Natzual History, Clinical Evolution,

and the Host-Parasite Interaction in

New World Cutaneous Leishmaniasis
KRISTEN WEIGLE, MD, MSH
NANCY GORE SARAVIA, MSc, PhD

I n the New World, human diseases caused by the Proposed parasite and host determinants of the clinical
genus Leishmania are widespread, ranging from diversity of New World Leishmania are addressed later
southern Texas to Northern Argentina and the Ca- in this review.
ribbean Islands. This review will address the natural The number of cases of ACL has been estimated to be
history of the Leishmania that primarily affect skin and 59,300 yearly. Fifty-nine million persons reside in areas
upper respiratory mucosa of humans. This group of where the ACL-causing Leishmania species are transmit-
diseases will be referred to as American cutaneous ted.i5 In the United States L. (L.) mexicarzn is transmitted
leishmaniasis (ACL). only in southern Texas near the border with Mexico. To
ACL is produced by a group of genetically related date, only nine cases have been reported from this area,
species, each of which has characteristic manifestations including one case of DCL.16 Consequently, nearly all
and areas of endemnicity (Table 1)le3; however, none of ACL patients that present to physicians practicing in
the clinical manifestations is unique to a particular spe- the United States will have acquired their lesions while
cies, because there is considerable overlap between traveling outside the United States.14F17 Travelers who
clinical spectrums. Likewise, in a given locale several have acquired ACL are usually not typical tourists or
Leishmania species may be transmittede4 All the listed business travelers. They invariably have had contact
species can cause simple cutaneous lesions. Mucosal with forested and/or rural areas either during activities
lesions are mostly characteristic of the Leishmania sub- such as field biological studies, community service,
genus Viannia, particularly L. (V.) braziliensis and L. V. military excursions, or ecotourism. In a series of 59
panamensis, but have also been caused by LO’.) guy- cases of ACL in U.S. travelers, the diagnosis and treat-
anensis’ and L. (L.1 amazonesis.6 Diffuse cutaneous leish- ment were frequently delayed, in part due to physi-
maniasis (DCL) is a rare form of leishmaniasis caused cians‘ lack of knowledge about ACL.17 It appears that
by I,. (L.) mexicana in the United States, Mexican, Cen- more physicians, particularly dermatologists and those
tral American, and Caribbean regions and by L. (L.) working in travelers’ clinics, need to become familiar
anzazonensis and L. iL.1 zlenezuelensis in South America.7*g with the spectrum of clinical manifestations and course
These species more frequently cause simple cutaneous of ACL.
leisl~maniasis.y8’0 L. (L.) mexicana is also associated with During the past decade we have conducted a series
chronic lesions of the external ear (chiclero’s ulcer?’ in of investigations of L. (Viannia) infection in Colombia to
the Yucatan peninsula of Mexico. describe the natural history of ACL and its clinical
Despite these well recognized associations between manifestations and examine host and parasitic determi-
Leishmania subspecies and clinical manifestations, nants of variations in natural history of these Leishmrania
anecdotal reports indicate that Leishmania species occa- species. Consequently, this article will first describe in
sionally produce clinical manifestations beyond their detail clinical evolution of lesions caused by L. Wian-
recognized spectrum.‘2-‘4 The reasons why a given nia). We will describe more concisely the cutaneous
Leishmarda will produce differing manifestations in a manifestations of other New World Leishmnniu species.
different host or setting is not completely understood. Then the current understanding of the pathogenesis of
ACL will be reviewed, including mechanisms of dis-
semination, and host and parasite determinants of dis-
From fhr Fundacion Cenfro lnternacional de Entrenamiento e lnuestiga-
ciones Medicas fCIDEIMI (NGSI, Cali, Colombia, and the Department of ease expression.
Epidemiology, University of North Carolina .%/zoo2 of Public Healfh (KW),
Chapel Hi//, NC, USA. Clinical Relevance
Addw>:: correspotufencc to Nancy Gore Saravia, MSc, PhD, Director, of the Natural History of ACL
Fundacion Centro International de Entrrnamiento e lnvestiguciones Medi-
ras iC[PtflMJ, Apartado Acrro 5390, Aoenida I Norte N” 3-03, PB The clinical course of ACL is complex due to a variable
6682163, ruli, Colombia incubation period, subclinical infection, spontaneous
434 WEIGLE AND GORE SARAVIA Clinics in Dennatolog~y l 1996;14:433-450

Table 1. Geographical Distribution and Clinical Manifesfation of Leishmania Species Most Commo~dy Associated with Americau
Cutaneous Leishmaniasis

Parasite Clinical Manisfestation Colltztry

L. (V.) hruzihsis Cutaneous Argentina, Belize, Bolivia, Brazil, Colombia, Costa Rica, French Guiana, Guatemala,
Mucocutaneous Honduras, Mexico, Panama, Paraguay, Peru, Venezuela

L. (V.) puMnmetlsis Cutaneous Colombia, Costa Rica, Ecuador, Honduras, Nicaragua, Panama, Venezuela
Mucocutaneous

L. (V.) guyanensis Cutaneous Brazil, Colombia, French Guiana, Guyana, Peru, Surinam
Mucocutaneous (rare)

L. (V.) peruviana Cutaneous Peru

L. (L.) mexicana Cutaneous Belize, Colombia, Costa Rica, Dominican Republic, Guatemala, Honduras, Panama,
Diffuse cutaneous Ieishmaniasis United States (Texas)

L. (L.) amazonensis Cutaneous Bolovia, Brazil, Colombia, Ecuador, French Guiana, Panama, Peru, Venezuela
L. (L.) uenezuelensis Mucocutaneous (rare)
Diffuse cutaneous leishmaniasis

healing, metatastic spread, latency, reactivation, rein-
fection, and chronic lesions. Members of the L. G%mzia>
subgenus have a particularly intriguing, highly vari-
able, natural history.” One aspect of the natural history
of ACL that is relevant to diagnosis and management is
the capacity of Leishmania to persist in humans. It has
been suggested that Leishmaniu infections persist for
life. i9,” Therefore, physicians must recognize that ACL
lesions may present at any time after infection, includ-
ing many years after leaving an area of endemic trans-
missior? and may recur. Reactivation of latent Leish-
mania occurs in immunocompetent patients but may be
precipitated by an immunosuppressive event, such as
administration of drugs and HIV infection.22,23 These
possibilities should be taken into consideration when
evaluating chronic mucosal and skin lesions in immuo-
suppressed patients. The possibility of recurrence
should also be considered in describing prognosis of
ACL to patients and planning follow-up care.
The concept that the natural history of ACL varies by
Leishmania species is pertinent to patient management.
In some settings where resources are limited, cost ben-
efit considerations have led to a policy of treating the
more severe lesions.24 Since the spontaneous healing
rate of lesions caused by L. (I,.) mexicana is high, at least
68%,” and current drug therapy is costly, potentially
toxic, and requires parental administration, it may be
appropriate to only treat with antimonials when lesions
have not healed spontaneously. Furthermore, antimo-
nial therapy appears to modify the clinical course of
lesions due to L. (V.) bruziliensis but not those caused by
L. (I,.) mexicana, so the value of treating the latter with
antimonials is questionable.25 Unfortunately, only the
randomized clinical trials of ACL conducted in Guate-
mala by Navin and colleagues have been able to evalu-
ate Leishmania species as a modifier of treatment effi-
cacy.” Further controlled clinical trials should examine
whether the efficacy of drug therapy varies by Leish-
mania species.
Overview of the Natural History of ACL
Despite the importance of the natural history of ACL to
its clinical management, investigations describing natu-
ral history are limited, primarily because the necessary
prospective studies require following mobile, geo-
graphically distant and widely dispersed patients dur-
ing several years. Also, due to the variation of natural
history by species, numerous prospective studies are
needed to describe the clinical evolution of each species.
Consequently, the current picture of clinical evolution
is derived from piecing together information on the
three major stages of Leishmania infection: infection to
initial manifestations; initial lesions to healing; healed
lesions to recurrence.
The spectrum of natural history of an infectious
agent can be characterized rather simply by three terms:
infectivity, pathogenicity, and virulence (Fig 1). Infec-
tivity describes the relative ease with which contact
with a microbe results in infection. Pathogenicity de-
scribes the degree to which an infection leads to clinical
manifestations, rather than asymptomatic infections.
Pathogenicity can be estimated by measuring the num-
ber of persons who develop lesions among those who
are newly infected. Among the agents causing ACL, the
pathogenicity appears to vary by species and locale.
Virulence describes the degree to which a clinically
manifest infection progresses to more severe or pro-
longed manifestations (Fig 2). A description of the viru-
lence of the parasites causing ACL should include the
frequency of very large lesions, multiple lesions,
chronic lesions, metastasis, and subsequent reactiva-
tion. Because different mechanisms may contribute to
pathogenicity and virulence, their distinction will fur-
 Naive Host I
Chronic Lesions
I
Latent -
Infection and lnfsction and
Immune
Figure 2. Conceptual model, natural history of Leishmania
(Viannia) infection in residents of endemic area. Each box
represents potential stage in clinical progression; transitions are
indicated by solid vertical line (steams) and are identified by
encircled numbers. Nodes (0) indicate wkere branches may lead
to similar outcomes. Arrows pointing to encircled numbers
indicate that clinical course is repeated beginning at numbered
transition (from Weigle et al.,” Journal Infectious Diseases,
z&h permission)~
ther our description of the complex natural history of
ACL. For example, L. pevuviann, the agent of Uta in the
Peruvian Andean region, appears to be highly patho-
genic but of relatively low virulence.26 In contrast, L.
Wiannia) infections in rural Tumaco, Colombia, are
relatively less pathogenic, but more virulent.18~27
We have found that a conceptual model of the natu-
ral history of L. (Viannia) infection furthers our ability to
examine the details of acquisition and progression of
this infection. In the first step, 1, a naive host, lacking
history of contact, infection, or sensitization must come
into contact with the Leishmania parasite, usually by
contact with an infective sandfly vector. This contact
may or may not lead to an infection, 2, replication of the
parasite in human cells. Once the infection is estab-
lished in macrophages and tissue histiocytes it may
progress to a clinically manifest lesion or remain
asymptomatic, 3. The course of primary lesions, 4,
ranges from rapid, spontaneous healing to chronic le-
a b C d
PEagewtyr b+ctd+e
Total hfected = wbtc+d+e
virulence = - SeveremdFatalcaseS = Mt$++
Total Apparent Cases btc+d+e
Figure 2. Estimrztivn of pathogen&y and Gru/etlc~~ based on
the relative numbers of clinical apparenf cows ~:rti fr:ilci,
moderate, severe, and fatal cases.
sions. Given time, even chronic lesions may heal, 5,
however the healing of chronic lesions is accelerated by
therapy, such as antimonials. Eventually, a quiescent
phase is reached, 6, through varying pathways. In this
quiescent phase all lesions are healed, defined as com-
plete re-epithelization and the absence of signs of in-
flammation in all lesions. However, persons in the qui-
escent phase vary in their potential for subsequent ACL
lesions. At this point, two factors will determine wheth-
er a person in the quiescent phase has the potential to
develop subsequent lesions: (1) whether persistent, la-
tent Leishmania remain in intracellular sanctuaries and
(2) whether the host has acquired a protective immune
response that will resist subsequent contacts with Leish-
mania. The four possible combinations of these factors
are represented by the four boxes below step 6 as
shown in Figure 1. Only those who have both rid their
body of Leishmania and acquired a protective immune
response are certain to remain free of ACL, indicated by
the furthermost left box in the model: “cured” parasite-
free and immune. Those persons whose acquired im-
mune response to Leishmania is not protective will re-
main susceptible to exogenous Leislrnmnia infection.
Depending on their exposure to this organism they may
become exogenously reinfected, 2. Quiescent hosts who
harbor latent parasites may progress over time in three
ways, 7. Some may eventually eliminate the latent Leish-
mania and become “cured and parasite-free.” The infec-
tion may reactivate in others, leading once again to
clinically apparent lesions, 4. Others may maintain a
persistent asymptomatic infection throughout their life.
The clinical evolution from the stage of chronic in-
fections, 5, is actually more complex and dynamic than
depicted in the model. While the initial lesion is healing,
satellite lesions and/or nearby subcutaneous nodules
may develop. These nodules may enlarge and necrose
centrally, becoming new ulcers. Likewir;e as the central
436 WEIGLE AND GORE SARAVIA Clinics in Dermatology l 2996;74:433450

lesion heals the satellite lesions often enlarge. Less often

new lesions develop distant from the initial lesion. Over
time these cycles may repeat. During the same time
interval some lesions may repeatedly heal and reacti-
vate while other lesions remain continuously active or
1 2 3 4
continuously healed. This dynamic situation is consis-
tent with the concept that a very localized immune re-
sponse, which is not capable of controlling Leishmania
replication in other skin sites, lymphatics, or blood mac- Figure 3. Progression of an acute lesion caused by L.
Wiannia). (1) Early nodule, (2) expanded nodule, (3) ulcerated
rophages, may contribute to the healing of skin lesions. nodule,and (4) characteristic utter with a raised, indurated
border.
Clinical Presentation and Evolution of ACL
Braziliensis Complex (Viannia) Subgenus infiltrate. Multiple nearby simultaneous infective sand-
Primary Infection fly bites39 produce lesions of similar size and duration
Humans usually acquire Leishmaniu infection when fe- on the same extremity.
male sandflies take blood meals required for sandfly
Histoputhology
reproduction. During the sandfly bite, infective stage,
Early descriptions of the histopathology of ACL classi-
“metacyclic” promastigotes are preferentially re-
fied lesions along a spectrum similar to that developed
leased’* and injected along with a potent vasodilator.29
for leprosy4’ ranging from the “lepromatous” extreme
L. (Viunniu) infection can also be acquired by accidental
with numerous amastigotes to the “tuberculoid” ex-
injection of laboratory-grown Leishmunk3’ The para-
treme characterized by organized granulomas and
sites causing visceral leishmaniasis (VL) can be trans-
sparse amastigotes. This classification system has not
mitted parentally3’ and vertically.32 Since parasitemia
been reproduced in studies of L. (Viannia) models because
occurs less often in ACL caused by L. Wiunniu) than in
VL,33,34 the same lesions often contain elements of both granu-
parental and vertical transmission of L. (Viun-
locytic necrosis and macrophages, only some of which
niu) are biologically plausible, but probably rare events.
are organized into granulomas.36,37,41-3The epidermis
After promastigotes are injected, specific receptors
undergoes an intense hyperplasia in the areas that are
on tissue histiocytes permit their entry into these cells.
not ulcerated and denuded of the upper epithelium.37
Intracellularly, promastigotes transform into amasti-
The most consistent histological association is that le-
gotes, become rounded, and lose their flagella. Amas-
sions of longer duration have fewer amastigotes.36,44
tigotes replicate in the parasitophorous vacuole of the
However, in a study of 221 lesions caused by L. (Viun-
macrophage by binary fission. The sandfly bite pro-
niu), the majority of lesions contained abundant lym-
duces only a small red macule which often goes unno-
phocytes (82%), abundant histiocytes (92%), and granu-
ticed and disappears rapidly.14 During the incubation
lomas (78%).36 Fewer lesions contained amastigotes
period, which lasts from 2 weeks to many years, a series
(40%), eosinophils (8%); giant cells (22%), epithelioid
of cellular events occur, culminating in the first cutane-
cells (16%), areas of necrosis (34%). Persons who had
ous manifestation,35 a papule or small nodule which
scars typical of an earlier Leishmuniu lesion had a greater
may itch but is usually painless.
frequency of a “healing” pattern of histology, that is,
This nodule is produced by a dermal mass contain-
fewer amastigotes and a greater frequency of giant cells
ing Leishmaniu-ladened vacuolated macrophages and a
and epithelioid cells than did those who lacked such
lymphocytic infiltrate. 36,37As the nodule expands it ne-
scars (Table 2). In contrast, those with lymphadenopa-
croses in the center, perhaps due to pressure on the
thy had a histological pattern more in the direction of
epidermis (Fig 3). As the dermal infiltrate extends out-
ward, the area of central necrosis enlarges, producing
the classical lesion of L. (Viunniu), a round or oval ulcer Table 2. Comparison of the Presence of Amastigotes in the
with raised, indurated, well-defined borders. The ulcer Biopsies of Active Dermal Leishmaniasis in Patients With and
Without Scars Indicative of Prior Leishmaniasis
base is usually flat and moist if it has been frequently
washed but may be crusted with granulation tissue. The Previous Lesion (Typical Scar)
presence of frank pus or golden crusts is indicative of
No Yes
superinfection with skin flora, presumably Stuphylucoc- Amastigotes
cus uweus or Streptococcuspyogenes.38If the lesion is not in Biopsy nlN % W %
superinfected it is usually surprisingly painless. Satel- Absent 68/129 35 18/26 69”
lite lesions often occur along the periphery of the raised Present 124/129 65 8/26 31
borders. These small papules contain amastigotes and l p < 0.001, Chi squared test.
are likely to be a direct extension of the initial dermal Adapted from Gufierrez ef al. ”
ongoing parasite spread and primary infection (more est in Ecuador, where 75% of patients healed in 6 weeks
frequent amastigotes, less frequent giant cells and epi- and in Guatemala among patients with lesions caused
thelioid ceils) than did those without adenopathy. by L. CL.) mexicana, where 68% healed in 14 weeks.
In lesions that have healed, complete re-epitheli- However, only 8% of persons with I,. iV.1 bvrlziliensis
zation occurs, accompanied by fibrosis and a marked lesions in Guatemala healed in 14 weeks and none of
reduction in inflammatory cell infiltrates.37 Relative to the 11 persons with L. (V.) panamensis healed during the
active lesions, necroses and epithelial changes are rare. 6 weeks of follow-up in Panama. This wide variation in
In healed lesions the remaining infiltrates consist of spontaneous healing rates indicates that the natural his-
perivascular lymphocytes, and occasional organized tory of ACL varies by species and geographic location
granulomas. However, re-epithelization and a “healed” and that the apparent efficacy of drug treatment should
histological pattern are not a guarantee of elimination be judged relative to the course of disease in untreated
of Leishmanii7.“7.“’ patients.
Typical Scars Chrotzic Cutaneous Lesions
Classical lesions of L. (Viannia) usually produce scars Patients with chronic lesions have an increased morbid-
that are somewhat unique. The scar is often smoother ity not only because of the length of their illness but
and therefore more reflective than the surrounding because chronic lesions tend to be larger and more di-
skin. Its surface is slightly depressed relative to the level verse in their clinical manifestations. Because chronic
of the surrounding skin. Pigment changes are often ob- lesions may no longer possess the fairly unique clinical
served. Although skin scars of any type were very com- picture of acute lesions, they are easily confused with
mon in Tumaco, a rural area of Colombia in which L. other chronic skin diseases, explaining why terms such
(Viarznia) is endemic, only typical scars were strongly as psoriasiform, eczematous, varicelliform, verucous,
associated with a positive leishmanin skin test.” There- keloidal, chromomycoid, and carcinomalike were
fore, the presence of a typical scar may be useful in the coined to describe the atypical manifestation of chronic
clinical diagnosis of past ACL, especially in persons ACL.“9,50 Therefore, leishmaniasis should be considered
who have Iong resided in an endemic area. in the differential diagnosis of any chronic skin lesions
We found that among persons who were leishmanin in patients who have visited or resided in endemic ar-
skin test positive, the presence of a typical scar was a eas. Unfortunately, conventional diagnostic methods
strong predictor of subsequent new active lesions dur- for ACL, such as microscopy, culture, and histopathol-
ing the next 3 years.i8 Among persons who were skin ogy, are Iess sensitive in chronic lesions due to the low
test positive and had no active lesion when first exam- density of amastigotes.44 During the last decade we
ined, 0.2% of those who lacked a typical scar developed have diagnosed leishmaniasis parasitologically in nu-
new lesions per year, whereas 2.3% of those who had merous patients who had been diagnosed and treated
typical scar developed a new lesion each year, an elev- for other diseases. In general these patients had chronic
enfold increase. Very few of the persons with scars had and atypical forms of ACL. On the other hand, we have
received antimonial treatment for their initial lesions. established a different diagnoses in many patients who
Evidently, something about L. (Viannia) infection that were referred to us for evaluation of leishmaniasis.
produced lesions severe enough to leave a lasting scar With the help of dermatologists and pathologists (Table
also increased the risk of a clinically apparent recur- 3), during a 3-year period 17 diagnoses other than leish-
rence. One explanation may be that the nature of the maniasis were established in 72 such cases. Of these, the
host’s immune response determines the susceptibility
to clinically apparent infections in this setting where the Table 3. Di,fferential Diagnosis of Amnican C~r~irr~tcw~
circulating parasites usually produce asymptomatic in- Leiskmanias (ACL), Etiology of 72 Chronic S/&i I~sicrw
fections. This variation in host susceptibility may not be Evulunted for Possible ACL Betuwn f74rw 7. ?P&?. out?
/me 30,1991*
observed in a setting where the circulating Leishmania is
highly pathogenic. The low pathogenicity of the L.
(Viannia) transmitted in the Tumaco area has allowed
us to examine host variations in susceptibility, as dis-
cussed later.

Although it has long been recognized that some lesions

caused by Leishmania heal spontaneously,4h the fre-
quency and early time course of healing was described
recently by following the placebo arms of three ran-
domized clinical trials in Panama, Ecuador, and Guate-
mala. i”,17,4-x The rate of spontaneous healing was high-
438 WEIGLE AND GORE SARAVIA
most frequent were sporotrichosis and bacterial skin
infections5’
Leishmaniasis recidiva cutis (LRC), also known as
lupoid leishmaniasis and leishmaniasis recidivans, is a
form of chronic cutaneous leishmaniasis associated
with L. tropic infection in the Old World, that has rarely
been reported in the New World.49,52 It contains inflam-
matory papules and nodules on the periphery or inside
of a classical cutaneous leishmaniasis lesion. They may
appear before the classical ulcer has healed or after
complete re-epithelization has occurred. These patients
have vigorous cellular immune responses but low an-
tibody titers. The histopathology is one of a well-
defined granuloma, with few amastigotes and no ne-
crosis. Although we have not systematically looked for
cases of LRC, it is our impression that it is relatively
frequent among our cases of chronic and recurrent
ACL, and is probably more common than reported in
the New World.
Chronic cutaneous lesions are most common in set-
tings where access to antimonial therapy has been lim-
ited or in reference centers to which persons with
chronic lesions are willing to travel. During our first
year of case detection for ACL in rural Tumaco, 46% of
cases had chronic cutaneous lesions, defined as lesions
of 6 months or longer durationz7 Now, 12 years later,
chronic cases are very rare in this setting. Obviously,
the chronic lesions that were prevalent when the case
detection began had been accumulating over may de-
cades. Once chronic cases were treated, new cases
emerged either from new infections or reactivation of
latent infections.45 We have found that lesions caused
Figure 4. Comparison of L. (V.) braziliensis and L. (V). panamensiswith respect to the reported duration of cutaneous lesions at
time of diagnosis. For each species the percent of patients who report each duration is depicted in a histogram, as are the mean and median
duration in months (from Sarauia et al.,lO’ Journal of Infectious Diseases,zuith permission).
/
N = 56
I-. m m
12 24 36 46 60 72
Median = 2
N = 30
Clinics in Dermatology l 1996;16:433450
by L. (V.) brazilierzsis are more frequently chronic than
lesions caused by L. (V.) panamensis (Fig 4).
Recurrence of ACL
The term recurrence of ACL describes the onset of
active lesions after a time of quiescence, that is, after
an interval in which all previous lesions have re-
epithelized. The frequency of recurrences among per-
sons with some evidence of previous ACL in three
population-based studies in Brazil, Colombia, and Peru
were 2.7% of 369 cases,2.0 per 100 person years, and 2.9
per 100 person years, respectively,‘8,26,53 but may have
been influenced by whether the earlier lesions had been
treated and the methods of surveillance. Recurrences
may be due to reactivation of latent parasites at the
same skin site as earlier lesions, or at other metastatic
locations, or due to exogenous reinfections acquired
from a new exposure to infected sandflies. Reactiva-
tions occur most often at or near the same locations of
an earlier lesion and usually occur within a year after
healing of the initial lesion.26*45,53
The frequency of re-
activation appears to be determined by the species of
Leiskmaniu, the treatment received for earlier lesions,
and the immunological competence of the host. Reacti-
vation of healed lesions due to L. Wiannia) appear to be
less frequent in those treated with 20 mg/kg/d or more
of antimonium for 20 days.38,54In a total of 59 patients
whose acute lesions healed after they received this dose
intravenously in the form of sodium stibogluconate
(Pentostam@), only one relapsed during 3 to 12 months
of f0110WUp?s~ss These patients were all soldiers who
were not at risk for reinfection, so the one relapse was
L. v. braziliensis
L. v. panamensis
F
64 96 106 120 132 144 156 166 160 192 204 216 226 240
DURATION OF DISEASE
thought to be due to a reactivation. Hopefully this low the arm. Leishmaniacan be cultured from these nodules,
reactivation rate will be reproduced in patients with proof that this lymphangitis is due to Lrtshmanictrather
more long-standing lesions and with the more widely than a bacterial superinfection. The nodular lymphan-
available antimonium, meglumine antimoniate (Glu- gitis of ACL is clinically very similar to that caused by
cantime@), which is administered intramuscularly. Sporofhrix schenckii, both of which produce painless ul-
Between 1983 and 1990 we followed 498 parasitologi- cers and nodules. Other common causes of nodular
tally diagnosed patients with ACL due to L. (Viannia) lymphangitis, including Nocardia bmsiliarsis, Mycobacte-
for up to 4 years to understand the pattern and deter- rium maritrm, Mycobactrrium chelottnc~,md I-nrm%elln
minants of recurrences following what was at that time tularensis, are usually more tender but should be con-
a standard treatment regimen of Glucantime. By com- sidered in the differential diagnosis ot sporotrichoid
paring the initial L&hmania isolate with the isolate from leishmaniasis.”
recurrent lesions from 24 patients in terms of enzyme The high frequency and relevance of regional lymph-
phenotype and genotype, we determined that half of adenopathy in ACL has been only recently recog-
these recurrences were likely to be due to new infec- nized.27,-59-h’This bubonic form of leishmaniasis ap-
tions.” As would be expected, the 12 lesions that were pears to be more common than nodular lymphangitis
considered to be due to reinfections occurred longer and may comprise 77% of casesof L. (iii) braziiiensis in
after the initial lesions and more often distant from the some settings.h1 Both nodular lymphangitis and re-
initial lesions than was the case for the lesions due to gional lymphadenopathy may appear together.” in
reactivations. During the entire 4 years of follow-up, hamster models of L. (Viannia) infection, spread to re-
l6% of the cases recurred (Fig 5). The highest rate of gional lymphatics occurred as early as 5 days after in-
recurrence was in the first year following healing of the oculation, preceding the clinical appearance of lesions
earlier lesion, after which time the rate of recurrence at the site of inoculation.6’,h” In these models Leishmania
was relatively constant. spread to the spleen, bone marrow, and liver as early as
30 days after inoculation, and was recovered from these
Lymphatic Spread organs as late as 9 months postinfection. Similarly, in
Clinically apparent spread of L. Wiannia) can involve humans with L. (V.) bradiensis infection, Iymphade-
two components of the lymphatic system: the localized nopathy can precede the presentation c?f cutaneous le-
lymphatic chain and the regional lymph nodes draining sions.hflJ61,h’In a recent study of 169 cases of ACL with
the area of the skin lesions. A well-recognized entity of lymphadenopathy, the lymphadenopa thy preceded the
nodular lymphangitis also known as sporotrichoid onset of skin lesions in 69.2% of the case>by an average
leishmaniasis, Pian Bois and Bush Yaws, involves the of 2 weeks.6’ Adenopathy was associated with a less
local lymphatic channels proximal to a skin lesion in an frequent history of past ACL, consistent with the con-
extremity.““-” Most classically a lesion of the hand or cept that spread to lymph nodes usually occurs early in
forearm is followed by a streak of erythema and a cord the course of a primary infection, alxdcJgOUS to the
of small beadlike nodules marching up the long axis of pathogenesis of primary pulmonary tuberculosis. Pa-
tients with adenopathy had more frequcnl fever, hepa-
Figure 5. Accwm~lated rate of recurrence by month of tomegaly and splenomegaly, suggesting that the ham-
follow-r4p. Rrcurrrwce rates for each folloz4~4p time calculated by ster model of L. Wiannia) metastasis may replicate this
life-tab/e arlalysis for 498 patierlts with ACL due to L. (Viannia) spectrum of the clinical evolution in humans.
in the ?nwliciplity of Twnaco 1985-1990. Involvement of the lymphatic system by 1,. (Vinwzia)
has several implications for clinical management. When
adenopathy accompanies skin lesions, the lymph node
may be a preferable site for culture of i.rlshrnnr~in.“’ Both
nodular lymphangitis and adenopathv will regress as
the skin lesion is treated with antimonial.5 and do not
require excision or drainage of the invrjlved nodes.
When lymphadenopathy precedes the clnset of skin le-
sions, leishmaniasis must be considered in the difieren-
tial diagnoses of adenopathy along ~:it-h tuberculosis,
mycosis, toxoplasmosis, cat scratch dise;lstt, plague, and
lymphoma. If Leishania is established as the cause of
the adenopathy, then antimonial therapy &tppearsto be
/ indicated since most patients whv present with only
0 k __ 30 36 42 46 adenopathy will develop skin lesion if nt.)t treated.“”
0 3 6 12 18 24
Although the sporotrichoid form cif Ieishmaniasis
Period of Follow-up (months) has been classically associated with f ,. (le.! :~z~~pmmis. it
440 WEIGLE AND GORE SARAVIA
has been observed in other members of the L. (Viannia)
subgenus. Adenopathy associated with ACT in Brazil
was caused by L. (V.) braziliensi~.~~~~’In Colombia we
have found that lymphadenopathy occurs with a simi-
lar frequency in patients with lesions due to L. (V.) bra-
ziliensis (30 out of 75, or 40%), L. (V.) panamensis(144 out
of 360, or 40%), and L. (V.) guyanensis (5 out of 14, or
36%).
HematogenousSpread and Mucosal Lesions
Most patients with ACL due to L. Wiunnia) present with
single cutaneous lesions. Among those who present
with multiple lesions, the secondary lesions are usually
on the same extremity as the primary lesion.‘0,35,38,53
However, secondary lesions at distant body sites occur
in about 33% of those with multiple lesions or about 8%
of patients overall, some of which are probably due to
dissemination and others to multiple bites.53 In unusual
reports of disseminated cutaneous leishmaniasis, with
20 or more lesions due to L. (Vianniu), hematogenous
spread is assumed.65Cases who develop lesions at dis-
tant sites from their healed primary lesions after leaving
the endemic area provide indisputable evidence for
both latency and hematogenous metastasis.*’ Further-
more, L. (Vianniu) has been recovered from the blood of
cases of mucosal leishmaniasis.33,34
Mucosal leishmaniasis (ML) involves the mucosa,
soft tissues, and cartilage of the upper respiratory tract,
most commonly the nasal septum. Early lesions present
with symptoms of nasal congestion.27r66-68As nasal le-
sions progress, destruction of the nasal septum cartilage
leads to collapse of the nasal architecture and the clas-
sical “tapir” profile. Spread through the nasal floor in-
volves the hard and soft palate. Less commonly the
tissues of the lips, oral cavity, pharynx, larynx, and tra-
chea are affected, producing more devastating conse-
quences, including malnutrition and respiratory ob-
struction, and rare fatalities. Amastigotes are usually
sparse in mucosal lesions, many of which have been
present for many years before being diagnosed. The
lack of bone destruction distinguishes ML from the le-
sions of syphilis and yaws. Although ML is most often
associated with L.W.) braziliensis in South America,
L.W.) panamensis has frequently been isolated from
cases of ML in the Pacific coast of Columbia.67 How-
ever, ML is very rare in Central America despite the
prevalence cutaneous leismaniasis caused by these two
members of the L. (Viunnia) subgenus in this region. L.
(V.) guyanensis also rarely causes ML.5
Classically, mucosal leishmaniasis presents years af-
ter the healing of cutaneous lesions.21,66The average
time between the cutaneous lesions and mucosal lesions
was reported as 2 and 6 years in two case series from
Brazi1.53,69However 8 to 16% of ML caseslack a history
of cutaneous lesions,53,66,69 suggesting that a bite pro-
duced an initially asymptomatic infection that later dis-
Chits in Dermntolo,qy l 19962M33-450
seminated. Clinical presentations of ML in Colombia
have suggested that facial lesions may occasionally
spread to the mucosa directly and through the lymphat-
ics2’
Mexicana Complex, L. (Leishmania) S&genus
Diffuse cutaneous leishmaniasis (DCL) is a rare form of
ACL caused by members of the Mexicana complex,
which presents initially as a macule, papule, or nodule,
usually on the face or extremities, then progresses over
many years to numerous nodules and plaques which
may coalesce, especially over the face and ears to pro-
duce the classical “leonine” faces.68,70 The lesions,
which are painless and usually nonulcerating, contain
large numbers of amastigotes within vacuolated mac-
rophages, but a limited lymphocytic infiltrate. This lack
of inflammatory reaction is consistent with these pa-
tients’ lack of Leishmaniu-specific cellular immune re-
sponse.68Other characteristic features of DCL include
absence of visceral involvement, a poor response to an-
timonials, frequent relapses, and widespread dissemi-
nation with rare involvement of the anterior nares. DCL
has been most frequently reported from Brazil, Venezu-
ela, Mexico, and the Dominican Republic.8,69,71,72
L.(L.) mexicana usually produces cutaneous ulcers
that are smaller and have more abundant amastigotes
as compared to lesions caused by L. (V.) bruziliensis, and
often heal spontaneously. lo Relative to L. (V.) brazilien-
sis, this species more often produces lesions on the face
and ears, including characteristic chronic lesions of the
ear and ear cartilage, called “chicleros u1cer.“70,11,73 Cu-
taneous lesions due to this species have been reported
from the United States, Mexico, Belize, and Guate-
mala. 10,11,16,38
Lesions caused by L. CL.1amazonensisusually present
as a single ulcerated lesion that is very responsive to
treatment and may heal spontaneously. However, the
diversity of clinical presentation of this species appears
to vary by setting, perhaps due to differences in the
virulence of the local variants, or referral patterns. In 62
cases reported from Amazonian Brazil, nearly all had
relatively recent, single lesions with no dissemination to
other skin sites, mucosa, or viscera.’ In contrast, a more
diverse spectrum was observed among 40 cases from
Bahia, Brazil, including 11 cases of visceral leish-
maniasis, 4 cases of postkalazar dermal leishmaniasis
PKDL), 5 casesof ML, and 1 case of DCL.’ Among the
19 cases with cutaneous ulcers, 5 were considered to
have disseminated due to the presence of 5 or more
lesions. Similar to L. (Vianniu), L. (L.) amazonensismay
disseminate hematogenously despite evidence of a
Leishmania-specific cellular immune response. Such dis-
seminated caseshave a clinical presentation and natural
history that is distinct from that of anergic DCL, a much
rarer disease.65
Dermal Lesions Caused by Viscerotropic Leishmania
Leishmn~ia that cause visceral leishmaniasis in the New
World, I. chagasi/infunttlm, can also produce cutaneous
disease.74-7h Cutaneous lesions caused by I,. chagasi are
usually nodular,77 but occasionally ulcerate.75 Lesions
caused by L. chugusi are not easily distinguished from
lesions caused by the more prevalent dermatotrophic
Leishmaniu. Co-infection with HIV can result in unusual
cutaneous presentations of L. infuntum/chugasi infec-
tion7’ Exposure to endemic areas of transmission of L.
in~mfwrq’chagmi should raise suspicion that cutaneous
lesions may be leishmaniasis. The proportion of infec-
tions that result in visceral or cutaneous disease is un-
known, but does vary from one geographic region to
another. For example, L. chagasiinfection has only been
associated with cutaneous diseasein Costa Rica,79while
other countries in Central America report both visceral
leishmaniasis and cutaneous lesions caused by L. chu-
gusi. In Brazil, visceral disease appears to be the pre-
dominant outcome of infection with this parasite.80-s2
Because the point of entry of infection is the skin, it is
possible that cutaneous manifestations occur frequently
but are of minimal consequence and resolve quickly,
and thereby go undetected by the health system and the
patient. In areas where Leishmuniu that normally cause
ACL are concomitantly transmitted, the distinction of
etiologic agents may not be routinely ascertained and
result in an underestimate of the cutaneous pathology
attributable to L. chagusi.
Relevance of Natural History of ACL to
Its Control
Understanding the natural history of infections caused
by the members of the L. (Viunniu), braziliensis-complex
and L. (Leishmunia), mexicana-complex has implications
for control programs for residents of endemic areas and
travelers to endemic areas. Persons traveling to Leish-
mania-endemic areas should be advised to use personal
protective measures, such as clothing and use of DEET,
bed nets, and avoidance of outdoor activities during the
time of maximal sandfly biting.83-s6 Travelers should be
educated to recognize lesions that may be due to Leish-
mania and to seek prompt diagnostic and treatment ser-
vices.
Control of ACL in residents of areas with ongoing
Lrishrnurziu transmission is more challenging and must
be tailored to the local ecology of the zoonotic cycle,
epidemiology, and natural history of the local derma-
totropic species and available health resources. For in-
stance, in settings where ACL morbidity is high due
to prevalent lesions and reactivations rather than
newly acquired infections, diagnosis and treatment ser-
vices may be more appropriate than control measures
aimed at preventing new infections. The four key con-
trol strategies of vaccines, vector control, diagnoses/
surveillance, and treatment of lesions have made en-
couraging progress. Although prevention of all
Leishmuniu infections by vaccines or vector control is an
appealing goal, it may not be feasible or appropriate for
all areas of Leishmuniu transmission. Likewise, the ben-
efit of detecting and treating all cases should consider
the likelihood of the lesions progressing to the more
severe forms of ACL, that is ML, DCL, and RCL. There-
fore, further studies of the natural history of ACL are
needed to make informed policy decisrons regarding
the application of existing control measures and those
forthcoming. This is especially important with respect
to areas and species in which little is known about the
frequency and time course of progression from infec-
tion to the various disease forms.
Host-Parasite Interaction and the Outcome
of Infection
Dissemination and Pathogenesis of
Cutaneous Leishmaniasis
Dissemination of parasites from the site of inoculation
of infective promastigotes is effected by mononuclear
phagocytic cells. The first step in the process of dissemi-
nation involves phagocytic Langerhans cells in the epi-
dermis, which migrate to the dermis and then to drain-
ing lymph nodes in response to proinflammatory
cytokiness7 Early in experimental Lrishrtzania infection,
24-96 hours postinoculation, Langerhans cells migrat-
ing from the epidermis are the only cells with demon-
strable Leishmunia in draining regional lymph
nodes.‘“r8” Uptake of parasites evidently occurs in the
dermis during the transit of Langerhnns cells to the
lymph nodes.” These migratory antigen-presenting
cells, besides being a vehicle of Leishmaniu dissemina-
tion, are potent activators of lymphocytes in draining
lymph nodes. Later in infection, macrophages located
in lymph nodes are also found to express parasite an-
tigens and presumably harbor amastigotes.
Macrophages and blood monocytes ,-an disseminate
parasites through the vascular circulatory system and
its reticulendothelial compartments. f.,r+slzmnniuhave
been observed in’@ and cultured from peripheral
blood’“,“*,“’ spleen”’ and bone marrow’ of patients with
different forms of leishmaniasis caused by species nor-
mally associated with cutaneous disease. Although
more frequently associated with visceral leishmani-
asis,“3,9”
parasitemia has been further demonstrated in
cutaneous leishmaniasis by molecular hybridization
and amplification of the ribosomal DN:\ repeat unit of
L. bruziliensis in peripheral blood leuk~~cytes,‘”
Secondary lesions, whether contemporaneous with
primary lesions, have provided insight into the mecha-
nisms of metastatic disease. Mucosal disease”‘~““,h7and
secondary lesions outside of the route of lymphatic
drainage from the primary lesion sul:~port hematoge-
442 WEIGLE AND CORE SARAVIA
nous dissemination. Trauma has occasionally preceded
the development of lesions from which Leishmaniahave
been isolated,64,95-99suggesting that a nonspecific in-
flammatory response can trigger the pathogenesis of
dermal leishmaniasis. Experimental studies in animal
models corroborate hematogenous metastasis and the
localization of Leishmania”’ and development of sec-
ondary lesions at sites of injury and inflammation.62~‘0’
The sequence of events following epicutaneous con-
tact with environmental stimuli such as urushiol (the
chemical responsible for poison ivy) retinoic acid and
ultraviolet light may be pertinent to the role of trauma
and other inflammatory stimuli in the pathogenesis of
cutaneous leishmaniasis. Each of these stimuli induces
keratinocytes to produce TNF-c~ and IL-l .io2 These pro-
inflammatory mediators induce the expression of inter-
cellular adhesion molecules, the extravasation of leuko-
cytes, and their accumulation at the site of
inflammation. Similar events probably occur in the de-
velopment of cutaneous leishmaniasis lesions associ-
ated with trauma, which may propitiate the influx of
infected monocytes and/or “safe target” mononuclear
phagocytesio3 and the reactivation of infection and dis-
ease.Alternatively, in response to proinflammatory me-
diators, quiescent parasites present in normal skin of
infected individuals99 could be mobilized to draining
lymph nodes by Langerhans cells, where they trigger
the immune response and, ultimately, pathogenesis.
Host Determinants of Disease Expression
SameParasife CausesDistinct DiseaseForms in
Different Individuals
Clinical observation and the identification of Leishmania
have provided evidence of host determinants of disease
expression. The more widespread accessibility and uti-
lization of methods to identify Leishmaniahas revealed
the broad spectrum of disease caused by various taxa.
For example, Leishmania amazonensishas been isolated
from simple cutaneous, diffuse cutaneous, and mucosal
lesions as well as from spleen/bone marrow in cases of
visceral leishmaniasis in Brazil.8 The strains of L. ama-
zonensis isolated from patients with different disease
forms were phenotypically identical by isoenzyme and
monoclonal antibody typing.8
Patient sera, on the other hand, recognized different
antigenic determinants and shared antigens in this
same set of strains of L. amazonensis.‘04Although the
patterns of serologic reactivity were not associated with
disease form, these results illustrate the distinct “per-
ception” by the immune system of individual human
hosts of a single species of Leishmania.
Cell-Mediated Host ResponseDistinguishes Severe
DiseaseForms
The immune response to Leishmaniais a major determi-
nant of the outcome of infection. Severe disease forms
Clith3 in Dermatology l 2996;24:433450
are instructive in this regard. The refractory diffuse
form of cutaneous leishmaniasis, which in the New
World is essentially restricted to the mexicana complex,
is the result of induced antigen-specific immune paraly-
sis. Successful treatment is accompanied by the recov-
ery of cell-mediated responsiveness to Leishmania.h8~‘“”
Experimental human infections conducted by Convit et
a1.70m ’ Venezuela established the host response as the
pivotal determinant of disease expression in infections
with Leishmania of the mexicana species complex. In-
oculation of volunteers with organisms isolated from
the typically nonulcerating cutaneous lesions of DCL
patients, who are characteristically anergic to intrader-
ma1 challenge with leishmanin, invariably resulted in
self-limiting, simple cutaneous lesions and skin test
conversion. In vitro analyses of the immune response to
Leishmaniaantigens has subsequently documented an-
tigen-specific suppression of lymphocyte responses by
monocytes from patients with DCL.‘06 These experi-
ments and the rare sporadic occurrence of diffuse leish-
maniasis amid more frequent casesof simple cutaneous
leishmaniasis7’ highlight the contribution of the human
host to the outcome of infection with organisms of the
mexicana complex. Chronic cutaneous and mucosal
disease caused by Leishmania of the Viannia subgenus
are characterized by pronounced hypersensitivity to
Leishmaniaantigens at the tissue and systemic levels.‘07
In contrast with the antigen-specific anergy in nonheal-
ing DCL, clinical observations of patients infected by L.
(Viannia) support an association between antigen-
specific hypersensitivity and chronic, tissue-destructive
disease presentations.‘08-‘09 Hence, nonhealing disease
can result from either antigen-specific anergy or hyper-
reactivity.
More recently, cutaneous hypersensitivity to leish-
manin and previous, scarring cutaneous leishmaniasis
were found to be determinants of new clinically appar-
ent disease episodes among endemically exposed indi-
viduals.” Chronic lesions may, therefore, provide a
marker for susceptibility to disease in humans analo-
gous to the nonhealing BALB/c/L. major model of cu-
taneous leishmaniasis.
Prospective population-based epidemiological inves-
tigations have revealed information on the asymptom-
atic and mild disease outcomes of infection that are not
detected by passive case detection (Fig 6). More severe
and nonresolving disease presentation generally consti-
tute a larger proportion of passively detected cases.One
important finding has been the recognition of the oc-
currence of subclinical infections in endemic areas.isz6
Differences in host susceptibility are likely to underlie
the occurrence and frequency of subclinical infection as
well as the spectrum of disease severity. The bases of
natural host susceptibility are not fully understood.
However, the target cell of infection, the mononuclear
phagocyte, is a critical determinant of the course of in-
Clinics it1 Devmatctlo~y l 1996;14:4334.50
fection. Recent in vitro studies of macrophages differ-
entiated from peripheral blood monocytes from indi-
viduals who had either experienced subclinical
infection or chronic disease due to L. panamensis,
showed the cells from the latter to be more susceptible
to infection by promastigotes as well as to support the
intracellular survival of amastigotes.“’ Consistent with
these observations, messenger RNA of proinflamma-
tory cytokines that down-regulate microbicidal func-
tions of macrophages is increased in chronic lesions
caused by L. mexicana.” As suggested by experimental
models of cutaneous leishmaniasis, the local expression
of these and other cytokines may influence both the
course of infection and disease in the human host.“2~1’3
ImmunostlppressionAlters the Spectrum of Infection
and Disease
Further evidence of the host contribution to the out-
come of infection derives from the unusual and fre-
quently devastating and refractory disease presenta-
tions associated with immunosuppression. Reactivation
of prior infection”’ and exacerbation of disease23occur
in HIV-positive individuals. Other illnesses and immu-
nosup ressive conditions such as diabetes,‘i5 malnutri-
tion,” if tuberculosis,“” radiation therapy,96 and trans-
plantation-related immunosuppression”7 have also
been associated with disease progression.
Genetic Basesfor Distinct Host Response
The response to Leishmania infection in naturally ex-
posed human populations is heterogeneous. Whether
the differences in response phenotype are genetically
determined has not been established. However, genetic
Figure 6. Schematicillustrating the biastowardsevereand
more difficult to diagnose chroSc disease presentations among
patientsreachingthe medicalcaresystemthrough passivecase
defection.
NO MEDICAL ATTENTION
SOUGHT
TRADITIONAL Rx
FAILURE TO DIAGNOSE
HEALING BEFORE Dx
CASES REACHING
MEDICAL CARE SYSTEM
NEW WORLD CUTANEOI,‘; LFlFf iW:IN14% 443
analyses of the outcome of Leishmania infection in in-
bred and congenic strains of mice have provided evi-
dence that susceptibility and resistance phenotypes are
indeed associated with genotype,“HS”’ and that hemo-
poetic cells transfer the phenotype.‘2’ Both the leish-
manicidal comportment of subpopulations of phagocyt-
ic monoculear cells”4-‘28 and the Th, or Th,
lymphocyte response profile129 correlate with the resis-
tant and susceptible phenotypes in genetically defined
strains of mice. The genes involved in macrophage ac-
tivation and natural immunity, and lymphocyte-
dependent resolution of disease, however, are distinct.
Major and minor histocompatibility complex genes
have been linked to some extent to the outcome of ex-
perimental cutaneous leishmaniasis’““,’ ”
Immunogenetic investigations of susceptibility to cu-
taneous leishmaniasis in humans have generally fo-
cused on possible associations with major histocompat-
ibility antigens, which would presumably have bearing
on lymphocyte-dependent immunity. A family study of
localized cutaneous leishmaniasis (LCL1 in Venezuela
yielded evidence of associations between HLA-I3W22
and DQw3 antigens and this presentaticm of American
cutaneous leishmaniasis.‘32 The HLA class II specificity
DQw3 was also found to be more frequent among Bra-
zilian patients with mucocutaneous disease than
healthy controls without a history of leishmaniasis.“”
To strengthen the evidence for a link between genotype
frequency and disease susceptibility, the history of ex-
posure and occurrence of subclinical infection in the
healthy comparison group, as well as the nonunifor-
mity of ACL, will need to be considered in the design
and analysis of future studies. For example, mucocuta-
neous disease may be a primary or secondary manifes-
tation, the result of contiguous spread or metastasis,
self-limiting or progressive and mutilating, and is
caused by a variety of species of Leishrr~at~ia.Since the
bases of susceptibility may differ according to the anti-
genie make-up of the etiologic agent and the mecha-
nism of pathogenesis, these distinction:, as well as the
heterogeneity of the immune response (antibody and
cell-mediated) are potentially important variables in the
classification of cases for immunogenetic studies.‘74
Acquired Resistance
Recurrent leishmaniasis is informative with respect to
acquired resistance as well as susceptibility. Evidence of
prior cutaneous leishmaniasis is commonly observed in
patients with mucosal leishmaniasis.5”‘hhLikewise, pa-
tients with active cutaneous lesions who reside in en-
demic areas of transmission of Leishmaniaof the Viannia
subgenus often have scars characteristic of previous
dermal leishmaniasis.‘8*26,45Regardless of the mecha-
nism of recurrent disease, reactivation, or reinfection, it
is clear that recovery from natural infection with Leish-
mania of the braziliensis complex does not alwavs con-
444 WEIGLE AND GORE SARAVIA Clinicsin Dermatology 2996;14:433450
l

fer resistance. Nevertheless, most individuals who have and resistance to leishmaniasis in humans have not yet
presented with American cutaneous leishmaniasis ex- been defined. Despite the limited understanding of the
perienced one episode of disease (Fig 5). Indeed, the mechanisms involved, immunotherapeutic interven-
relative infrequency of recurrent leishmaniasis provides tions have demonstrated the reversibility of clinical
evidence of acquired resistance. Histopathological susceptibility. Both the hyperreactive and hyporeactive
evaluation of recurrent lesions revealed a lower parasite expressions of dermal leishmaniasis can be ameliora-
burden in recurrent lesions in comparison with that ob- ted either transitorily or permanently by immuno-
served in lesions of patients without prior history of therapy.lo5
disease, suggesting the acquisition of partial resistance
Table 2.36 The decreasing incidence of disease in rela- Parasite Determinants of Disease Expression
tion to incidence of infection with age (Fig 7) is also Clinical and Epidemiology Evidence of Parasite
consistent with the acquisition of resistance following
Determinants of Disease
infection.18f26
Just as unusual clinical presentations of infection with a
Individuals who experience subclinical infection
particular Leishmania species serve to illustrate the in-
may differ from those who experience disease, particu-
fluence of the host response on disease expression, the
larly chronic disease, with respect to natural and ac-
finding of a particular disease form to be predomi-
quired resistance. ‘lo Parasite determinants notwith- nantly associated with a species or taxonomic group of
standing, distinct frequencies of subclinical and
Leishmania indicates the existence of parasite determi-
clinically apparent infection in different foci reflect dif- nants of disease. Diffuse cutaneous leishmaniasis, for
ferences in both natural and acquired resistance among example, has only been observed in patients with infec-
individuals in a similarly exposed population. For ex-
tions by parasites pertaining to the Leishmania subge-
ample, the attack rate is high, yet subclinical infections
nus, specifically, L. mexicana, L. venezuelensis, and L.
also occur in situations of occupational exposure or amazonensis(mexicana complex) in the New World and
colonization of endemic areas by previously unexposed L. aethiopica in the Old World. Similarly, visceral leish-
populations.135,136 maniasis is principally caused by Leishmania of the
Experimental challenge infections in volunteers also donovani complex, L. donovani, L. infantum/chagasi,
provide evidence of acquired resistance following natu- though infections involving the bone marrow and/or
ral or experimental infection.14 Published experimental spleen and atypical visceral disease can be caused by
challenge infections with Leishmania that cause ACL dermatotrophic species L. tropica92,140and L. amazonen-
have been few and involved a total of seven subjects.137-
sis8 The self-healing nature of localized cutaneous le-
139 Nevertheless, infection with L. mexicana protected
sions caused by L. mexicana as compared with the
against disease upon homologous challenge in four out
chronic and often progressive lesions produced by L.
of five subjects. Infection with L. mexicuna did not pro- braziliensis in the same population of soldiers” further
tect against heterologous challenge with L. braziliensis,
substantiates the existence of intrinsic biological differ-
while infection with L. braziliensis protected against ho-
ences among Leishmania.
mologous challenge. Although the generalizability of
Population-based studies of incident infection and
these limited experiences is unknown, the results pro-
disease allow the pathogenicity of the Leishmaniabeing
vide direct evidence of acquired resistance following
transmitted in a particular focus to be evaluated. Based
clinically apparent infection.
upon the definition of pathogenicity as no.diseased/
The cellular and molecular bases of susceptibility
no.infected, L. peruviana with 9.3 incident casesand 11.2
incident infections/100 person years26 would be con-
Figure 7. The ratio of incident disease to incident infection by
age, Inguapi del Guadal and 14 neighboring villages, rural area of sidered more pathogenic than L. panamensiswith 0.47
the municipality of Tumaco, Colombia, 1987-1989, illustrating incident cases and 6.6 incident infections/100 person
the decrease of clinically apparent infection with increasing age of years.i8
residents.
Experimental Evidence of Parasite Determinants of Disease
The propensity of the various taxa to cause distinct
disease forms is even more clearly evident in geneti-
cally defined mice in which different Leishmania spe-
cies produce distinguishable and characteristic patterns
of disease in the same genetically homogeneous strain
of mice. While BALB/c mice develop progressive dis-
ease when infected with L. major and L. mexicana, le-
sions fail to develop when this highly susceptible
o-9 10-29 130 strain is infected with L. braziliensis.‘4’,‘42 Leishmaniaof
Age raw (yea@ the mexicana and braziliensis complexes also differ
Clinics ij7 Drr7nntolu~y l 1996;24:433450
radically with respect to disease expression in the ham-
ster.lb3 Likewise, the severity of primary lesions and
the frequency of metastases in the hamster differs
among species and strains of the braziliensis complex
(Fig 81.“”
Experimental studies have established that the infec-
tivity of Leishmnnia major differs according to growth
phase as well as the length of passage in culture.rU
Metacyclogenesis has since been shown to accelerate
during the stationary phase and to correlate with infec-
tivity.‘4s However, Leishmafzia of the Vianniu subgenus
do not show strict growth-phase-dependent infectivity;
furthermore, the growth kinetics and point of maxi-
mum infectivity differ among species.‘46 Differences in
infectivity are an important consideration when experi-
mentally analyzing pathogenicity and/or virulence
since some expressions of disease are linked to the dose
and route of the infective inoculum. Metastasis in the
hamster model on the other hand, was found to be a
dose-independent trait of particular strains of L. guy-
anensis and L. pannmensis.h”
Little is known about virulence factors or the mo-
lecular basis of parasite pathogenicity. Infectivity, on
the other hand, has been analyzed in exquisite detail
both at the biochemical and molecular genetic levels.
Several lines of evidence support the participation of
lipophosphoglycan (LPG) in infectivity’47 and intracel-
lular survival.‘4s,‘44 Mutants lacking LPG are unable to
establish infection’s0 and LPG evidently subverts mac-
rophage activation,r5’,‘s’ thereby propitiating parasite
survival and replication. Stage-specific changes in the
structure of LPG are consistent with the participation of
Figure 8. Frequency of cutaneous metastasis in the golden hamster when experimentally
and L. ,quyanensis (from Martinez et al.,‘” with permission).
this dominant surface glycoconjugate in the relation-
ship of Leishmnnia with its invertebrate and vertebrate
hosts.‘47,‘53LPG structure and composition vary among
the Lrishmanin taxa that have been examined; differ-
ences in the constitution of LPG may influence the
course of infection and disease that characterizes par-
ticular species or taxonomic groups of parasites.
Among New World Leishmania that cause dermal dis-
ease, only the lipophosphoglycan of 1.. nuirana has
been characterized.‘s”
The major surface glycoprotein antigen, gp63, may
also participate in infectivity since the expression of
gp63 correlates with resistance to complement medi-
ated lysis”5 and with infectivity. r “’ Carbohydrate moi-
eties on this metalloprotease,ls7 nnd LPC’5x,‘5” act as
ligands with macrophage receptors that mediate phago-
cytosis such as complement and mannose/fucose re-
ceptors, thereby promoting entry into the host cell.“‘”
Whether gp63 is causally linked to infectivity, that is,
that it is necessary and sufficient, is not known. The
relationship of gp63 and other parasite molecules with
disease expression (i.e., pathogenicitv and virulence) re-
mains to be determined.Jh’
Advances in recombinant genetics ot Lt’ishmania to-
gether with appropriate experimental models of patho-
genicity and virulence should reveal the molecular
bases of parasite determinants of disease. Nevertheless,
because the host response is tightly linked to the out-
come of infection, it is conceivable that the parasite mol-
ecules that elicit particular cytokine repertoires and the
genes that code and/or regulate their expression, will
constitute virulence factors.
infected with difererit sfrar?Ji :)f I ,m7~7777~~~~?;i’:
446 WEIGLE AND GORE SARAVIA Clinicsin Dermatology 1996;14:433450
l

Acknowledgments 13. Barral A, Badaro R, Barral-Neto M, et al. Isolation of

Leishmaniamexicanaamazonensis
from the bone-marrow
The work of the authors included in this review was sup- in a case of American visceral leishmaniasis. Am J Trop
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national Development Center of Canada; grants 5 PO1 14. Melby PC, Kreutzer RD, McMahon-Pratt D, et al. Cuta-
AZ16315 and 5 P50 A230603 of the U.S. NIAID; COL- neous leishmaniasis: Review of 59 cases seen in the Na-
CIENCIAS grant No. 229-005-001-87 and 2229-04-001-92; tional Institutes of Health. Clin Infec Dis 1992;15:924-927.
and from the United National Development Programme/ 15. Ashford RW, Desjeux I’, deRaadt I’. Estimation of popu-
World Bank/ World Health Organization SpecialProgramme lation at risk of infection and number of cases of leish-
maniasis. Parasitology Today 1992;8:104-105.
for Researchand Training in Tropical Diseases(TDRJ. The
16. Furner BB. Cutaneous leishmaniasis in Texas: Report of
assistanceof Diana Toro in the preparation of the manuscript
a case and review of the literature. J Am Acad Dermatol
and Iris Segura with the photography of figures is acknowl- 1990;23:368-371.
edgedwith gratitude. 17. Herwaldt BL, Stokes SL, Juranek D. American cutaneous
leishmaniasis in US travelers. An Int Med 1993;188:779-
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