• 1

    Zijlstra EE, El-Hassan AM, 2001. Leishmaniasis in Sudan: post-kala-azar dermal leishmaniasis. Tran R Soc Trop Med Hyg 95 (Suppl 1):S59–S76.

    • Search Google Scholar
    • Export Citation
  • 2

    Dutta M, Ghosh TK, 1983. Review of current status of leishmaniasis epidemiology, Proceedings of the Indo-UK Workshop on Leishmaniasis, New Delhi: Indian Council of Medical Research: 97–102.

  • 3

    World Health Organization, 1978. A Decade of Health Development in South-east Asia. South-east Asia Regional Publication Series No. 7. New Delhi: World Health Organization.

  • 4

    Ranjan A, Sur D, Singh VP, Siddique NA, Manna B, Lal CS, Sinha PK, Kishore K, Bhattacharya SK, 2005. Risk factors for Indian kala-azar. Am J Trop Med Hyg 73 :74–78.

    • Search Google Scholar
    • Export Citation
  • 5

    Bhattacharya SK, Sinha PK, Sunder S, Thakur CP, Jha TK, Pandey K, Das VNR, Kumar N, Lal CS, Verma N, Singh VP, Ranjan A, Verma RK, Anders G, Sindermann H, Ganguly NK, 2007. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 196 :591–598.

    • Search Google Scholar
    • Export Citation
  • 6

    Sharma MC, Gupta AK, Verma N, Das VN, Saran R, Kar SK, 2000. Demonstration of Leishmania parasites in skin lesions of Indian post kala-azar dermal leishmaniasis (PKDL) cases. J Commun Dis 32 :67–68.

    • Search Google Scholar
    • Export Citation
  • 7

    Salotra P, Singh R, 2006. Challenges in the diagnosis of post kala-azar dermal leishmaniasis. Indian J Med Res 123 :295–310.

  • 8

    Das VNR, Ranjan A, Bimal S, Siddique NA, Pandey K, Kumar N, Verma N, Singh VP, Sinha PK, Bhattacharya SK, 2005. Magnitude of unresponsiveness to sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar. Natl Med J India 18 :131–133.

    • Search Google Scholar
    • Export Citation
  • 9

    Thakur CP, Narain S, Kumar N, Hasaan SM, Jha DK, Kumar A, 1997. Amphotericin B is superior to sodium antimony glucon-ate in the treatment of Indian post kala-azar dermal leishmaniasis. Ann Trop Med Parasitol 91 :611–616.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

Development of Post–Kala-Azar Dermal Leishmaniasis (PKDL) in Miltefosine-Treated Visceral Leishmaniasis

View More View Less
  • 1 Division of Clinical Medicine, Division of Pathology, Division of Biochemistry, Division of Immunology, Division of Epidemiology, Division of Microbiology and Molecular Biology, and Division of Biostatistics, Rajendra Memorial Research Institute of Medical Sciences (Indian Council of Medical Research), Agamkuan, Patna, Bihar, India

We report two cases of post–kala-azar dermal leishmaniasis (PKDL), which had subsequently developed after successful treatment of visceral leishmaniasis with miltefosine. Both patients had maculo-nodular lesions all over the body, and they were diagnosed as PKDL by parasitologic examination for Leishmania donovani bodies in a skin snip of lesions. Patients were put on amphotericin B and responded very well for nodular lesions with one course of treatment. However, longer duration of the treatment is needed for total clearance of macular lesions from body surface in PKDL cases. This is the first case report of PKDL in India, which developed after successful treatment of visceral leishmaniasis with miltefosine.

INTRODUCTION

Post–kala-azar dermal leishmaniasis (PKDL) is a dermatosis that usually occurs after visceral leishmaniasis (VL) caused by Leishmania donovani and characterized by macular, maculo-papular, and nodular skin lesions on the whole body surface. PKDL is mainly found in India (5–10%), Sudan (50%), and Nepal (reported) after incomplete or partial treatment of VL cases with sodium stibogluconate (SSG). In India, 20% of cases of PKDL have no history of VL and its treatment, but on investigation, L. donovani bodies can be shown in skin snips or biopsy. This type of skin lesion of PKDL may develop from asymptomatic cases of VL where no kala-azar development occurs but who had infection in the past. Previously, very few cases have been reported in which PKDL and VL has been associated. In India, PKDL development was noticed in patients who were treated with SSG and pentamidine, either with irregular or incomplete treatment of VL as well as with full course. However, there is no such report with miltefosine to this date. The interval at which PKDL follows VL is 0–6 months in Sudan and 6 months to several years in India.1 Cases of PKDL are of considerable epidemiologic importance, because these acts as reservoirs of parasites. Transmission of parasite from PKDL cases to other individuals by sandflies may have been the cause of massive epidemic of kala-azar in Bihar in the 1970s. 2,3 Poverty, overcrowding, malnutrition, polygamy, illiteracy, and poor domestic conditions facilitate the growth of this disease, which is a major public health problem in India.4 SSG is the drug of choice in the treatment of VL and PKDL but has shown a high relapse rate or failed to achieve a good response in PKDL. Amphotericin-B has been used for a considerable length of time with a high efficacy rate. Miltefosine, an oral drug, whose Phase IV clinical trial was conducted recently, is also a relatively effective drug (efficacy rate, 95%).5 Two of these patients reported with skin lesions suggestive of PKDL.

CASE REPORT 1

A male patient 38 years of age presented with white hypop-igmented patches all over his body, which were more marked on the face and upper arm. On the face, maculo-nodular lesions were reddish in color without scales and were non-tender and non-ulcerative in nature. On touch, sensation was intact, and no thickness of the ulnar nerve was observed. On systemic examination, the following findings were observed—pulse, 78/min; blood pressure (BP) = 110/70 mmHg, no anemia, no dehydfration, no hepatosplenomegally, no lymphadenopathy, and no cardiac abnormality. On chest examination, bilateral ronchi and crepts were present. Examination of the other systems did not show any abnormality. The history of the patient showed that he was treated for visceral leishmaniasis with miltefosine 100 mg/d for 28 days 4 years ago under a Phase IV WHO/TDR/ICMR-sponsored clinical trial. During the trial, he was diagnosed on the basis of parasitologic positivity in spleen aspiration as per WHO guidelines. He became clinically and parasitologically cured after treatment. During follow-up of 6 months, he had no signs and symptoms for VL and PKDL. After 2 years of treatment with miltefosine, he developed skin lesions on the face, which spread to the whole body. Nodular lesions were found on the face, chin, and ear. A clinical diagnosis of post–kala-azar dermal leishmaniasis was made, and the patient was further studied.

On investigation, the white blood count (WBC) was as follows: total count, 6,900 mm3 (normal range, 4,000–11,000/ mm3; neutrophils, 58% (normal range, 40–70%); lymphocytes, 34% (normal range, 15–45%); monocytes, 2% (normal range, 2–5%); eosinophiles, 6% (normal range, 1–6%); hemoglobin, 13.0/dL (normal range, 11–14.5/dL; erythrocyte sedimentation rate (ESR), 18 mm in the first hour (normal range, 1–9 mm/h); thrombocytes count, 2,40,000/mm3. The renal and hepatic profile were as follows: fasting blood sugar, 86 mg/dL (normal range, 70–110 mg/dL); blood urea nitrogen (BUN), 12.22/dL (normal range, 10–50 mg/dL); serum creatinine, 0.97 mg/dL (normal range, 0.7–1.1 mg/dL); serum bilirubin, 0.7 mg/dL (normal range, 0.1–1.0 mg/dL); serum glutamate pyruvate transaminase (SGPT), 36.3 U/L (normal range, 9–43 U/L); serum glutamate oxaloacetate transaminase (SGOT), 26.4 U/L (normal range, 5–40 U/L). ELISA for HIV-I was done and found non-reactive. The patient was further investigated. Ultrasonography of the whole abdomen suggested no pathology. Chest radiology was normal. ELISA for Koch’s was negative with IgG, IgM, and IgA. The microscopic examination of imprint skin smear of the PKDL lesions showed presence of L. donovani bodies in macrophage. Bone marrow examination was negative for L. donovani bodies; the rk39-based immunochromatographic strip test and direct agglutination test (DAT) were positive. Polymerase chain reaction (PCR) from blood and skin snips was also positive for leishmania.

The patient was immediately put on amphotericin B 1 mg/kg body weight for 20 days on alternate days. The patient was given a second course of amphoterin B in the same dose after a 15-day interval and was found to have complete disappearance of the lesions. The patient was followed up for 6 months after the end of treatment.

CASE REPORT 2

A male patient 60 years of age had widespread tani nodular lesions all over the body like an allergic manifestation for a short duration of 2 weeks, which was more marked on the front and back of trunk. There was no white depigmentation, which is classic for PKDL clinical diagnosis. On touch, sensation was intact, and no thickness of the ulnar nerve was observed. On systemic examination, the following findings were observed: pulse, 78/min; BP = 110/70 mmHg; no anemia; no dehydration; liver enlargement of 3 cm; spleen enlargement of 6 cm; no lymphadenopathy; and no cardiac abnormality. On chest auscultation, no abnormality was detected. Examination of the other systems did not show any abnormality. The history of the patient showed that he was treated for visceral leishmaniasis with miltefosine 100 mg/ day for 28 days 4 years before under a Phase IV WHO/TDR/ ICMR-sponsored clinical trial. During the trial, he was diagnosed on the basis of parasitologic positivity by spleen aspiration as per WHO guidelines. He had shown clinical and parasitologic improvement after treatment. During follow-up of 6 months, he attended a clinic with fever and enlargement of the liver and spleen (symptoms for VL). At that time, he was treated with amphotericin B 1 mg/kg body weight for 15 infusions on alternate days as rescue therapy for relapse at RMRI (Patna). Again he had clinical and parasitologic cure at the end of therapy. After 8 months of amphotericin B treatment, he developed VL with skin lesions at the same time, which looked like a mole and spread to the front and back of trunk without white patches. A clinical diagnosis of PKDL associated with VL was made, and the patient was further investigated.

On investigation, the WBC count was as follows: total count, 2,900 mm3 (normal range, 4,000–11,000/mm3); neutrophils, 34% (normal range, 40–70%); lymphocytes, 63% (normal range, 15–45%); monocytes, 2% (normal range, 2–5%); eosinophiles, 1% (normal range, 1–6%); hemoglobin, 10/dL (normal range, 11–14.5/dL); ESR, 98 mm in the first hour (normal range, 1–9 mm/h); thrombocytes count, 64,000/mm3. The renal and hepatic profiles were as follows: fasting blood sugar, 102 mg/dL (normal range, 70–110 mg/dL); BUN, 16.00 mg/dL (normal range, 10–50 mg/dL); serum creatinine, 1.07 mg/dL (normal range, 0.7–1.1 mg/dL); serum bilirubin, 0.9 mg/dL (normal range, 0.1–1.0 mg/dL); SGPT, 26 U/L (normal range, 9.43 U/L); SGOT, 24 U/L (normal range, 5–40 U/L). ELISA for HIV-I was done and found non-reactive. The patient was further investigated. Ultrasonography of the whole abdomen suggested enlargement of the liver and spleen. Chest radiology was normal. The microscopic examination of imprint skin smear for PKDL and splenic aspiration for VL showed the presence of L. donovani bodies in macrophage. Immunochromatographic-based rk39 strip test and DAT were also positive. PCR from blood and skin snips was also positive for leishmania.

The patient was immediately put on amphotericin B 1 mg/ kg body weight for 20 days on alternate days as a first course and he responded very well. The patient was re-administered with two more courses of amphoterin B at an interval of 15 days and found cured of VL (in the very first course), with disappearance of PKDL lesions.

DISCUSSION

This is probably the first case report of PKDL that developed after successful treatment of VL with miltefosine. It was thought that PKDL occurs in VL cases after partial, incomplete, irregular, or even full courses of SSG treatment. It was also noticed that PKDL developed in cases without a history of VL and its treatment. Development of PKDL after treatment with other drugs such as amphotericin B and miltefosine, the most commonly used anti-VL drugs in India, particularly in Bihar, has not been reported as yet. Miltefosine, an anticancer drug used as a topical application in skin metastasis of breast cancer in the United States, showed very good efficacy (95%) against VL, with minimal side effects.5

Demonstration of L. donovani bodies in the slit smear or by culture of the skin tissue is considered to be the gold standard for diagnosis of PKDL.6 These relatively crude methods are invasive, less sensitive, and difficult to perform at the periphery level. These days, immunodiagnosis by detection of the parasite antigen in tissue, blood, and urine is becoming more popular. Also, detection of parasite DNA in tissue samples has greater sensitivity and specificity. Histopathology can show the parasite in 67–100% in nodular lesions, 36–69% in papular lesions, and 7–33% in macular lesions.7 Using leishmania-specific monoclonal antibodies in an immunohistochemistry assay can increase sensitivity of parasite identification.

Immunologic methods include immunobloting and ELISA. Recombinant DNA technology has produced sero-diagnostic antigens, which include rK39, A2, ORF F, rH2A, rH2B, rGBP, rLACK, rgp63, rP20, rPSA, and purified lipophospho-glycane (LPG). Other simple tests include direct agglutination test (DAT). Molecular methods like real-time polymerase chain reaction (PCR) are expensive, cumbersome, and require trained personal and costly equipment.7

The treatment aspect of PKDL is no less difficult sodium antimony gluconate (SAG), which used to be a very potent drug for treatment of VL, has now developed resistance, and the cure rate in the endemic districts of Bihar is as low as 30–40%.8 Moreover, its prolonged administration, as required in PKDL, can limit its use, particularly because of cardio-toxicity. Repeated courses of amphotericin B have been found to be superior to SAG9 for treatment of PKDL, with a smaller duration.

In conclusion, PKDL is a disease in which the exact mechanism and etio-pathogenesis are not definitely known. The disease has only cosmetic significance as far as the patient goes. However, there is great epidemiologic significance because PKDL cases are considered to be a reservoir of VL. The current VL elimination program focuses on treatment of VL with miltefosine. If development of PKDL continues after treatment with miltefosine, it will certainly affect the feasibility of the elimination program. Hence, post-treatment monitoring under a VL elimination program needs attention.

*

Address correspondence to Vidya Nand Rabi Das, RMRI of Medical Sciences (ICMR), Agamkuan, Patna 800 007, Bihar, India. E-mail: drkrishnapandey@yahoo.com

Authors’ addresses: Vidya Nand Rabi Das and Krishna Pandey, Division of Clinical Medicine, Neena Verma, Division of Pathology, Chandra Shekhar Lal, Division of Biochemistry, Sanjeev Bimal, Division of Immunology, Roshan Kamal Topno, Division of Epidemiology, Dharmendra Singh and Pradeep Das, Division of Microbiology & Molecular Biology, Niyamat Ali Siddiqui and Rakesh Bihari Verma, Division of Biostatistics, RMRI of Medical Sciences (ICMR), Agamkuan, Patna 800 007, Bihar, India.

Acknowledgments: The authors thank the sincere efforts of Brijnath Prasad, ALIO, N. K. Sinha, TA, and Umesh Kumar, Lab. Tech., for support in the work and manuscript preparation.

REFERENCES

  • 1

    Zijlstra EE, El-Hassan AM, 2001. Leishmaniasis in Sudan: post-kala-azar dermal leishmaniasis. Tran R Soc Trop Med Hyg 95 (Suppl 1):S59–S76.

    • Search Google Scholar
    • Export Citation
  • 2

    Dutta M, Ghosh TK, 1983. Review of current status of leishmaniasis epidemiology, Proceedings of the Indo-UK Workshop on Leishmaniasis, New Delhi: Indian Council of Medical Research: 97–102.

  • 3

    World Health Organization, 1978. A Decade of Health Development in South-east Asia. South-east Asia Regional Publication Series No. 7. New Delhi: World Health Organization.

  • 4

    Ranjan A, Sur D, Singh VP, Siddique NA, Manna B, Lal CS, Sinha PK, Kishore K, Bhattacharya SK, 2005. Risk factors for Indian kala-azar. Am J Trop Med Hyg 73 :74–78.

    • Search Google Scholar
    • Export Citation
  • 5

    Bhattacharya SK, Sinha PK, Sunder S, Thakur CP, Jha TK, Pandey K, Das VNR, Kumar N, Lal CS, Verma N, Singh VP, Ranjan A, Verma RK, Anders G, Sindermann H, Ganguly NK, 2007. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 196 :591–598.

    • Search Google Scholar
    • Export Citation
  • 6

    Sharma MC, Gupta AK, Verma N, Das VN, Saran R, Kar SK, 2000. Demonstration of Leishmania parasites in skin lesions of Indian post kala-azar dermal leishmaniasis (PKDL) cases. J Commun Dis 32 :67–68.

    • Search Google Scholar
    • Export Citation
  • 7

    Salotra P, Singh R, 2006. Challenges in the diagnosis of post kala-azar dermal leishmaniasis. Indian J Med Res 123 :295–310.

  • 8

    Das VNR, Ranjan A, Bimal S, Siddique NA, Pandey K, Kumar N, Verma N, Singh VP, Sinha PK, Bhattacharya SK, 2005. Magnitude of unresponsiveness to sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar. Natl Med J India 18 :131–133.

    • Search Google Scholar
    • Export Citation
  • 9

    Thakur CP, Narain S, Kumar N, Hasaan SM, Jha DK, Kumar A, 1997. Amphotericin B is superior to sodium antimony glucon-ate in the treatment of Indian post kala-azar dermal leishmaniasis. Ann Trop Med Parasitol 91 :611–616.

    • Search Google Scholar
    • Export Citation
Save