Transcript Malaria 9/24/10 Chairman`s Rounds

11 year old male with fever
and malaise
Chairman’s Rounds
September 24, 2010
David H. Rubin, MD
Department of Pediatrics
St. Barnabas Hospital
Professor of Clinical Pediatrics
Albert Einstein College of Medicine
PATIENT PROFILE
11 year old male with spiking
temperatures to 103F for 3 days,
vomiting, diarrhea, abdominal pain
 Recent 1.5 month visit to Togo (West
Africa)
 Labs  blood smear plasmodium
species 10.8%
 Treatment: quinidine
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MALARIA
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Derived from Italian….”mal’aria” meaning
“bad air” – association with marshy areas
End of 19th century, Charles Laveran, French
Army Surgeon: parasites in blood of patient
dying from malaria
Dr. Ronald Ross; British Army in India:
mosquitoes transmitted malaria
Professor Giovanni Grassi: human malaria
only transmitted by Anopheles mosquitoes
MALARIA
An ancient human disease
 Mentioned as early as 2700 BC in
European and Chinese writings
 European colonists imported malaria
to America (p vivax and p. malariae);
p. falciparum coincided with African
slave trade
 Prevention difficult, no drug
universally effective
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MALARIA
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2004: 350-400 million cases worldwide
Over 2 billion people (40% of world’s
population) at risk of contracting disease
Malaria deaths (1999-2004, WHO data)
estimated at 1.1-1.3 million
Cost (in Africa): $12 billion; 25% of all
deaths of children < 5 years of age
USA and Europe: health measures,
economic development have achieved near
elimination of disease
MALARIA
Transmitted through bite of Anopheles
mosquito (400 species-60 malaria
vectors)
 Malaria parasites are single celled
organisms of genus Plasmodium
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• Only 4 species can infect humans
• P. Falciparum, P. vivax, P. ovale, P.
malariae
GLOBAL BURDEN OF MALARIA
(Milner 2008)
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1.1-1.3 million deaths worldwide; primarily
young children with severe malaria
presenting as coma, severe anemia, or
respiratory distress
Current response: drugs, impregnated
bed nets, indoor spraying, DEET, long
sleeves, pants, and footware
Future goals: vaccine, improved treatment
of severe disease
MALARIA
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P. falciparum – severe potentially fatal
malaria; primary cause of malaria deaths of
young children in Africa
• Infected erythrocytes can obstruct small
vessels causing cerebral malaria
P. vivax – most commonly causes anemia
P. ovale – least common; primarily in West
Africa
COMPLICATIONS FROM
P. falciparum
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Massive hemolysis (Blackwater fever)
Renal failure
Pulmonary edema
Cerebral dysfunction
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 level of consciousness
Behavioral changes
Hallucinations
Seizures
LP is usually NORMAL
Local Mosquito-Borne Transmission United States, 1957-2005
SYMPTOMS OF MALARIAL
INFECTION
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Accumulation and sequestration of parasitic
infected RBC’s in brain, heart, kidney, lung, is
common
Symptoms: as early as 6-8 days after bite or
several months later
Typical attack: chills and tachycardia, high
temperature followed by a profuse diaphoresis
Also may have: cough, respiratory distress, joint
pain, headache, watery diarrhea, vomiting,
seizures
Severe malaria: jaundice, kidney failure,
severe anemia
DIAGNOSIS OF MALARIA
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Clinical observations, case history, and
diagnostic testing
Collect blood when temperature rising (best
yield)
Examine thick/thin smears;
1 parasite/200ųL blood can be detected –
CAUTION: these may be negative early
in illness; interpretation variable
Rapid diagnostic dip tests – expensive and
only falciparum can be diagnosed
TRANSMISSION (CDC)
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In rare cases malaria parasites can be transmitted
from one person to another without requiring
passage through a mosquito (from mother to child
in "congenital malaria", or through transfusion,
organ transplantation or shared needles)
Some species of monkeys and apes can be
experimentally infected with some of the four
"human" malaria parasite species, and in nature
some apes are infected with parasites similar to
those infecting humans. But for all practical
purposes the role of an animal reservoir is
negligible.
MANAGEMENT
Suspect in any febrile child from
endemic area
 CBC, platelets may show anemia and
thrombocytopenia
 See CDC “Guidelines for Treatment”
(www.cdc.gov/malaria/pdf/treatmentta
ble.prf)
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LIFE CYCLE
LIFE CYCLE
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Sporozoite entry into blood stream
(mosquito takes a blood meal)
• Infective sporozoites from salivary gland
of Anopheles mosquito injected into
human host (with anticoagulant saliva)
• Once in bloodstream, P. falciparum
sporozoites reach the liver, remain for 916 days and undergo asexual replication
(exo-erythrocytic schizogony)
LIFE CYCLE
 Each
sporozoite gives rise to
thousands of merozoites, which
invade RBC’s when released from
the liver
 This process takes 8-25 days
 Ensures protection of parasite
from host immune system
ERYTHROCYTIC
SCHIZOGONY
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Trophozoite development
• “Ring” form
• Multiple rounds of nuclear division
• Formation of schizonts, which contains 20
merozoites; released after RBC lysis to further
invade infected RBC’s
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Coincides with increase in temperature
Usually occurs at same time of the day
• Infected RBC’s (after lysis) stimulates TNF and
other cytokines producing clinical presentation
GAMETOCYTE
FORMATION
Small number of merozoites in RBC’s
differentiate to form micro- and
macro-gametocytes (male/female) and
have no other activity
 These gametocytes transmit the
infection to new hosts through female
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Anopheles
MALARIA AND RED
BLOOD CELLS
MALARIA AND THE RED
BLOOD CELL
 Malaria
defenses inherent in RBC’s
– constant creation and
destruction
 RBC defenses have arisen by
natural selection
 Mechanisms not well understood
Cell
Component
Alteration
Global
Distribution
Membrane
Duffy antigen wall
Africa
Hemoglobin
Melanesian
elliptocytosis
Hb S
Africa, Middle East,
India
Africa
Hb C
Africa
Hb E
SE Asia
 Thalassemia
Africa, Medit.,
India, SE Asia
Africa, India
 Thalassemia
RBC Enzymes
G6PD
Africa, Medit.,
India, SE Asia
MALARIA AND THE RED
BLOOD CELL
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Sickle Cell Trait
• Sickle cell trait offspring may have 1
gene for normal Hg and 1 for sickle
Hg transmitted to next generation
• Impairs malaria growth and
development
• Sickle cell trait is the genetic condition
selected for in regions of endemic
malaria
SPECIAL POPULATIONS
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Malaria especially dangerous to
• Pregnant women
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Parasitic infiltration of placenta
Associated with premature delivery,
low birthweight, increased mortality in
newborn
After repeated exposure to malaria,
pregnant women develop immunity
• Young children
MALARIA AND
PREGNANCY
Susceptibility to malaria greatest in 1st
and 2nd pregnancy
 Ability of infected erythrocytes to
accumulate in the maternal vascular
area of the placenta; other stages are
sequestered in the placenta
 Clinical trials now occurring
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CONGENITAL MALARIA
5 cases reported since 2000 (75 since
1950)
 Diagnosis when parasites are seen on
peripheral smear during 1st week of
life
 In the USA, presentation usually with
fever, splenomegaly, hepatomegaly,
irritability, icterus, fever
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TREATMENT
ANTIMALARIAL
MEDICATIONS
Chloroquine, mefloquine, doxycycline
do not prevent initial malarial
infections in humans; they act on
parasites that infect erythrocytes once
released from maturational phase in
the liver
 Currently high worldwide resistance of
p. falciparum to chloroquine
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MALARIA TREATMENT ALGORITHM
Griffith,
K.may
S. apply.
et al.
Copyright
restrictions
JAMA 2007;297:2264-2277.
?SAFETY OF
ANTIMALARIAL DRUGS
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Chloroquine
• Headaches, nausea, vomiting, blurred
vision, pruritis, itching
• Long term use: neuropathy (rare)
• Safe in pregnancy; but low safety margin
• Cardiotoxicity in overdoses a major
problem
• Contraindicated if H/O seizures, renal
disease, hepatic disease
?SAFETY OF
ANTIMALARIAL DRUGS
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Quinine
• Oral prep may cause “cinchonism” –
nausea, vomiting, vertigo, tinnitus,
headache, blurred vision; these are
reversible symptoms
• Increased insulin secretion; causes
severe hypoglycemia in pregnancy in
50% of patients
• May damage auditory nerve
MALARIA VACCINES
Clinical trials now underway using
target antigens at each parasite stage
 Vaccine and field trials extremely
expensive
 Sterile immunity NOT observed in a
large proportion of subjects
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• Are children in endemic areas ready for
multiple doses?
ETIOLOGY OF TRAVEL
RELATED FEVER
(Wilson, 2007)
Geosentinel Surveillance Network –
worldwide multicenter database
 From 3/97-3/06, N=24,920 travelers
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• 28% had fever
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26% hospitalized
• Malaria: 21%
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33% of all deaths (N=12)
• Others: Dengue fever, enteric fever,
rickettsioses
SUMMARY
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Malaria is caused by mosquito transmitted
parasite P. falciparum and is responsible for
deaths in tropical/subtropical regions
Genome of p. falciparum clone 3D7 already
sequenced – will be able to reveal drug
targets
Race is on to develop vaccines/drugs to
interrupt life cycle of parasite
Think of diagnosis with FUO and travel
history – watch for neurologic signs and
symptoms
REFERENCES
Tuteja R. Malaria – an overview. FEBS
Journal. 2007;274:4670-4679.
 Wilson ME, Freedman DO. Etiology of
travel related fever. Curr Opin Infect
Dis 2007;20:449-453.
 Hagmann et al. Congenital malaria.
Ped Emerg Care 2007:23(5):326-329.
 WWW.CDC.GOV
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REFERENCES
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Freedman D. Malaria prevention in short
term travelers. N Engl J Med 2008;359:60312.
Sharma S and Pathak S. Malaria vaccine: a
current perspective. J Vector Borne Dis
2008;45:1-20.
Milner DA et al. Severe malaria in children
and pregnancy: an update and perspective.
Trends in parasitology 2008;24:12:590-595.