Leishmaniasis

Leishmaniasis By: Dr Osman Sadig

The leishmaniasis are a group of diseases with a variety of clinical manifestations 1- Visceral leishmaniasis VL/ PKDL 2- Cutaneous leishmaniasis CL 3- Mucocutaneous leishmaniasis MCL 4- Diffuse cutaneous leishmaniasis DCL Over 20 pathogenic sp of leish parasites are known: 1- L donovani 2- L infantum 3- L archibaldi 4- L chagasi

5- L tropica 6- L major 7- L ethiopica 8- L braziliensis 9- L mexicana

The outcome of the infection depends on : 1- Parasite invasiveness & pathogenicity 2- dose of inoculum 3- parasite tropism 4- genetically determined host immune response A single leish sp can produce diff clinical syndromes and each of the syndromes can be caused by more than one sp e.g. Viscerotropic L tropica

Visceral leishmaniasis VL is usually fatal disease without TR. Epidemiology - About 500 000 new cases annually, 90% in India & Sudan - Infection is endemic in India, China Central Asia, East Africa, Middle east, Medit region and Latin America - VL is endemic in Sudan & has been reported since early 19 th century.

- Main endemic areas in Sudan are : 1- Eastern Sudan along Atbara & Rahad rivers 2- Sinnar & Blue Nile states 3- Upper Nile state 4- Eastern Equatoria around Kapoita 5- South Kordofan 6- South Darfor - VL is caused by L. donovani (LDB), L. infantum, L. chagasi & L. tropica ( usually mild disease)

- More than 24 600 cases & 1193 deaths had been reported in Sudan during 1996—2001. This is only reported cases and does not reflect actual dis transmiss - The dis affects mainly children & young adults and is commoner among poor people, farmers, labourers, malnourished, people visiting endemic areas for the 1 st time and in the immunosuppressed - Leishmania exists in 2 different forms:

Leishmania exists in 2 different forms : 1- Promastigote in the vector developing from amastigotes through series of intermediate stages in the digestive tract eventually migrating to the proboscis and inoculated to the skin of the host with the blood meal. It is pearl or spindle shaped 10—15 mc with flagellum . 2- Amastigote : develops in the human- being from promastigote & proliferate in the R/E system within macrophages. It is oval in shape.

The vector is Female sand fly - Phlebotomus orientalis - Phl martini (termite hill dweller) - Phl lutzomyia in new world leishma The reservoir - Depends on the leish sp & the vector - Rodents, dogs, wild animals & patients with VL (PKDL)

Transmission Depends on the presence of suitable reservoir , vector and susceptible human host 1- H uman to human ( anthroponotic) e.g. India (causing epidemics) 2- A nimal reservoir to human ( zoonotic transmission) e.g. dogs in the ME and Mediterranean where the dis. is sporadic in children and opportunistic in immunosuppressed – HIV patients 3- Congenital, sexual & BT are rare.

Out breaks - Mellut town 1940 - Southern Fung 1956 - Jum jum tribe 1958 (Satti) - Western Upper Nile 1984—1994 - Gedarif state 1996—200-

Immunity Out come of infection depends on the interplay between protective CMI respon at one hand & dis enhancing immune response on the other hand 1- Th1 CD4 cells are protective by producing IL2 & INF gamma which stimulate macrophage to inhibit the growth of amastigotes 2- Th2 CD4 cells produce IL4,5 which enhance disease progression

Leishmania infection results in life long latent immunity. With immunoparesis leishmania can become opportunistic pathogen through reactivation or new infection .

Clinical manifestations - Varies from asymptomatic self limitting dis to frank VL which is fatal if untreated , with mild dis in between. 1- Clinically suspect case is any pat who lives or had traveled to an endemic area presenting with fever of > 2/52 + spleenomegaly and/or Lymphadenopathy in whom malaria is ruled out or treated

2 - Probable case : suspect case + leucopenia 3 - Confirmed case : suspect case + positive parasitology Presentation - IP : 1—2/12 (2/52—10 years) - Onset : insidious , but may be acute - Fever (95%) : prolonged fever without rig It may be intermittent, remittent wz doubl spike or contin. Fever is well tolerated.

- Splenomegaly (95%) - Wt loss (80%) & wasting later - Anaemia (75%): chronic dis, bleeding, hemolysis, BM infilt wz parasites, hypresp haemodilution. - Hepatomegaly (60%) - LN (75%) - cough (75%) - anorexia (70%) - epistaxis (50%) - diarhoea (40%) - vomiting (15%) - jaundice (5%) - edema (5%) - ascites.

- skin pigmentation : The skin is dry, thin, scaly with sparse hair. Atypical cases present with: - mild symptoms and/or isolated splenomegaly - lymphadenopathy may be the sole presentation in India - Some present with PKDL - Some show sub clinical sero conversion - In immunosuppressed (e.g AIDS) fever and spleenomegaly may be absent

Differential diagnosis - Malaria must be ruled out - Enteric fever - H/S schistosomiasis - African trypansom - Miliary Tb - Brucellosis & relapsing fevers - AIDS - Liver abscess

- Histoplasmosis - infectious mononucleos - Other causes of gross splenomegaly - Malnutrition

Laboratory & diagnosis: - CBC & ESR: - anaemia (60-90%) - leucopenia (84%) - thrombocytopenia (73%) - high ESR - Liver biochemstry: albumin < 30 g/l (88%), globulin >30 g/l (78%), elevated ser bilirubin, transaminases and ALP - Renal profile & ECG

- Specific diagnosis depends on clinical suspicion & either 1- parasitology OR 2- serology . 1- Parasitology : specimen obtained from: - Gland puncture is easy & safe with 50—65% sensitivity - BM aspirate require trained person, painful & require sp needle wz 64—92% sensitivity - Splenic puncture : invasive & hazardous with 90—95% sensitivity

- rarely from puffy coat layer of blood - Culture in NNN media * Negative splenic aspirate does not exclude diagnosis * Parasitology is the only diagnostic method in relapse, HIV pat & infants < 6/12

2- Serology : in clinically suspected cases (FAT, DAT, ELIZA, Latex Agg test, PCR) - DAT is sensitive, specific, simple and can be easily performed under field conditions, but needs trained staff. Not useful for relapse diagn or TOC. Positive DAT (>1:64000) combined with negative LST in a clinical suspect is diagnostic. Positive LST rules out active VL even if DAT is positive.

- Katex detects Ag in urine, sensitive and specific - ICT 3 LST: measures type 1V hypersensitivity . It is negative in active VL, but becomes positive in 80% 3—6 months after TR It is valuable in epidemiological studies and augments DAT in the diagnosis if it is negative.

Treatment of VL: ( supportive/ specific) - TR ideally given to confirmed cases in hospital settings under med supervision - Trial of TR is only considered if there are no lab. facilities & after exclusion of other infections and occasionally in highly suspected cases despite –Ve lab. 1- Supportive TR include nutritional care, oral hygiene, Fe, folic acid, multivit, TR of infections, BT & correction of flu & E

2- Specific TR :- A- First line drugs: 1 - Sod stibogluconate is pentaval antimony (SSG) in 100mg/ml. Dose 20 mg/kg/d IV or IM for 30 days. - SE: include A,N,V, fatigue, headache arthralgia myalgia, cough, cardiotoxicity, renal damage pancreatitis, elevated ser amylase and transaminases, and local pain

- CI : cardiac dis, liver dis, renal fail, moribund pat & full blown AIDS. 2- Meglumine antimoniate is similar to SSG but in 85 mg/ ml B- Second line drugs : 1- Amphotericin B 1mg/kg EOD for 30 days Nephrotoxic. 2 nd line drug. 2 - Ambisome (amphotericin B lipid complex) is alternative 1 st line drug. 50 dollars for 50 mg vial & 600 dollars total TR. Dose 20—30 mg/kg over 2/52 in doses of 3—5 mg/ kg with

TOC in day 21. It is reconstituted and diluted in 5% dextrose and infused over 30—6o min. Main indications of ambisome are: - unresponsiveness to SSG - 3 rd relapse - cardiac disease - hepatic & renal impairment - moribund patients . 3- Pentamidine 3—4 mg/kg EOD for 10 doses 2 nd line drug

4- Paromomycin (aminosidine) 15mg/kg for 17 days IM or IV diluted in NS over 90 min. Usually used in combin with SSG. Oto/ Nephrotoxic. 5- Miltefosine : anti neoplastic. Oral, sp used in India 6- Allopurinol 7- ketoconazole 8- INF gamma

Follow up: - gen condition, temp, spleen, Wt, CBC - TOC at 25—30 day of TR to asses the parasitological cure. GP in routine use. - Initial cure = clinical cure + parasitologic cure by the end of TR - Definite cure = absence of symptoms and signs 6/12 after initial cure - Follow up at 3, 6, 12 M & if symptoms rec

- slow responder = pat with no clinical response & low grade parasitaemia after 30/d of TR. Extend TR to 60 days or until 2 consecutive –ve TOC - Non responder = patient with no clinical response & high grade parasitology after 30 days TR with SSG. Combine SSG + paramomycin OR go to ambisome for TR.

- Relapse (5%) = pat with clinical and parasitological confirmed case & past history of TR of VL. 1 st , 2 nd and 3 rd relapse - For 1 st relapse: SSG for 60 days or till 2 consecutive –ve TOC OR SSG + paramomycin - For 2 nd relapse: SSG + parmomycin OR go to ambisome - For 3 rd relapse ambisome Screen for HIV for non resp and relapse cases

Complications of VL - Intercurrent infections (Tb, otitis M, canc oris, pyoderma, viral) - Malnutrition & anaemia - Bleeding, hepatic failure - Neurological (P. neuropathy, GB, ataxia myelopathy, deafness) - PKDL : usually follows TR but can occur during TR or wz out history of clinical VL.

PKDL - grade 1 PKDL = rash on the face +/- upper chest & arms - grade 2 PJDL = dense rash most of the face, on the trunk, arm & legs. When extensive & black nodule = grade 2 severe - grade 3 = dense rash most of the body including hands & feet. Ulceration, crust scaling & mucosal spread (PKML) can occur.

- Parasites are scanty in PKDL which may serve as a reservoir of infection - PKDL should be differentiated from L. leprosy, measels, fungal infections, syphilis, yaws & T versecolor - TR is given for grade 3 & 2 severe. Dose 20 mg/k SSG daily till clinical cure up to 2/12

Causes of death in VL - intercurrent infection including HIV - hepatic failure - renal failure - bleeding - malnutrition - severe anaemia - cancrum oris - HF or cardiac arrest (SSG)

VL & HIV Co infection - Both are associated wz immune suppres and potentiate each other - Suspected in VL pat wz high parasitaemia , non responders & in relapsers - Clinical diagn may be diff . Fever, spleno and pancytopenia may not be present and clinical suspicion may be obscured by opportunistic infections . Presentation may be atypical .

- VL may be rapidly progressive & may have predominant GIT symptoms - CD4 < 200 & associated opportunistic infections are common - Serology is –ve in up to 50% due to depressed immune response - Diagn by parasitology . Parasites are abundant in LN or BM aspirates. It is +ve in 50% in the buffy coat of blood - TR is diff. Relapse rate & mortality high

and drug SE are more severe . - Combined anti leish & anti retroviral drugs for TR. - Response to anti leishmanial TR is poor due to depressed immune resp & increas parasite load. Relapse in 50% & relapses should only be treated if symptoms are severe

Leishmaniasis

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Leishmaniasis