Post-kala-azar dermal leishmaniasis is a dermal complication of VL , which has been frequently reported from the Indian subcontinent and from the Sudan, where 10–20 % and 50–60 % respectively, of the patients who were treated for VL developed PKDL [6, 7]. In Brazil, only one patient with PKDL was reported and this was associated with AIDS .
Visceral leishmaniasis has a worldwide distribution and is considered a public health problem in 88 countries, including Brazil . It is caused by species of the Leishmania donovani complex, transmitted by the bite of a female sand fly (Phlebotomus spp and P. argentipes) [6, 10]. In Latin America, the main causative agent of VL is Leishmania (L) infantum chagasi transmitted by Lutzomiya longipalpis [11, 12]. In Brazil, asymptomatic infections and mild forms (low symptomatic) of the disease are more frequent than the classic VL (Kala-azar) . The asymptomatic forms occur especially in children and may heal spontaneously. The determinant factor in spontaneous healing or evolution to fatal classic disease is malnutrition .
The symptomatology of kala-azar reactivation in immunosuppressed patients is very variable depending on the type and the duration of immunosuppression (transplantation or autoimmune disease), or the time and the duration of immunosuppression by HIV and others diseases . The clinical forms of VL, particularly in these conditions are very variable. In general, the classic symptoms such as bowel and gastric dysfunctions are not highlight to the diagnosis [16, 17].
In India, the human being is the only known reservoir of VL. This is of epidemiological importance, particularly between epidemic periods of VL. The Leishmania parasites survive and propagate intradermally rendering the exposed skin lesions as an easy access area for the sand fly vector to ingest Leishmania parasites, get infected and develop the promastigotes in their midgut enabling them to transmit the parasite. The presence of only 0.5 % of PKDL patients during a VL epidemic can potentially succeed in making VL endemic . In other areas such as the Sudan, transmission may be anthroponotic and zoonotic, with rodents and canines as candidate reservoirs . In Brazil, VL is zoonotic with canines as the reservoir host .
The causative agent of PKDL in the Sudan and on the Indian subcontinent belongs to the L. donovani sp. Of these species L. (L) infantum chagasi was also found in the skin lesions of Brazilian patients with VL . In Europe and in South America, PKDL may be considered to be a rare clinical entity among Aids patients with L. infantum as the prime causative agent . The same species was also found in the patient reported here.
Post-Kala-azar dermal leishmaniasis may develop during or after treatment of VL [6, 21]. However, some patients have no history of VL and they are easily misdiagnosed as having other skin disorders . In the Sudan, the PKDL cases occur 60 % after VL treatment, 15 % at the same time as VL (called paraKDL), and 10 % even without a history of VL . Indian PKDL appears 6–12 months after the cure of VL , whereas in the majority of the Sudanese patients, PKDL occurs within the first 2 months following treatment of VL . It was also reported in HIV/VL co-infected patients receiving HAART . Our patient developed PKDL 6 months after the end of VL treatment, similar to that reported in the Indian patients.
Possible risk factors for developing PKDL include previous VL treatment, its duration and the type of drug used, young age, malnutrition, HIV infection, genetic factors and the parasite strain . Parasite clearance during treatment may have an important influence. Zijlstra et al.  reported that patients with a negative tissue aspirate (lymph node or bone marrow) on PCR after VL treatment did not develop PKDL, whereas 36 % of those who were PCR-positive developed PKDL. The patient reported here was PCR-positive in the 4th month of treatment for VL. The presence of a large spleen during VL was also linked to an increased risk of PKDL as were the high serum levels of C-reactive protein as seen in our patient too (data not shown) before treatment for VL, the high level of IL-10 in the peripheral blood and in the normal looking skin during VL [6, 20, 25, 26]. Among all these, incomplete or short treatment of VL seems to be the major risk factor . Our patient had received liposomal amphotericin B (4 mg/kg/day) during 5 days to treat her VL as recommended by the Ministry of Health in Brazil  with clinical improvement in few days.
It was argued that after VL treatment there was a subsequent immune activation that could force the parasites to seek refuge within the dermis making this tissue a reservoir for the parasites . Despite the demonstration of PKDL after inadequate therapy for VL in the Sudan, many authors reported PKDL even after adequate treatment with sodium antimony gluconate (SAG), amphotericin B and miltefosine [28, 29]. Today, PKDL is no longer considered to be a specific drug-dependent manifestation .
Post-Kala-azar dermal leishmaniasis is clinically characterized by hypo-pigmented macules, erythematous plaques, papular or nodular lesions with Leishmania parasites [5, 30]. The lesions generally begin on the face and gradually increase in size. They may also spread to the neck, the trunk and the extremities . Papular or nodular lesions are more common in the Sudanese PKDL, whereas a polymorphic presentation with macules, papules and nodules is more common in the Indian patients [6, 31, 32]. Unusual clinical variants such as papillomatous, verrucous, hypertrophic, xanthomatous, annular and lupoid lesions have also been reported [33, 34]. Mucosa involvement in PKDL is very rare . No constitutional symptoms have been reported .
Although clinical forms may differ in different countries, the hypopigmented macules on the face are generally the first lesions to appear in PKDL. Single lesion occurs in up to 5 % and 10 % respectively, of the PKDL cases in Africa and India [30, 37]. Our patient presented with only a few hypopigmented papules on her forehead as the unique manifestation of the disease.
The diagnosis is established after assessing the clinical signs and symptoms . History of VL, living in an endemic area and positive antibody tests are helpful in the diagnosis [20, 38]. According to Zijlstra et al. , it is important to observe the type of rash as well as its distribution (in the Sudan, the rash generally begins around the mouth, then spreads to the nose and the cheeks and finally to other parts of the face and the body) and the time relation to VL treatment. However, the ideal diagnostic method is to demonstrate the parasite in smears, culture or PCR [18, 20].
In all clinical types of PKDL, histopathological examination of the skin biopsy shows an epidermis with hyperkeratosis, acanthosis or atrophy and hydropic degeneration of the basal layer. The presence of parasites in biopsies varies with the type of the rash and the duration of the lesions. The biopsy from macular lesions usually consists of sparse inflammatory infiltrate of lymphocytes, histiocytes and a few plasma cells predominantly around the vessels of the superficial vascular plexus. Leishmania amastigotes are usually absent in such lesions, but the presence of plasma cells is an important clue in favor of PKDL. Biopsies from the papules and plaques show a moderate to dense lymphocytic inflammatory infiltrate in the mid-dermis, with histiocytes and plasma cells. In nodular lesions, the histopathological examination of the biopsy shows a diffuse dermal inflammatory infiltrate consisting of histiocytes and plasma cells in large numbers. Compact epithelioid granulomas may also be observed .
The Leishmania amastigotes are intracytoplasmic structures in histiocytes. Amastigotes are observed in 25–50 % of the hematoxylin-eosin-stained biopsies of nodular and plaque lesions of PKDL [39, 40]. In the patient reported here, the papular lesion had Leishmania amastigotes, which was also confirmed by immunohistochemistry with an anti-Leishmania polyclonal antibody.
Neuritis involving small cutaneous nerves similar to that in leprosy was reported in PKDL. However, peripheral large nerves are not involved in PKDL [6, 36].
Leprosy is the main differential diagnosis in PKDL because of the clinical and histopathological similarities , but their differentiation may be very difficult [36, 41, 42]. The small hypopigmented lesions seen in PKDL are very similar to those in borderline and lepromatous leprosy [30, 41]. The patients with leprosy and PKDL usually come from the same geographical location where both diseases are endemic . However, leprosy is associated with hypoesthetic lesions . Arora et al. reported that the center-facial involvement and the sparing of ear lobes in PKDL may be distinguishing features from leprosy . Histologically, PKDL displays epithelioid cell granulomas, similar to tuberculoid leprosy. The parasites may be absent in the macular variant of PKDL making it essential to exclude other diseases . Perineural infiltration in PKDL was reported to cause great difficulty in differentiating PKDL from leprosy [30, 35]. However, the main histological difference between these diseases is that in the macular lesions of leprosy, the inflammatory infiltrate is centered in the neurovascular plexus in the lower dermis. Besides this, in the nodular lesions of lepromatous leprosy, the peripheral limits of the infiltrate are infiltrative, whereas those in nodular PKDL have a fairly sharp margin .
Leprosy and leishmaniasis are both spectral diseases and co-infections have been reported. Although it is a rare association, it occurs in countries such Ethiopia and India where both diseases are endemic . The case reported here of co-infection with PKDL is the first in Brazil.
Leishmaniasis and leprosy share a lot of similarities. Both diseases are caused by obligate intracellular organisms. The clinical and pathological expressions depend on the host response, probably due to genetic determination and environmental influences [42, 43]. At the hyperergic pole, the patient shows localized lesions with well-formed granulomas with few or absent organisms, whereas at the anergic pole, the lesions are widespread, there is no epithelioid granulomatous reaction and there are numerous parasites .
It was suggested by Bansal et al. that there is a cross-protection between Mycobacterium and Leishmania infection since both diseases increase macrophage activation. However, the immune deficiency in leprosy is apparently specific for M. leprae only and does not dictate the immune response in leishmaniasis. They reported a patient in whom the macular variant of PKDL (‘low-resistance’) coexisted with ‘high-resistance’ borderline tuberculoid leprosy . Our patient presented subpolar lepromatous leprosy with a VL co-infection considered as an anergic pole of both diseases (Th2 response). After developing PKDL, the immunological response changed to the hyperergic pole (Th1 response) of the Leishmania infection, when she showed papules with epithelioid granulomas, but she remained at Th2 pole of leprosy indicating that the immune defect was specific for each microorganism [42, 43].
To date, there is no consensus and no large studies on the best available treatment for PKDL. Moreover, the evolution of this disease differs in different geographical regions. Fifty per cent of the Sudanese PKDL is self-limiting and heal spontaneously, whereas all Indian PKDL cases required treatment [6, 20, 33]. In cases of severe lesions or lesions persisting for more than 1 year in the Sudan, treatment with sodium stibogluconate (SSG) 20 mg/kg/day for 1–2 months was instituted [6, 10]. Miltefosine administered orally was an effective and safe treatment for Indian visceral leishmaniasis. It may protect against PKDL because it is given for a much longer period. It may be helpful in regions where the parasites are resistant to the current agents [15, 44].
In cases of SSG-unresponsive treatment, amphotericin B 2 mg/kg/day for 20 days was reported to be effective [6, 10, 20]. Other therapeutic options include miltefosine, ketoconazole and pentamidine [6, 10]. Clinical cure may differ according to the PKDL type. Usually nodules and plaques disappear in 120 days and macular lesions in 200 days [6, 10]. However, parasitological cure may precede the clinical cure, and long treatment regimens need to be carefully monitored . Our patient received liposomal amphotericin B (3 mg/kg/day for 7 days), with clinical healing of the skin PKDL lesions in 3 months.
At this moment the patient is in good health and without skin lesions indicative of PKDL. She has only regressive macules of leprosy. However, at present she received the 10th dose of a newly started MDT-MB treatment because she had the first symptoms of tibial neuritis about 5 year after leprosy treatment. It is likely that the previous treatment for 14 months may have been inadequate.