++
The leishmaniasis comprise a group
of clinical syndromes that include ulcerative skin lesions, destructive
mucosal inflammation, and disseminated visceral infection caused
by protozoan Leishmania species parasites, which
are transmitted through the bite of female sand flies.The
infection occurs in nature in a wide range of vertebrate hosts but is
particularly common in canids; rodents; and primates, including humans.
++
Leishmaniasis is caused by an obligatory intracellular protozoan
parasite that is of the Leishmania genus and belongs
to the order Kinetoplastida and family Trypanosomtidae.4 To
date, over 20 different species of Leishmania have
reportedly infected humans. These have been grouped in different
complexes, according to biochemical and genetic characteristics. Leishmania species
traditionally have been classified according to biological, clinical,
and epidemiological features as belonging to three major clinical
disease groups (Table 351-1).4 Most
populations affected by leishmaniasis, either alone or in association
with human immunodeficiency virus (HIV) infection, live in developing
countries where there is poor access to appropriate medical intervention;
this defines leishmaniasis as a neglected disease.
++
Worldwide, there are 12 million people infected with Leishmania, and
2 million new infections are reported every year; 1 to 1.5 million
with the cutaneous form and 0.5 million with visceral disease. The
disease is endemic in over 88 countries of tropical and subtropical
regions around the world, including southern Europe, North Africa,
the Middle East, the American continent, and the Indian subcontinent.1
++
The disease is associated with 2.4 million disability-adjusted
life years and close to 70,000 deaths per year. Over 90% of
the cutaneous form of leishmaniasis occurs in Afghanistan, Pakistan,
Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru; 90% of
visceral leishmaniasis occurs in India, Bangladesh, Nepal, Sudan,
and Brazil.1 In the last two decades, the coinfection of
leishmaniasis and HIV has been identified in 35 countries, mainly
Mediterranean nations, the North African region, India, and Brazil.
The adult group is the most affected, as this coinfection mainly strikes
intravenous drug users (IVDU); however, there is evidence of mother-to-child
transmission.5,6 Recently, leishmaniasis has gained importance
within the United States due to infection of military personnel
exposed to endemic areas in the Middle East.7 Global-warming
models predict a dramatic rise in the incidence of leishmaniasis
due to increase of vector range and propagation.8
++
The Leishmania parasite is transmitted through
the bite of female sand flies. Most of Leishmania infections
are zoonotic, as nearly all reservoir hosts are wild or domestic
mammals, ranging from rodents and marsupials to primates. Humans
become infected when accidentally exposed. Only two Leishmania species
can maintain anthroponotic, human-human cycle: L donovani,
which is responsible for visceral leishmaniasis (VL) in India and East
Africa, and L tropica, which is responsible for
cutaneous leishmaniasis (CL) in the Old World.5 Occasionally,
sand flies are not involved in the transmission, and VL can be directly
initiated by amastigotes via blood (shared needles, transfusion,
transplacental spread) or organ transplantation.1,2
++
Leishmania organisms have two stages in their life
cycle: (1) the amastigote found within human macrophages, which
is the obligate host cell of the parasite, and (2) the promastigote
form, found in the lumen of the sand fly gut; this form is injected into
the human when the sand fly ingests a blood meal. The amastigote
is a nonmotile, round or oval organism measuring 2 to 5 μm
and containing a central nucleus and a small rod-shaped kinetoplast associated
with a flagellar rudiment. The amastigote multiplies by longitudinal
binary fission and spreads to new host cells after destruction of
earlier infected cells (Fig. 351-1).1 Sand
flies feeding on infected hosts ingest cells containing amastigotes,
which rapidly transform into promastigotes; these multiply extracellularly
in the lumen of the sand fly gut and progressively change to infective metacyclic
promastigotes, which move forward to the pharynx, buccal cavity,
and mouthparts of the insect. The promastigote form is 15 to 20 μm
in length and 1.5 to 3.5 μm in width and has a
single anterior flagellum, a single central nucleus, and a kinetoplast
at the anterior end.1
++
++
After parasite inoculation into the host skin by an infected
sand fly, metacyclic promastigotes rapidly attach to and enter cells
of the mononuclear phagocyte system, where they transform into amastigotes
that reside and multiply within phagolysosomes.1 Promastigote
surface molecules, including the lipophosphoglycan and the glycoprotein
gp63, play a key protective role during parasite escape from cytotoxic
serum components. They function as ligands for macrophage receptors, facilitate
survival within phagolysosomes, and modulate the T lymphocyte immune
response.11 Although a clear humoral antibody response
is induced during leishmanial infection in humans and experimental
hosts, the protective immune response appears to be primarily cell-mediated. Acting
in coordination, innate and acquired immune
responses dictate overall outcome of infection, including spontaneous
healing and prevention of reactivation; in addition, the infecting Leishmania species
determine the clinical expression of the disease and the response
to treatment.1
++
Two subsets of CD4+ cells with a distinct profile of
cytokine production that influences the outcome of infection have
been identified.Accordingly, T lymphocytes that produce
interleukin-2 (IL-2) lymphotoxin; tumor necrosis factor-beta (TNF-β);
and interferon-γ (INF-γ), which
are known as TH1 cells, augment cell-mediated immune responses
by activating macrophages to kill or inhibit parasite growth, resulting
in resolution of L major infection in C57BL/6
mice.12 A macrophage cytokine, IL-12, promotes the expansion
of TH1 cells and induction of INF-γ synthesis from
natural killer cells and induces host resistance. On the other hand,
T lymphocytes that produce IL-2, IL-4, IL-5, IL-6, IL-10, and IL-13,
which promote antibody production, the TH2 cell subset, augment
humoral responses and downregulate some cell-mediated immune responses;
this leads to disseminated and fatal infection in BALB/c
mice.1,11,12
++
Another mononuclear cell cytokine, transforming growth factor-β,
exhibits potent downregulatory effects on macrophage function and
influences the T lymphocyte cytokine pattern during Leishmania infection,
favoring parasite survival.1 In murine models of disease,
innate susceptibility to L major and L
mexicana infections segregate according to genes that have
been provisionally mapped on mouse chromosomes 11 and 4, respectively.
Differences in resistance and susceptibility to L donovani infection
are under the control of the Lsh gene, located on chromosome 1.4
++
In humans, a cell-mediated immune response to Leishmania antigens
usually develops during both cutaneous and mucocutaneous diseases,
and a direct correlation exists between delayed-type hypersensitivity,
level of lymphoproliferative response, production of INF-γ,
and healing. In visceral leishmaniasis, there is depression of the cellular
immune response, and progression of disease is related to reduced
lymphocyte proliferation and decreased production of IL-2 and INF-γ.
Anti-Leishmania antibody titers are generally low in
the sera of patients with cutaneous and mucocutaneous disease but
are moderate to high in patients with visceral leishmaniasis.1 Thus,
the spectrum of clinical manifestations associated with human leishmaniasis
appears to correlate with differences in humoral and cell-mediated
responses. In cutaneous disease, manifestations include diffuse
cutaneous leishmaniasis, with multiple skin lesions containing abundant
parasites; complete cutaneous anergy; and leishmaniasis recidivans
with a low number of parasites and exaggerated hypersensitivity,
which is responsible for tissue damage. However, an appropriate
lymphocytic response usually develops in self-healing localized
cutaneous disease.
++
Similarly, many cases of visceral leishmaniasis in patients with
suitable immune responses are subclinical and self-healing. Following
infection, delayed hypersensitivity is usually suppressed, specifically
to leishmanial antigens and nonspecifically to tuberculin and other
unrelated antigens, and nonspecifically to tuberculin and other
unrelated antigens. Specific cellular immunity is regained slowly
after successful treatment, and individuals who have recovered are considered
immune to reinfection. Protective immunity generally develops only
against the homologous species causing the initial infection, although
there may be a degree of cross-reactive immunity between species
that is not reciprocal.12
+++
Clinical Manifestations
and Diagnosis
+++
Visceral Leishmaniasis
++
Visceral leishmaniasis typically is caused by organisms of the L
donovani species complex (L donovani, L infantum, and L
chagasi). L donovani is responsible for
the disease in India, Bangladesh, Nepal, Sudan, China, Ethiopia,
and Kenya; L infantum in the Mediterranean region
and Middle East, and L chagasi in Central and South
America.1 However, L tropica has been
isolated sporadically from patients with typical visceral leishmaniasis
or with post-kala-azar dermal leishmaniasis. In countries bordering
the Mediterranean shoreline, infection usually occurs in children
ages 1 to 4 years. Similarly, in South America, China, and southwest
Asia, young children are likewise affected most frequently, but
in Africa and India, visceral leishmaniasis is usually a disease
of adolescents and young adults; men are infected twice as frequently
as women, due probably to greater occupational exposure.1
++
After inoculation of metacyclic promastigotes by the vector,
the infection begins locally in the dermal macrophages at the site
of the sand fly bite and disseminates throughout the mononuclear-phagocytic
system, particularly to the spleen, liver, bone marrow, and lymph
nodes. As a result, after an incubation period ranging from 2 weeks
to several months or years, the infection can present with a variety
of clinical syndromes that range from asymptomatic infection to
disseminated visceral leishmaniasis.1 The onset is generally
insidious, with intermittent low-grade fever, sweating, weakness,
weight loss, and progressive enlargement of the liver and spleen.1 Fever
can be continuous, intermittent, or remittent, often reaching 40°C.
In some patients, the course of disease is acute (eg, high fever, chills,
malaise), and death can occur within a few weeks, but the disease
may follow a subacute or chronic course and may be oligosymptomatic
or floridly symptomatic. Anemia is invariably present and often
severe and is due to bone marrow infiltration that compromises both
the erythropoietic and the granulocytic series. Hypersplenism, autoimmunity,
and iron deficiency can also be present.
++
In addition, jaundice, petechiae, ecchymoses, and purpura can
also occur. Some patients have a prolonged illness characterized
by nonspecific clinical manifestations or can have weight loss and cachexia,
with marked abdominal distention secondary to splenomegaly and hepatomegaly
(Fig. 351-2). Femoral and inguinal
lymph nodes are moderately enlarged, but generalized lymphadenopathy
is rare and can be present in patients only in certain geographic
areas (eg, Sudan). Darkening of the skin, especially on hands, feet,
abdomen, and forehead, commonly occurs in light-skinned patients,
giving rise to the name kala-azar (black fever)
in India. In dark-skinned individuals, warty eruptions can develop.1,2 Oral
and nasopharyngeal mucosal lesions occasionally occur in patients
in India, East Africa, and Sudan, appearing as nodules or ulcers
of the gum, palate, tongue, or lip. Lesions of the nasal mucosa can
perforate the septum.1,2 Mortality of untreated persons with
established disease ranges from 75% to 95%, and
death usually occurs within 2 years as a complication of intercurrent
bacterial infections, hemorrhage, or progressive emaciation.
Bacterial pneumonia can develop as a consequence of severe neutropenia,
and pulmonary tuberculosis is a common complication.1,2
++
++
Some patients with visceral leishmaniasis develop a syndrome
called post-kala-azar dermal leishmaniasis (PKDL),
which is characterized by skin lesions (eg, macules, papules, nodules,
or patches that are pigmented or depigmented) that typically are
most prominent on the face. The syndrome may develop several years
after therapy (eg, as has happened in India) or during or within
a few months of therapy (eg, as has happened in East Africa). Lesions
may be fleeting or persistent and sometimes are associated with
relapse of the visceral infection. In settings such as India, where
the dermal lesions can be persistent and associated with plentiful
parasites, persons with PKDL serve as chronic reservoirs of infection.1
++
Since the first HIV/VL coinfection case was reported
in 1985, the spread and overlap of both infections in the major
foci of VL (India, Brazil, and eastern Africa) has become a serious
worldwide concern.2 This is because both HIV and VL infection
induce a deficit in humoral and cellular immune responses that limit
the diagnostic value of serological tests for coinfected patients.
In addition, patients with HIV may have a shorter duration of symptoms,
a poor response to treatment, a higher rate of relapse after therapy,
and higher mortality.1,2 Visceral leishmaniasis is now
recognized as an opportunistic infection of HIV-infected individuals, as
AIDS patients are at a hundred- to a thousandfold higher risk of visceral
leishmaniasis,14 and coinfection generally occurs when
patients’ CD4 cell count is less than 200 cells/mm3.2,14Following
the introduction of highly active antiretroviral therapy (HAART)
in southern Europe, the number of coinfected cases fell sharply,
but access to HAART in developing countries, where the problem is
expanding, remains inadequate.2
++
VL can also occur as an opportunistic infection in other immunosuppressed
persons, including individuals with renal transplants and hematologic
malignancies.15The differential diagnosis for VL includes
other parasitic diseases (eg, malaria with tropical splenomegaly
syndrome, African trypanosomiasis, and schistosomiasis), as well
as mycobacterial and bacterial (eg, miliary tuberculosis, typhoid
fever, brucellosis), fungal (eg, histoplasmosis), and noninfectious
diseases (eg, leukemia, lymphoma).1,10
+++
Cutaneous Leishmaniasis
++
Cutaneous leishmaniasis is widely distributed in diverse tropical
and subtropical areas of the world. Over 90% of cases occur
in Afghanistan, Algeria, Brazil, Iran, Iraq, Saudi Arabia, Sudan,
Syria, and Peru.1 This leishmanial syndrome is divided
into Old World cutaneous leishmaniasis, which is caused by L
tropica (ie, “urban disease”), L
major (ie, “rural disease”), and L
aethiopica, and American (New World) cutaneous leishmaniasis,
which typically is caused by organisms of the L mexicana and L
braziliensis species complexes.1,10,16
++
Cutaneous leishmaniasis of the Old World is caused by L
tropica, L major, and L aethiopica,
all members of the L tropica complex and transmitted
by sand flies of the genus Phlebotomus (P).10,16 New
World cutaneous leishmaniasis is a zoonosis caused by members of
the L mexicana complex and the subgenus Viannia (V),
which are transmitted by sand flies of the genus Lutzomyia (Lu).4 The
disease is endemic in the Americas, from southern Texas to most
of Central and South America as well as the Caribbean, where it
is restricted to tropical and subtropical regions from sea level
to altitudes greater than 3600 feet.18,19 The infections
occur in persons residing or working in rural areas and in travelers
to forested regions (explorers, tourists, scientists, missionaries,
hunters, and military personnel).20
++
Cutaneous leishmaniasis is mostly diagnosed in children between
the ages of 2 and 3 years with equal sex distribution in endemic
areas, although all ages are susceptible.16 When the illness
is present in adult populations, men are infected more frequently
than women, probably as a result of occupational exposure. After
an incubation period that can range from 3 weeks to 6 months, the
first sign of clinical disease appears as a small papule at the
site of the sand fly bite, most commonly on exposed areas of the
body (ie, face, ears, neck, arms, hands, legs, and feet), rarely on
the trunk, and never on the palms, soles, or hairy scalp.1The
lesions generally evolve from painless papules to nodules to depressed
ulcerative lesions with raised indurate borders but may be persistently
nodular16 (Fig. 351-3). Pain, pruritus,
and regional adenopathy may develop, depending on the case severity or
secondarily to bacterial infection. Independent of the etiologic agent,
Old World cutaneous leishmaniasis is self-limited and confers lifelong
protective immunity, at least to the homologous strain. New World
CL lesions may heal in months to years and may cause an atrophic
scar or may migrate through the lymphatic channels to produce distant
nodules that cause sporotrichoid-like lesions, as is the case of
species of the Viannia subgenus.
++
++
In any case, multiple skin lesions can result from the bites
of multiple sand flies or can be a local dissemination of infection.
Satellite lesions may form near a primary lesion and may ultimately
merge with the primary lesion.1,16 On the other hand, dry
lesions of L tropica infections are typically single
and may not ulcerate. L aethiopica infections resemble
the dry form but produce more chronic lesions lasting several years. L
mexicana lesions occur on the face and ears (40% to
60% of the cases) and are usually single papules, nodules,
or ulcers that heal spontaneously in about 6 months; however, ear
lesions (chiclero ulcer) with destruction of the pinna are more persistent.22L (V) braziliensis produces
large single or multiple lesions that heal in 6 to 18 months. Both L (V) guyanensis and L (V) panamensis produce
multiple skin ulcers and involve lymphatic nodules, occasionally
with nasopharyngeal lesions.1,10 Viscerotropic leishmaniasis, caused
by L tropica infection was reported in military personnel
in Saudi Arabia during Operation Desert Storm and also from Kenya
and Israel.23 The differential diagnosis includes pyogenic
nodules, insect bites, tertiary syphilis, yaws, tuberculosis of
the skin, lupus vulgaris, and leprosy.
++
Two unusual variants of cutaneous leishmaniasis that cause difficult-to-treat
chronic disease are diffuse cutaneous leishmaniasis (DCL), which
is an anergic variant with plentiful parasites, and leishmaniasis
recidivans, which is a hyperergic variant with scarce parasites.24Diffuse
cutaneous leishmaniasis develops in some persons who are infected
with L aethiopica or organisms in the L
mexicana complex who have specific anergy to leishmanial
antigens. This clinical form of leishmaniasis begins as a localized
papule and disseminates to cause many persistent, nonulcerative,
indurated skin lesions resembling lepromatous leprosy.1The
histopathology shows few lymphocytes but abundant parasites in vacuolated
macrophages. Leishmaniasis recidivans is a relapsing form of cutaneous
disease that has been associated only with L tropica infections;
it is found primarily in Iran, Iraq, and neighboring areas.
++
The lesions often begin on the face and may persist for 20 years
or more. Satellite lesions appear at the margins of healing primary
lesions, forming small, painless, hard papules. Parasites are rare,
the delayed skin-test reaction is positive, and the condition is
considered a hypersensitive reaction.16
+++
Mucocutaneous
Leishmaniasis
++
Mucosal leishmaniasis is the metastatic complication of cutaneous
leishmaniasis in which nasal, buccal, pharyngeal, and sometimes
laryngeal tissues become infected because of lymphatic or hematogenous
dissemination of parasites; this occurs in up to 5% of
individuals infected with L (V) braziliensis species
complex, L panamensis, or L guyanensis.
The disease occurs after several months to years (within 2 years
of infection in 50% of cases) after the initial cutaneous
lesion has healed. This illness should be considered in patients
who develop persistent, unusual nasal symptoms such as epistaxis
or nasal obstruction. Inflammation of the nasal, pharyngeal, and
oral mucosa is followed by progressive ulceration and destruction
of the nasal septum, nasal turbinate tissue, palate, lips, pharynx,
and larynx. The uvula is swollen and subsequently can be destroyed.
Rarely, trachea, bronchi, and esophagus can be involved. Untreated
disease can progress to naso-oropharyngeal tract destruction, and
patients may die from aspiration pneumonia, starvation, or secondary
bacterial infection. Adequate treatment of the original cutaneous
lesion(s) is assumed to further reduce the risk of developing metastatic
disease. Parasitological confirmation is difficult, because amastigotes
typically are scarce. Therefore, the diagnosis commonly is based
on the clinical manifestations and on supportive laboratory data
(eg, presence of antileishmanial antibodies, positive skin test).24 Differential
diagnoses to consider include paracoccidioidomycosis, histoplasmosis,
rhinoscleroma, syphilis, tertiary yaws, midline granuloma, sarcoidosis,
and neoplasm.
+++
Visceral Leishmaniasis
++
The diagnosis of visceral leishmaniasis is confirmed parasitologically
by demonstrating the parasite in stained smears (Fig.
351-4) or cultures of a splenic aspirate, bone marrow aspirate,
liver biopsy specimen, lymph-node aspirate, biopsy specimen, or buffy-coat
preparation. In Indian cases of kala-azar and in HIV-infected patients,
parasites may be found more frequently than usual in circulating
blood monocytes. Splenic aspiration has a higher diagnostic yield
than bone marrow aspiration (ie, as high as 98% vs. 80–85%)
and is less painful, but it is also potentially more dangerous.1 The
indirect fluorescence antibody test (IFA) is positive in more than
95% of patients. The enzyme-linked immunosorbent assay
and the direct agglutination test have sensitivities greater than
90%. Except for some HIV-infected or otherwise immunocompromised persons,
as well as some persons who are infected with L tropica, most
patients with active visceral infection have moderate to high titers
of antileishmanial antibodies. In contrast, delayed-type skin-test reactivity
is noted only after recovery.
++
++
Using peripheral blood in combination with PCR technique allows the
detection of up to one Leishmania-infected macrophage
in 8 mL of blood with 90% sensitivity and 100% specificity.
In a study of Sudanese patients with visceral leishmaniasis, PCR
was able to detect parasite DNA in 37 of 40 (92%) blood
samples.1,25
++
Laboratory abnormalities include pancytopenia and a reversal
of the albumin:globulin ratio because of hypergammaglobulinemia
(primarily IgG) from a striking polyclonal B-cell activation and hypoalbuminemia.
The transaminase values sometimes are modestly elevated. Bone marrow infiltration
and hypersplenism partially explain the leukopenia and the anemia,
which typically is normochromic and normocytic; Coombs-positive
hemolysis, bleeding, and hemodilution also can contribute to the
anemia. Patients with leukopenia typically have neutropenia, marked
eosinopenia, and a relative lymphocytosis and monocytosis. As visceral dissemination
occurs in the context of anergy to leishmanial antigens, the leishmanin
skin test is negative and there is a lack of lymphocyte proliferation.
On histopathology, the spleen is markedly enlarged and congested,
with hyperplasia of reticuloendothelial cells, atrophy of paracortical
zones and areas of infarcts, and fibrosis.1,25
+++
Cutaneous and
Mucocutaneous Leishmaniasis
++
For cutaneous leishmaniasis (CL), definitive diagnosis requires
microscopic demonstration of the parasite by identification of amastigotes
in lesion scrapings, aspirates, and biopsy specimens. Material from
the ulcer base usually has the highest yield, but as lesions age,
parasitological confirmation becomes more difficult because amastigotes
become more scarce. For ulcerative lesions, one should examine multiple
Giemsa-stained thin smears of lesion scrapings and should obtain cultures
of lesion aspirates or biopsy specimens. Through this technique,
the diagnosis can be established with certainty in approximately
70% of persons with CL and in up to 50% of persons
with mucocutaneous leishmaniasis (MCL). Parasite culture in biphasic
media is technically difficult and may last up to 30 days before becoming
positive. However, combining microscopy evaluation and culture increases
diagnostic sensitivity to more than 85%.
++
Species identification of isolated parasites by immunocytochemical methods,
isoenzyme analysis, or DNA probes is available in research or in
some field laboratories. Specific antibodies can be demonstrated
in 70% to 80% of infected individuals by IFA or
enzyme-linked immunosorbent assay (ELISA), but antibody levels decline
over 4 to 5 months after successful therapy and fail to distinguish
between previous and current infection in persons from endemic areas.
However, ELISA, based on the detection of Leishmania-specific
IgG, may be useful in clinical and epidemiological studies and control
programs, as it can detect up to 89% of individuals with
cutaneous leishmaniasis.26
++
The Leishmania skin-test reaction (Montenegro test)
is positive in 80% to 100% of persons with cutaneous
and mucocutaneous disease within 3 months of infection but is consistently negative
in persons with disseminated cutaneous leishmaniasis and localized
cutaneous leishmaniasis of less than 1 month in duration. A skin
reaction is considered positive if induration is greater than 5
mm in diameter, but such a reaction is not species-specific, and
cross-reactions with Trypanosoma and Leptomonas are
frequent. This test has limited value in endemic areas, as it cannot
distinguish between recent or previous exposure to the parasite.1,24
++
New approaches for detecting parasites include standard PCR on skin
biopsy specimens, on aspirates, or on imprint smears on nitrocellulose
paper, but its potential use in routine diagnosis has been hampered
by the complexity of the procedures. PCR that uses oligonucleotide
primers directed to Leishmania’s minicircle
kinetoplast DNA (kDNA) is highly sensitive, as it measures femtogram
quantities of DNA. It has a reported sensitivity of 87% and
100% for complex and species identification.24,25 Likewise,
identifying parasite species with 95% sensitivity and 100% specificity
using skin scrapings collected with a toothpick was demonstrated
in Bolivia by using PCR–RFLP.27
++
A more rapid and highly specific diagnosis can be established
with recently developed technologies such as real-time PCR, whereby primer
sets coupled with a fluorescent probe allow monitoring of amplification
of specific DNA sequences as the reaction occurs. With this method,
up to 96% sensitivity was demonstrated on ethanol-preserved
tissue of CL patients from Panama.28 Histopathologic analysis
is the least sensitive method of diagnosis, although Giemsa staining
improves detection over routine hematoxylin and eosin staining. The
initial lesion is characterized by a large number of parasitized macrophages
and by mild infiltration of granulocytes, mononuclear cells, and
eosinophils in association with hyperplasia of the epidermis and
necrosis of the dermis. Older lesions may have a heavy infiltration
of lymphocytes and plasma cells and a granulomatous reaction with
epithelioid, multinucleated giant cells with fewer parasites.1,24
++
In MC leishmaniasis, lesions show massive necrotizing inflammation
with a variable number of lymphocytes, small histiocytes, plasma cells,
and few amastigotes. There is an exaggerated, antigen-specific,
cell-mediated immune reaction, and levels of serum antibodies are high.24
++
In diffuse cutaneous leishmaniasis, large numbers of infected mononuclear
cells are seen, but lymphocytic infiltration is negligible. Both
in vivo and in vitro antigen-specific cell-mediated immune reactions
are absent. The antibody response, however, is conserved and often
increased. Delayed-type skin-test reactivity to leishmanial antigens
that is usually present in persons with simple cutaneous or leishmaniasis
recidivans is absent in persons with diffuse cutaneous leishmaniasis.1,24
++
All cases of visceral leishmaniasis and mucocutaneous leishmaniasis
must be treated because the disease may be lethal without treatment.
The treatment of CL may depend on the geographic distribution, the
parasite species involved, and the clinical manifestations, because
lesions due to different species vary in both their severity and
their response to treatment.29 American CL tends to be
more severe and longer lasting than Old World CL, in which case
a large number of lesions heal rapidly without treatment. The rate
of self-healing depends on several factors, including parasite load
and virulence, host immune response, location of the lesion, and
the presence or absence of secondary bacterial infection.29 Over
60% to 70% of cases caused by L major heal
spontaneously within 3 months.1 In this case, an expectant
approach with local care and prevention of bacterial infection may
be appropriate for small single and uncomplicated lesions. This
approach is particularly pertinent for those patients living in
endemic areas, because spontaneous healing is associated with the
development of protective immunity. On the other hand, lesions caused
by L tropica infection do not self-heal rapidly and
can be difficult to treat expectantly.1,29
++
Local treatment with paromomycin ointment combined with methylbenzethonium
chloride seems promising, with a cure rate of 74% to 87% of
early noninflamed lesions; however, it might cause local inflammatory
reactions.29 Any case of Old World CL lesions on cosmetically
or functionally important sites such as the face or hands, and any
case in patients with associated lymphangitis, with multiple or
persistent lesions, and with compromised immune systems should receive
systemic treatment. Small single cutaneous lesions caused by L
mexicana infection have a self-cure rate of over 75% at
3 months. However, observation alone has not been assessed formally,
and a short 10-day course of parenteral antimonials is recommended.1
++
In American CL, the crucial step is to decide whether or not
a member of the L braziliensis complex could be
the infecting organism (ie, likely infection in Belize, Colombia,
Costa Rica, Guiana, Honduras, Surinam, Panama, Venezuela, Brazil,
the western slopes of the Andes, and the Argentinean highlands),
because all such cases must be considered capable of progressing
to mucocutaneous disease and therefore require adequate systemic
therapy.1,29 Similarly, leishmaniasis recidivans and diffuse
cutaneous leishmaniasis must receive systemic treatment.
++
Pentavalent antimonials (SbV) remain the drugs of choice
for all clinical forms of leishmaniasis and for all regions, except
for Bihar State in India, where only 35% of cases respond
to treatment, and in southern Europe, where liposomal amphotericin
B is the preferred drug because of lower toxicity and higher efficacy.1 In
the rest of the world regions, two closely related pentavalent antimonials
currently are used: sodium stibogluconate (GlaxoSmithKline) and
meglumine antimoniate (Glucantime; Sanofi-Aventis).2 The
recommended dosage of SbV is 20 mg/kg per day,
given intramuscularly (IM) or intravenously (IV) without restricting
the daily dose (as was previously done); treatment should last for
20 days in the case of CL and for 28 days in the case of MC and
VL. In the United States, sodium stibogluconate is available through
the CDC Drug Service (daytime: 404-639-3670; other times: 404-639-2888).10 In
Latin America, meglumine may be the drug of choice in the treatment
of MCL, as it offers a cure rate of 88%, which is superior to
stibogluconate (51%) and similar to amphotericin B.30 Patients
should be monitored weekly with serum hepatic enzyme levels and
with electrocardiogram twice weekly. Freedom from clinical relapse
for at least 6 months of follow-up is the best indicator of permanent
cure. Cure rates with antimony therapy range from 80% to
95%, and relapses should be treated with the same drug
for at least twice the previous duration.1,10 Patients
with VL become afebrile within 4 to 5 days of therapy initiation,
and the various hematologic abnormalities and hypoalbuminemia usually
improve substantially during therapy; reappearance of eosinophils
in the peripheral blood is a good sign. However, laboratory abnormalities
may take weeks to months to resolve. Likewise, regression of splenomegaly
may take months.
++
One of the major difficulties with SbV treatment compliance
is the frequency and severity of adverse effects, characterized
by pain at the injection site, myalgias, arthralgias, abdominal
pain, nausea, thrombocytopenia, leukopenia, raised levels of amylase
and lipase, and cardiotoxicity with electrocardiographic changes.1
++
Amphotericin B is the drug of choice for VL in Bihar India and
for antimony-resistant mucocutanous disease. A dosage of 0.5 to
1.0 mg/kg daily, or every-other-day IV, for a total dose
of 7 to 20 mg/kg is considered to be very effective (98–100% success
rate).1,10 Liposomal amphotericin B is the preferred drug
to treat HIV/VL coinfected patients; it is used in southern
Europe to treat VL of immunocompetent patients because of fewer
side effects.1,2 For immunocompetent individuals, the drug
is given at a dose of 1 to 3 mg/kg for 5 days and has a cure
rate up to 97%. In another study, amphotericin B lipid
complex, at a dose of 3 mg/kg administered every other
day for five injections, was 100% successful in patients
with antimony-resistant kala-azar.1 For HIV/VL
coinfected patients, doses of 1 mg/kg per day for a total dose
of 20 mg/kg have been effective in up to 88% of
cases.2,31 With this regimen, parasitological cure was
achieved, and relapses were present most often in patients not receiving
antiviral HAART treatment.2
++
Paromomycin, an aminoglycoside similar to aminosidine, was recently
licensed in India to treat VL of immunocompetent patients. An IM
dose of 15 mg/kg per day for 21 days achieved a cure rate
of 93% to 97%.1,2 This broad-spectrum
antibiotic has a good safety profile and is well tolerated; its
main side effect is reversible elevation of liver enzymes in 1% of
patients. Paromomycin is considered an alternative to amphotericin
B in India and a potential substitute for antimony worldwide, due
to its high efficacy level, minimum toxicity, and low cost.1,2 Indeed,
this antibiotic might be a suitable drug for topical treatment of
cutaneous disease, as ointment formulations of 15% paromomycin
in combination with 12% methylbenzethonium chloride gave
a cure rate of 74% to 85% in Old World CL.1,29
++
Miltefosine is the first oral treatment for VL, including antimony-resistant
infection. A dose of 2.5 mg/kg per day for 28 days gave
a cure rate of 94% to 96% for VL in India. However,
variable cure rates had been reported for CL in Colombia (91%),
Guatemala (53%), Afghanistan (63%), and Bolivia
(88%).32,33 The agent is active in adults and children,
and common adverse gastrointestinal reactions are transient. However,
it has a potential teratogenic effect, which limits its use in pregnant
or lactating women and women of childbearing age not taking contraceptives.2
++
Pentamidine was used to treat VL and CL at a dose of 2 to 4 mg/kg daily,
or every-other-day IV or IM, for a total of 15 doses.29 However,
the treatment has now been abandoned due to severe side effects
(such as irreversible diabetes mellitus in up to 12% of
the cases2)and poor efficacy.
++
Combined therapy of SbV with the immunomodulatory molecule
imiquimod is currently under investigation for CL.34 Similarly,
sitamaquine, an orally active 8-aminoquinoline analog, is under
evaluation for VL treatment.34
++
To date, no effective human vaccines are available, despite the
great need due to drug resistance, toxicity of chemotherapy, and
the increase of disease incidence in immunocompromised subjects.
However, considerable effort has been devoted to vaccine development,
generating several candidates based on parasite antigens—such as
LACK, LeIF, TSA, LmSTI1, H1, CpA + CpB, KMP11, and NH36—that
have proved their effectiveness in animal models.35
++
As there is no effective form of chemoprophylaxis against Leishmania, and
an adequate method of vaccination is not yet available, the control
of leishmaniasis depends on the prevalent local epidemiological
characteristics. Measures of control include treating infected individuals,
reducing reservoir hosts, and spraying to eliminate vector insects.1,37 Where
humans are the sole reservoir, as in India, case detection and treatment,
followed by DDT spraying for phlebotomine control, help to contain
the spread of disease.35 On the other hand, where canines are
important reservoirs, identifying, destroying, and replacing infected
dogs has not been an effective control method, as new dogs were
infected in a short time period.38
++
Similarly, when rodents or wild animals are involved, control
is even more difficult. Vector control using bednets impregnated with
pyrethroids or DDT and other residual insecticides had a significant
effect in reducing visceral leishmaniasis in many parts of the world,
as sand fly bites was reduced at a rate of 64% to 100%.1 Insect
repellents, protective clothing, and fine mesh netting can provide
temporary protection in areas where leishmaniasis is primarily zoonotic,
as in the New World.1 Similarly, deltamethrin-soaked collars
for dogs had a protective effect.