Leishmaniasis (Kala azar and other forms)

Leishmaniasis

(Kala azar and other forms)

Nedim Çakır

Etiology

• A protozoan disease caused by Trypanasomidae family

• Twenty of total 30 species may cause diseases in mamalians

• Last classification

Etiology-2



• Human cutaneous – mucucutaneous leishmaniasis :

1. L. braziliensis complex : L. braziliensis, L. panamensis/ L. guyanensis, L. shawi and L. Peruviana

2. L. mexicana complex: L. mexicana, L. amazonensis, L. Venezuelensis, L. lainsoni, L. Naifi ve L. lindenbergi.

3. L. tropica complex: L. tropica, L. anmdL. aethiopica,

• Human visceral leishmaniasis agents:

– Leishmania donovani (includ. L. archibaldi’yi) and L. infantum/ L.

chagasi

Etiology-epidemiology

• Old World: L. İnfantum

• New World: L. chagasi

• Bu iki son etken eskiden ayrı türler gibi kabul edilmişse de yapılan analizlerde bunların tek tür oldukları anlaşılmıştır

• L infantum may cause also cutaneous form without systemic

infection

Global epidemiology-1

• All over the world except Australia, Oceania, Pasific Isld.s

• Hyperendemic areas: Afghanistan, Brasil, Sudan

Global epidemiology-2

Most of patients (90 %)

• Visceral form: Bangladesh, Basil,India, Nepal and Sudan

• Muco-cutaneous form: Bolivia, Brasil, and Peru

• Cutaneous form : Afghanistan, Brasil, Iran, Peru, Saudi Arabia, Syria

• Mainly undeveloped countries and areas

Global epidemiology-3

• Totally 350 million patients

• 350 million people are at risk worldwide (in six countries: Bangladesh, Ethiopia, Brazil, India, South Sudan and Sudan)

• 12 Milionnew cases every year

• Equal in rural and urban areas

• HIV co-infections are at higher severity risk

Transmission:

• Via biological vectors:

– Phlebotomus and – Lutzomyia,

• Each leishmania species adoptto and can survive in few phlebotomus species

• Only female phlebotomus are responsible from transmission

• Effect of seasonal conditions:

– Dry and windless seasons, – Higher humidity

– Time:Dawn and evening hours

– Daytime: If they were disturbed in their hollow



Vector

• Female phlebotomiade members

– Old world Phlebotomus

Phlebotomus papatasi

– New world Lutzomyia

Lutzomyia mignoei  Vector of L infantum

♀ ^♂

♀



Transmission:



• Natural habitat:

– Daytime

• Animal shelters

• Tree hollows,

• evlerin görece serin ve nemli yerleri

– Nighttime

• Lighting attracts

• Mechanical vectors:

– Ticks(Dermacentor variabilis and Rhipicephalus sanguineus), dog’s flea

• Dother transmission routes:

– Asymptomatic individuals, – Blood transfusions,

– Transplacental route (Vertical transmissions): Dogs, rats,and humans, Dog’s

urine, tear, saliva or other secrets like semen,

L infantum amastigotes in dog

macrophages

Lifecycle of leishmaniasis

Life cycle of Leishmania-1

Two stages have been detected:

• Promastigot stage: Flagellated.. In vectors gut

• Amastigot stage: Seen in mammary cells as intracellulary form

• Only female Phlebotoms can transmit promastigots by biting

• Parasites engulfed by macrophages and dendritic cells in dermis



Life cycle of Leishmania-2



• Losts flagels within dendritic cells amastigot form

• Engulfed parasite remains alive in phagolysosomes

• İnvades lymphatic and vasculary tissues

• İnvades mocytic anda macrophages in RES

 Bone marrow infiltration, heptomegaly, splenomegaly,

lymphadenopathy,

Epidemiology of VL

• L. infantum infections  Mainly immune deficient patients and infants

• L. Donovani  All ages

• Global epidemiology: Yearly

– 500,000 new cases – 50,000 death

• The second most important parasitic infection after

malaria

Epidemiolgy of L donovani,

L infantum and

L chagasi

Layşmanyoz klinik epidemiyolojisi

Clinical picture of Leishmaniasis

Layşmanyoz klinik tipleri

• Cutaneous (Dermal leishmaniasis) (CL)

– Localised cutaneous leishmaniasis (Oriental sore, Şark çıbanı) – Diffuse cutaneous leishmaniasis

– Leishmaniasis residivans

– Post kala azar dermal eishmaiasis (PKDL)

• Mucocutaneous leishmaniasis (MCL)

• Visceral leishmaiasis (Kala azar) (VL)

• Viscerotropic leishmaiasis (VTL)

Cutaneous leishmaniasis

• Dermal involvement

• Single lesion  multiple (Dozens)

• Appearance of lesion:

Depend upon the clinical types

– Ulcers, – Nodules,

– Düz plaklar veya

– hyperkeratotic wart-like lesions

CL (Şark çıbanı)

• Initial lesions: Papule at phlebotomus bite site

• Lesions can remain antry-sites  (Not as a rule)

• Secondary lesions:

– Lymphatic involvement

– Skin and mucosal involvement – Secondary lymphanenopathy

• Characteristics of cutaneous lesions:

– Painless

– Secondary lesions can be painful – Generally painful if auricular lesions – Mainly no subcutaneous incolvement

– Outcome:

– Spontaneous recovery depend upon clinical pictures – Few monthsfew years

– Some forms remain in permanent scars (oriental sore)

• Severe clinical forms:

Cutaneous leishmaniasis (Oriental sore: Şark çıbanı)

Orld World cutaneous leishmaniasis:

ORİENTAL SORE  ŞARK ÇIBANI

CL: Disseminated form

• Fairly seldom

• Seen in :

– L. amazonensis infections

• More frequent in New World

– Esatern hemisphere:

• in HIV coinfections

• İmmune deficiency

Diffuse cutaneous leishmaniasis(DCL):

• In L aethiopica/mexicana komplex infections

• Chronic, prgressive, anerjiic variant

• Nodules cannot turn ulcerative forms 

• Invades skin.

• Deep tissues invasion also

Leishmaniasis rezidivans (Lupoid leishmaniasis) (LR):

• L tropica and L braziliensis

• After recovery of primary lesions

• As satellite lesions around recovered cutaneous form

• No spontaneous recovery.

Mucocutaneous llwishmaniasis (Espundia) (MCL):

• Most patient from Latin America

• Agent(s):

– L. braziliensis braziliensis (generally)

– L. panamensis/ L. Guyanensis (seldomly)

• Due to extension of local skin disease into the mucosal tissue via

– direct extension, – bloodstream or – lymphatics.

• Appearance of syptoms:

– Few years after healing of CL

– Sometimes together  Epistaxis

• Initial lesions:

Mucocutaneous llwishmaniasis (Espundia)

(MCL)(Cont’d)

• Clinical pictures:

– Inflamation  Tissue destruction – İnvades to nasal septa

– Pharyngeal and/or laryngeal invasion – Septal perforation

– Malformations (Papağan gagası, deve burnu görünümü) – Obstruction of pharynx and/or larynx

– Rarely invasion of genitalia

• No spontaneous healing, Patients need treatment

Visceral Leishmaniasis (VL)

Kala azar

Dum Dum fever

Clinical signs: General

• Incubation period: 2-6 mo.

• Persistant systemic signs: Fever, malaise, fatigue, loss of apetite

• Organomegaly:

– Hepatomegaly – Splenomegaly

• Other RES involvement: lymphatic

Other caharacteristics of VL

• Agent(s):Leishmania donovani complex

• May fatal if not treat

• Systemic symptoms

• Leishmania infantum: Common in TRNC and Middle

East Europe- NorthAfrica, and Latin Americada

Other caharacteristics of VL(Cont’d)

Clinical types of VL

• Zoonotic VL (ZVL):

– Reservoir: Animals – Vector: Phlebotom

– Life cycle : Animals – Phlebotom - Humans

• Anthroponotic VL (AVL):

– Reservoir: Humans

– Vector: Phlebotom

ZVL – AVL: Epidemiologic characteristics

• In Past: Genrally ZVL Seldomly AVL

• Nowadays: ZVL-AVL Common

• Günümüzde etken frkları

– L infantum: Still ZVL

– L donovani: AVL biçiminde bulaşır

Visceral leisahmaniasis: (VL)

• Patinets from endemic area

– Insidious onset and turn to chronic phase

• Patients from non-endemic area and history of endemic area visits

– Acute onset

• In some African cases dermal granulomas can be detected

• Clinical picturee:

– Persistant intermittent fever, – Weigh loss,

– Loss of apetite, – Anemia,

– Abdominal discomfort

– Hepato-splenomegaly

Causes of anemia in VL

• Persistan inflamatory stage

• Hipersplenism

• Bleedings

VL

• Thrombositopenia:  Petechia hemorrhage or mucosal bleeding

• Leucopenia:  Secondary infections

• Other findings: Cough, chronic diarrhoea, skin hyperpigmentation, lymphadenopathychronic renal involvement

• Mild clinical forms can heal spontaneously.

• Untreated cases: secondary complications fatal outcome

• Fulminant and fatal cases:

– In HIV Co-infections

• Asymptomatic infections:

– Some patints may present live parasite despite adequate treatment – Asymptomatic carrier state + Immune defficiency

Kala azar pentade

1. Fever

2. Weigh loss

3. Organomegalies:

Soft and palpable

4. Pansitopenia

Severe thrombocytopenia epistaxis, petechias

5. Hypergamaglobulinemia

Geographic varations of VL’s clinical pictures

Clinical findings can be changed due to geographic area

• Lymphadenopathy:

– Seldom in India

– Frequent in Sudan Sudan

• Dermal hyperpigmentation

– Frequent in India

– Only during prolonged infections in other endemic regions

• Conclusion: Regional symptomatic varaiations should be

determined by authorities

Outcome of VL

• Splenomagaly may increase in delayed phase

• Abdominal symptoms:

– Abdominal swelling – Gastric pain

– Hepatomegaly

• Bacterial co-infections: Pneumonia, diarrhoea, activation of tuberculosis

• Untreated patients:

– Primary outcomes:

VL’de epidemic polymorphism

No relations between contamination and (Apparent, clinical) infection...

( Rate is not 1:1)

• Asymptomatic infection: Apparent infection rates

– Sudan1:2,62  11:1’e – Kenya: 4:1

– Etiopia 5,6:1 – Iran 13:1,

– Brasil 8:1 18:1 – Spain 50:1

• Q: Why are immunisation programs unsuccesful for some persons ?

• Q: Why are there a difference between contamination and infection?

Neden her etkeni alan hastalanamaz?

• A: Host-spesific cellulary immunity has great effect on clinical pictures

Post-kala azar dermal leishmaniasis (PKDL):

• Etiology: L. donovani

• After recovery of VL

• In some patients

• Peri-oral area

– Maculopapullary, – Macular or

– nodullary rashes

• African patient

• Can be seen in...

– 6. moths

– Spontaneus healing even if not trated

– Successful treatment cannot

(PKDL)

• One of complication of VL

• Common in Sudan

• Less frequent in other Eastern African countries and Indian subcontinent

• Immuncompromised patients in L infantum endemic area

• Very contagious  vivid parasites present in nodulary

lesions

Genetic characteristics of tendency to VL

• Severe T-cell irresponsiveless to L donovani antigens

• İnterleucin 10 production , CD25-Foxp3 that responsible to secret them

• Concomitant diseases like Malnutrition and HIV that altered immun reactions

• Others

– Young ages

– Diminished interferon-X production, – TNF –y gene-40 Promoter polymorfism

• Controlling factors on macrophage activation:

– Solute taşıcarrier gene family11 A1 (SLC11A1; previously NRAMP1) – Gene poliymorphism controls L4 productions

Preventing strategies VL

• Two control srategies :

– Controlling of reservoir – Vector controll kontrolü

• Immunisation programs still ongoing

Control of reservoirs

• ZVL: L. İnfantum main reservoirs: Canines

• Gradually ZVL decreases

• Serologic sreening of canines ????

• Treatment or killing the seropositive-animals ????

• C0mments:

– Animal treatment will not stop re-infections

– Widely use of anti -ZVL drugs will cause resistant strains ilaçlarının yaygın kullanımı dirence yol açar

• Protection of domerstic animals :Deltamethrin impregnated dog-collars

– Prevention of animals from phlebotoms (54%)

– Can be adopted to school collar stud: Prevents children: (43%)

Vector control

• Insecticides : Effect,ve on Phlebotomes and pther mosquitos

– Ör: DDT

• Disadvantage: Repeated growth of mosquitos

• resistance to insecticides İnsektis

• Alternatives : DDT embedded nets

Early diagnosis and treatment:

• Goal of early diagnosis and treatment:

– Prevents new cases – Patient’s health

– Prevention of AVL cases

• Management of aditional problems:

– Anemia, – Malnutrition

– Treatmen of secondary infections

Diagnosis: Non-leishmanial tests

• Pancytopenia (anemia, eucopeniai vehrombocytopenia)

– Bu bulgunun özgünlüğü yüksek (%98) – Duyarlılığı düşük (%16)

• Formol gel test (FJT) or aldehyde test:

– Detects typical polyclonal hipergamaglobulinemias – Easy and chip

– Low sensitivity (35%)

Diagnostic tests: Detection of parasytes

• Direct diagnosis method by staining specimen:

Amastigotes forms by direct staining methods

– LenLymph nodes biposy, – Bone marrow

– Splenic aspiration (Dangerous)

• Evaluation of direct microscopy:

– Highly spesific – Sensitivity

• Splenic aspiration:93-99 %

• Bone marrow aspirates: 53-86%

• Lymph nodes biopsy: 53-65%

• Attention to splenic sapirates by biopsy: May fatal results in ~ 0,1 % May cause abundant bleeding

• May need blood transfusiun and surgical support

• Üculture methods: Highly sensitive

– Culture parasytes itself

Culture methods

• Culture in synthetic media

• Culture media:

– Novy-MacNeil-Nicole (NMN), – Brain-Heart infusion (BHI),

– Evan’s modifiyed Tobie (EMTM), – Grace

– Schneider’in Drosophila

• Inoculation to hamsters:

– If specimen is contaminated – If parasytes are very few

• Time for test: 5-30 days

Diagnosis: Antibody screening tests

• Good antigenic in character  May cause antibody tests possible

• Validation of tests:

– Satisfactory treatment may cause decreases in antibody levels 

– But not dissapears  May detected few years

• Interpretation Problems:

– Definite diagnosis of relapses: İmpossible

– Some symptomless and no clinical history persons who live in endemic area can be detected as «seropositive»

• The standardization of tests are difficulte

Diagnosis: Antibody detecting tests

• Methods: IFAT, Direct agglutination testi (DAT),

immunochromatographic tests (ICT), Fast agglutination screening test(FAST)

– DAT test:

• Antigen  Stained promastigotes

• Spesificity and senstinity:over 90%

• Validity: Geographic area and species of Leishmania canno affect results

– FAST: Rapid agglutination test

• 1/800 vand 1/1600 in dilution

• Compleeted within 2-3 hours Very applicative

– ICT: method ELISA

• Antigen rK39 Amino acid lines.. 39 aminoacidic chain

Diagnosis: AntiAntigen detecting tests

• Low false results

• Latex agglutination:

– Specimen: Urine

– Saptanan antijen: Isıya dayanıklı ve küçük moleküllü karbonhidrat – Low sensitivity (48–87%)

– But correlation with treatment: Good (97–100%)

– False positivity:Should required boiling the test urine inorder to prevent false positivity

– Weak positivity cannot be interpreted

Principles of visceral leishmaniasis treatment: General principles

• Give spesific anti-leishmanial drugs

• Consider other antiinfectives to treat superinfections

• Antianemic drugs if anemia detected

• Give parenteral liquids

• Malnutrition

Spesific antileishmanial treatment:

Pentavalent antimony compounds

• Pentavalent antimony drugs were used for seventy years.

– Meglumin antimonate or – Sodium stiboglukonat

• Toxic in character.Side effects:

– Severe arryhmia (can be mortral) – Acute pancreatitis

• Slow effective: This can cause mortal risks

– Infants less than 2 years old – Over adults over 45

– Patients who has severe malnutrition

Treatment

• Anti-leishmanial drugs: Pentavalent Antimony comp.:

– Sodium Stibogluconate: Pentostam (Britania) – Meglumine Antimonate: Glucantime (France)

• 80-100 %

• Similar effect

Second line treatment: Amfoterisin B

•If antimony treatment failed

•Side effects during the first line treatment

– Chill, shivers – Hypokalemia, – Nephrotoxicity

– Anaphlaxy at during initial dose

•  Liposomal amphotericin B

– But expensive

Alternative treatment: Miltefosine

• Primarily oncologic durg

• Treatment rate:82 %,

• Side effects:

– GİS complaints (rare) – Increase of creatinin

– İncrease of AST and ALT

• Less effective in HIV co-infections

• Teratogenic effect  No indication in pregnancy

• Serum half life: 150 hours

• Licenced animals(Dogs) leishmaniasis in Europe

  some L infantum strains have miltefosin resistant

Alternative treatment: Paromomycin .... in combined treatment

Paromomycin

• Low toxicity and high safety

– Ototoxicity

– İncrease in liver enzymes

• Monoherapy or combination with stibogluconate

• Has also antibacterial effect

Other combinations

• Miltefosine + Liposomal amfotherycin B

Morbidity – mortality:

• Temperate regions

• Seasonal contaminations

• In temperate months  Mosquitos become active

• 1-1,5 million/year CL, 500.000 VL cases

• Real amount??

• L. Donovani  infect all ages group

• L. İnfantum 

– Healthy adults are more resistant

– Asymptomatic infections are more frequent – Most cases are...

• Childhood ages

• Immuncompromised adults

• Insufficient nutritions

• Case/mortality rates untreated patients :75–95 %

References

1. http://www.who.int/leishmaniasis/resources/documents/VL_NMR_1 107_ok.pdf

2. http://www.cfsph.iastate.edu/Factsheets/pdfs/leishmaniasis.pdf 3. http://www.who.int/leishmaniasis/resources/TURKEY.pdf

4. http://leishinfonet.com/clinical.php Books

1. Chatterjee,K.D. (2009). Parasitology. New Delhi, CBS Publishers &

Distributors PVT. LTD, pp. 64-89

2. Cook, G.C. and Zumla, A. (2003). Manson’s tropical diseases, 21st ed, Educational Low Priced Sponsored Texts.pp. 1339- 1364.

3. Murray,H.W., Berman, J.D., Davies, C.R. and Saravia, N.G.

(2005). Advances in leishmaniasis. Lancet, 366:1561-1577.