Blood and Tissue Protozoa
Mark F. Wiser
Department of Tropical Medicine
School of Public Health
Protozoa of Blood and Tissues
Organism Vector
Trypanosoma gambiense Tse-tse fly
and T. rhodesiense
Trypansosma cruzi Triatomine bugs
Leishmania Sand flies
Plasmodium Mosquitoes
Babesia Ticks
Toxoplasma gondii -
Disease Causing Kinetoplastids
• African trypanosomes
• sleeping sickness
Kinetoplast • Trypanosoma cruzi
• Chagas’ disease
• S. and Central America
Nucleus • Leishmania species
• leishmaniasis
• focal distribution worldwide
KT = mitochondrial DNA
Comparison of African Trypanosomes
T. rhodesiense T. gambiense
tse-tse vector Glossina morsitans Glossina palpalis
dry bush or rainforest, riverine,
ecology
woodland lakes
transmission animal-fly-human,
ungulate-fly-human
cycle human-fly-human
non-human
wild animals domestic animals
reservoir
endemic, some
epidemiology sporadic, safaris
epidemics
disease slow (~1 yr) acute
rapid, often fatal
progression chronic
parasitemia high low
asymptomatic
rare common
carriers
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 Late Stage
No CNS involvement CNS involvement
• suramin • melarsoprol
• pentamidine • eflornithine (resurrection
• excellent prognosis 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, Old World Cutaneous,
Mucocutaneous, and Recidivans, and Visceral
Diffuse Leishmaniasis Diffuse Leishmaniasis Leishmaniasis
Mexicana Complex L. tropica L. donovani
L. mexicana (old world)
L. amazonensis L. major
L. infantum*
Braziliensis Complex L. aethiopica (Mediterranea)
L. braziliensis
L. panamensis L. infantum* L. chagasi**
L. guyanensis (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-
• 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
Paroxysm moderate mild to
mild severe
Severity to severe moderate
Average 50,000-
20,000 9,000 6,000
(per mm3) 500,000
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 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%
Possible
Pathophysiology
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
Selected Anti-Malarials
Drug Class Examples
choloroquine (+ other 4-aminoquinolines),
quinine, quinidine, mefloquine, antifolates
Fast-acting blood
(pyrimethamine, proquanil, sulfadoxine,
schizontocide dapsone), artemisinin derivatives
(quinhaosu)
Slow-acting blood
doxycycline (other tetracycline antibiotics)
schizontocide
Blood + mild tissue
proquanil, pyrimethamine, tetracyclines
schizontocide
Anti-relapsing primaquine
Gametocidal primaquine, 4-aminoquinolines (limited?)
Fansidar (pyrimethamine + sulfadoxine),
Combinations 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)