6/12- Protozoans 2: Leishmaniasis, Chaga, African Trypanosomiasis Flashcards
Breakdown of the Phylum Protozoa?
PHYLUM PROTOZOA
Apicomplexa (IC parasites)
Zoomastigophorea (flagellated protozoan)
–Kinetoplastic infxns (tissue protozoan)
Sarcodina (amebas)
Ciliophora (ciliated protozoan)
What are some etiologies of tissue infections?
- Leishamnia spp
- Trypanosoma cruzi
- Trypanososoma brucei/gambiesis
- Others: toxo, malaria…
Etiology of Leishmaniasis?
(organism, vector, tranmission)
Leishmania spp
- > Sandfly -> BITE/vomit -> Human
- > Leishmaniasis
Etiology of Trypanosoma cruzi?
(organism, vector, tranmission)
Trypanosoma cruzi
- > Reduviid gut -> BITE/scartch -> human
- > American Trypanosomiasis
Etiology of Trypanosoma brucei/gambiesis?
(organism, vector, tranmission)
Trypanosoma brucei/gambiesis
- > TseTse fly -> BITE -> Human
- > African Trypanosomiasis
What are the different forms of Leishmaniasis?
- Visceral Leishmaniasis (VL)- aka Kala-azar
(major cause of morbidity/mortality; opportunistic infection in HIV/AIDS)
- Cutaneous Leishmaniasis (CL)
- Mucocutaneous Leishmaniasis
What organs does visceral lesh attack?
- Bone Marrow
- Liver
- Spleen
What is the vector for Leishmaniasis?
What serves as a major reservoir?
Vector: Sandfly
Reservoir: canines
Are the different forms of Leishmaniasis Old or New world?
- Visceral: mostly old
- Cutaneous: ?
- Mucocutaneous: ?
Life cycle of Leishmania
- Sandfly takes blood meal (injects promastigote [flagellated] stage into skin)
- Promastigotes are phagocytized by macrophages
- Promastigotes transform into amastigotes inside macrophages
- Amastigotes multiply in cells (including macrophages) of various tissues; result in nests/granulomas of parasites
- Sandfly takes a blood meal (ingests macrophages infected with amastigotes)
- Ingestion of parasitized cells
- Amastigotes transform into promastigote stage in midgut
- Divide in midgut and migrate to proboscis
What species cause Visceral Leishmaniasis? Where?
- L. donovani (Asia-Africa)
- L. Infantum (Southern Europe)
- L. chagasi (Brazil)
90% of new cases in: India, Bangladesh, Brazil, and Sudan
Often found in jungle-like areas because that’s where the sandflies are
Treatment for Visceral Lesh?
until 1990, limited to pentovalent antimony (sodium stibogluconate), once daily for 28 days (poorly tolerated)
What are some of the problems being encountered with the prevalence/treatment of Visceral Lesh?
- State of Bihar contains 90% of infections; large scale resistance
- Emerging opportunistic infection among AIDS
- Prohibitive costs of lipid formulations of Amphotericin B
Clinical Features of Kala-Azar (“Black Fever”) or Visceral Leshmaniasis?
- Majority of infections are self-resolving
For full-blown Kala-azar:
- Fever
- Weight loss
- Hepatosplenomegaly (spleen becomes very hard due to concentration of amastigote; some vasoconstriction and decreased blood flow); picture shows massive spleen (marker)
- Neutropenia
- Hypergammaglbulinemia
- Hyperpigmentation (“Black Fever”)
What age group is most susceptible to visceral lesh?
Children under 5 yo
What does the temperature curve look like in Leishmaniasis?
- Hyperpigmented, active border
- Kind of a heal-center
- Biopsy on the border (not scarred/healed area)
How is Kala-Azar (Visceral Lesh) diagnosed?
- Fine needle aspiration of spleen (>90% sensitivity; hemorrhagic complications)
- Bone marrow aspiration
- Poor sensitivity and specificity of ELISA
- Intradermal Leishmanin skin test (often injected in girl’s buttocks to prevent contraction of dz, like early vaccine to avoid facial disfigurement)
What is this?
Leishmania on microbiology
- Donovan body! Nidus of infection: macrophage with many amastigotes ready to burst out (top pic)
- Leishamnia in bone marrow (bottom pic)
What is the difference in splenomegaly with visceral lesh vs. something like mono?
In mono, the spleen is soft rather than rock hard like in Visceral Lesh
Case:
- 30 yo man from Ethiopia admitted for fever (103’F), pancytopenia, and hepatosplenomegaly
- CBC: WBC 3.5 Hg 9.7 Plt 98K
- HIV + (AIDS 156 Vload 2.5 million)
- Work-up negative. Started on TB treatment and after 6 wks, started on Atripla
- Returns with fever, WBC 0.5
- Diagnosis?
Leishmaniasis and HIV co-infection
Countries reporting Leishmaniasis/HIV co-infection?
- Mediterranean area
- Ethiopia, Angola
- Brazil, Peru, Colombia
- India
Treatment of Visceral Lesh?
Pentavalent Antimony (SbV)
- Common side effects: nausea, vomiting, abdominal pain, chemical pancreatitis, ECG changes (prolonged QT with risk of arrhythmias)
- Documentation of cure by symptomatic improvement
New, less toxic alternatives:
- Ointments (paromycin + gentamicin)
- Azole (but resistance!)
Using Amphotericin B for Kala Azar (Visceral Lesh)
- Why use?
- What form?
- Different forms have what?
- Single dose regimen?
- Cost?
- Use promoted by Sb resistance in India
- Lipid formulation of AmphoB allows for short course (90% cure with Abelcet over 5d)
- Extensive regional variation of Abelcet vs. Ambisome vs. Amphotec
- Single dose regimen: 90% cure with AmBisome (5-7.5 mg/kg)
- Not cost effective ($700)!
What is Miltefosine?
- Structure
- Form
- Used for
- Cure rate
- Adverse reaactions
- Membrane active phospholipid
- Hexadecylphosphocholine
- Oral medicine
- Originally use as anti-neoplastic
- 95% cure rate (phase 3 studies in Bihar)
- Adverse reactions: Teratogenicity in animals
Case
- 38 yo woman from Cuba comes to the Tropical Medicine clinic due to a non-healing ulcer in her arm
- What is this?
Cutaneous Leishamniasis
- Notice dryness around
- Satellite lesions
Commonly seen in people immigrating in from Cuba as they sleep in rural areas near rivers and avoid healthcare
What are other names of Cutaneous Lesh?
- Baghdad boil
- Delhi boil
- Chiclero’s ulcer
- Uta
- Aleppo Evil
What are causes of Cutaneous Lesh in New world? Old world? Location of each?
New world CL:
- L. mexicana (OK and TX)
- L. amazonensis
- L. Braziliensis
Old world CL:
- L. major (S. Russia, Iran, Middle E, Subsaharan W Africa)
- L. tropica (Middle E, India, Pakistan, Central Asia, W China)
Symptoms of Cutaneous Lesh?
Develops at site where parasites are inoculated
- Wet lesion: pizza-like with raised borders and overlying purulent exudate
- Dry lesion: smaller and covered with crust
Diffuse Cutaneous Leishmaniasis:
- Cutaneous nodules and plaques
- More common in HIV/AIDS
What is this?
Mucocutaneous Leishmania (wet in top picture, dry in bottom)
Treatment of Cutaneous and Mucocutaneous Lesh?
Pentavalent Antimony (SbV)– last resort
- Sodium stibgluconate (Pentosam)
- Meglumin antimonate (Glucantime)
Ketoconazole and Itraconazole
Topical paromomycin
Immunotherapy with BCG
Sbv + IFN-gamma for DCL
Prevention with Leishmaniasis vaccine (in process)
- Proof of concept based on Leishmanization
- Multiple strategies
- Polyprotein by IDRI (Seattle, Washington)
What is Chagas?
American Trypanosomiasis
Highest disease burden of Chagas?
Bug likes to live in cracks in the adobe houses (originated in Brazil; now see in TX, often under bark and at deer leases in deer blinds)
- Bolivia
- Gran Chaco: Lowland Plains
- Argentina
- Bolivia
- Paraguay
- Central America
- Honduras
- El Salvador
- Southern mexico
- Andean
- Amazon
What is the vector for American Trypanosomiasis? Reservoir?
Vector = kissing bug: Triatoma or Rhodnius
Reservoir = canine, now also marsupials and mice
Life Cycle of American Trypanosomiasis?
- Triatomine bug takes a blood meal (passes metacyclic trypomastgotes in feces, trypomastgotes enter bite wound or mucosal membranes like conjunctiva)
- Metacyclic trypomastigotes penetrate various cells at bite wound site. inside cells they transform into amastigotes
- Amastigotes multiply by binary fission in cells of infected tissues
- IC amastigotes transform into trypomastigotes, then burst out of the cell and enter the bloodstream
**Trypomastigotes can infect other cells and transform into IC amastigotes in new infxn sites; clinical manifestations can result from this infective cycle**
- Triatomine bug takes a blood meal (trypomastigotes ingested)
- Epimastigotes in midgut
- Multiply in midgut
- Metacyclic trypomastigotes in hindgut
- Triatomine bug takes a blood meal…
CAN CAUSE CARDIOMEGALY IF GOES TO HEART, OR MEGACOLON IN GUT (?)
Life Cycle of Trypanosoma cruzi (American Tryposomiasis)? Different presentation
- Blood sucking vector bites and defecates on skin after blood meal
- Metacyclic trypomastigote rubbed into wound made by biting vector or into eyes
- Trypomastigotes enter cell by phagocytosis. Reproduces intracellulary as amastigote
- Cell dies releasing amstigotes which infect new cells
- Amastigotes in circulation transform into trypomastigotes. These remain in circulation
- Blood sucking insect ingests amstigotes or trypomatigotes
- Trypomastigotes reproduced in gut of insect (asexual)
- Metacyclic trypomastigotes migrate into rectum of vector
Symptoms of acute Chagas Disease?
- Chagoma: indurated lesion at site of parasite entry
- Romana’s sign when conjunctiva is port of entry
- Malaise, fever, facial, edema
- High parasitemias, lymphocytosis
- Severe myocarditis with ECG changes
What is this?
Romana Sign of Chaga’s Disease
Symptoms of chronic Chaga’s Disease?
Cardiomyopathy (chamber enlargement)
- 10-30% of pts develop this yrs after infxn
- Left ventricular aneurysm
- Conduction deficits; can cause AV blocks or other problems leading to Vtac (one of the most common causes of strokes in S America)
Megacolon and Megaesophagus
How many people move from indeterminate (latent) Chaga’s to active (chronic) disease?
About 1/3
What causes reactivation of Chaga’s?
Depressed cellular immunity
What is this?
Trypanosome amastigotes (Chaga’s parasites) in the heart
So overall, what are the three course of Chaga’s disease?
- Acute
- Chronic
- Reactivation
Diagnosis of Chaga’s Disease: Acute? Chronic?
Acute:
- Mycoarditis in epidemiological setting
- Parasite detection
- Parasite cultivation and xenodaignosis
- T. cruzi IgM
Chronic:
- T. cruzi specific IgG
- Abbott Labs, Gull Labs
- PCR
What is this?
Microbiology of Trypanosoma cruzi (of blood)
Treatment of Chaga’s Disease?
- Antiparasitic drugs limited
- Nifurtimox (parasitologic cures only 50%)
- Benznidazole- treatment of choice due to anti-inflammatory effects and shorter treatment time
- Cardiac: pacemakers, cardiac transplantation (reactivation of acute disease occurs b/c of postoperative immunosuppression)
Characteristics of Benznidazole:
- Treatment course
- Toxicities
- Long treatment: 60 days
- Toxicities: rashes, nausea, kidney and liver failure
Characteristics of Nifurtimox:
- Treatment course
- Toxicities
- Long treatment: 90 days
- Toxicities: rashes, nausea, kidney and liver failure
- Also seizures and other CNS disorders
Strategies for preventing disease?
Vector transmission targets (has worked well in Southern Cone)
- Spray with insecticides
- Education
- Housing improement
- 100% donor screening to prevent TRANSFUSION TRANSMISSION
Have seen decline in number of insects, especially in Brazil where this is implemented
Globalization of Chaga’s Disease (picture)
Chagas disease is in the US Autochthonous transmission Lousiana, Mississippi, Tennessee
What is HAT? Other Names?
HAT = Human African Trypanosomiasis
- Aka “Sleeping Sickness”
(blocked European exploration of Africa)
What subspecies of trypanosomes cause African Tryp?
- Trypanosoma b. gambiense (Gambian HAT); W Africa
- Trypanosoma b. rhodesiense (Rhodesian HAT); E Africa
What is the vector for HAT? Reservoir?
Vector = tsetse fly (Gambien; fly for Rhodesian)
- Likes the colors black and blue!
Reservoir = cattle association (“N’gana” disease in cattle)– only for Rhodesian (no vector for Gambian)
Pattern of illness with HAT?
Two stage illness:
- Early stage: asymptomatic; Trypas found in blood and LNs
- Late stage; CNS involvement and trypas in CSF
Life cycle of tsetse fly?
- Tsetse fly takes a blood meal (injects metacyclic)
- Injected metacyclic trypomastigotes transform into bloodstream trypomastigotes, which are carried to other sites
- Trypomastigotes multiply by binary fission in various body fluids, e.g. blood, lymph, and spinal fluid
- Trypomastigotes in blood 5. Tsetse fly takes a blood meal (bloodstream trypomastigotes are ingested)
- Bloodstream trypomastigotes transform into procyclic trypomastigotes in the tsetse fly’s midgut. Procyclic tryposmatigotes multiply by binary fission
- Procyclic trypomastigotes leave the midgut and transform into epimastigotes
- Epimastigotes multiply in salivary gland. they transform into metacyclic trypomastigotes
No specific site where they cluster! (difference)
Clinical manifestations of HAT?
Gambian HAT (W Africa)
- Winterbottom’s cervical adenopathy
- Asymptomatic months-yrs
- Intermittent fever: antigenic variation (febrile attacks with high parasitemia last days-wk followed by period of relative improvement and low parasitemia)
- Hallmark is chronic and recurrent fever (headache, malaise, anorexia, night sweats) with lymphadenopathy and hepatosplenomegaly
- Weight loss
- CNS involvement: diurnal somnulence, nocturnal insomnia, constant headaches, behavior changes
Rhodesian HAT (E Africa):
- Weeks not months or years
Diagnosis of HAT?
Nonspecific laboratory elevations:
- ESR
- Hypergammaglobulinemia
- Elevated IgM Microsocpy
- LN aspirates
- Blood Anion-exchange centrifugation
Late stage disease: exmaination of CSF sediment
What is this?
Trypanosoma (gambiense/rhodesiense) in blood smear
- S-form, flagellated
Treatment of HAT?
Suramin
- Early stage Rhodesian HAT
Pentamidine
- Early stage Gambian HAT
- Painful injections
- 1% of pts die Melarsoprol
- Arsenical, highly toxic
- Late stage CNS disease
- Eflornithin for Gambian late stage)
Prevention of HAT?
Gambian HAT:
- No zoonotic reservoir
- Case detection and management
Rhodesian HAT:
- Cattle zoonotic reservoir
- Vector control
- Veterinary control
Summary: Leishmania
- Transmission
- Species classification
- Types of disease
- Treatment
Summary: Leishmania
- Transmission: Leishmania spp -> sandfly -> BITE/vomit -> Human -> Leishmaniasis
- Species classification: many species; old and new world
- Types of disease: Visceral, Mucocutaneous, Cutaneous
- Treatment: antimonials
Summary: Trypanosoma cruzi
- Transmission
- Geography
- Treatment
Summary: Trypanosoma cruzi
- Transmission: Trypanosoma cruzi -> Reduviid gut -> BITE/scratch -> Human -> American Trypanosomiasis
- Geography: America
- Treatment: Benznidazole and Nifurtinox are the current drugs of choice
Summary: Trypanosma brucei/rhodesiense
- Transmission
- Geography
- Types of disease
- Treatment
Summary: Trypanosma brucei/rhodesiense
- Transmission: Trypanosma brucei/rhodesiense -> fly -> BITE -> human -> African Trypanosomiasis
- Geography: E Africa
- Types of disease: Acute disease
- Treatment: Suramin, Pentamidine, Berenil
Summary: Trypanosma brucei/gamblesis
- Transmission
- Geography
- Types of disease
- Treatment
Summary: Trypanosma brucei/gamblesis
- Transmission: Trypanosma brucei/bamblesis -> tsetse fly -> BITE -> human -> African Trypanosomiasis
- Geography: W Africa
- Types of disease: Chronic disease (Winterbottom’s sign)
- Treatment: Suramin, Pentamidine, Berenil
