leishmaniasis

Pathogenesis of LeishmaniasisAL – Abbasi A.M. PhD, FRCP, DCN, DTM&H.Professor of Infectious Diseases & Clinical immunology,Baghdad College of Medicine

Cinderella Of Tropical Medicine

OverviewVarious clinical syndromes caused by obligate intracellular protozoa of genus LeishmaniaVector – borne zoonosisEmerging disease in relation to the HIV

Major Leishmania species causing diseases in humans

Subgenus Leishmania
Clinical syndromes
L. donovani complex:
L. donovani
VL (PKDL, OWCL)
L. infantum
VL (OWCL)
L. chagasi
VL (NWCL)
L. Mexicana Complex:
L. mexicana
NWCL (DCL)
L. amazonensis
NWCL (ML, DCL, VL)
L. tropica
OWCL (VL) Viscerotropic & Leish. recidivans
L. major
OWCL
L. aethiopica
OWCL (DCL)

Subgenus Viannia

L.(V.) braziliensis
NWCL (ML)
L.(V.) guyanensis
NWCL (ML)
L.(V.) panamensis
NWCL (ML)
L.(V.) peruviana
NWCL uta


Classification: Geographical, Clinical, Epidemiological & Morphological are less valid PCR, biochemical means (isoenzyme pattern & DNA peptide mapping). Monoclonal antibody specificity.


Factors governing Leishmanial infection: 1- Vector governs geographical distribution. 2- Parasite governs tissue involved. 3- Host governs course of infection. Innate & acquired immune response influence tissue damage & intra cellular killing.

Route of infection / infectivity: Bite of infected sand fly, lutzomia Congenital Transfusion Sharing needles.

Splenomegaly and hepatomegaly are hallmarks of classic visceral leishmaniasis.

Immunology: Cinderella of Tropical Medicine Paradigm for studies of T cells subsets & cytokines govern intra cellular resistance of pathogen. INF-8 TH1 & NK cells Resistance IL 12 naive T cells TH1 TH1&NK cells INF-8 IL-4 TH2 susceptibility, progression of disease IL10 associated with pathology TH1 macrophage activation for promastigote killing

Pathogenesis / Course of visceral Leishmaniasis:

Insignificant local lesion
amastigote
Inoculation
killed
unrestained
Well contained
Parasitic dissimination
type
size
virulence
Weeks / months
Healing + local immunity
Death if not treated
No local / visceral lesion
promastigote
Asymptomatic visceral (Scanty liver granuloma)

Role of serum

Recovery
Asymptomatic + Focal lesion + Liver granuloma
Genetics HLA
Symptomatic
Role of CMI
Parasitemia & dissemination
Death
Great lyses in - vitro
Single gene linked to H2
High responders
low responders
Not treated
treated
nutrition
virulence
amount
HIV
pyrexia
emaciation
Secondary infection
Altered tropism parasite+ skim test+ Antigen alteration
Skim test ++ Relapse: rare PKDL 6%


Mechanism of anemia in Kala Azar:
Anaemia
Ineffective erythropoesis
RBC life span
splenomegaly
Antigens (coombs+ve in 30%)
Complement activated on RBCs
immunoconglutinins
TIBC
serum iron
iron absorption
plasma volume


In Symptomatic Cases: Immune exhaustion (compared to African trypanosomiasis) Emaciation Secondary infection Pyrexia (Similar to that of endotoxin) Hepato splenomegaly

Decreased T cells Increased B cells Increase IgG, IgM, (Formal gel test) Immune complex disease Rheumatoid factor positive in 70% Anemia of chronic infection

Pathogenesis / Course of Cutaneous Leishmaniasis

Non healing
Degree of deficiency
Cell recruitment
Tissue damage
Healing
Repair
Solid immunity
recideva
Lymphocyte population
Lympho toxin
Cytotoxic cells
Non ulcerating
ulcerating
104 x 4
inculation
dose
Cutanous lesion
Size of inoculum
Amount of replication
3/52
Macrophage enzymes


Incubation period: inversely proportional to size of inoculumsRural: multiple, parasite + Urban: single, longer IP, parasite +3 – 4 months later leishmanin test +ve

Pathogenesis / Summery Conclusion from clinical studios: Parasite determines the site:

VISCERAL
Asymptomatic
Fatal course
High responders
Low responders
Size of inoculum ?Genetics

Compared to Lepromatus Leprosy

Ineffective response
Diffuse coetaneous
Parasite +++ No ulceration No healing Lymphocytes +
Oriental sore
normal response Wet or dry Depends on Property of the Parasite
Parasites + Lymphocytes ++ Macrophages ++ Ulceration & healing



CHICLEROS ULCER & Espundia
Antigen ulteration
PKDL
Exajurated response
Mucosal Espondia
Exaggerated response
Parasites –Lymphocytes ++Macrophages ++ Ulceration No healing
Compared to tuberculoid Leprosy
Tuberculoid Lesion Parasite + Massive tissue destruction
Uttered tropism Parasites + Skin test +
History: any point in sputum of coetaneous Leishmaniasis

TT Chicleros

BT
BB
BL
LL DCL
+
++
+++
+
++
+++ Bacilli in billions
number
Resistance
Bacilli
Lepromintest Liehmanin test
Similarity in clinical spectrum between leishmaniasis & Leprosy


CLINICAL

Splenomegaly and hepatomegaly are hallmarks of classic visceral leishmaniasis. The spleen is firm and nontender and frequently becomes massively enlarged. Lymphadenopathy Wasting can be pronounced in chronic infection. Hyper pigmentation. Jaundice is occasionally present. Later patients may experience epistaxis, gingival bleeding, and petechiae. Edema and ascites as a result of hypoalbuminemia.


laboratory examination anemia, thrombocytopenia, neutropenia, and Hyper gammaglobulinemia are common. The anemia usually normocytic and normochromic unless complicated by blood loss. The white blood cell count may be as low as 1000/ mL; eosinopenia is common.

Hemophagocytosis observed in bone marrow specimens. ESR and CRP are elevated.

Levels of gamma globulin are markedly increased, at times in the range of 9 to 10 g/dL, as a consequence of polyclonal B-cell activation. Circulating immune complexes, autoantibodies, and rheumatoid factors are present in many patients. Glomerulonephritis may develop, but renal failure is rare. Liver enzyme and bilirubin levels are elevated in some. Hypertriglyceridemia and hypofibrinogenemia have also been reported.

Bone marrow aspirate smear: visceral leishmaniasis

Viscerotropic LeishmaniasisIn the L. tropica–related “viscerotropic” syndrome observed in American military personnel during Operation Desert Storm, symptoms included chronic low-grade fever, malaise, fatigue, and in some instances, diarrhea. The troops did not experience massive splenomegaly or the progressive wasting associated with classic visceral leishmaniasis.

Differential Diagnosis of Leishmaniasis

Cutaneous leishmaniasis Bacterial skin infections Blastomycosis Cutaneous anthrax Eczema Fungal skin infections Leprosy Mycobacterium marinum Myiasis Sarcoidosis Skin cancer Sporotrichosis Syphilis Tuberculosis Yaws

Reasons to Treat Cutaneous Leishmaniasis

Cosmetically unacceptable lesions Chronic lesions Large lesions Lesions in immune suppressed patients Lesions over joints Mucosal disease Multiple lesions Nodular lymphangitis Worsening lesions

Treatment of Cutaneous Leishmaniasis

Pentavalent antimony Meglumine antimoniate (Glucantime) and sodium stibogluconate (Pentostam); cure rate 94 percent; eliminated by kidneys Dosage: 20 mg per kg per day for 20 days Stibogluconate supplied as 100 mg Sb per mL light-sensitive solution Calculated dose (12 to 20 mL for adults) is diluted in 50 mL of 5 percent dextrose in distilled water, infused intravenously over 10 to 15 minutes Amphotericin B (Fungizone) Reserved for antimony failures Dosage: 0.5 to 1.0 mg per kg every other day for up to eight weeks; total dosage is 1.5 to 2 g for the treatment period

Pentamidine isethionate (Pentam 300) Dosage: 2 mg per kg intramuscularly every other day for seven days Toxic effects: damage to pancreas, kidney, or bone marrow may be irreversible May induce diabetes mellitus Others Topical paromomycin is effective with L. major and L. mexicana. It can be combined with antimonials to reduce the number of injections. Oral antifungals have demonstrated conflicting results, although some good results have been achieved with L. mexicana19 and L. major.18 Allopurinol (Zyloprim) incorporates into parasite RNA with lethal effect. Studies are conflicting, and it is not recommended, although there is synergistic activity with antimonials.11-14 Heat15-16 and cryotherapy17 show good results in uncontrolled trials. Excision is not recommended because of the high risk of local relapse and disfiguration.