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Blood and Tissue Protozoa Mark F. Wiser Department of Tropical Medicine School of Public Health


Protozoa of Blood and Tissues Organism

Vector

Trypanosoma gambiense and T. rhodesiense

Tse-tse fly

Trypansosma cruzi

Triatomine bugs

Leishmania

Sand flies

Plasmodium

Mosquitoes

Babesia

Ticks

Toxoplasma gondii

-


Disease Causing Kinetoplastids • African trypanosomes

Kinetoplast

• sleeping sickness

• Trypanosoma cruzi • Chagas’ disease • S. and Central America

Nucleus

KT = mitochondrial DNA

• Leishmania species • leishmaniasis • focal distribution worldwide


Comparison of African Trypanosomes tse-tse vector ecology

T. rhodesiense

T. gambiense

Glossina morsitans dry bush or woodland

Glossina palpalis rainforest, riverine, lakes animal-fly-human, human-fly-human

transmission cycle

ungulate-fly-human

non-human reservoir

wild animals

epidemiology disease progression parasitemia asymptomatic carriers

domestic animals

high

endemic, some epidemics slow (~1 yr) acute → chronic low

rare

common

sporadic, safaris rapid, often fatal


Disease Course and Symptoms • invasion of blood characterized by irregular fever and headache (acute stage) • T. gambiense can be self-limiting or progressing to a more serious disease (chronic) • includes invasion of lymphatics and CNS

• parasites crossing blood-brain barrier result in CNS involvement and nervous impairment • • • •

described as meningoencephalitis increased apathy and fatigue confusion and somnolence motor changes including tics, slurred speech, incoordination • convulsions, coma, death


Diagnosis and Treatment Clinical Features • travel or residence in endemic area • irregular fever and enlarged lymph nodes • behavioral changes/mental symptoms

Laboratory Diagnosis • serological tests • demonstration of trypanosomes in blood, lymph node aspirates, cerebral spinal fluid

Early Stage No CNS involvement • suramin • pentamidine • excellent prognosis

Late Stage CNS involvement • melarsoprol • eflornithine (resurrection drug)


Trypanosoma cruzi and Chagas Disease • Transmitted by triatomine bugs • Inefficient transmission (parasite in feces of bug) • Associated with infestation of houses with triatomines (rural poverty) • Urban transmission associated with blood transfusions • Leading cause of cardiac disease in S. and central America


Clinical Course of Chagas • Acute Phase - active infection (1-4 months) - most are asymptomatic (children most likely to be symptomatic)

• Indeterminate Phase - 10-30 years of latency - seropositive with no detectable parasitemia

• Chronic Phase - 10-30% of infected exhibit cardiomyopathy - arrhythmias and conduction defects - congestive heart failure - thromboembolic phenomenon


Leishmaniasis • focal distribution throughout world, especially tropics and subtropics • new world: southern Texas to northern Argentina • old world: Asia, Africa, middle east, Mediterranean

• transmitted by sand flies • new world: Lutzomyia • old world: Phlebotomus

• parasite replicates within macrophages of vertebrate host • a variety of disease manifestations


Clinical Spectrum of Leishmaniasis Cutaneous Leishmaniasis (CL) most common form, relatively benign self-healing skin lesions (aka, localized or simple CL)

Mucocutaneous Leishmaniasis (MCL) simple skin lesions that metastasize to mucosae (especially nose and mouth region)

Visceral Leishmaniasis (VL) generalized infection of the reticuloendothelial system, high mortality


Some Leishmania Species Infecting Humans New World Cutaneous, Mucocutaneous, and Diffuse Leishmaniasis Mexicana Complex L. mexicana L. amazonensis Braziliensis Complex L. braziliensis L. panamensis L. guyanensis

Old World Cutaneous, Recidivans, and Diffuse Leishmaniasis L. tropica

Visceral Leishmaniasis L. donovani (old world)

L. major L. aethiopica L. infantum*

L. infantum* (Mediterranea) L. chagasi** (Americas)

*Both dermotrophic and viscerotrophic strains exist. **L. chagasi (Americas) may be the same as L. infantum (Mediteranean)


Diagnosis • geographical presence of parasite • demonstration of parasite in skin lesion or bone marrow • delayed hypersensitivity skin test (cutaneous forms) • serological tests (visceral disease)

Treatment • pentavalent antimonials • amphotericin B (less toxic, expensive) • miltefosine (phase IV, no hospitalization)


MALARIA • causative agent = Plasmodium species • 4 human Plasmodium species

• 40% of the world’s population lives in endemic areas • primarily tropical and sub-tropical

• 3-500 million clinical cases per year • 1.5-2.7 million deaths (90% Africa) • increasing problem (re-emerging disease) • resurgence in some areas P. falciparum • drug resistance (↑ mortality) P. vivax P. ovale P. malariae


Life Cycle • transmitted by Anopheles mosquitoes • sporozoites injected with saliva • sporozoites invade liver cells • undergo an asexual replication • 1000-10,000 merozoites produced • hypnozoites and relapses in Pv and Po


Life Cycle • merozoites invade RBCs • repeated rounds of asexual replication • 6-30 merozoites formed


Life Cycle • some merozoites produce gametocytes • gametocytes infective for mosquito • fusion of gametes in gut • sporogony on outside of gut wall • asexual replication • sporozoites invade salivary glands


Clinical Features • due to the blood stage of the infection • no symptoms during liver stage (~ incubation period)

• characterized by acute febrile attacks (malaria paroxysms) • periodic episodes of fever alternating with symptom-free periods

• manifestations and severity depend on species and host status • • • •

acquired immunity general health nutritional state genetics


Malaria Paroxysm • paroxysms associated with synchrony of merozoite release • 48 or 72 hr cycles • release of antigens, etc ∀↑ TNF-α • temperature is normal and patient feels well between paroxysms • falciparum may not exhibit classic paroxysms • continuous fever • paroxysms become less severe and irregular as infection progresses


Disease Severity Pv

Po

Pm

Pf

moderate Paroxysm mild to mild severe Severity moderate to severe Average 50,00020,000 9,000 6,000 500,000 (per mm3) Maximum 50,000 30,000 20,000 2,500,000 (per mm3) Anemia ++ + ++ ++++ Duration Disease 3-8 w 2-3 w 3-24 w 2-3 w Infection 5-8 y* 12-20 m* >20 y 6-17 m Complications renal cerebral** *true relapses (≠ recrudescence) due to dormant hypnozoite stage in liver **plus many other organs


P. falciparum expresses ‘knobs’ on the surface of infected erythrocytes. Knobs mediate cytoadherence to endothelial cells.


Falciparum Complications • sequestration of Pfinfected erythrocytes • immune evasion • primarily in brain, heart, lungs, and gut • leads to complications

• cerebral malaria • consciousness ranges from stupor to coma • convulsions frequently observed • onset can be gradual or sudden • mortality 30-50%


Possible Pathophysiology cytoadherence ↓ cerebral ischemia ↓ hypoxia, metabolic effects, cytokines (eg, TNF-α) ↓ coma ↓ death


Severe falciparum malaria • potentially high parasitemias • sequestration • complex (and not fully understood) host-parasite interactions


Malaria Diagnosis • symptoms: fever, chills, headache, malaise, etc. • history of being in endemic area • splenomegaly and anemia as disease progresses • microscopic demonstration of parasite in blood smear (distinguish species) • thick film: more sensitive • thin film: species identification easier

• repeat smears every 12 hours for 48 hours if negative • antigen detection ‘dipstick’ • ParaSight-F, OptiMal, etc


Selected Anti-Malarials Drug Class

Examples

Fast-acting blood schizontocide

choloroquine (+ other 4-aminoquinolines), quinine, quinidine, mefloquine, antifolates (pyrimethamine, proquanil, sulfadoxine, dapsone), artemisinin derivatives (quinhaosu)

Slow-acting blood schizontocide Blood + mild tissue schizontocide Anti-relapsing Gametocidal Combinations

doxycycline (other tetracycline antibiotics) proquanil, pyrimethamine, tetracyclines primaquine primaquine, 4-aminoquinolines (limited?) Fansidar (pyrimethamine + sulfadoxine), Maloprim (pyrimethamine + dapsone), Malarone (atovaquone + proquanil)


Treatment Strategies chloroquine sensitive (all species) • chloroquine • CQ + primaquine (vivax/ovale) chloroquine resistance (or unknown) • Fansidar, mefloquine, quinine, artemisinin derivatives severe malaria • i.v. infusion of quinine or quinidine (or CQ, if sensitive) • i.v. artemisinin derivatives (if available)


Blood protozoa good