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Clinical Features and Management of Visceral Leishmaniasis
Visceral Leishmaniasis can remain subclinical or can become symptomatic, with an acute, sub acute, or chronic course. The incubation period usually ranges from weeks to months. The classical clinical features of VL are mailase, Fever, Anorexia, weight loss and spleno-hepatomegaly. Fever is usually of low grade and sometimes of high grade. Fever often peaks twice daily, with chills and sweats. Spleno-hepatomegaly usually occurs due to reticulo-endothelial cell hyperplesia. Hyper-pigmentation of skin, especially on the hands, feet, abdomen and fore head, is marked in light-skinned patients. Pete chiae, bleeding from nose and gums, jaundice, oedema and ascitis may occur. Emaciation is usually found. Atypical features of the disease may also occur.
If untreated at right time the mortality rate of VL is very high. Most common causes of death are severe haemorrhage, septicemia and inter current infection. To prevent mortality early diagnosis and treatment is essential.
Diagnosis of VL depends upon the demonstration of amastigote form of parasite in splenic aspirate or bone marrow smear. Other tests which can be used for supportive evidence are ELISA, PCR and rk39. The abnormal laboratory findings associated with disease may be pancytopenia i.e. anemia, leucopenia (neutropenia, eosinopenia, relative lymphocytosis and monocytosis), and thrombocytopenia. There may be associated hypergammaglobulinemia and hypoalbuminaemia.
Significant progress has been made in the development of Drugs for VL. Pentavalent antimony compound the main stay of therapy and Pentamidine has gone out of use due to unresponsiveness and toxicity respectively. At present Amphotericin B and Oral Miltefosine are the sheet anchors of treatment of VL. In future Paromomycin and Liposomal Amphotericin B may occupy a prominent place.
 
 
1.
Visceral Leishmaniasis, a major health problem affecting 61 countries world wide including India, is caused by intra-macrophage protozoa Leishmnia Donovani. About 20,000 cases of Visceral Leishmaniasis ( Kala-azar) are reported annually from India. (Ashford et al, 1992).
1. Pentavalent Antimony: Pentavalent antimony compound Sodium Stibogluconate was first introduced in early 1940. Treatment of VL has revolved around this drug for more than five decades. It is a water soluble compound containing 1/3rd antimony by weight. The mechanism of action is not very clear, probably – SH dependent enzymes are inhibited and bioenergetics of parasite is interfered with. It also blocks glycolytic and fatty acid oxidation path ways.
Because of frequent failures with 10 mg/kg/day, dose used earlier, the WHO now recommends a dose of 20 mg/kg/day (Max. 850 mg) for 30 days. AT this dose also cure rate is 35% in Bihar and 86% in Uttar Pradesh. (Sunder et al 1999).
Common side effects of Sodium Stibogluconate are Nausea, Vomiting, Metallic taste, Cough, Pain abdomen, Pain and stiffness of injected muscle, sterile abscess. Liver and kidney damage and ECG changes may occur. Few cases of shock and sudden death are also recorded.
   
2.
Pentamidine: Pentamidine is a polymine and was reported to be highly effective as second line drug in antimony resistant patients (Jha TK 1983).

Pentamidine probably interacts with kinetoplast DNA and inhibits aerobic glycolysis.  The recommended dose of Pentamidine is 4 mg/kg intramuscularly or slow intravenous infusions on alternate days for 15-20 doses.
This drug is very expensive and extremely toxic.  It causes histamine release responsible for acute reactions i.e. - palpitation, fall in B.P., vomiting and rigor.  IM route may cause local tissue necrosis. Other side effects are kidney and liver damage and fatal cardiac arrhythmia may occur. Most importantly it causes cytolysis of pancreatic B cells causing hypoglycemia initially and Insulin dependent diabetes mellitus later on.  Because of high toxicity and cost this drug is not used now a day.

   
3.
Amphotericin B:  Amphotericin B is a polyene antibiotic.  It inhibits biosynthesis of ergosterol, membrane sterol of leishmania, leading to increased membrane permeability and ultimate killing of leishmania.

At present Amphotericin B is the first line drug in the treatment of kala-azar.  The recommended dose of Amphotericin B is 0.5 to 1 mg/kg daily or every alternate day, given intravenously for 15 dose. (Total dose is 7-20 mg/kg).
Infusion related hyper pyrexia, vigor and thrombophlebitis occur as a rule.  Other uncommon side effects are hypokalemia, renal dysfunction, hepatic toxicity, bone marrow suppression and myocarditis. In spite of these toxicities its long term cure rate in >97%.

   
4.
  1. Lipid associated Amphotericin B: As Amphotericin B is a toxic drug, to improve its tolerability, various lipid formulations have been developed.  At present, three such lipid complexes are available-
  2. Liposomal Amphotericin B (Ambisone)
  3. Amphotericin B lipid complex.
  4. Amphotericin B colloidal dispersion.

After infusion, these compounds are taken up by the cells of reticuloendotheual
system thus reducing the toxicity and targeting to those very cells, which harbour the LD bodies .
            Ambisone produces 100% cure rate at the dose of 5 infusion of 3 mg/kg body wt. (total 15 mg/kg body weight).  Fever and chills occur routinely without any major side-effect.

   
5.
Paromomycin (Aminosidine):  Paromomycin is an aminoglycoside used previously for bacterial and intestinal parasitic infections. The dose recommended by WHO is 15 mg/kg of body weight IM for 21 days. 

Being an aminoglycoside, potential adverse effects of Paromomycin include nephrotoxicity and ototoxicity. Due to its antibacterial activity, paromomycin has the additional advantage in the treatment of co-exiting bacterial and amoebic infections, which are common with VL.

   
6.
Miltefosine: Its chemical name is hexadecyl phosphocholine, and it was first developed as an antitumor drug.  It is the first oral drug effective in the treatment of VL.

Dose of Miltefosine for VL is 2.5 mg/kg/day in children age group and 100 mg/day for Adults for 28 days.
            A principal side effect of miltefosine at this dose is vomiting and less commonly diarrhea. In some patients asymptomatic elevation of hepatic enzymes occur which is reversible. Its cure rate is about 97%.

   
7.
Sitamaquine; It is a primaquine derivative first developed for the treatment of Malaria.  After its effectiveness on hamsters infected with L. donovani, it was tried on VL patients at lower doses.  50% patients were cured and improvement was seen in others.

            Asymptomatic methemoglobinemia and mild elevation of hepatic enzymes were the principal side effects.

   
8.
Other drugs: In addition to these Allopurinol, ketoconazole and may other drugs have been tried but neither of these are effective.