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Report
Oxford, UK
International
IJD
Blackwell
0011-9059
41
Science,
Journal
Ltdof Dermatology
2002
Presence of Leishmania organisms in specific and non-specific
skin lesions in HIV-infected individuals with visceral
leishmaniasis
Leishmania
Bosch
et al. organisms in skin lesions
Ricardo J. Bosch, MD, Ana B. Rodrigo, MD, Purificación Sánchez, MD, María V. de Gálvez, MD,
and Enrique Herrera, MD
From the Department of Dermatology,
University Hospital, School of Medicine,
Malaga, Spain
Correspondence
Ricardo J. Bosch, MD
Departamento de Dermatología
Facultad de Medicina
Universidad de Málaga
29010, Malaga
Spain
E-mail: [email protected]
Abstract
Background Leishmania coinfection is frequently seen in human immunodeficiency virus
(HIV)-infected patients in endemic areas, and from time to time the protozoan is detected in
cutaneous biopsies.
Objective To establish the characteristics and possible ethiologic role of the presence of
Leishmania in these lesions.
Methods We studied 12 cutaneous biopsies with Leishmania organisms from nine HIVinfected patients (seven men and two women) with visceral leishmaniasis, diagnosed by bone
marrow examination, seen over a period of 9 years.
Results Based on clinical characteristics, evolution and response to anti-leishmanial
treatment, cutaneous alterations were found to be related to the presence of the protozoan in
six cases, whereas in the other six cases it was not considered responsible for the
dermatological lesions (dermatofibroma, and lesions of psoriasis, Reiter’s syndrome, bacillary
angiomatosis, cryptococcosis and oral aphthae). Of note was the high prevalence of specific
mucocutaneous manifestations, usually accompanied by intense pruritus, great variability, and
a tendency to relapse after treatment stopped. On two occasions, detection of the protozoa in
skin biopsies led to the diagnosis of a previously unsuspected visceral leishmaniasis.
Conclusions Cutaneous detection of Leishmania is frequent in HIV-infected individuals with
visceral leishmaniasis. Sometimes Leishmania is associated with changes attributable to other
dermatological processes, and its presence does not imply a causative role. A clear relationship
between the systemic process and the therapeutic response is necessary to demonstrate an
ethiologic role.
Introduction
670
Leishmaniasis, caused by a protozoan of the genus Leishmania, includes a series of diseases which vary widely depending
on the infecting species, the reservoir, the transmitting agent
and the susceptibility of the host.1
Spanish dermatologists, especially in certain Mediterranean areas, quite often see children with the cutaneous form
of leishmaniasis, generally caused by Leishmania tropica
minor, and in which Phlebotomus papatasi acts as the vector.
However, despite the fact that visceral leishmaniasis, usually
caused by L. donovani or L. infantum, is also endemic in this
area, cutaneous manifestations are rare, and are most often
associated with non-specific eruptions during the acute phase,
showing macular lesions and dischromatic, erythematous or
nodular lesions of postkala-azar dermal leishmaniasis.2
International Journal of Dermatology 2002, 41, 670 –675
In a 9-year period we have detected the histopathological
presence of Leishmania in various cutaneous biopsies from
human immunodeficiency virus (HIV)-infected patients with
visceral leishmaniasis. Although its presence does not imply
that it is the cause of the dermatological process, we feel it is
necessary to establish criteria to determine whether Leishmania is responsible for the disease. Current ease of travel
requires specialists working outside endemic areas to be
aware of these infections and their presentations.3,4
Patients and methods
Nine HIV-positive patients, seven men and two women, with
different degrees of immunosuppression (Table 1) showed
12 mucocutaneous lesions in which, by means of biopsy, we
detected the presence of Leishmania.
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Bosch et al.
Leishmania organisms in skin lesions Report
Table 1 HIV-positive patients with visceral leishmaniasis and the presence of mucocutaneous Leishmania
Patient
Sex
Age
(years)
1
F
21
24
1
Hyperpigmented facial areas
2
M
46
3
M
27
128
250
320
2
3
4
Tattoo infiltration
Disseminated papular eruption
Disseminated papulae
4
5
M
F
31
33
220
116
5
6
Flat-topped violaceous lesions
Extensive infiltrated plaques
6
M
34
32
420
46
7
8
7
M
32
72
9
Indurated papulo-nodule
Papulosquamous lesions; balanitis
Onychodystrophy; arthritis
Papuloglobular lesions
8
M
27
191
10
9
M
28
30
300
114
11
12
CD4/mm3
Chart
Tumors, papulae, and disseminated
violaceous nodules
Erythematous desquamative plaques
Relapsing ulceration in mouth
All the patients were diagnosed with visceral leishmaniasis
through bone marrow examination. In seven cases the diagnosis
was known before the apparition of the dermatological alterations
leading to the consultation, and five of them had previously
received antiprotozoan therapy, two with liposomal amphotericin
B (patients 3 and 4) and three with antimonial compounds
(patients 1, 6 and 8). In two cases (patients 2 and 5), the detection
of Leishmania in skin biopsies led to the diagnosis of a previously
unsuspected visceral leishmaniasis.
Eight patients were or had previously been intravenous
drug abusers, with the one remaining woman (patient 1)
denying any history of drug addiction, having presumably become
infected through her work as a prostitute. They were seen at
our dermatology department between 1990 and 1998 and
had all resided in the province of Malaga, on the Mediterranean
coast in southern Spain, with none of them reporting any
travel to other areas or countries. The cutaneous manifestations
for which they initially presented were very varied.
The common characteristic leading to their grouping
in this study was the pathological finding of Leishmania
organisms.
The responsibility of Leishmania for the dermatological process
was established based on the presence of lesions which were
suggestive of well-known cutaneous manifestations of visceral
leishmaniasis and which were not clinically or pathologically
consistent with any other known cause. Parallelism among the
cutaneous process and visceral leishmaniasis was also
considered. Moreover, in all cases we verify the response of the
cutaneous lesions to antileishmanial therapy, whereas other
treatments had already failed.
© 2002 The International Society of Dermatology
Histopathology
(Leishmania presence)
Clinical features
Increased epidermal melanine
Lymphohistiocytic infiltrate
Deep well-defined granulomas
Slight lymphohistiocytic infiltrate
Psoriasiform dermatitis
Lymphohistiocytic infiltrate
Superficial granulomas
Massive histiocytic infiltrate
Dermal band respected
Dermatofibroma
Psoriasiform dermatitis
Lymphohistiocytic infiltrate
Cryptococcosis gelatinous pattern
Cryptococcus spore coexistence
Vascular proliferation with Warthin-Starry + bacilli
Typical psoriasis
Non-specific ulcer
Results
The presence of Leishmania in the dermis was considered
responsible for the processes leading to the biopsy of the
cutaneous alterations of patients 1–4 and the extensive infiltrated plaques of patient 5. The facial itching hyperpigmentation in patient 1 disappeared with antiprotozoan treatment,
whereas it persisted with systemic antihistamine derivatives
and topical steroids. The evolutionary correlation with visceral leishmaniasis was especially evident in patient 2, in
whom the appearance of infiltration over a tattoo (Fig. 1) was
simultaneous with hematological involvement. This same
patient later developed an itching papulo-erythematous eruption (Fig. 2), in which leishmanias were also detected whereas
no leishmanias were found in a biopsy of nearby unaltered
skin taken at the same time. This same situation, with pruritus
and top-flattened papules, also occurred in patient 3. The presence
of a greater degree of infiltration was more obvious in patient
4, with the presentation of disseminated papules, and even
more obvious in patient 5, who showed large infiltrated plaques
(Fig. 3). The last two patients also had intense pruritus.
In contrast, in the indurated nodule of patient 5 and the
cutaneous disorders of patients 6– 9, the presence of Leishmania was considered a chance biopsy finding, and Leishmania
was not therefore considered to be the cause of the cutaneous
process for which the patients had originally consulted. This
conclusion was reached after the clinical, analytical, and
pathological demonstration of another disorder responsible
for the manifestations, after the detection of leishmanias in
areas of non-affected skin, or after verifying independence to
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Report Leishmania organisms in skin lesions
Figure 1 Papulonodular lesions over a tattoo which infiltrated
and disappeared under systemic antileishmanial therapy
Bosch et al.
Figure 3 Intensely itchy erythematous eruption with an intense
parasitic infiltration of the histiocytes
Figure 2 Pruriginous flat-topped papular eruption observed in
Figure 4 Presence of large amounts of leishmanias in the biopsy,
three of the six cutaneous lesions attributed to the presence of
leishmanias in the skin
which is usual in these patients, enabling them to be seen easily
with a hematoxilin-eosin stain
antileishmanial therapy. The presence of protozoa was
detected in cutaneous lesions associated with Reiter’s syndrome, cryptococcosis, bacillary angiomatosis, psoriasis or
oral aphthae and in a dermatofibroma which had been
removed to rule out the possibility of Kaposi’s sarcoma.
Of note in the pathological examination was the existence
in most sections of a large number of leishmanias, both intracellularly and extracellularly, clearly visible even with the
usual hematoxilin-eosin stain (Fig. 4). In those cases attributable to the presence of leishmanias, the histological features
ranged from scarce lymphohistiocytic infiltrate, via the presentation of dermal granulomas, to the existence of a massive
infiltration of histiocytes laden with leishmanias which only
respected a narrow band of collagen in the superficial dermis
(Fig. 5). In six cases the lymphohistiocytic infiltrate with
leishmanias coexisted with histopathological changes typical
of other processes, on occasions as characteristic as those of
bacillary angiomatosis or the striking presence of spores of
Cryptococcus neoformans.
After dermatological study and clinical and hematological
evaluation of the patient, therapy was initiated on nine occasions, seven with antimonial compounds (cases 1, 2, 3, 5, 6, 8
and 11), and two with liposomal amphotericin B (cases 4 and
9). The response to these treatments was important for establishing or discarding the causal role of Leishmania. Two
patients (6 and 8) treated with antimonial compounds died.
International Journal of Dermatology 2002, 41, 670 –675
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Figure 5 Subepidermal band respected by the parasite-laden
histiocytes, similar to that seen in lepromatous leprosy.
Some role of cardiac side-effects of these drugs in conjunction
with other alterations was suspected, but the actual cause could
not be determined as permission for autopsy was not granted.
Discussion
Over recent years, the natural immune response has been
altered in many patients by the action of HIV. Although the
repercussions for cutaneous and mucocutaneous leishmaniasis have not been great, several reports have appeared of unusual forms of these diseases in HIV-positive patients.5–13 In
contrast, in countries around the Mediterranean basin,
including Spain, where the infection is endemic, there is a high
prevalence of visceral (“kala-azar”) leishmaniasis among HIVpositive patients,14–18 with an estimated 1–3% of these patients
being infected.19 In fact, although leishmaniasis is not at present
included among the definitive criteria for acquired immunodeficiency syndrome (AIDS), its inclusion has been proposed.20–23
This high prevalence is mainly a result of reactivation of a
latent infection by immunosuppression, with antileishmania
serology tests and CD4+ T-cell counts being proposed for its
prophylactic and therapeutic control.24,25 The influence of
immunosuppression is also supported by the frequent treatment failures in these patients and by the reduction of these
observations over recent years, since the use of antiretroviral
therapy has prevented situations of severe immunosuppression. The predominance of intravenous drug abusers among
our patients is the result of intravenous drug abuse being the
most common risk factor in our area, although the possibility
has also been suggested that these patients act as reserves for
transmission by contaminated needles.26,27
© 2002 The International Society of Dermatology
Leishmania organisms in skin lesions Report
Paralleling the increase in cases of visceral leishmnaisis in
HIV-positive patients are reports of different cutaneous
manifestations in which leishmanias have been detected, though
the etiologic and pathogenic significance of this finding with
regard to cutaneous manifestations may be different, as we
suggested in our initial report some years ago.28 Occasionally,
the presence of protozoa in dermal histiocytes is attributable
solely to the existence of a general impregnation of the
macrophagocytic system, which is especially intense in immunosuppressed patients. The detection therefore of cutaneous
amastigotes in a patient with visceral leishmaniasis does not
necessarily imply that they are the cause of the dermatological process under study. Leishmanias have been noted in
healthy skin29 as well as in lesions from widely different processes including Kaposi’s sarcoma,30–33 herpes simplex and
zoster,34,35 and a dermatofibroma.36 From our cases, it is
possible to include within this group the clinically and histopathologically typical psoriasis and the erythematous desquamative eruption seen in a typical case of Reiter’s syndrome.
Moreover, their coexistence with the infectious agents
responsible for bacillary angiomatosis and cryptococcosis,
which has not previously been reported, was clear. Finally,
they were also detected in a dermatofibroma and in an ulcerated lesion of the oral mucosa, which from its evolution and
features was an oral aphtha. In two cases this incidental
observation led to the diagnosis of an unsuspected visceral
leishmaniasis, which in the absence of clinical and hematological data should be confirmed by bone marrow study, including cultures in adequate media.
Although not mentioned in comparative studies,37 cutaneous involvement during the course of visceral leishmaniasis
seems to be more frequent in HIV-positive patients than in
immunocompetent persons. Manifestations reported comprise a wide range of changes, such as hyperpigmented
lesions, which gave rise to the term “kala-azar” (black fever) in
one of the languages of India, and diverse papular and nodular eruptions, more or less extensive and florid, which indicate
the involvement or persistence of cutaneous leishmanias.38–42
Other manifestations with varying clinical aspects have also
been reported, including erythroderma, dermatomyositis and
psoriasis.43–45 Our experience confirms this great clinical and
pathological variability. The presence of infiltration over a
tattoo has been reported previously36 and in our case it is gaudy,
the infiltrative relapses coinciding with systemic worsening.
Of note in three of the patients (cases 3, 4 and 5) was the
papular eruption, mainly involving the extremities, with certain clinical features resembling lichen planus. An important
clinical detail, also present in another two of the six cases, attributable to the presence of leishmanias was the intense pruritus
accompanying the lesions. This symptom may well be of use
when considering the possibility of visceral leishmaniasis as
an explanation for these specific cutaneous manifestations. At
no time did we see any lesions in the oral mucosa, which could
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Report Leishmania organisms in skin lesions
have been considered attributable to the direct activity of
Leishmania, although this has been reported on occasion.27,46–48
The histopathological findings in cutaneous lesions are
variable and often atypical,42,49 as in other organs.50 Of interest
in our series, together with the non-specific images and variable
granulomatous appearance, was the case with an intense
histiocytic infiltrate laden with leishmanias respecting a
narrow band in the superficial dermis, similar to that seen in
lepromatous leprosy. Its coincidence with severe immunosuppression confirms it as an anergic form and suggests the
existence in leishmaniasis of a similar situation to leprosy,
with clinical and pathological differences depending on the
immune response.
The large amount of leishmanias present in most cases
enabled them to be seen easily with routine stains, and emphasizes the importance of the histopathological study of these
lesions. In fact, it led to the diagnosis of clinically non-specific
lesions, and on two occasions resulted in the diagnosis of a
previously unsuspected visceral leishmaniasis. The demonstration
of leishmanias is essential but, as we have seen, does not necessarily indicate that they have a causal role in the lesions
under study. It is necessary to discard other processes and,
more especially, to demonstrate a good evolutionary correlation with the systemic symptoms and with the response to
antiprotozoan therapy.
Seven of the nine patients in which leishmanias were
detected had lymphocyte counts ≤ 250 CD4/mm3, many of
these corresponding to the period prior to the introduction of
multiple antiretroviral therapy, when situations of severe
immunosuppression were common. At that time the HIV
viral load was not determined, but later studies showed the
existence of a relationship between this and the quantification
of leishmanias in bone marrow, as well as their influence in
the response to antileishmanial therapy.51 The tendency of the
infection to persist is demonstrated by the fact that eight of the
cases in which leishmanias were detected arose in patients
who had previously received antimonial or liposomal amphotericin B treatment. The prognosis in these patients is uncertain, so they should undergo close follow-up and be given
secondary prophylaxis52 at least until there is a clear improvement in their immune status.53
Acknowledgments
The authors thank Ian Johnstone for help with the English
language version of the paper.
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