Transcript malaria - SBH Peds Res

5 year old with fever
and vomiting
David H. Rubin, MD
Department of Pediatrics
St. Barnabas Hospital
Professor of Clinical Pediatrics
Albert Einstein College of Medicine
PATIENT PROFILE
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5 year old male with recent visit to Guinea
for 2 months without any prophylaxis for
malaria; home x 1 week
Poor intake
PE:
• Barely responsive
• Dehydrated
• Impressive splenomegaly and tenderness
PATIENT PROFILE

Abdominal ultrasound?
• Deferred
Lab: blood smear showed plasmodium
species 35%, platelets 25,000
 Treatment
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• IV quinine
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Discharged home after 7 days
MALARIA
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Derived from Italian….”mal’aria” meaning
“bad air” – association with marshy areas
1890’s: Charles Laveran, French Army
Surgeon: parasites in blood of patient dying
from malaria
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Dr. Ronald Ross (British Army in India):
mosquitoes transmitted malaria
Dr. Giovanni Grassi: human malaria only
transmitted by Anopheles mosquitoes
MALARIA
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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KING TUT DIED OF MALARIA
(>3,000 YEARS AGO)
MALARIA
(WHO)
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2004: 350-400 million cases worldwide
Endemic in over 90 countries
Over 2 billion people (40% of world’s
population) at risk of contracting disease
1.1-1.3 million deaths/year
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
 Disease
is transmitted through
bite of Anopheles mosquito
 Malaria parasites are single celled
organisms of genus Plasmodium
• Only 4 species can infect humans
• P. Falciparum, P. vivax, P. ovale,
P. malariae
MALARIA
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95% of human infections caused by p. vivax (80%) and
p. falciparum (15%)
• 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
2004 – p. knowlesi causes sporatic human cases in SE
Asia
GLOBAL IMPACT OF MALARIA
(Milner 2008)
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1.1-1.3 million deaths/year are 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 footwear
Future goals: vaccine, improved
treatment of severe disease
INCREASED
INCIDENCE
OF MALARIA
RELATED TO
DESTRUCTION
OF FORESTS
WHAT ABOUT THE
USA?
MALARIA MAP
EASTERN USA 1870
Local Mosquito-Borne Transmission United States, 1957-2005
MALARIAL INFECTION
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Pathophysiology: 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
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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: may be negative early in
illness; interpretation variable
Rapid diagnostic dip tests – expensive and
only falciparum can be diagnosed
TRANSMISSION
(CDC)
“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) “
 The role of an animal reservoir in
malaria transmission is negligible
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MANAGEMENT OVERVIEW
Suspect in any febrile child from any
endemic area
 CBC, platelets may show anemia and
thrombocytopenia
 Constant updates from CDC web site:
“Guidelines for Treatment”
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PEDIATRIC SEVERE
MALARIAL ANEMIA
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What risk factors contribute to severe anemia
(Hg<5 g/dl) seen in children with malaria?
Potential risk factors
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•
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•
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Malaria
Bacteremia
HIV
Hookworm
Vitamin A, B12 deficiency
G6PD deficiency
Anemia results in deformability and uptake of uninfected
erythrocytes by monocytes and macrophages
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
LIFE CYCLE
LIFE CYCLE 1: EXO-ERYTHROCYTIC
STAGE (Human Liver Stage)
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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 (contains anticoagulant
saliva)
• Once in bloodstream, P. falciparum
sporozoites reach the liver, remain for 916 days and undergo asexual replication
LIFE CYCLE 1: EXO-ERYTHROCYTIC
STAGE (Human Liver Stage)
 Each
sporozoite gives rise to
thousands of merozoites, which
invade RBC’s when released
from the liver (8-25 days)
 Ensures protection of parasite
from host immune system
LIFE CYCLE 2: ERYTHROCYTIC
STAGE (Human Blood Stage)
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Trophozoite development
• “Ring” form
• Multiple rounds of nuclear division
• Formation of schizonts released after RBC lysis
to further invade infected RBC’s
•
•
Coincides with increase in temperature
Usually occurs at same time of the day
• Infected RBC’s stimulate TNF and other
cytokines producing clinical presentation
LIFE CYCLE 3: SPORE FORMATION
AND RELEASE (Mosquito Stage)
 Mosquito
takes a blood meal; spore
formation begins
 Small number of merozoites in RBC’s
differentiate to form gametocytes
 Release and transmission of
infection to new hosts through
female Anopheles
MALARIA AND RED
BLOOD CELLS
MALARIA AND RED
BLOOD CELL DEFENSE
 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 DEFENSE
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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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•
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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
•
At risk for overwhelming disease
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
 Vaccine 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
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Chloroquine, mefloquine, doxycycline
do not prevent initial malarial
infections in humans
• Targets are parasites that infect
erythrocytes released from liver
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Worldwide resistance of p. falciparum
to chloroquine
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
 Are children in endemic areas ready
for multiple doses?
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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
•
26% hospitalized
• Malaria: 21%
•
33% of all deaths (N=12)
• Others: Dengue fever, enteric fever,
rickettsioses
APPROACH TO ILL CHILD AFTER
INTERNATIONAL TRAVEL
(Tolle 2010)
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Travel history
• Countries visited, length of stay, onset of
symptoms
• Consider diff diagnosis based on
incubation time and setting risk
•
Febrile child 3 days after return from 1 week
visit to Brazil – more likely dengue fever than
malaria
APPROACH TO ILL CHILD AFTER
INTERNATIONAL TRAVEL
(Tolle 2010)
 Travel
physical examination
• Countries visited, length of stay,
onset of symptoms
• Focus on physical signs associated
with tropical illness
•
Splenomegaly (malaria, typhoid) or
rash (dengue)
APPROACH TO ILL CHILD AFTER
INTERNATIONAL TRAVEL
(Tolle 2010)
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Differential Diagnosis
• Associated with travel
•
Tropical or nonendemic area?
• Not associated with travel
•
Longer symptoms are present the less
likely associated with travel (although p.
vivax can present months after visit to
tropics
APPROACH TO ILL CHILD AFTER
INTERNATIONAL TRAVEL
(Tolle 2010)
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Diagnostic evaluation
• Driven by differential diagnosis
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Thrombocytopenia and hyperbilirubinemia
seen with malaria
Leukopenia with typhoid, dengue
Treatment
• Resolution should be achieved
INCUBATION PERIODS FOR
TROPICS ILNESSES
(Tolle 2010)
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≤14 days
• Dengue, malaria, yellow-fever,
chikungunya, typhoid fever, rickettsial
infections, leptospirosis
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15-30 days
• Malaria, typhoid fever, leptospirosis,
hepatitis A and E (2-6 weeks), viral
leshmaniasis, acute schistosomiasis,
tuberculosis
INCUBATION PERIODS FOR
TROPICS ILNESSES
(Tolle 2010)
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>30 days
•
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Malaria
Hepatitis A and E
Acute schistosomiasis
Visceral leshmaniasis
Tuberculosis
COMMON
PRESENTATIONS -FEVER
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Malaria
Dengue
Typhoid
Rickettsial diseases
Leptospirosis
Workup: CBC, LFTs, UA and culture, blood
culture, peripheral blood smear, serologic
assays for dengue, rickettsiae,
schistosomes, leptospirosis
DENGUE FEVER
Most common diagnosis for travelers
returning to USA from tropics except
Africa
 Usually a short, self limited illness
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• Exception  250,000 cases/year of
hemorrhagic shock
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Most commonly transmitted in urban
areas during the daytime (malaria rural
areas at night)
Dengue Fever mosquito
(Aedes Aegypti)
DENGUE FEVER
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Clinical presentation: rash, leukopenia,
thrombocytopenia
Treatment is supportive; ICU for severe dengue
CHIKUNGUNYA VIRUS
Transmitted by Aedes spp mosquito
 Location overlaps with geographic
location of dengue
 Unique clinical presentation: febrile
arthralgia syndrome
 Severe disease is rare
 Treatment symptomatic
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TYPHOID/PARATYPHOID
FEVER
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Caused by fecal oral transmission of
salmonella typhi, salmonella paratyphi
Fever, abdominal pain, myalgias,
nausea, vomiting, diarrhea
 “Stepladder” fever pattern
 Relative bradycardia, splenomegaly
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TYPHOID/PARATYPHOID
FEVER
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Lab: Normal or reduced WBC, increased
LFTs
Diagnosis by culture – bone marrow
cultures most sensitive (80-95%), blood
most sensitive 1st week of illness (70%),
stool most sensitive as disease progresses
Complications: highest in young children, ill
>14 days
• Most dangerous: GI bleeding, perforation
TYPHOID/PARATYPHOID
FEVER
 Treatment
dependant on where
disease was contracted
• Latin America, Caribbean 
amoxicillin, TMP-SMZ, quinilones
• SE Asia multidrug resistance; use
azithromycin or cefixime
RICKETTSIAL
INFECTIONS
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African Tick Bite Fever (rickettsia
africae)
Prevalent in southern African game
parks
 Primary eschar at tick bite, followed by
flu like illness and generalized rash
 Diagnosis by serology
 Treatment: docycycline
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LEPTOSPIROSIS
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Recreational exposure to water or soil
contaminated with infected animal urine
especially seen after heavy rainfall
Clinical: systemic illness with negative
malaria testing and conjunctival
inflammation
May progress to jaundice, renal failure and
hemorrhage
Treatment: ampicillin or tetracycline; severe
disease: IV ceftriaxone or penicillin G
GASTROINTESTINAL
SYMPTOMS
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Traveler’s diarrhea
• > 2 years usually bacteria (salmonella, shigella)
• < 2 years usually viral (norovirus, rotavirus)
• Persistent (>2 weeks)  protozoal (giardia,
cryptosporidium)
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?History of antibiotic exposure  test
for c. difficile
Stool culture, giardia antigen, hemocult,
stain for fecal leukocytes
GASTROINTESTINAL
SYMPTOMS/Persistent Diarrhea
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Tropical sprue (usually seen after travel to SE
Asia)
• Inflammatory cells in small intestine.
• Low levels of vitamins A, B12, E, D, and K, as well as
albumin, calcium, folate
• Excess fat in feces
• Thickened small bowel folds seen on barium swallow
• Limited to within about 30 degrees north and south of
equator
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Viral hepatitis  febrile jaundice
• Hepatitis A and E
• Both have fecal oral routes of transmission
DERMATOLOGIC
SYMPTOMS
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Cutaneous larval migrans
• Seen after exposure of bare skin to sand
• Subcutaneous movement of larval stage of the
dog hookworm
• Treatment: albendazole, ivermectin

Myiasis
• Fly larva infests the skin, creating a painful boil
• Treatment: petroleum jelly and remove larva
MYIASIS
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
When treating ill child after travel consider
most likely diagnoses based on history and PE
REFERENCES
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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 and
www.cdc.gov/malaria/pdf/treatmenttable.prf
REFERENCES
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Freedman D. Malaria prevention in short term
travelers. N Engl J Med 2008;359:603-12.
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.
Tolle M. Evaluating a sick child after travel to
developing countries. J Am Board Fam Med
2010;23:704-713.