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Monday, 24 November 2014

What is new in eliminating Visceral Leishmaniasis (VL) in India?    Published at BMJ as Letter  21 November 2014

By  Professor Pranab Kumar Bhattacharya MD(Cal.Univ) FICPath, WBMES

Visceral Leishmaniasis (VL) is a fatal disease characterized by irregular fever, weight loss, hepato-splenomegaly and anemia. 90% of VL cases occur in India, Nepal, and Bangladesh and in Brazil. Each year 500,000 new cases occur worldwide and 50,000 die of VL. The disease is grossly under reported in India, and about 100,000 cases are estimated to occur annually in the state of Bihar, with West Bengal accounting for than 90% of cases in India. The disease is endemic in the eastern part of India mainly in 31 districts of Bihar, 4 districts of Jharkhand, 11 districts of West Bengal and in Eastern Uttar Pradesh. The epidemic of VL usually recurs every 15 years in India (two post independence big epidemics were in 1997 and 1992). Though VL was eliminated from the state of Assam it is reported to be re-emerging as sporadic cases and also as outbreaks. There are also emerging epidemic sites of cuteneous leishmaniasis in Himachal Pradesh (along the Salute River Valley) and Rajasthan, where the ausative agent is L. tropica and the dog is the reservoir of the parasite .Elsewhere in India, untreated VL and PKDL is the reservoir of the parasite. In 2008, when blood samples were tested by PCR from human, goats, cows and buffalos in VL epidemic areas of Nepal, 6% of humans and 16% of goats were found to be harbours of Leismania DNA.
RK 39 immunochromatographic strip tests using a drop of the patient’s blood is a major breakthrough in diagnosing VL. Strip testing of the patient’s urine with the same strip test is as good as blood testing and the test can be done by peripheral field workers. However, a new latex agglutination test (KA Tex) has come to the market for detection of leishmania antigen in the urine of VL patients and has been tested in Indian and Nepalese VL patients. This test has good specificity (90-100%) but sensitivity varies (50-90%). KA Tex becomes positive in 87% of cases and at the end of treatment 3% remain positive.
rK28 is another antigen introduced as a candidate for serological diagnosis of VL. In Micro ELISA format, the sensitivity is 99.6% and specificity in endemic, non endemic healthy and disease controls is 94-100%. A novel L Donovan antigen 37KD protein (BHuP2) has a sensitivity of 94% whereas specificity in different control groups is 97%-100%. In a sophisticated laboratory PCR for DNA or RNA gene is a powerful tool for diagnosis of VL.
The advantages are
* Detection of very low level parasitemia
* Prediction of Cure
* Identification of strain and VL/HIV co-infection.
PCR can be performed in peripheral blood, lymph nodes, skin and urine. Urine based PCR shows 96% sensitivity and 100% specificity. Oligochromatography provides a rapid dipstick format for detection of PCR products. PCR products can be visualized on dipstick testing by hybridization with gold conjugated probe allowing species specific PCR product detection. This test takes 5-10 minutes and requires no instruments other than a water bath and a pipette.
The orally effective drug miltefosine has revolutionized the treatment of VL. A multi center pivotal phase III study established a cure rate of 94%. Following this a phase IV study was done in which 1132 patients were enrolled and the final cure rate was 82%. The real problem with miltefosine is that it is resistance prone as it has a very long half life of 150-200 hours, so that a tail of low level drug persists for long periods. Moreover it is teratogenic.
Sitmaquinnine developed by Walter Reed Army Research US is 8 amino quinine and has high antileishmanial activity. But there is a lack of linear co-relation between dose of drug and cure rate. In phase II study in India 89% were cured with 28 days of 1.75 mg/kg body wt/day sitamaquine. Peculiarly higher doses are not effective and nephropathy can develop.
WHO, Institute of One world health and the Bill and Melinda Gates Foundation have successfully resurrected paramomycin as the cheapest effective anti-leismanial drug. A phase III trial has been completed in India. Treatmen is once a day im injection 15mg/Kg for 21 days. Result showed it non inferior to amphotericin B (1mg/kg IV infusions on alternate days to a total of 15 infusions) with a final cure rate of 94% versus 99%. None of the patients developed nephrotoxicity or permanent ototoxicity. The only adverse effect was a 3 fold rise in ALT level in 6% patients. So monitoring of LFT must be done in VL; such monitoring is available in India at a reasonable cost.
Combination chemotherapy may be the future strategy in present scenario of emerging drug resistance - even against amphotericin B. Increasing rates of relapse are seen in all kinds of VL drugs. The benefits of combination therapy are:
* Synergistic activity
* Preventing drug resistance
* Lowering dose requirements
* Reducing side effects - thus increasing efficiency and therapeutic life span of existing anti kala-azar drugs.
Liposomal Amphotericin B 5mg/kg + 7 days Miltofosine or single dose Liposomal Amphotericin B 5mg/kg + 10 days Paramomycin or 10 days Miltofocin + Paramomycin may be now choice of therapy of VL

Acknowledgement to  Author is grateful  for contributions while doing this work and publishing it in journal  BMJ  as Rapid Responses to following
*Miss Upasana Bhattacharya, **Mr. Rupak Bhattacharya ** Mr. Ritwik Bhattacharya ** Miss Rupsa Bhattacharya *** Mrs Dalihia Mukherjee , ***Miss Oindrila Mukherjee *** Mr.Debasis Mukherjee*** Miss Ayshi Mukherjee and **Mr. Hindole Mukherjee
* Daughter of Prof PKBHattacharya & Student ** of residence 7/51 Purbapalli PO-Sodepur, Dist- 24 parganas(north) Kolkata-70110 West Bengal India; *** Swamiji Nagar . South Habra, Dist- 24 parganas(north) , Kolkata - West Bengal India
Competing interests: No competing interests
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