Protozoa 2- Malaria, Leishmaniasis, Babesiosis

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Why is malaria so problematic?

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-Almost 50% of world’s population is at risk for malaria
-In 2010, 225 million people diagnosed with symptomatic disease
-In 2010, malaria killed 1.2 million people
-90% of deaths occur in sub-Saharan Africa
-85% of deaths in children < 5 years of age i.e. most vulnerable population (1 death every 45 sec)
-Most important single infectious killer of children on the planet
-Drug resistance is prevalent nowadays

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Life Cycle and Pathogenesis of Falciparum Malaria:
-∆s b/t falciparum and vivax/ovale, malariae

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-mosquito injects SPOROzoites --> liver 5-15 days
*P. vivax/P. ovale: form dormant form in liver called HYPNOzoites; must treat this formant phase with primoquin*

-sporozoites replicate to MEROzoites & attach to RBCs. 48 hr cycle in the blood *malariae 72 hrs*

-RBCs burst and toxic hemozoin pigment is released. Symptoms ensue.

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Malaria strains: 5

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Genus: Plasmodium
Species: falciparum (worldwide)
vivax (S. America, Asia)
ovale (Africa)
malariae (Africa, S. America, Asia)
knowlesi (primarily primates, Asia)

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What spreads malaria?

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anopheles mosquito

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anopheles mosquito, M & F

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What genetic ∆s determine susceptibliity to vivax malaria?

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-In Africa, people don't have a receptor for P. vivax (Duffy antigen)

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Genes involved in malaria:
4

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Malaria selected for mutations erythrocyte-associated genes:

-sickle cell anemia gene (heterozygous is protective against malaria)
-B-thalassemia gene
-G-6PD gene
-Duffy antigen (receptor for P. vivax)

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Plasmodium falciparum
(malaria)
-dark spots are nuclei

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Different forms of the malaria parasites as they mature/reproduce in the body:

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-sporozoites (injected, swim to liver, multiply into...)
-merozoites (made in liver from sporozoites, swim to RBCs, multiply into...via asexual cycle)
-gametocytes (from asexual cycle)

-hypnozoites (only in vivax/ovale)

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-Sexual form (gametocyte) of falciparum malaria parasite.

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Mild malaria:
-signs/sx

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-severe flu like syndrome
*headache
*myalgia
*bone pain
*abdominal pain, diarrhea
*recurrent chills/fever followed by defervescence (fever breaks).

-anemia/splenomegaly

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-vivax and falciparum follow a "tertian" fever pattern (1st/3rd day)
-malariae follows a "quartan" pattern (1st/4th day)

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Severe malaria syndromes: 9
-deadliest one?
-key point about malariae

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*cerebral malaria falciparum (deadliest)
severe anemia falciparum
placental malaria falciparum
*algid malaria falciparum (bacterial sepsis)
pulmonary/GI malaria falciparum (not common)
blackwater fever falciparum
hypoglycemia falciparum (deadly, quinine can aggravate)
splenic rupture vivax
*nephrotic syndrome malariae* (hypoalbuminemia)

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How does P. falciparum cause disease?

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-Infected red cells have KNOB-LIKE protrusions on their surface.

-Knobs contain parasite proteins which STICK to walls of BLOOD VESSELS.

-Infected red cells stick and clog small blood vessels and capillaries.

-Location of clog dictates type of symptoms.

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-What kind of receptors are being seen here?

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-Ruptured RBC from malaria; knob visible on its surface.
-Lots of receptors on the knobs; most well-described is CD36.

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-Malaria infected blood cells in the brain.
-Note there's not much inflammation.

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Epidemiology of malaria--ages

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-Peak as young kids-- <5 y/o
-disease gets milder at around 10 y/o
~20 y/o --> asymptomatic infections
-you build up immunity over time

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WHO eradication plan:

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-In 1950’s, WHO sponsored a DDT/chloroquine eradication plan

-initially great success

-insects and parasites rapidly became RESISTANT to both interventions

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Chloroquine sensitive REGIONS:

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-Central America (west of Panama Canal)

-Haiti & Dominican Republic

-Middle East
*Chloroquine resistant EVERYWHERE ELSE. Huge issue.

*MULTI-RESISTANT MALARIA IN SOME PLACES

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Goals to Reduce morbidity and mortality from malaria:
limitations? 3

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-Anti-malarials to treat and cure symptomatic cases

-Limitations:
*no vaccine yet
*multi-drug resistance emerging
*distribution & cost of drugs

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Issues with malaria in pregnancy:
-what kind of mothers are effected most?
-what do parasites bind?
-adverse effects?

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-primigravid > secundigravid >>> multigravid

-Parasites bind placental chondroitin sulfate A (CSA) via PfEMP1

-major cause of IUGR (intra-uterine growth retardation), low birth weight, prematurity, perinatal infant mortality and anemia, and mortality in mother

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Diagnosis of malaria:
5

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1) Critical to obtain travel history!

2) Microscopy
blood smears: thick for diagnosis and thin for speciation and quantitation
at least 3 blood tests if smear neg and suspicion high

3) rapid diagnostic tests
e.g. BinaxNOW; Paracheck

4) PCR (research, not rapid)

5) leucopenia, anemia, thrombocytopenia, transaminitis (+liver enzymes), hyperbilirubinemia

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Prevention of malaria:
current: 4
long-term: 3

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-long-acting insecticide-treated bednets
-indoor residual spraying (IRS)
-reduce mosquito breeding sites
-Intermittent preventive therapy in pregnancy

-LONG-TERM SOLUTION: effective vaccine, effective/cheap medications, and diverse control measures

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Which of the plasmodium species causes most serious complications in humans?

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Plasmodium falciparum

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Which statement about Plasmodium falciparum is NOT correct?

A) causes more severe disease in pregnancy
B) is the only malarial parasite causing greater than 20% parasitaemia
C) infection is typically associated with thrombocytopaenia
D) is associated with recurrent relapses after initial treatment because of liver hypnozoites
E) is the only cause of cerebral malaria

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D) is associated with recurrent relapses after initial treatment because of liver hypnozoites

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Leishmaniasis- overview
-kind of bug transmitting it?
-where is it?
-3 forms?

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-parasitic disease transmitted by the bite of infected female sandflies (dusk to dawn)
*>20 species of parasite transmitted by 30 species of sandfly (Phlebotomus and Lutzomyia).

-found in >90 countries worldwide (tropics, subtropics, Middle East and southern Europe)

-3 forms:
*cutaneous: involving the skin at the site of bite (L. tropica, L. major, L. mexicana, L. braziliensis)
0.7-1.2 million new cases/year
*mucocutaneous: involving mucous membranes of the mouth and nose after spread from a nearby cutaneous lesion (L. braziliensis)
*visceral: involving liver, spleen, and bone marrow (L. donovani) 0.2-0.4 million new cases/year (most dangerous)

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5 main countries

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Geographic distribution of visceral Leishmaniasis
*opportunistic infection for HIV, immunocompromised

90% of all visceral leishmaniasis occurs in Bangladesh, India, Nepal, Sudan, and Brazil

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6 main countries

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Geographic distribution of cutaneous Leishmaniasis
90% of cutaneous leishmaniasis occurs in Afghanistan, Iran, Saudi Arabia, Syria, Brazil and Peru

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Where is mucocutaneous leishmaniasis most common? 3

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90% of mucocutaneous leishmaniasis occurs in Bolivia, Brazil and Peru

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Stages of Leishmaniasis:

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L. donovoni amastigotes in spleen
Leishmaniasis

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amastigotes in spleen
Leishmaniasis

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Cutaneous Leishmaniasis:

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-Most common form
-Characterized by one or more sores, papules or nodules on the skin
-Sores can change in size and appearance over time
-Often described as a volcano with a raised edge and central crater
-Sores are usually painless but can become painful if secondarily infected
-Swollen lymph nodes may be present near the sores (under the arm if the sores are on the arm or hand)

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Describe the lesions in Cutaneous Leishmaniasis:

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lesions develop within weeks to months of the sandfly bite

lesions can heal on their own, but this can take months or even years

leave scars and can be disfiguring esp. if on face

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-lesion in Cutaneous Leishmaniasis

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-lesion in Cutaneous Leishmaniasis

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-lesion in Cutaneous Leishmaniasis

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-lesion in Cutaneous Leishmaniasis

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-lesion in Cutaneous Leishmaniasis

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Mucocutaneous Leishmaniasis:
-location/species
-lesions

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-L. braziliensis in Central and South America
-rarely L. tropica in the Middle East

-cutaneous lesion on the face spreads to involve the nose or mouth

-months to years after original skin lesion
-lesions can be very disfiguring

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-lesion in Mucocutaneous Leishmaniasis
"espundia" is local term

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-lesion in Mucocutaneous Leishmaniasis
"espundia" is local term

Front 43

Visceral Leishmaniasis:
AKA?
-prognosis
-course
-lab values

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-Kala-azar: Hindi for “fatal fever/illness”
-most severe form of the disease, may be fatal if left untreated

-spiking fever, weight loss, and an enlarged spleen and liver

-anemia (low RBC), leukopenia (low WBC), and thrombocytopenia (low platelets) are common (=pancytopenia)

-lymphadenopathy may be present

-Opportunistic infection in HIV/AIDS

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Describe symptoms in visceral leishmaniasis:

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-symptoms usually occur months after sandfly bite
- Soldiers from Desert Storm presented up to five months after leaving the Persian Gulf

-because symptoms are non-specific there is usually a delay in diagnosis

-visceral leishmaniasis should be considered in any chronic FEVER patient returning from an endemic area.

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-Splenomegaly in visceral leishmaniasis

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-Splenomegaly in visceral leishmaniasis

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When should you suspect visceral leishmaniasis?

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-Heightened awareness -- think of Leishmania in exposed individuals

-Lesions that do not heal need to be referred for evaluation

-Exposed individuals with fevers, weight loss, gastrointestinal complaints, anemia, abnormal liver tests should be referred for evaluation

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Diagnosis: cutaneous Leishmaniasis:

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-Biopsy is required for diagnosis: Giemsa-stain of tissue smears

-Biopsy specimens can be sent to Walter Reed (WRAIR) for diagnosis -Leishmania Diagnostics Laboratory
- microscopy, culture and PCR
- mail out kits/instructions available

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Diagnosis: visceral Leishmaniasis:
-when should you suspect it
-what tests can you run?
-diagnosis requires?

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-Must be considered if diagnosis is to be made

-Presentation is usually very non-specific and should be considered in febrile patients with exposure

-Antibodies to Leishmania (Kalazar Detect™) may be present in patient’s serum but this will not distinguish between past or current infection and cross-react with Trypanosomiasis

-Diagnosis requires finding Leishmania on biopsy of bone marrow, liver, enlarged lymph node, or spleen (macrophages contain amastigotes)

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Treatment: cutaneous and mucocutaneous leishmaniasis:

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-Miltefosine for both cutaneous and visceral disease

-Antimony (Pentostam®, Sodium stibogluconate) is former drug of choice
*20 days of intravenous therapy (long, $$)

-Fluconazole may decrease healing time in L. major infection
*Biopsy and culture to determine species is required
*6 weeks of therapy is needed

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Treatment: visceral leishmaniasis:

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-Liposomal amphotericin-B (AmBisome®) is the drug of choice
*IV 3 mg/kg per day on days 1-5, day 14 and day 21

-Pentostam® (sodium stibogluconate) is an alternative therapy
*28 days of therapy is required

-Oral miltefosine
*99% cure rate at 6 months

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Prevention of leishmaniasis:

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-control the reservoir: rodents
-control the vector: sandfly
-indoor residual spraying with insecticide
-prevent sandfly bites: personal protective measures
*most important at night
*cover skin with clothes
*insect repellent with DEET
*permethrin treated bed nets

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Sandfly causing leishmaniasis

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Babesiosis:

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-Quite similar to malaria
-Transmitted by ticks

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-Ixodes ticks
-NE, midwest, and Pacific NW U.S.
-transmits babesiosis, Lyme (borrellia) , and olichia (anaplasma)

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Life cycle of Babesia:

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-sporozoites
-merozoites
-has a stage in mouse that completes the cycle

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-what is this?
-how do you diagnose this?

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-Babesiosis stages
-Diagnose w/ thick smear (look for Maltese cross-in C)
-Use thin smear, stain it to quantify parisitemia

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-How is babesiosis like malaria? 5
-risk factors for death from it?
-treatment? 2/2

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-mimics mild malaria: fever, hepatosplenomegaly, hemolytic anemia, thrombocytopenia, jaundice

-ASPLENIA and immunosuppression are main risk factors for death

-Rx: clindamycin/quinine or atovaquone/azithromycin (more recent) *these are malaria meds*