LEISHMANIASIS

Introduction• Caused by unicellular flagellate intracellular

protozoa belonging to the genus Leishmania • Several diverse clinical syndromes – visceral leishmaniasis (VL, kala-azar) – cutaneous leishmaniasis (CL) – mucosal leishmaniasis (ML).

• Zoonotic transmission • Reservoirs -Chiefly canine and rodent, Human- in

India and Sudan • Vector-phlebotomine sandfly

Distribution of Visceral leishmaniasis

VISCERAL LEISHMANIASIS (KALA-AZAR)

• Leishmania donovani complex• Vector Phlebotomine sandfly• Common in India , Bangaladesh , Nepal ,Brazil,

Sudan and humid climate of Mediterranean sea

• Disease can present unexpectedly in immunosuppressed patients-after renal transplantation and in AIDS

Transmission

TransmissionFeeding Female phlebotomine sandfly bite - saliva ( Flagellate promastigote)

Promastigote taken by macrophage and lost their flagella(Amastigote)

Invade immunity and lysis of macrophage and infection of other cell

Bite of sand fly –amstigote transforms into promastigote in the gut of vector ready to

infect new host

Life cycle

Pathogenesis

• The great majority of people infected with flagellar promastigotes remain asymptomatic and control the infection

• Those unable to do so develop clinical disease• In visceral diseases the spleen, liver, bone

marrow and lymph nodes are primarily involved

Clinical features

• On the Indian subcontinent both adults and children are equally affected

• On other continents it is predominantly a disease of small children and infants, except in HIV co-infection (adult disease)

• Malnutrition increases susceptibility to the visceral disease

• The incubation period ranges from weeks to months (occasionally several years)

Clinical features• The first sign -fever -rigor and chills• Fever intensity decreases over time and patients

may become afebrile for intervening periods ranging from weeks to months

• Splenomegaly• Hepatomegaly occurs later, to a lesser degree

than splenomegaly. • Lymphadenopathy in Africa, the Mediterranean

and South America but is rare on the Indian subcontinent

Clinical features• Blackish discoloration of the skin -in advanced

illness• Moderate to severe anemia, Thrombocytopenia

to Pancytopenia common feature. • Congestive cardiac failure • Hepatic dysfunction • Bleeding from retina, gastrointestinal tract and

nose.• In progressive disease, hypoalbuminaemia may

manifest as pedal oedema, ascites and anasarca

Clinical features

• In Advances disease, there is profound immunosuppression

• Secondary infections are very common. – Tuberculosis, pneumonia, severe amoebic or bacillary

dysentery, gastroenteritis, herpes zoster and chickenpox infections, boils, cellulitis and scabies are common occurrences.

• Without adequate treatment most patients with clinical VL are likely to die

• Death mostly due to sepsis

Investigations

• CBC--Pancytopenia is the most dominant feature, with granulocytopenia and monocytosis.

• Polyclonal hypergammaglobulinaemia, chiefly IgG followed by IgM, and hypoalbuminaemia

• Serology-– Immunofluorescence antibody test-- specific – Direct agglutination test – Rapid immunochromatographic k39 strip test – Formal gel (aldehyde) or other similar tests based on

the detection of raised globulin

Investigations

• PCR• Culture –NNN media• ELISA • Buffy coat-demonstration of parasite in

immunosupressed• Bone marrow-LD bodies• Splenic aspirate-98% sensitive

Splenic smear showing amastigote

Diagnosis

• Patient from Endemic area• History of fever• Features of pancytopenia• Moderate to huge splenomegaly• K39 positive or demonstration of LD bodies in

Bone marrow or splenic aspirate

Differential diagnosis

• Malaria• CML• Myelofibrosis• Disseminated TB• Typhoid• Many other neoplastic and infectious

conditions

Treatment

• Pentavalent antimonials- Stibogluconate• Pentamidine isetionate• Antifungal –Amphotericine B• An aminoglycoside-Paromomycin• Alkyl phospholipid-Miltefosin, oral

preparation

Pentavalent antimonials

• First drug / Remain the main stay of treatment• Upcoming resistant in Indian subcontinent• Sodium stibogluconate (100 mg/ml)• Meglumine antimoniate (85 mg/ml)• Daily dose is 20 mg/kg body weight, IV/IM for 28-30 days• Side-effects -common

– Arthralgias, myalgias, raised hepatic transaminases, pancreatitis– Severe cardiotoxicity--prolongation of QTc > 0.5 msec,

ventricular ectopics, runs of ventricular tachycardia– Torsades de pointes, ventricular fibrillation and sudden death

Amphotericine B• Conventional Amphotericin B /liposomal • Amphotericin B deoxycholate given once daily or on

alternate days at a dose of 0.75-1.00 mg/kg for 15-20 doses, is used in patients with Sb failure or as a first-line drug in regions with a significant level of Sb unresponsiveness

• Liposomal-10-15 mg/kg is adequate,100% cure rate• Side-effects-

– Infusion-related- high fever with rigor, thrombophlebitis, diarrhoea and vomiting,

– Renal or Hepatic toxicity, hypokalaemia, thrombocytopenia, myocarditis and occasional sudden death

Miltefosine

• Approved in India, Germany and Colombia for the treatment of VL

• A daily dose of 50 mg (patient's body weight < 25 kg) to 100 mg (≥ 25 kg), or 2.5 mg/kg body weight for children, for 28 days

• Cures over 90% of patients• Side-effects include– Mild to moderate vomiting and diarrhoea, – Skin allergy or Nephrotoxicity.– Teratogenicity --C/I in pregnancy– Female patients are advised not to become pregnant for

the duration of treatment and another 2 months

Paromomycin /An aminoglycoside

• Recent drug• Undergone trials in India and Africa• Approved by FDA• Highly effective • IM at 15 mg/kg body weight daily for 3 weeks • No significant auditory or renal toxicity is seen

Pentamidine isetionate

• This was used to treat Sb-refractory patients with VL

• Abandoned- • Declining efficacy• Serious side effects

• Side-effects– Type 1 diabetes mellitus,– Hypoglycaemia– Hypotension

Response to treatment • A good response results in abatement of fever • Feeling of well-being,• Gradual decrease in splenic size, • Weight gain and recovery of blood counts. • Follow for at least 6 months to detect relapse• Relapse is indicated by enlargement of the spleen,

return of fever, weight loss and decline in blood counts. • Depending upon the geographical location, patients can

be retreated either with Sb or conventional or lipid amphotericin B.

HIV-visceral leishmaniasis co-infection

• HIV-induced immunosuppression increases the risk of contracting VL 100-1000 times.

• Most cases of HIV-VL co-infection have been reported from Spain, France, Italy and Portugal, although the numbers are increasing in Africa (mainly Ethiopia) and Brazil and on the Indian subcontinent

HIV VL-coinfection

HIV-VL Presentation • Atypical clinical presentations of VL in patients co-infected

with HIV pose a diagnostic challenge. • Clinical triad of fever, splenomegaly and hepatomegaly

<50% the patients with a CD4 count under 50 cells/mm3. • VL may present with gastrointestinal involvement

(stomach, duodenum or colon), ascites, pleural or pericardial effusion, or involvement of lungs, tonsil, oral mucosa or skin.

• Diagnostic principles remain the same as those in non-HIV patients.

• Parasites are numerous and easily demonstrable, even in buffy coat preparations, Bronchial fluid, other body fluid

Treatment in VL-HIV coinfection• Essentially the same as in immunocompetent

patients• Conventional amphotericin B (0.7 mg/kg/day for

28 days) may be more effective in achieving initial cure than Sbv (20 mg/kg/day for 28 days)

• Co-infected patients-tendency to relapse within 1 year.

• Prevention of relapse, the role of maintenance chemotherapy is debatable.

• Highly active antiretroviral therapy (HAART)

VL-Prevention and control

• A multipronged approach is needed. • Vector control -insecticide spray is very

important. • Mosquito nets or curtains treated with

insecticides will keep out the tiny sandflies. • In endemic areas with zoonotic transmission,

infected or stray dogs should be destroyed.

VL-Prevention and control

• In areas with human to human transmission, early diagnosis and treatment of human infections

• Reduce the reservoir and control epidemics of VL

• Serology is useful for screening of suspected cases in the field

• No vaccine is currently available.