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ONLINE ONLY - CASE REPORT
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 56

Diagnosis of post kala azar dermal leishmaniasis in nonendemic Areas: A clinical challenge


1 Department of DVL, GSL Medical College, Rajahmundry, Andhra Pradesh, India
2 Quantum specialty diagnostics, Visakhapatnam, Andhra Pradesh, India
3 Department of pathology, Molecular Biology Laboratory, ICMR-National Institute of Pathology, New Delhi, India
4 Department of DVL, GITAM Medical College, Visakhapatnam, Andhra Pradesh, India

Date of Submission21-Jul-2020
Date of Decision06-Oct-2020
Date of Acceptance03-Feb-2021
Date of Web Publication25-Feb-2022

Correspondence Address:
Gandikota Raghurama Rao
Department of DVL, GSL Medical College, Rajanagaram, Rajahmundry - 533 296, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_110_20

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  Abstract 


Leishmaniasis is a heterogeneous group of disease caused by protozoans of the genus Leishmania, transmitted by Phlebotomus sandflies. Human leishmaniasis is usually classified as visceral, cutaneous (localized, diffuse, disseminated), mucocutaneous, and post-kala-azar leishmaniasis. Post-kala-azar leishmaniasis is a sequel of visceral leishmaniasis (VL) caused by Leishmania donovani (LD) and seen in India, Bangladesh, Nepal, and Sudan. In India, it develops in 5%–15% of treated VL cases within 2–5 years. It is characterized by multiple papular, nodular, and pleomorphic lesions over the sun-exposed areas such as face, neck, and arms, without systemic manifestations. It mimics a wide range of dermatoses, particularly leprosy in endemic areas for both the diseases. Inadequate immune response (Th1 and Th2) to infection during and after the treatment of VL plays a role in the pathogenesis. It is thought to be a good reservoir of LD and plays an important role in the treatment of VL. Post-kala-azar dermal leishmaniasis (PKDL) is usually diagnosed by skin smears, immunological tests such as rK39, cutaneous leishmaniasis detection tests, and polymerase chain reaction. A combination of liposomal amphotericin B and miltefosine is the first line of treatment. PKDL is a forgotten clinical entity in the nonendemic areas. We report a case of PKDL in a 52-year-old male from Andhra Pradesh, a nonendemic area for leishmaniasis. This case was treated successfully with combination therapy, liposomal amphotericin B, and miltefosine.

Keywords: Amphotericin B, miltefosine, pathogenesis, polymerase chain reaction assays, post-kala-azar dermal leishmaniasis


How to cite this article:
Rao GR, Ratna Kishore M R, Singh R, Haritha K. Diagnosis of post kala azar dermal leishmaniasis in nonendemic Areas: A clinical challenge. Clin Dermatol Rev 2022;6:56

How to cite this URL:
Rao GR, Ratna Kishore M R, Singh R, Haritha K. Diagnosis of post kala azar dermal leishmaniasis in nonendemic Areas: A clinical challenge. Clin Dermatol Rev [serial online] 2022 [cited 2022 Sep 25];6:56. Available from: https://www.cdriadvlkn.org/text.asp?2022/6/1/56/338577




  Introduction Top


Post-kala-azar dermal leishmaniasis (PKDL), a neglected complication of visceral leishmaniasis (VL), is caused by Leishmania donovani (LD) transmitted by Phlebotomus sandflies in the Indian subcontinent. It develops in 5%–15% of the treated VL cases[1] within 2–5 years and may persist for as long as 20 years without treatment. In a small portion of cases (6%–10%), no preceding history of VL is available. The highest number of cases was reported from Sudan and Indian subcontinent, especially Bangladesh with a prevalence of up to 16/10,000 population.[2] In India, there is a prevalence of 4.4–7.8/10,000 in endemic areas of Bihar[3] and other endemic areas are Jharkhand, West Bengal, Assam, and Uttar Pradesh. PKDL is almost a forgotten clinical entity and rarely reported from nonendemic areas of the country.[4],[5] We report a case of PKDL in a 52-year-old man from Andhra Pradesh, a nonendemic area, and the challenges we have come across in establishing the diagnosis, treatment, and the burden of these undetected cases on the VL elimination program which are discussed.


  Case Report Top


A 52-year-old healthy male from Korba, Chhattisgarh, presented with multiple asymptomatic reddish nodules over the face, neck, trunk, forearms, and thighs for 8 years. The patient approached us for cosmetic reasons and insisted on immediate treatment. After careful counseling, he revealed that though he was born in Bihar, he has been living in Chhattisgarh for the past 32 years. At the age of 19 years, he had a fever for which he was given 14 injections around the abdomen in his native place and the details of this treatment were not available. The present lesions started 8 years ago as small asymptomatic nodules around his nose and gradually increased in size and number to involve other areas in a cephalocaudal manner. He tried traditional medicines for 2 years. As his clinical condition worsened, he consulted a dermatologist and it was diagnosed as leprosy. He had anti-leprosy (multibacillary-multidrug therapy) drugs for 6 months. On physical examination, the muzzle area of the face was predominantly involved with multiple, nontender, erythematous nodules. Similar lesions were also seen in other areas [Figure 1]. Psoriasiform thick plaques were present over the extensor areas of the forearms, fingers, and toes [Figure 2]. No lesions were seen in the oral cavity and over the genitalia. There were no hypopigmented macules or plaques. No lesional, glove-and-stocking pattern of sensory loss, motor weakness, or thickening of peripheral nerves was detected. Systemic examination was normal. There were no organomegaly and no generalized lymphadenopathy. The history, clinical features, and chronic nature of the disease prompted us to consider the following differential diagnoses: PKDL, lepromatous leprosy, sarcoidosis, chromoblastomycosis, and mycosis fungoides. The case was investigated accordingly: All hematological biochemical tests were within normal limits. Chest radiograph and ultrasound abdomen were normal. Serological tests for syphilis, hepatitis B, and HIV were negative. Skin smears from the nodules and earlobes were negative for acid-fast bacilli. Fine-needle aspiration cytology and slit skin smears from the nodules demonstrated many Leishman–Donovan bodies (LD bodies) both intracellularly and extracellularly [Figure 3]. Skin biopsy specimens showed atrophic epidermis with clusters of compact epithelioid cell granuloma with lymphoplasmacytic cells, Langhans giant cells, and histiocytes with numerous intra- and extracytoplasmic LD bodies in the dermis [Figure 4]a and [Figure 4]b. These findings lead to the diagnosis of PKDL. For further confirmation, the patient sera sample was positive for anti-rK39 antibodies a characteristic of LD infection. The split aspirate from the lesion was positive for Leishmania amastigote antigen peroxiredoxin detected by cutaneous leishmaniasis (CL) detection™ rapid test (InBios International Inc. USA). Specific polymerase chain reaction (PCR) assay and the sequence analysis confirmed the presence of causal organism as LD. The parasite load in the patient slit smears was 5559 parasites/μL. The patient was treated with liposomal amphotericin B 5 mg/kg per dose twice a week for 3 weeks (total 30 mg/kg), and the response was excellent and the side effects being negligible. After 4 weeks, oral miltefosine 100 mg per day for 12 weeks was also given. Almost all the lesions regressed except a few thick plaques over the forearms which were treated with cryotherapy. The patient was under follow-up for the past 5 months, and no relapse of lesions was observed [Figure 5].
Figure 1: Multiple erythematous nodules over the face

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Figure 2: Psoriasiform lesions over the forearms

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Figure 3: Fine-needle aspiration cytology of nodule (oil immersion) showing intra- and extracellular Leishmania donovani bodies

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Figure 4: (a) Diffuse granulomas with lymphoplasmacytic cells, plasma cells, and Langhans giant cells and histiocytes (H and E, ×10). (b) Histiocytes showing numerous intra- and extracellular Leishmania donovani bodies (H and E, ×100)

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Figure 5: Complete regression of lesions

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  Discussion Top


Leishmaniasis is the second most neglected disease after malaria. There are four forms of leishmaniasis: VL (kala-azar), CL, mucocutaneous leishmaniasis, and PKDL. VL is fatal if untreated in over 90% of cases. An estimated 50,000–90,000 cases occur worldwide each year. More than 95% of new cases are from Bangladesh, India, Nepal, China, and Sudan. VL is caused by LD and Leishmania infantum. A few cases caused by Leishmania tropica have been reported. The onset of VL can be acute or insidious, and the incubation period can be between 2 weeks and 8 months. Persistent irregular fever, massive splenomegaly, pancytopenia, hepatomegaly, hypergammaglobulinemia, anorexia, and weight loss are the features of VL. In India, hyperpigmentation of the skin is a characteristic feature. Malnutrition and secondary bacterial infection are the main causes of death. With the complete and adequate treatment, clinical cure is obtained with regression of splenomegaly. In a proportion of patients, parasites may persist in the skin for a long period. 5%–10% of such patients may develop PKDL in due course.

CL is not life threatening but can lead to substantial cosmetic morbidity and social stigmatization. CL of the old world (Asia, Africa, and Europe) is caused by five species of Leishmania: L. infantum, L. tropica, Leishmania major, Leishmania aethiopica, and LD. In the new world (South America), CL is caused by multiple species of both Leishmania and Viannia subgenera – Leishmania braziliensis, Leishmania mexicana, and Leishmania panamensis. The cutaneous features of CL tend to vary between and within regions, and different species of parasites. CL (oriental sore or Baghdad boil) is caused by L. tropica and L. major and is the most common form seen in India and neighboring countries. Single or multiple ulcers develop at the site of inoculation of the parasite after an incubation period of 6 months–1 year. The ulcer heals spontaneously over months or years leaving a scar. There may be regional lymphadenopathy. Leishmanin skin test is positive. A wide spectrum of clinical presentations has been reported.[6]

Leishmania recidivans also known as lupoid or tuberculoid leishmaniasis is a chronic form of anthroponotic CL that may last for many years. The slowly progressing lesions on exposed areas are characterized by scar with peripheral activity. Untreated, the disease is destructive and disfiguring.

Diffuse CL (anergic form) caused by L. aethiopica (old world/Leishmania amazonensis new world) is characterized by widely disseminated cutaneous macules, papules, nodules, or plaques or by diffuse infiltration of the skin resembling lepromatous leprosy and PKDL. There is no ulceration; mucosal involvement is around the borders of nostrils and lips. This disease does not heal spontaneously; relapses are frequent after treatment. There is a superabundance of parasites in lesions. Internal organs are not invaded, and there is no history of kala-azar. The leishmanin test or other tests of cellular immunity are negative.

Disseminated CL is caused by L. braziliensis and other species. It is characterized by extensive, numerous, nodular ulcerated lesions with frequent involvement of nasal mucosa. This form of CL is common in the new world. The delayed-type hypersensitivity response to Leishmania antigen and antibody is intact. These lesions respond partially to treatment.

Mucocutaneous leishmaniasis is very uncommon in the old world. For all practical purposes, this form of mucocutaneous leishmaniasis is correctly applied to new world disease which is caused by L. braziliensis or L. panamensis. Most cases are reported in Bolivia, Brazil, and Peru. Mucocutaneous lesions can present from several months to 20 or more years after a cutaneous lesion. The main common risk factors are malnutrition, immunosuppression, multiple primary lesions and the site of primary lesion above the waist. Nasal lesions are always present with nodules and infiltration of anterior septal cartilage leading to obstruction of the nostril and later perforation of the septum with collapse and broadening of the nose. In one-third of patients, the pharynx, palate, larynx, trachea, and upper lip are also involved. Local lymphadenopathy is frequent. Mucocutaneous leishmaniasis almost never heals spontaneously. Secondary bacterial infections are frequent and intercurrent pneumonia being the most common cause of death.

PKDL occurs almost exclusively with VL caused by LD. It can also be caused by L. infantum in HIV-infected patients. It is common in East Africa and Indian subcontinent, where up to 50% and 10% of kala-azar, respectively, develop the condition. It is characterized by papular, nodular, and polymorphic lesions, especially on the face and other sun-exposed areas. In Indian PKDL, hypopigmented or erythematous macules over the body are also seen. Occasionally, mucosal lesions such as buccal, genital, and conjunctival lesions are also reported in PKDL. PKDL heals spontaneously in a proportion of cases in Sudan but rarely in patients in India. Para PKDL are cases in which patients have VL and PKDL at the same time. Such cases are common in Sudan, but uncommon in Indian subcontinent. PKDL cases are thought to be a sole reservoir of LD, and the relative infectiousness of PKDL is 0.9, compared with VL (1.0) making PKDL cases equally infectious.[7] Therefore, these patients play a crucial role in the interepidemic spread of VL in India, where VL is anthroponotic.[8] Theoretically, the presence of a single PKDL case is a risk for new outbreak of VL, and these cases pose a threat to VL elimination program.

Pathogenesis of PKDL is immune mediated and complex. According to available literature,[9],[10] antileishmanial drugs, ultraviolet (UV) light, parasite persistence/reinfection, tissue-specific T-cell memory, and genetic factors are hypothesized to interplay and operate in the immune pathogenesis of PKDL. One of the key points in the pathogenesis is an inadequate immune response to infection during and after treatment of VL. In VL, the predominant immune response is a Th2 response, whereas in PKDL, there is a mixed Th1 and Th2 response with persistence of interleukin (IL)-10 and interferon-γ (INF-γ). As a result of antileishmanial treatment of VL, the PKDL patient is no longer systemically ill and has no fever and the liver and spleen are no longer enlarged. Only in the skin, parasites persist that may have been there since VL. The immune response in PKDL is thus partially characterized by immune reconstitution, while at the same time, there is a dissociation of immune response between the skin and the viscera. The immune mechanism of Sudanese and the Asian PKDL differs. In Sudanese PKDL, because of shorter time lag between cure from VL and development of PKDL, the disease-associated immune involvement minimizes the scenario of immune reactivation after the cure from VL. The peripheral blood monocyte cells from Sudanese PKDL patients react and proliferate and secrete more INF-γ, while IL-10 was produced primarily from CD4+ T-cells. By contrast, South Asian PKDL is more chronic due to longer gap between cure from VL and disease onset. Hence, CD8+ T-cells predominated in lesions and in circulation. In Indian PKDL patients, two distinct immune mechanisms operate in the skin and periphery (circulation). In the skin, the immunity is regulated by IL 10 and FOXP3,because despite the enhanced levels of INF γ and TNF α, their receptors are downregulated. In addition, in the skin, there is an increased presence of TL-17 cells and IL-17. These lead to parasite persistence in the skin for long time. By contrast, peripheral immunity is controlled mostly by CD8+ T-cells that are the major source of IL-10 and are anergic in nature. Lack of co-stimulation was also evident because decreased CD28 and CD86 were formed in circulatory CD8+ T-cells and CD4+ monocytes, respectively. These findings lead to decreased antigen-specific proliferation. In the majority of the patients, PKDL skin lesions develop on sun-exposed areas. This supports the concept that UV exposure plays a contributory role in the pathogenesis of PKDL. The potent immunosuppressive property of UV light damages the antigen-presenting Epidermal Langerhans cells (E LCS) and other cells. UVB light-induced immune suppression can also operate through its chromophore cis-urocanic acid and Vitamin D3. This leads to decreased number of E-LCS and alters their morphology. The subsequent events promote increased levels of IL-10; this, in turn, increases TREGS regulatory T cells. In addition, transforming growth factor-beta (TGF-β) from infected macrophages also activates TREGS which can produce more TGF-β, facilitating parasite persistence. Increased Vitamin D3 in the sun-exposed skin inhibits Toll-like receptor-induced activation of macrophages, downregulates pro-inflammatory cytokines, and also induces TGF-β and IL-1. In this way, Vitamin D3 facilitates the alternative activation of macrophages. In addition, the increased presence of TREGS promotes IL-10 secretion, thereby suppressing the local immune response and supporting parasite persistence. Clothing habits of individuals also contribute to UV-induced pathogenesis.

The question arises whether PKDL is a reinfection or parasite persistence. In PKDL, evidence of parasite persistence after clinical cure exists like in tuberculosis, herpes, and tryptomaniasis. These parasites reside within fibroblasts and keratinocytes during latency period and when reactivated cause PKDL. In mouse model, the parasites that persisted were genetically similar to parental clone. In Sudan, the onset of PKDL following VL is much shorter due to parasite persistence. Those patients cured of VL develop PKDL even after relocating to areas where VL is not pandemic. An important factor possibly preventing reinfection could be that recovery from leishmaniasis infection is often associated with development of a strong newly immune response that in humans confers lifelong protection against reinfection. However, under certain immune-suppressive conditions such as HIV/AIDS, the infection-induced immunity may be impaired reducing the host susceptibility to reinfection and/or reactivation of latent parasite; despite the acquisition of systemic protective immunity, organ-specific deposits do occur in the skin. The present evidence indicates that PKDL is due to the persistence of parasite rather than reinfection.

Genetic polymorphism may be responsible for the differences in clinical presentations of PKDL from region to region. In Sudan, genetic studies have shown decreased expression of the interferon-gamma receptor 1 gene (IFNGR1) in patients with PKDL; this was not found in patients with VL. This was also detected in skin biopsies with uniform low expression IFN-γ and IFNGR1, possibly a persistence of parasite. Similar downregulation of the IFN-γ receptors was found in biopsies in a study from India. So far, there has been no evidence for polymorphism in the IL10 gene promotion.

PKDL closely resembles a wide range of dermatoses such as leprosy, sarcoidosis, lupus vulgaris, secondary syphilis, vitiligo, pityriasis versicolor, and acne. In nonendemic areas for PKDL, it is a big challenge for dermatologists to diagnose this condition. The diagnosis of PKDL is usually clinical based on the characteristic presentation and previous history of VL. However, in the nonendemic areas for PKDL where leprosy is endemic, it is not always possible to differentiate these two conditions on clinical ground alone. Although demonstration of parasite under microscopy is a gold standard investigation for diagnosis of PKDL, it is less sensitive.[11] LD bodies are seen in slit skin smears of 44.9% of cases and in the tissue 28.4% of cases. LD bodies were not seen in macular forms.[12] Histopathology of PKDL is nonspecific, similar to that of other granulomatous conditions. Immunological diagnosis using rK39 strip test is not reliable for PKDL, since antibodies could be persisting due to past episodes of VL. Specific DNA-based “PCR” assays are definitive and determine the species and load of the parasites in the infected person.[11] These are available only in limited centers. A high index of clinical suspicion and awareness of the disease is an essential prerequisite for clinicians to identify such rare cases in their otherwise routine practice. The currently recommended combination therapy of I.V. liposomal amphotericin-B and oral miltefosine is very well tolerated with minimal adverse effects and less relapse rates.[1],[13]

Counseling and educating all concerned regarding the important role of PKDL in the transmission of VL, early detection of cases, and treatment adherence should be prioritized in kala-azar elimination programs.

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.

Acknowledgment

We are highly thankful to Dr. V. Ramesh Professor DVL, Safdarjung Hospital, New Delhi, for encouraging us to start combination therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization. Post Kal-Azar Dermal Leishmaniasis: A Manual for Case Management and Control. Report of a WHO Consultative Meeting; July 2-3, 2012; Kolkata, India. WHO/HTM/NTD/IDM/2013.1. Available from: http://apps.who.int/iris/bitsteam/106657/786081/1/9789241504102_eng.pdf. [Last accessed on 2014 Oct 14].  Back to cited text no. 1
    
2.
Mondal D, Hamano S, Hasnain G, Satoskar AR. Challenges for management of post kala-azar dermal leishmaniasis and future directions. Res Rep Trop Med 2014;5:105-11.  Back to cited text no. 2
    
3.
Singh RP, Picado A, Alam S, Hasker E, Singh SP, Ostyn B, et al. Post kala-azar dermal leishmaniasis in visceral leishmaniasis-endemic communities in Bihar, India. Trop Med Int Health 2012;17:1345-8.  Back to cited text no. 3
    
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Bhandare P, Shukla P, Bhobe M, Pai VV. Post kala-azar dermal leishmaniasis: A diagnostic dilemma in a nonendemic area. Indian Dermatol Online J 2014;5:122-4.  Back to cited text no. 4
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Kumar S, Aggarwal D, Radotra BD, Vinay K. Nodular skin lesions and geographic skin plaques over face and trunk. Int J Dermatol 2020;59:37-8.  Back to cited text no. 5
    
6.
Bari AU, Rahman SB. Many faces of cutaneous leishmaniasis. Indian J Dermatol Venereol Leprol 2008;74:23-7.  Back to cited text no. 6
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Le Rutte EA, Zijlstra EE, de Vlas SJ. Post-kala-azar dermal leishmaniasis as a reservoir for visceral leishmaniasis transmission. Trends Parasitol 2019;35:590-2.  Back to cited text no. 7
    
8.
Ramesh V, Kaushal H, Mishra AK, Singh R, Salotra P. Clinico-epidemiological analysis of Post kala-azar dermal leishmaniasis (PKDL) cases in India over last two decades: A hospital based retrospective study. BMC Public Health 2015;15:1092.  Back to cited text no. 8
    
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Mukhopadhyay D, Dalton JE, Kaye PM, Chatterjee M. Post kala-azar dermal leishmaniasis: An unresolved mystery. Trends Parasitol 2014;30:65-74.  Back to cited text no. 9
    
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Zijlstra EE. The immunology of post-kala-azar dermal leishmaniasis (PKDL). Parasit Vectors 2016;9:464.  Back to cited text no. 10
    
11.
Salotra P, Singh R. Challenges in the diagnosis of post kala-azar dermal leishmaniasis. Indian J Med Res 2006;123:295-310.  Back to cited text no. 11
    
12.
Singh A, Ramesh V, Ramam M. Histopathological characteristics of post kala-azar dermal leishmaniasis: A series of 88 patients. Indian J Dermatol Venereol Leprol 2015;81:29-34.  Back to cited text no. 12
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13.
Ramesh V, Avishek K, Sharma V, Salotra P. Combination therapy with amphotericin-B and miltefosine for post-kala-azar dermal leishmaniasis: A preliminary report. Acta Derm Venereol 2014;94:242-3.  Back to cited text no. 13
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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