Leishmaniasis (Kala azar and other forms)
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Transcript of 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
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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
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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
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Global epidemiology-1
• All over the world except Australia, Oceania, Pasific Isld.s
• Hyperendemic areas: Afghanistan, Brasil, Sudan
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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
• In 33/88 countries unreported/
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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
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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
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Vector
• Female phlebotomiade members
– Old world Phlebotomus Phlebotomus papatasi
– New world Lutzomyia
Lutzomyia mignoei Vector of L infantum
♀ ♂
♀
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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
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L infantum amastigotes in dog macrophages
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Lifecycle of leishmaniasis
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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
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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,
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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
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Epidemiolgy ofL donovani, L infantum
and L chagasi
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Layşmanyoz klinik epidemiyolojisi
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Clinical picture of Leishmaniasis
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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)
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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
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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
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Cutaneous leishmaniasis (Oriental sore: Şark çıbanı)
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Orld World cutaneous leishmaniasis:
ORİENTAL SORE ŞARK ÇIBANI
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CL: Disseminated form
• Fairly seldom
• Seen in : – L. amazonensis infections
• More frequent in New World
– Esatern hemisphere: • in HIV coinfections• İmmune deficiency
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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
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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.
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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
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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
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Visceral Leishmaniasis (VL)Kala azar
Dum Dum fever
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Clinical signs: General
• Incubation period: 2-6 mo.
• Persistant systemic signs: Fever, malaise, fatigue, loss of apetite • Organomegaly:
– Hepatomegaly– Splenomegaly
• Other RES involvement: lymphatic
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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
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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
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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
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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
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Causes of anemia in VL
• Persistan inflamatory stage
• Hipersplenism
• Bleedings
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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
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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
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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
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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
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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
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(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
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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
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Preventing strategies VL
• Two control srategies :
– Controlling of reservoir
– Vector controll kontrolü
• Immunisation programs still ongoing
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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
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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
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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%)
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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
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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
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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
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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...
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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
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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
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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
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Treatment
• Anti-leishmanial drugs: Pentavalent Antimony comp.:– Sodium Stibogluconate: Pentostam (Britania) – Meglumine Antimonate: Glucantime (France)
• 80-100%• Similar effect
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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
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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
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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
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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 %
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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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