Mark F. WiserDepartment of Tropical Medicine

School of Public Health

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

Kinetoplast

Nucleus

•African trypanosomes• sleeping sickness

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

•Leishmania species• leishmaniasis• focal distribution worldwide

KT = mitochondrial DNA

Comparison of African Trypanosomes T. rhodesiense T. gambiense tse-tse vector Glossina morsitans Glossina palpalis

ecology dry bush or woodland

rainforest, riverine, lakes

transmission cycle

ungulate-fly-human animal-fly-human, human-fly-human

non-human reservoir

wild animals domestic animals

epidemiology sporadic, safaris endemic, some epidemics

disease progression

rapid, often fatal slow (~1 yr) acute chronic

parasitemia high low

asymptomatic carriers

rare common

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 TreatmentClinical 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

Late StageCNS involvement• melarsoprol• eflornithine (resurrection

drug)

Early StageNo CNS involvement• suramin• pentamidine• excellent prognosis

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 LeishmaniasisCutaneous 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

Old World Cutaneous, Recidivans, and

Diffuse Leishmaniasis

Visceral

Leishmaniasis

Mexicana Complex L. mexicana L. amazonensis

Braziliensis Complex

L. braziliensis L. panamensis L. guyanensis

L. tropica

L. major

L. aethiopica

L. infantum*

L. donovani (old world)

L. infantum* (Mediterranea)

L. chagasi** (Americas)

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

Diagnosis

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

• geographical presence of parasite• demonstration of parasite in skin

lesion or bone marrow• delayed hypersensitivity skin test

(cutaneous forms)• serological tests (visceral disease)

Treatment

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• drug resistance ( mortality)

P. falciparumP. vivaxP. ovaleP. 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

• paroxysms associated with synchrony of merozoite release• 48 or 72 hr cycles• release of antigens, etc TNF-

• 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

Malaria Paroxysm

Disease Severity Pv Po Pm Pf Paroxysm Severity

moderate to severe

mild mild to

moderate severe

Average (per mm3)

20,000 9,000 6,000 50,000-500,000

Maximum (per mm3)

50,000 30,000 20,000 2,500,000

Anemia ++ + ++ ++++ Duration

Disease Infection

3-8 w 5-8 y*

2-3 w 12-20 m*

3-24 w >20 y

2-3 w 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.

• sequestration of Pf-infected 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%

Falciparum Complications

PossiblePathophysiology

cytoadherence

cerebral ischemia

hypoxia, metabolic effects,

cytokines (eg, TNF-)

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

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

doxycycline (other tetracycline antibiotics)

Blood + mild tissue schizontocide

proquanil, pyrimethamine, tetracyclines

Anti-relapsing primaquine Gametocidal primaquine, 4-aminoquinolines (limited?)

Combinations Fansidar (pyrimethamine + sulfadoxine), Maloprim (pyrimethamine + dapsone), Malarone (atovaquone + proquanil)

Selected Anti-Malarials

Treatment Strategieschloroquine 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)