leishmaniasis (kala azar and other forms)
DESCRIPTION
CAKIR: LEISHMANIASIS 2014-2015 Etiology A protozoan disease caused by Trypanasomidae family Twenty of total 30 species may cause diseases in mamalians Last classification Leishmanialar Trypanasomidae ailesi içinde yer alan protozoalardır. Bu cins içinde yer alan 30 türün 20 tanesi memelilerde hastalık yapar. En son sınıflamada ise aşağıdaki sınıflama kullanılmaktadır CAKIR: LEISHMANIASIS 2014-2015 2TRANSCRIPT
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/
CAKIR: LEISHMANIASIS 2014-2015
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
CAKIR: LEISHMANIASIS 2014-2015
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
♀ ♂
♀
CAKIR: LEISHMANIASIS 2014-2015
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
CAKIR: LEISHMANIASIS 2014-2015
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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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
CAKIR: LEISHMANIASIS 2014-2015
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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