Abstract
Post kala-azar dermal leishmaniasis (PKDL) is a mucocutaneous disease usually seen in apparently cured, inadequately treated or untreated cases of visceral leishmaniasis and is endemic to many parts of India, Nepal, Bangladesh, and eastern Africa (Sudan, Ethiopia, Kenya). The disease usually manifests as a variable combination of hypopigmented patches, erythematous succulent papulo-plaques, and nodular lesions on the face and upper body and sometimes extending on the extremities, genitalia, and tongue. Atypical morphology and presentations are not uncommon, especially in endemic areas, which include photosensitivity, verrucous, hypertrophic, xanthomatous, and ulcerative lesions. Recognition of spectrum of mucocutaneous changes helps physicians in early initiation of treatment and in reducing disease transmission in the community. The differential diagnosis depends on the pattern of manifestations, but lepromatous leprosy is the closest mimicker. Since PKDL does not cause significant morbidity, at least initially, but the affected patients continue to act as a reservoir of the disease, active case detection is required to identify cases early to control the disease transmission in the community.
KEY WORDS: Active surveillance, India, Leishmania donovani, para kala-azar dermal leishmaniasis, post kala-azar dermal leishmaniasis, Sudan, visceral leishmaniasis
Introduction
Post kala-azar dermal leishmaniasis (PKDL), as the name suggests, is a sequel of kala-azar or visceral leishmaniasis (VL) and the disease was recognized as a distinct clinical entity separate from other forms of cutaneous leishmaniasis by Dr U. N. Brahmachari in 1922.[1] He established that the causative agent is Leishmania donovani which causes VL and hypothesized that the cutaneous manifestations were a result of antimonial treatment that attenuated the organism so that it was limited to the skin sparing the internal organs. He named the entity as “dermal leishmanoid” in tune with the fact that small-pox modified by vaccines was called “vaccinoid.” In the subsequent years, many such similar entities were identified from Calcutta School of Tropical Medicine and Madras Medical College.[2,3,4,5] The name “post kala-azar dermal leishmaniasis” was coined by Acton and Napier in 1927 to differentiate it from oriental sore which was referred to as “dermal leishmaniasis” and there was much of a debate regarding the nomenclature of this condition.[6,7] The suffix “-oid” was questioned and the fact that this clinical entity does not have any resemblance to any previously described leishmania lesion precluded the name “leishmanoid.”[7] Working on the analogy of “syphilide” some researchers suggested the term “leishmanide.” The fact that few patients do not exhibit features of kala-azar led to the suggestion of the name “post-generalized dermal leishmaniasis.” At the end, the medical community accepted the term PKDL which is more descriptive and was recognized that there is no difference in clinical feature of those who suffered kala-azar and those who do not.[7] Meanwhile, PKDL was described from Sudan, Africa in 1938 when attention was to skin eruption which occurred in patients of kala-azar after completion of treatment.[8,9] It was regarded as a marker of good prognosis in Sudan since it indicates the complete cure of kala-azar.[9]
Researchers had been working on the clinical manifestations of PKDL since its recognition as a new clinical entity and identified the myriads of clinical manifestations that are associated with it. Depigmented areas, erythema/butterfly rash, and nodules were identified as the common manifestations, whereas verrucous, papillomatous, hypertrophic, and xanthoma types were considered uncommon varieties.[10,11] In addition, researchers have also identified unusual clinical types which included mucous membrane lesion, ulcerated lesion, and extensive erythema.[10] The disease has been classified by the early researchers as “mixed lesions (nodules with other lesions), nodules only, depigmentation and erythema, and erythema only.”[12] In recent times, researchers have tried to classify PKDL into “polymorphic” (combination of two or more manifestations) and macular.” Later on “micropapular” entity was also added to the list from researchers in Sudan.[13] The grading of PKDL is also proposed which includes the type of lesions and the distribution (vide infra).
PKDL and VL: Latent period
It is recognized from the very beginning that patients of VL develop PKDL but the time-lag differs in different study populations and/or case series. This time lag is referred to as the incubation period or latent period and the interval between VL and PKDL shows a different trend in India and Sudan. While in India, PKDL develops 2–7 years after the episode of VL, in Sudan, PKDL usually develops concomitantly or within 3–6 months of VL. However, recent studies have documented a decreasing interval between VL and PKDL in India too (up to 36% of cases presented within 1 year after VL).[14]
The interval between VL and PKDL appears to be influenced by prior treatment for VL and the age of the patient. In an Indian study by Ramesh et al., the mean interval reported was 36 months, 48 months, and 21 months when VL was treated with sodium stibogluconate, amphotericin deoxycholate, and miltefosine, respectively.[15] In another Indian study, the interval was noted to be higher for sodium stibogluconate treated VL patients as compared to patients treated with AmBisome (liposomal amphotericin B) (2.9 years and 1.2 years, respectively).[16]
Type of skin lesion also showed differences in latent period and in the earliest description, it was noted that macular lesions have a short latent period (mean lag period of 2.3 years) than the nodular lesions (mean lag period 2.8 years). A similar observation was noted in recent studies with macular lesions having a latent period of 2.99 ± 3.59 years, while the polymorphic lesions of 9.68 ± 12.39 years.[11]
Another addition to the understanding of PKDL occurred after active surveillance was started and was found that the latent period was found to be furthermore decreased (median latent period of 3 years with active surveillance and 4 years with passive surveillance).[17] This highlights the fact that health-care seeking behavior is low in cases of PKDL.
Uncommonly, skin lesions may be noted at the time of visceral involvement and the condition is best described as para kala-azar dermal leishmaniasis (paraKDL). While paraKDL appears to be common in Sudan (up to 18% cases), there are only isolated case reports of paraKDL in India.[14]
Of note, PKDL may be seen in patients without any previous history of VL and such cases may account for up to 10%–23% of cases. In the earliest report documented by Napier and Gupta, history of kala-azar was found to be absent in 23.5% cases in whom Leishmania was found and 14.4% cases in whom Leishmania was not found.[11] This trend is similar in both Indian and Sudanese PKDL cases.[14]
Mucocutaneous lesions
The clinical features of PKDL are highly variable and treating physicians must be aware of the spectrum of mucocutaneous changes for early diagnosis and thereby efficient management. Patients may have clinical features ranging from macules/patches, papules/plaques, nodules, photosensitivity and in rare cases ulcerated, vegetative, or keloidal lesions, etc.[11,18] These categories of lesions may occur alone or in various combinations. Many authors have classified patients of PKDL into monomorphic lesions (e.g., hypopigmented macules or nodules) or mixed/polymorphic lesions (macules and patches, papule, plaques, and nodules) [Figures 1–3].[10,19,20] However, this classification of the disease does not always reflect the true progression of the disease and is used for research purposes to evaluate the immunological parameters. The classical description of disease evolution with progression from initial hypopigmented macular lesions to papules to plaques and nodular lesions in untreated cases is sometimes not followed and patients may start with plaques or nodules from the very beginning. Irrespective of the type of lesions at the onset, the advanced cases usually show the entire spectrum of the cutaneous lesions; though there are exceptions with some patients remain macular without showing any progression to develop plaque or nodule [Figure 4].[21] Of note, plaques and nodular lesions do not necessarily originate from preexisting patches and plaques and may develop de-novo too [Figure 5].[21] Another unique thing about cases developing plaques and nodules de novo is the distribution of the lesions; the lesions are mainly seen around the joints of the extremities, especially around knee, feet, elbow, and hands.[22]
Figure 1.
Monomorphic macular lesions of PKDL on the trunk
Figure 3.
Polymorphic lesions with guttate hypopigmented macules on trunk, plaques on left forearm, and nodules on abdomen
Figure 4.
Polymorphic lesions with macules on back, papules on nape of neck, and nodules on earlobe
Figure 5.
Papular and nodular lesions developing de-novo near the elbow and wrist
Figure 2.
Monomorphic macular lesions which have coalesced together
The disease starts as nonscaly, shiny macules or papules in the muzzle area of the face [Figures 6 and 7]. The macules have a tendency to coalesce to form bigger patches [Figure 1]. Over a period of months to years, patients may develop extensive disease involving trunk and extremities [Figures 8–11]. In untreated patient, not only the areas of affection increase but also macules and patches evolve to papules, plaques, and nodules, as mentioned earlier [Figures 12 and 13]. The papules, nodules, and plaques are shiny and have a typical juicy or succulent appearance—an important clinical clue [Figures 14–17]. The lesions are typically asymptomatic; however, patients may occasionally complain of itching.[18] It has been observed by the authors (MC, NKD) that the lesions involve the folds of axilla and groin but spare the skin of the vault [Figure 18].[21] Photosensitivity is a feature which is identified as a typical of PKDL which involves mainly the cheeks and sometimes sides of alae nasi, tips of nose, and chin. It is transient in the initial phase but later becomes permanent[10] [Figure 19] and the authors (MC, NKD) found photosensitivity as the presenting symptom before the hypopigmented macules develop [Figure 20].
Figure 6.
Macules developing around “muzzle area of face” and then spreading to rest of face
Figure 7.
Papules and nodules on the “muzzle-area of face”
Figure 8.
Macules spreading on the lower extremities
Figure 11.
Nodules on the foot
Figure 12.
Papule developing over a patch near the lower lip
Figure 13.
Nodules developing over the patch near the elbow
Figure 14.
Papules and succulent nodules over the nose
Figure 17.
Papules and succulent nodules over the entire face
Figure 18.
Hypopigmented patches and papules occupying the anterior and posterior axillary folds but spare a small island of skin near the vault of axilla
Figure 19.
Photosensitivity with nodules on nose and tongue
Figure 20.
Photosensitivity was the presenting feature in the case who went on to develop hypopigmented patches later
Figure 9.
Nodules spreading on the dorsa of hands
Figure 10.
Nodules extending onto the palms
Figure 15.
Papules and succulent nodules over the nose and ear
Figure 16.
Succulent nodules over ears
The disease course as described above deviates from the usual in many patients, leading to many atypical presentations and morphologies. Uncommon presentations too are known and should be kept in clinical differentials in relevant cases, especially in endemic areas. Notable clinical variations include:
Atypical presentations - Micropapular form (Measles like), erythrodermic form, photosensitivity with erythema of butterfly area of the face[18,21]
Atypical morphology - annular, warty/verrucous,[23] papillomatous, fibroid, and xanthomatous types and even spontaneous ulceration[18,21] [Figure 21].
Figure 21.
Spontaneous ulceration developing on top of nodules in PKDL which became secondarily infected
One of the authors (PK) had observed a case presenting with ulcerated paronychia like lesions with hypopigmented macules and patches (who went on to develop characteristic juicy papules and nodules in perioral area and on chin).[24]
Mucosal and genital involvement may be seen in severe cases with extensive lesions. The mucosal lesions present as infiltrated nodules on lips, angle of mouth, tongue, buccal mucosa, and the palate [Figures 22 and 23]. Genital involvement is manifested as papules, nodules, and plaques on the inner surface of prepuce, glans penis, and the shaft of penis [Figures 24 and 25].[18,21] Isolated mucosal and/or genital involvement is known and the diagnosis of such cases requires high index of suspicion.[25] It must also be remembered that PKDL affects the children as well as the female gender; hence, a thorough inspection of the covered areas of the body is essential if lest the diagnosis is missed [Figure 26].
Figure 22.
Nodules on the tongue and upper lip
Figure 23.
Nodules on the lips and tip of tongue
Figure 24.
Nodules on the genitals with confluent hypopigmented patches on the thighs
Figure 25.
Nodules on the genitals
Figure 26.
Hypopigmented macules on the covered area of back in a young girl
Though clinical features noted in PKDL patients from India are largely similar to those from Sudan, there are some notable differences, outlined in Table 1.
Table 1.
Clinical features in Indian vs. Sudanese patients with PKDL
Features | India | Sudan |
---|---|---|
Frequency of PKDL after VL | 5%-10% | 5%-60% |
Usual interval between VL and PKDL | 2-3 years (range: 6 months-32 years) | 0-6 months (range: 0-13 months) |
PKDL in absence of VL | Yes | Yes |
PKDL with VL | Yes | Yes |
PKDL while patient is on treatment for VL | No | Yes |
Age group | Young adults | Children (mean age 6 years) |
Common lesions | Erythema, Infiltration, macular, papulonodular | Papulonodular > maculopapular > micropapular > macular |
Distribution | Face > trunk > arms > legs | Face > trunk > arms > legs |
Lymphadenopathy | Rare | Frequent |
Distribution of lesions
The skin lesions characteristically first appear in “muzzle area” and extend to involve other areas of face, upper extremities, trunk, and lower extremities. As a result of this characteristic progression, the density and severity of lesions are most intense in perioral area and upper body. Exposure to ultraviolet rays (UV) has been implicated in the pathogenesis of PKDL lesions and, hence, the lesions follow the characteristic distribution. UV-induced immune suppression, mediated through down-regulation of antigen-presenting epidermal Langerhans cells, down-regulation of major histocompatibility complex (MHC) class II and its costimulatory molecules CD80 and CD86, up-regulation of immunosuppressive cytokine IL-10 and through vitamin D metabolism [active form of vitamin D plays a role in the inhibition of Toll-like receptor (TLR)-induced activation of macrophages, down-regulation of costimulatory molecules and proinflammatory cytokines, and induction of TGF-β and IL-1], is thought to play a role in increased persistence of the parasite and, hence, the disease.[26,27]
Papules and nodules follow this distribution more consistently, while the macular lesions may be more widespread. The characteristic of the disease depending on the progression of the lesions in PKDL results in three clinical grades as follows:[18,28]
Grade 1-Scattered maculopapular or nodular lesions on the face with or without a few lesions on the upper chest and arms
Grade 2-Dense maculopapular or nodular lesions on the face and extend to the chest, back, upper arms, and legs. There are only scattered lesions on the forearms and legs
Grade 3-Dense maculopapular or nodular lesions all over body, including hands and feet.
Ulceration is not a common feature of Indian or Sudanese PKDL; however, grade 3 cases may develop ulceration and crusting. In addition, grade 3 cases are most likely to have mucosal lesions, involving lip, tongue, and palate.[18,21]
PKDL: Concern about drug-dependent phenomenon!
PKDL is usually seen in VL patients presumed to be receiving inadequate treatment. Varying incidence of PKDL due to VL patients receiving different treatments supports this hypothesis. In a study on 85 PKDL patients, the number of patients receiving sodium antimony gluconate (SAG) for prior VL was 62 (73%). The similar number of PKDL cases developing in VL patients receiving amphotericin B, AmBisome, miltefosine, miltefosine–amphotericin B, or paromomycin was 13, 2, 2, 1, and 5, respectively. This study suggests that VL patients receiving SAG are more likely to develop PKDL as compared to patients receiving other treatments.[29] In another study, patients receiving 20 mg/kg of amphotericin B for VL developed PKDL less frequently as compared to patients receiving 15 mg/kg. Thus, the choice of drug and dose may influence the development of PKDL. It is postulated that lower dose and shorter duration of the treatment may kill the visceral parasites, but not the parasites from the skin.[30] Differential drug concentration in the skin and system might be responsible. Therefore, if there is no drug resistance, SAG can still be used to treat PKDL but it requires longer duration of therapy (4 months) as compared to VL where 3 weeks of treatment suffice.
Extracutaneous lesions
ParaKDL patients are special cases where lesions of PKDL are present while the patients are suffering from kala-azar. They are considered somewhere in between the spectrum of VL and PKDL. The parasites can be demonstrated in skin as well as in lymph node or bone marrow. The spleen in such patients is usually larger than PKDL patients but smaller than VL patients.
Decreasing parasite load and an immune response against parasite alter the clinical manifestations. The parasite load in PKDL is usually low and can be demonstrated in skin only, not in lymph node, spleen, or bone marrow. PKDL patients in general enjoy good health and do not show any febrile/toxic features, accounting for late presentation. Lymphadenopathy may be seen in Sudanese PKDL, but is rarely noted in Indian PKDL.[18,28] Similar to skin involvement (as in PKDL) in treated cases of VL, other organs too might be affected. Post kala-azar mucosal leishmaniasis, uveitis, conjunctivitis and blepharitis, laryngitis and colitis have been described in both Indian and Sudanese cases.[18,21]
PKDL in HIV
Clinical manifestations of leishmaniasis including PKDL depend on immune response to parasites. Immunologically, PKDL is characterized by mixed Th1/Th2 immune response with persistence of IL-10 in the skin and the peripheral blood. As a result of antiinflammatory nature of such an immune response, parasites continue to persist in the skin. Clinical resolution (spontaneous/treatment-induced) is heralded by IL-2 stimulation and INF-γ production. INF-γ-activated macrophages eliminate the Leishmania parasites/antigens. HIV coinfection is associated with decreased IFN-γ and higher levels of TNF-α which is associated with continued replication of the Leishmania parasites and increased severity of the clinical disease.[31,32] The lesions of PKDL in HIV coinfected persons (with CD4 counts usually less than 200/mm3) may be more extensive and may show more acral involvement. The usual spread of lesions from face to other parts of the body as seen in classical PKDL may not be present. The parasites are abundant and are easily demonstrable.[32,33] Usually, VL is not accompanied by cutaneous lesions in immunocompetent hosts. But with HIV coinfection, VL patients may show florid and extensive nodular lesions (paraKDL) clinically mimicking PKDL. Other atypical manifestations include subcutaneous nodules, erythroderma like presentation, scaly plaques mimicking psoriasis, and nodules mimicking Kaposi's sarcoma.[32]
Diffuse and disseminated cutaneous leishmaniasis
Other leishmanial diseases which may mimic PKDL clinically are diffuse and disseminated cutaneous leishmaniasis. Diffuse CL is observed when the infected person shows Leishmania specific anergy due to defective cell-mediated immunity. As a result, there is uncontrolled parasite growth and patient presents with numerous papules, plaques, and nodules. These cases are highly resistant to standard treatment and may show frequent relapses. Disseminated CL is noted in immunosuppressed patients as numerous papulonodular lesions. In contrast to diffuse CL, disseminated CL may show frequent mucosal involvement and lesions may develop ulceration. In addition, Leishmanin skin test remains positive in disseminated CL and the parasite load is less as compared to that in diffuse CL.[34]
Differential diagnosis
The differential diagnoses of PKDL depend on the predominant skin lesions and have been summarized in Table 2.[18,21,28]
Table 2.
Differential diagnosis of Post Kala-azar dermal leishmaniasis
Lesions of PKDL | Differential diagnosis |
---|---|
Hypopigmented macules and patches | Lepromatous leprosy (glove and stocking anesthesia, peripheral nerve thickening, and madarosis), pityriasis versicolor (scaling, perifollicular lesions), vitiligo vulgaris (depigmented lesions, leukotrichia, and Koebnerization), progressive macular hypopigmentation (central trunk), hypopigmented mycosis fungoides (sun covered areas, elderly people) |
Papules | Lepromatous leprosy, xanthoma (yellow-orange lesions), maculopapular drug reaction (acute onset) |
Plaque and nodular lesions | Lepromatous leprosy, sarcoidosis (lung involvement, elevated angiotensinconverting enzyme level), cutaneous T cell lymphoma (elderly population, ulcerated plaques), cutaneous lymphoid hyperplasia, tuberous xanthoma (dyslipidemia), secondary syphilis, cutaneous leishmaniasis (early lesions before ulceration occurs) |
Photosensitive form | Systemic lupus erythematosus (joint and systemic involvement), Rosacea |
Conclusion
PKDL will continue to intrigue the clinician with its protean manifestations and a high index of suspicion is required to help in the diagnosis of the condition. The disease is localized to specific geographical pockets in eastern Africa (e.g., Sudan, Ethiopia, Kenya) and India (esp. State of Bihar, West Bengal, Jharkhand) as also adjoining countries, like Bangladesh and Nepal. Thus, physicians need to be extra vigilant in these areas. Involvement of tongue and genitalia, sparing of the vault of axilla and groin, and presence of photosensitivity are the tale-tell signs which can come in aid to differentiate it from its closest mimicker, lepromatous leprosy. Active surveillance with a door-to-door survey will help in better understanding of the disease.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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