Leishmaniasis (Kala azar and other forms)

Leishmaniasis (Kala azar and other forms)

Nedim ÇakırNeu-med.

Etiology

• A protozoan disease caused by Trypanasomidae family

• Twenty of total 30 species may cause diseases in mamalians

• Last classification

2CAKIR: LEISHMANIASIS 2014-2015

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

CAKIR: LEISHMANIASIS 2014-2015


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

• In 33/88 countries unreported/



• 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, – Dogfights or dog lickings may responsible to transmissions l


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 ofL 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 monthsfew years – Some forms remain in permanent scars (oriental sore)

• Severe clinical forms:– HIV co-infections– Other immune deficiency patients


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

• Resistant to treatment


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: – Hyperemia around nostrils


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– Life cycle: humans – Phlebotom - Humans


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 pentade1. 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: – Secondary infections: Bacterial co-infections Few weeks – few months


VL’de epidemic polymorphism

No relations between contamination and (Apparent, clinical) infection..... ( Rate is not 1:1)

• Asymptomatic infection: Apparent infection rates– Sudan1:2,62 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

42CAKIR: LEISHMANIASIS 2014-

2015

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

prevent PKLD


(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– Detecting spesific gene areas by PCR


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• Excellent sensitivity(93–100%) and spesificity (97–98%) Widely used...


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_1107_ok.pdf

2. http://www.cfsph.iastate.edu/Factsheets/pdfs/leishmaniasis.pdf3. http://www.who.int/leishmaniasis/resources/TURKEY.pdf4. http://leishinfonet.com/clinical.php

Books1. 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.


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Leishmaniasis (Kala azar and other forms)