a second

course of treatment. In Peru, topical imiquimod (5–7.5%) plus

parenteral antimonials have been shown to cure CL more rapidly

than antimonials alone. Azoles and triazoles have been used with

mixed responses in both Old and New World CL but have not

been adequately assessed for this indication in clinical trials. In L.

major infection, oral fluconazole (200 mg/d for 6 weeks) resulted

in a higher rate of cure than placebo (79% vs 34%) and also cured

infection faster. Adverse effects include gastrointestinal symptoms

and hepatotoxicity. Ketoconazole (600 mg/d for 28 days) is 76–90%

effective in CL due to L. (V.) panamensis and L. mexicana in Panama

and Guatemala. Miltefosine has been used in CL in doses of 2.5 mg/

kg for 28 days. This agent is effective against L. major infections. In

Colombia, where CL is due to L. (V.) panamensis, miltefosine was

also effective, with a cure rate of 91%. For L. (V.) braziliensis infections, however, the results with miltefosine are less consistent. In

Brazil, miltefosine cured 71% of patients with L. (V.) guyanensis

infection. Other drugs, such as dapsone, allopurinol, rifampin,

azithromycin, and pentoxifylline, have been used either alone or

in combinations, but most of the relevant studies have had design

limitations that preclude meaningful conclusions.

Small lesions (≤3 cm in diameter) may conveniently be treated

weekly until cure with an intralesional injection of a pentavalent

antimonial at a dose adequate to blanch the lesion (0.2–2.0 mL). An

ointment containing 15% paromomycin sulfate, either alone or with

0.5% gentamicin or 12% methylbenzonium chloride, cured 70–82%

of lesions due to L. major in 20 days and may be suitable for lesions

caused by other species. Heat therapy with an FDA-approved radiofrequency generator and cryotherapy with liquid nitrogen have also

been used successfully.

Diffuse Cutaneous Leishmaniasis (DCL) DCL is a rare form

of leishmaniasis caused by L. amazonensis and L. mexicana in South

and Central America and by L. aethiopica in Ethiopia and Kenya. DCL

is characterized by the lack of a cell-mediated immune response to

the parasite, the uncontrolled multiplication of which thus continues

unabated. The DTH response does not develop, and lymphocytes do

not respond to leishmanial antigens in vitro. DCL patients have a

polarized immune response with high levels of immunosuppressive

cytokines, including IL-10, transforming growth factor (TGF) β, and

IL-4, and low concentrations of IFN-γ. Profound immunosuppression leads to widespread cutaneous disease. Lesions may initially be

confined to the face or a limb but spread over months or years to

other areas of the skin. They may be symmetrically or asymmetrically

distributed and include papules, nodules, plaques, and areas of diffuse

infiltration. These lesions do not ulcerate. The overlying skin is usually erythematous in pale-skinned patients. The lesions are teeming

with parasites, which are therefore easy to recover. DCL does not heal

spontaneously and is difficult to treat. If relapse and drug resistance

are to be prevented, treatment should be continued for some time after

lesions have healed and parasites can no longer be isolated. In the New

World, repeated 20-day courses of pentavalent antimonials are given,

with an intervening drug-free period of 10 days. Miltefosine has been

used for several months with a good initial response. Combinations

should be tried. In Ethiopia, a combination of paromomycin (14 mg/

kg per day) and sodium stibogluconate (10 mg/kg per day) is effective.

■ MUCOSAL LEISHMANIASIS

The subgenus Viannia is widespread from the Amazon basin to

Paraguay and Costa Rica and is responsible for deep sores and for ML

(Table 226-1). In L. (V.) braziliensis infections, cutaneous lesions may

be simultaneously accompanied by mucosal spread of the disease or

followed by spread years later. ML is typically caused by L. (V.) braziliensis and rarely by L. amazonensis, L. (V.) guyanensis, and L. (V.)

panamensis. Young men with chronic lesions of CL are at particular

risk. Overall, ~3% of infected persons develop ML. Not every patient

with ML has a history of prior CL. ML is almost entirely confined to the

Americas. In rare cases, ML may also be caused by Old World species

like L. major, L. infantum (L. chagasi), or L. donovani.

Immunopathogenesis and Clinical Features The immune

response is polarized toward a TH1 response, with marked increases

of IFN-γ and TNF-α and varying levels of TH2 cytokines (IL-10 and

TGF-β). Patients have a stronger DTH response with ML than with

CL, and their peripheral-blood mononuclear cells respond strongly

to leishmanial antigens. The parasite spreads via the lymphatics or

the bloodstream to mucosal tissues of the upper respiratory tract.

Intense inflammation leads to destruction, and severe disability ensues.

1748 PART 5 Infectious Diseases

FIGURE 226-6 Mucosal leishmaniasis in a Brazilian patient. There is extensive

inflammation around the nose and mouth, destruction of the nasal mucosa,

ulceration of the upper lip and nose, and destruction of the nasal septum. (Courtesy

of R. Dietz, Universidade Federal do Espírito Santo, Vitória, Brazil.)

Lesions in or around the nose or mouth (espundia; Fig. 226-6) are

the typical presentation of ML. Patients usually provide a history of

self-healed CL preceding ML by 1–5 years. Typically, ML presents as

nasal stuffiness and bleeding followed by destruction of nasal cartilage,

perforation of the nasal septum, and collapse of the nasal bridge. Subsequent involvement of the pharynx and larynx leads to difficulty in

swallowing and phonation. The lips, cheeks, and soft palate may also

be affected. Secondary bacterial infection is common, and aspiration

pneumonia may be fatal. Despite the high degree of TH1 immunity and

the strong DTH response, ML does not heal spontaneously.

Laboratory Diagnosis Tissue biopsy is essential for identification

of parasites, but the rate of detection is poor unless PCR techniques are

used. The strongly positive DTH response fails to distinguish between

past and present infection.

TREATMENT

Mucosal Leishmaniasis

The regimen of choice is a pentavalent antimonial agent administered at a dose of 20 mg of SbV/kg for 30 days. Patients with ML

require long-term follow-up with repeated oropharyngeal and nasal

examination. With failure of therapy or relapse, patients may receive

another course of an antimonial but then become unresponsive,

presumably because of resistance in the parasite. In this situation,

AmB should be used. An AmB deoxycholate dose totaling 25–45

mg/kg is appropriate. There are no controlled trials of LAmB, but

administration of 2–3 mg/kg for 20 days is considered adequate.

Miltefosine (2.5 mg/kg for 28 days) cured 71% of ML patients in

Bolivia. The more extensive the disease, the worse is the prognosis;

thus, prompt, effective treatment and regular follow-up are essential.

■ PREVENTION OF LEISHMANIASIS

No vaccine is available for any form of leishmaniasis, although several

candidates are in early phases of development. Inoculation with live

L. major (“leishmanization”) is practiced in Iran; 80% of recipients

were protected, according to one report. Anthroponotic leishmaniasis is controlled by case finding, treatment, and vector control with

insecticide-impregnated bed nets and curtains and residual insecticide

spraying. Control of zoonotic leishmaniasis is more difficult. Use of

insecticide-impregnated collars for dogs, treatment of infected domestic dogs, and culling of street dogs are measures that have been used

with uncertain efficacy to prevent transmission of L. infantum. In

Brazil, canine vaccines have been found to promote a decrease in the

human and canine incidence of zoonotic VL. Two vaccines, Leishmune

and Leish-Tec, are licensed in Brazil; Leishmune provides significant

protection to vaccinated dogs. CaniLeish and LetiFend are the two

licensed canine vaccines approved for use in Europe. Personal prophylaxis with bed nets and repellants may reduce the risk of CL infections

in the New World.

■ FURTHER READING

Aronson NE, Joya CA: Cutaneous leishmaniasis: Updates in diagnosis and management. Infect Dis Clin North Am 33:101, 2019.

Burza S et al: Leishmaniasis. Lancet 392:951, 2018.

Chakravarty J, Sundar S: Current and emerging medications for

the treatment of leishmaniasis. Expert Opin Pharmacother 10:1251,

2019.

Monge-Maillo B, López-Vélez R: Treatment options for visceral

leishmaniasis and HIV coinfection. AIDS Rev 18:32, 2016.

Van Griensven J, Diro E: Visceral leishmaniasis: Recent advances

in diagnostics and treatment regimens. Infect Dis Clin North Am

33:79, 2019.

Myriads of protozoan parasites of the genus Trypanosoma infect plants

and animals worldwide. Among these, three are of clinical significance

for humans: T. cruzi causes Chagas disease, and T. brucei gambiense

and T. brucei rhodesiense cause human African trypanosomiasis

(HAT), which is also known as “sleeping sickness.” Despite obvious

differences in their geographic distribution, parasitic life cycle, clinical

presentation, treatment, and outcome, these vector-borne diseases are

archetypal examples of neglected tropical diseases. More broadly, these

infectious diseases affect neglected populations of the lowest socioeconomic class who have limited access to care and who live either in

remote rural areas of low- or middle-income tropical/subtropical countries or in urban areas of both endemic and nonendemic countries. The

drugs to treat these conditions are several decades old, their availability

is limited, and their efficacy and/or safety is suboptimal.

Other trypanosome species (e.g., T. congolense and T. evansi) predominantly cause nonhuman zoonoses and only occasionally cause

illness in humans.

CHAGAS DISEASE (AMERICAN

TRYPANOSOMIASIS)

■ DEFINITION

First described in 1909 by Carlos Chagas, Chagas disease (American

trypanosomiasis) is a zoonosis caused by the flagellated protozoan

T. cruzi. After a frequently asymptomatic acute phase, 30–40% of

patients develop life-threatening chronic cardiomyopathy and/or

227 Chagas Disease and

African Trypanosomiasis

François Chappuis, Yves Jackson

1749CHAPTER 227 Chagas Disease and African Trypanosomiasis

digestive tract dysfunction over the course of decades. Acute reactivation may occur in immunocompromised patients. Chagas disease

imposes an important human and social burden in Latin America

and has recently spread outside its natural boundaries to become a

global public health problem. A vast majority of affected individuals

are unaware of being infected and do not have access to appropriate

clinical management and counseling.

■ TRANSMISSION

Vectorial Transmission T. cruzi infection is primarily a zoonosis

transmitted to a range of wild and domestic mammals by bloodsucking triatomine bugs. Sylvatic, peridomiciliary, and intradomiciliary vectorial cycles sometimes overlap. Over a large geographic area in

the Americas (from northern Argentina to the southern United States),

most human infections are intradomiciliary, arising from a triatomine

bite during nighttime sleep. Feces released by triatomines during a

blood meal contain the infective metacyclic form of T. cruzi that enters

the human body through cutaneous breaks, mucosae, or conjunctivae.

Despite recent laboratory research showing the potential for transmission by bedbugs, there is no evidence that bedbugs actually transmit

T. cruzi to humans.

Nonvectorial Transmission Other modes of transmission can

cause infection in both endemic and nonendemic regions. T. cruzi can

be transmitted congenitally from mother to newborn, by transfusion of

blood products, by tissue or organ transplantation, or by ingestion

of contaminated food or drink. Congenital infection occurs in 1–10%

of newborns of infected mothers. The risk of infection from contaminated blood products is low (1.7% overall, 13% for platelet recipients,

and close to 0 for recipients of red blood cells and plasma). Transmission by infected organ and tissue transplants mostly affects heart, liver,

and kidney recipients. Oral transmission is increasingly reported after

ingestion of contaminated food (berries) or drinks (fruit or sugar cane

juice) and occasionally causes outbreaks.

■ EPIDEMIOLOGY

An estimated 6 million people are infected by T. cruzi, including

>1 million individuals with chronic cardiomyopathy. However, the true

global burden of Chagas disease is in fact uncertain. The highest numbers of infected individuals reside in Argentina, Brazil, and Mexico; the

prevalence is highest in Bolivia (6.1%), Argentina (3.6%), and Paraguay

(2.1%). In highly endemic regions of these countries, the prevalence

may exceed 40%. Formerly restricted to poor rural populations, the

distribution of cases—and, to some extent, T. cruzi transmission—has

progressively extended to cities in the context of rapid urbanization

and rural migration. A recent history of migration from a rural area is

the main risk factor in urban settings.

Overall, the prevalence and incidence of Chagas disease have sharply

declined in recent decades because of improved housing and socioeconomic conditions as well as public health interventions, including regional vector-control initiatives, implementation of systematic

screening of blood products, and improved detection of congenital

transmission. Several countries have been declared free of domiciliary transmission as a result of sustained residual insecticide-spraying

campaigns. This progress is threatened by adaptation of the vector to

the periurban environment, its resurgence in areas where spraying has

been discontinued, the development of resistance to pyrethroid insecticides, and the persistence of peridomiciliary transmission. A growing

number of localized outbreaks are being reported in previously stable

areas, with the Amazon basin particularly at risk.

Chagas disease distribution has recently expanded to nonendemic

countries in the context of increased global travel, with cases reported

more frequently in North America, Western Europe, Australia, and

Japan. The United States harbors up to 300,000 cases, mostly among

immigrants from Central America. In addition, sporadic vector-borne

infections occur in the southern states. Western Europe has 68,000–

123,000 cases, and Japan and Australia report a few thousand cases.

Despite the implementation of blood bank screening and of some

dedicated medical programs, only a small proportion of cases have

FIGURE 227-1 A cluster of Trypanosoma cruzi amastigotes with an inflammatory

infiltrate in the placenta of a congenitally infected newborn infant.

been identified and properly managed to date. A low level of awareness

among health care professionals and difficulties experienced by some

groups in accessing care appear to be major drivers. At-risk migrant

communities are frequently subject to factors that render them socially,

legally, or economically vulnerable. Moreover, the cultural perception

of Chagas as a disease embedded in poverty can create a social stigma

that complicates its management at the community level. In contrast

to immigrants, international tourists visiting endemic countries are

at very low risk of being infected, whether by reduviid bug bites or by

other routes, and reports of Chagas disease in travelers are rare.

■ PATHOLOGY

Several T. cruzi strains have been identified. These strains have partially overlapping transmission cycles and geographic distributions, but

no definitive evidence supports an association of certain strains with

specific clinical manifestations or with variation in disease severity.

The rarity of digestive tract involvement north of the Amazon basin

suggests that specific parasitic and host genetic factors may influence

the disease course. The pathogenesis of Chagas disease results from

the complex interactions between the pathogen and the host immune

response. Many questions about the relative importance of these interactions, including the role of autoimmune mechanisms, remain unanswered. After local penetration of trypomastigotes, parasites rapidly

enter the bloodstream and disseminate through the body, infecting a

wide range of nucleated cells in which they differentiate into amastigotes (Fig. 227-1). The innate immune response triggered by parasite

mucins and DNA leads to a predominantly T helper 1 response. The

production of various proinflammatory cytokines and the activation

of CD8+ T lymphocytes reduce parasitemia to a subpatent level within

4–8 weeks, a point marking the end of the acute phase.

Immune evasion mechanisms allow persistent low-intensity proliferation of amastigotes and their release into the bloodstream, with

subsequent infection of potentially all types of nucleated cells—notably

cardiac, skeletal, and smooth-muscle cells. Mechanisms that have been

postulated to determine the pathogenic evolution toward cardiomyopathy include the parasites’ persistence and the host’s inability to

downregulate the initial immune response, resulting in cell-mediated

damage and an imbalance of T helper 1 and 2 responses with excessive

production of proinflammatory cytokines. Secondary mechanisms,

such as microcirculation abnormalities and dysautonomia, may also

influence the progression of tissue damage.

In the myocardium, chronic inflammation results in cellular

destruction and the development of fibrosis leading to a segmental

loss of contractility and dilatation of the chambers, with the associated

risk of left ventricle apical aneurism. Focal hypoperfusion and tissue

damage are sources of ventricular arrhythmias, while scarring lesions

mostly affect the conduction system. Autonomic cell destruction leads

1750 PART 5 Infectious Diseases

TABLE 227-1 Characteristics of the Stages of Trypanosoma cruzi Infection

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

Acute 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 Mortality: 0.1–5% with

oral transmission or

myocarditis/encephalitis

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

Chronic

(determinate form)

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 5-year mortality: 2–63%,

depending on extent of

cardiac damage; most

important causes of death:

cardiac failure and sudden

death, followed by stroke

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

Abbreviation: ECG, electrocardiography.

to vagal and sympathetic denervation whose exact clinical significance

remains to be clarified.

T. cruzi appears to have a direct toxic effect on digestive tract intramural autonomic ganglion cells. Over time, the loss of neural cells

affects muscular tone, leading to motility disorders and ultimately to

organ dilatation (megaviscera syndrome). The esophagus and colon

are primarily affected, but lesions may occur along the whole digestive

tract. Inadequate relaxation of the lower esophageal sphincter causes

symptoms of achalasia, whereas damage to the colon ultimately mimics

Hirschsprung’s disease, with severe constipation and the risk of volvulus and toxic dilatation.

Factors reducing the cellular immune response, such as HIV

infection, posttransplantation immunosuppressive therapies, or hematologic malignancies, may increase intracellular replication of amastigotes, with increased parasitemia (reactivation). Lesions develop

predominantly in the central nervous system (CNS), the heart, and the

skin. Among HIV-positive patients, the risk of reactivation is ~20%

in the absence of antiretroviral therapies and occurs when the CD4+

T cell count falls to <100/μL. Clinically manifest T. cruzi reactivation is

an AIDS-defining opportunistic infection.

■ CLINICAL MANIFESTATIONS

The clinical manifestations of T. cruzi infection vary greatly among

individuals. The infection course is divided into two phases that are

associated with different clinical features, duration, and prognosis

(Table 227-1). The acute phase remains undetected and undiagnosed

in most individuals. While 5–10% of these early infections spontaneously resolve without treatment, T. cruzi persists for life in the vast

majority of individuals (the chronic phase); 60–70% of these individuals never develop apparent tissue damage (the indeterminate form),

but the remaining 30–40% progress toward detectable organ damage of

variable severity over decades (the determinate form). These chronic

complications include cardiac (20–30%), digestive (5–20%), or mixed

(5–10%) disorders. There is no predictor of evolution toward clinical

manifestations during the chronic phase. In patients with cardiomyopathy, bundle branch blocks are usually the first signs and may cause

no symptoms for years until more severe conduction system disease,

arrhythmias, and left ventricular dysfunction occur. Advanced cardiac

damage entails a worse prognosis than other cardiomyopathies—

notably, ischemic heart disease.

APPROACH TO THE PATIENT

Chagas Disease (American Trypanosomiasis)

More than 90% of infections go undiagnosed, and cases are frequently identified at a late stage once chronic complications develop.

The vast majority of T. cruzi–infected individuals are asymptomatic

(i.e., in the indeterminate form of the chronic phase). An awareness

of potential Chagas disease is important for general practitioners

as well as for physicians from various specialties, including gastroenterologists, cardiologists, neurologists, obstetricians, pediatricians, and infectious disease specialists. Outside endemic areas,

screening for Chagas disease should be proposed when any Latin

American individual has evocative symptoms and signs, including

abnormalities on electrocardiography (ECG) or increased risk of

(1) T. cruzi infection (Chagas disease in the mother or other family

members; origins in a highly endemic country or area; history of

unscreened blood transfusion in Latin America); (2) transmission

to others (e.g., via pregnancy or blood or organ donation); or (3)

reactivation (current or pending immunosuppression). Screening

of the relatives of an index case will probably identify additional

cases.

■ DIAGNOSIS AND STAGING

Diagnostic Confirmation Diagnostic strategies depend on the

clinical phase (Table 227-2). Detection of circulating parasites by

microscopy of the blood with concentration (e.g., by the Strout method,

microhematocrit) or by nucleic acid–based assay (polymerase chain

reaction [PCR]) is the best diagnostic approach when the parasitemia

level is high—i.e., during the acute phases, including reactivation. Once

parasitemia becomes undetectable by microscopy (a point marking

the end of the acute phase), diagnosis relies on immunologic tests

that detect anti–T. cruzi IgG. The most common techniques include

a conventional or recombinant enzyme-linked immunosorbent assay

(ELISA) and immunofluorescence assays. Two positive serologic tests

using different techniques and targeting different antigens confirm the

diagnosis of Chagas disease during the chronic phase. In the presence

of discordant serologic results, a third serologic test is warranted.

Some of the immunochromatographic rapid diagnostic tests on the

market have sufficient sensitivity and specificity to be used as first-line

1751CHAPTER 227 Chagas Disease and African Trypanosomiasis

TABLE 227-2 Diagnostic Procedures of Choice for Clinical Stages of

T. cruzi Infection

STAGE

TECHNIQUE OF

CHOICE SAMPLE DIAGNOSTIC CRITERIA

Acute Microscopy after

concentration,

PCR

Peripheral blood,

cerebrospinal or

other body fluids

Positivity in one test

Acute (early

congenital

during first 9

months of life)

Microscopy after

concentration,

PCR

Cord or peripheral

blood

Positivity in one test

Chronic

(indeterminate

and

determinate

forms)

Serology Peripheral blood Positivity in two

tests with different

techniques and

antigens

Reactivation Microscopy after

concentration,

PCR

Peripheral blood,

cerebrospinal or

other body fluids

Positivity with

evidence of increasing

parasitemia on serial

samples or extremely

high parasite load

Abbreviation: PCR, polymerase chain reaction.

D1 V1

V2

V3

V4

V5

V6

D2

D3

AVR

AVL

AVF

FIGURE 227-2 Electrocardiogram of a 43-year-old patient shows bradycardia with high-grade atrioventricular blocks.

screening tests where laboratory facilities are not easily accessible. If

the rapid diagnostic test result is positive, at least one conventional

serologic assay is necessary to confirm infection.

Diagnosis of congenital infection relies on examination of cord and/

or peripheral blood by microscopy or PCR during the first days or

weeks of life. A test conducted after 4 weeks of age is most accurate:

PCR earlier in life may be falsely positive, likely because of the passage

of T. cruzi DNA fragments from the mother to the child. If results are

negative, serologic tests should be performed at 9 months of age, once

maternal antibodies have been cleared.

During the chronic phase, the limited sensitivity (50–80%) of PCR

restricts its usefulness for primary diagnosis; however, PCR can document therapeutic failure if it yields positive results after the completion

of treatment. In the United States, the Centers for Disease Control and

Prevention (CDC) provides reference laboratory testing (see contact

information in the treatment section).

Disease Staging Once T. cruzi infection is confirmed, clinicians

should assess the presence of complications and concomitant factors

that may influence the course of the disease. The initial evaluation

includes a thorough cardiac, neurologic, and digestive history and

a clinical examination. Twelve-lead ECG with a 30-s strip is a good

screening test for Chagas-associated cardiomyopathy. The most frequently found abnormalities are right bundle branch block, left

anterior fascicular block, ventricular premature beats, repolarization

disorders, Q waves, and low QRS voltage (Fig. 227-2). An abnormal

ECG result or the presence of suggestive cardiac symptoms warrants

further investigation. Echocardiography and the 24-h Holter test are

the preferred methods for assessment of chamber dilatation, apical

aneurysm, ventricular dysfunction, and arrhythmias. Depending on

the findings, the workup can be supplemented by MRI or electrophysiologic studies. Gastroenterologic investigations are performed

in patients with suggestive symptoms, such as dysphagia and severe

constipation. Barium esophagraphy and enema are first-line diagnostic

procedures, which can be supplemented by esophageal manometry.

Megacolon is diagnosed when the sigmoid or descending colon diameter is ≥6.5 cm.

Comorbidities, including other cardiovascular risk factors, immunosuppressive conditions, and other chronic infections (e.g., with

Strongyloides stercoralis or HIV) should be investigated.

TREATMENT

Chagas Disease (American Trypanosomiasis)

ETIOLOGIC TREATMENT

Only two drugs, benznidazole and nifurtimox (Table 227-3), have

shown persistent efficacy against T. cruzi infection when administered for ≥30 days. While these drugs have been used since the early

1970s, many questions remain about their mode of action and efficacy at the different stages of infection. The treatment goal depends

on the clinical stage; the overall objectives are to cure patients who

1752 PART 5 Infectious Diseases

TABLE 227-3 Chagas Treatment Regimens and Adverse Reactions to Benznidazole and Nifurtimox

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%

Nifurtimox 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%)

6–44%

Source: From C Bern: Chagas’ Disease. N Engl J Med 373:456, 2015. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts

Medical Society.

have recent infection or reactivation, to reduce morbidity, and to

prevent transmission at later stages. Treatment is most effective

during the acute (including congenital) phase and the early chronic

phase (i.e., in patients <18 years of age), with a 60–100% cure rate.

The efficacy of treatment during the indeterminate form of the

chronic phase in patients >18 years old is not known; however,

treatment may protect against the development of cardiac damage

later in life and eliminate the risk of vertical transmission when

given before conception. In adults with chronic cardiomyopathy,

benznidazole has no impact on disease progression and mortality

risk. Neither benznidazole nor nifurtimox is effective against digestive complications. Treatment is contraindicated during pregnancy

and in advanced renal or hepatic failure. Preferred regimens and

drug tolerance vary with age. Adverse events are more frequent

among adults, who are therefore at increased risk of premature

treatment discontinuation (Table 227-3). As benznidazole seems

better tolerated than nifurtimox in adults, it is the recommended

first-line drug in this age range. Close (e.g., weekly) clinical and biological monitoring is necessary during treatment. While treatment

is usually prescribed for 60 days, the optimal duration remains a

matter of debate, with a growing interest in shorter courses.

Treatment should be undertaken for all children, women of

child-bearing age, patients in the acute phase, and patients with

reactivation. Given the uncertainties about the impact of treatment,

the decision to treat patients >18 years old who have the indeterminate form of the chronic phase should be made on an individual

basis after discussing the pros and cons with the patient. A negative

pregnancy test is mandatory before initiating treatment as the recommended drugs have not been proven to be safe in pregnancy.

The efficacy of second-line treatment (e.g., nifurtimox after failure

with benznidazole) has not been evaluated to date.

The limited efficacy of current regimens and the understanding

that living parasites are a driver of immunopathologic processes

have fueled interest in novel therapeutic approaches. These include

the addition of immunomodulatory interventions to antiparasitic

treatment and the use of combinations of antiparasitic drugs.

Drugs can be obtained through the CDC (Parasitic Diseases Public Inquiries line [404-718-4745] or parasites@cdc.gov), the CDC

Drug Service (404-639-3670), or the CDC Emergency Operations

Center (770-488-7100). In 2017, benznidazole was approved by

the U.S. Food and Drug Administration for treatment of children

2–12 years of age.

NONETIOLOGIC TREATMENT

The management of Chagas cardiomyopathy generally follows the

management guidelines for heart failure, conduction disturbances,

or ventricular arrhythmia of other etiologies. Given the high risk

of sudden death, early initiation of treatment with amiodarone or

implantation of a cardioverter defibrillator should be considered in

the presence of pathologic electrophysiologic abnormalities. Anticoagulation is recommended for primary and secondary prevention

of cardioembolic events in the presence of an intramural thrombus

or apical aneurysm. Strict control of other cardiovascular risk

factors is warranted. Chagas cardiomyopathy is a prominent indication for heart transplantation in Latin America; some evidence

indicates that the results are better than in cardiomyopathy of other

etiologies. Posttransplantation immunosuppression requires close

monitoring, given the high risk of reactivation.

Treatment of digestive dysmotility includes dietary counseling

and meals rich in fiber and hydration, with smaller portions eaten

more frequently. Drugs releasing the lower esophageal sphincter

(e.g., nifedipine or isosorbide dinitrate before meals), pneumatic

balloon dilatation, or laparoscopic myotomy improves upper gastrointestinal symptoms in the early stage. Use of botulinum toxin

is effective but requires repeated injections. Laxatives and enemas

alleviate chronic constipation in most patients. Surgery is indicated

in patients with distressing symptoms that are refractory to medical

treatment.

CLINICAL FOLLOW-UP

Defining the optimal cure after treatment remains very challenging

and is a crucial topic of research. While the search for biomarkers

(including through proteomics) to identify early indicators of treatment response holds some promise, serologic follow-up remains the

cornerstone of posttreatment monitoring in the acute phase. In the

chronic phase, there is no assay of proven value for documentation

of response. The time needed for negative seroconversion after

treatment indeed depends on the duration of infection. The interval

is short (usually months, sometimes up to 2 years) when infection

is treated during the acute (including congenital) phase. In contrast,

decades are required in adults infected during childhood. A positive

result in a posttreatment PCR indicates treatment failure, but a negative result cannot be interpreted because of the low sensitivity of

PCR during the chronic phase. The status of patients with negative

PCR results but persistent positive serology is therefore uncertain,

but these patients should be considered potentially infective as long

as serologic tests continue to yield positive results. All patients,

treated or not, should be regularly monitored. The basic yearly

assessment includes history-taking for detection of new symptoms,

clinical examination, and 12-lead ECG.

■ PREVENTION

In the absence of a vaccine, preventive measures—primary (prevention

of T. cruzi transmission), secondary (avoidance of complications), and

tertiary (reduction of morbidity and mortality)—are necessary. Screening of blood donations is being progressively implemented in endemic

areas and in countries to which high-risk groups are immigrating, and

screening should be extended to organ donation. When sustained over

prolonged periods, vector control is an effective and cost-effective

strategy to curb intradomiciliary transmission. Insecticide-impregnated

bed nets (as used for malaria) provide individual protection against

reduviid bug bites. Screening of child-bearing-age and pregnant Latin

American migrant women has been highly cost-effective in Spain,

although the cost per case detected varies with the prevalence of infection in the targeted population. Early identification of cases through