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Cold Shivers After A Hot Trip
Subsection A-2
USTFMS
General Data
• 33 y/o
• News correspondent
History of Present Illness
• He had a 3 month assignment in Palawan
• Took chloroquine weekly for malaria prophylaxis
•Fever, chills, and headache
 2 weeks
•Treated with sulfadoxine-pyrimethamine (Fansidar)
•2 other companions also experienced similar symptoms
Physical Examination
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Ill-looking but well-nourished male
Temperature – 40˚C
PR 110 bpm
RR 22 breaths per minute
BP 120/60
Pale palpebral conjunctiva
Icteric sclera
Pupils equally reactive to light
JVP is normal
(-) thyromegaly
Heart and Lungs are normal
Traube’s space is obliterated
No skin lesions nor pedal edema
Objective Findings
Positive
• High Fever
• Tachycardia
• Tachypnea
• Icteric Sclera
• Splenomegaly
Negative
• Absence of skin
lesions
If this is malaria, what are the
probable reasons for this patient to
have another episode of malaria?
Relapsing Malaria
• Parasites can remain dormant (inactive or
hibernating) in the liver cells
• Some of these dormant parasites can remain
even after a patient recovers from malaria
• Patient can get sick again
http://www.medicinenet.com/malaria/page2.htm#5whatis
Relapsing Malaria
• P. vivax and P. ovale infections
– a proportion of the intrahepatic forms do not
divide immediately but remain dormant for a
period ranging from 3 weeks to a year before
reproduction begins
• HYPNOZOITES = dormant form
Harrison’s Principle of Internal Medicine, 17th ed.
Malaria Pathogenesis
• Two phases of development: exoerythrocyticand erythrocytic
phase.
– Exoerythrocyticphase involves infection of the liver.
– Erythrocyticphase involves infection of the erythrocytes, or red blood
cells.
• When an infected mosquito pierces a person's skin to take a blood
meal, sporozoites in the mosquito's saliva enter the bloodstream
and migrate to the liver.
• Within 30 minutes the sporozoites infect hepatocytes, multiplying
asexually and asymptomatically for a period of 6–15 days.
• In the liver, these organisms differentiate to yield thousands of
merozoites.
• Following rupture of their host cells they escape into the blood and
infect red blood cells.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Malaria Pathogenesis
• In the RBC’s, parasites multiply again asexually,
periodically breaking out of their hosts to invade fresh
red blood cells.
– Several amplification cycles occur. Waves of fever arise
from simultaneous waves of merozoites escaping and
infecting red blood cells.
• Some P. vivax and P. ovalesporozoites do not
immediately develop into exoerythrocytic-phase
merozoites.
– Produce hypnozoites that remain dormant for periods
ranging from several months to years.
– Reactivation will then occur producing more merozoites.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Malaria Pathogenesis
• Circulating infected blood cells are destroyed in the spleen.
• P. falciparumdisplays adhesive proteins (i.e. PfEMP1) on the
surface of the infected blood cells to overcome this aspect.
– Blood cells stick to the walls of small blood vesselswhich sequester the
parasite from passage through the general circulation and the spleen.
– “Stickiness" is the main factor giving rise to hemorrhagic complications
of malaria.
– High endothelial venulescan be blocked by the attachment of masses
of these infected red blood cells.
– Blockage of these vessels causes symptoms such as in placental and
cerebral malaria.
– Have extreme diversity so not good targets for the immune system.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Malaria Pathogenesis
• Some merozoites turn into male and female
gametocytes.
• When a mosquito pierces the skin of an infected
person, it potentially picks up gametocytes within
the blood.
• Fertilization and sexual recombination of the
parasite occurs in the mosquito's gut
• New sporozoites develop and travel to the
mosquito's salivary gland, completing the cycle.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Malaria Pathogenesis
• There are at least 60 variations of the red blood
cell surface adhesive proteins (called PfEMP1, for
Plasmodium falciparum erythrocyte membrane
protein 1)within a single parasite and effectively
limitless versions within parasite populations.
• The parasite switches between a broad repertoire
of PfEMP1 surface proteins, thus staying one step
ahead of the pursuing immune system.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Complications of Severe
Falciparum Malaria
Cerebral Malaria
• Manifests as diffuse symmetric
encephalopathy
• Focal neurologic signs are unusual
• Passive resistance to head flexion may be
detected and signs of meningeal irritation are
lacking
• The eyes may be divergent and a pout reflex is
common.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Cerebral Malaria
• The corneal reflexes are preserved, except in
deep coma.
• Muscle tone may be either increased or
decreased.
• The tendon reflexes are variable, and the plantar
reflexes may be flexor or extensor
• The abdominal and cremasteric reflexes are
absent.
• Flexor or extensor posturing may be seen.
• Retinal hemorrhages
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Cerebral Malaria
• Convulsions, usually generalized and often
repeated
• Coma is a characteristic and ominous feature
• Neurologic sequelae:
– hemiplegia, cerebral palsy, cortical, blindness,
deafness, and impaired cognition and learning
– Language deficit
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Hypoglycemia
• Due to failure of hepatic gluconeogenesis and an
increase in the consumption of glucose.
• Quinine and quinidine- stimulants of pancreatic
insulin secretion
• In severe disease, the clinical diagnosis of
hypoglycemia is difficult:
– the usual physical signs(sweating, gooseflesh,
tachycardia) are absent
– neurologic impairment caused by hypoglycemia
cannot be distinguished from that caused by malaria.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
ACIDOSIS
Acidosis
• Results from accumulation of organic acids.
– Hyperlactatemia commonly coexists with hypoglycemia.
– Renal impairment compounds the acidosis in adults (rare in children)
– Ketoacidosis in children may also contribute.
• Lactic acidosis is caused by:
– Anaerobic glycolysis in tissues due to sequestered parasites interfering
with microcirculatory flow
– Lactate production by the parasites
– Failure of hepatic and renal lactate clearance.
• Manifestations:
– Acidotic breathing
– Circulatory failure refractory to volume expansion or inotropic drugs.
– Respiratory arrest.
• The prognosis of severe acidosis is poor.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
NON-CARDIOGENIC PULMONARY
EDEMA
Non-Cardiogenic Pulmonary Edema
• The pathogenesis of this variant of the adult
respiratory distress syndrome is unclear.
– Can be aggravated by overly vigorous
administration of IV fluid.
• Noncardiogenic pulmonary edema can also
develop in otherwise uncomplicated vivax
malaria, where recovery is usual.
• The mortality rate is >80%.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
RENAL IMPAIRMENT
Renal Impairment
• Common in adults with severe falciparum malaria, but rare in
children.
• The pathogenesis may be related to erythrocyte sequestration
interfering with renal microcirculatory flow and metabolism.
• Manifests as acute tubular necrosis, although renal cortical necrosis
never develops.
• Acute renal failure may occur simultaneously.
• In survivors, urine flow resumes in a median of 4 days, and serum
creatinine levels return to normal in a mean of 17 days.
• Early dialysis or hemofiltration considerably enhances the likelihood
of a patient’s survival, particularly in acute hypercatabolic renal
failure.
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Hematologic Abnormalities
• Anemia results
– accelerated RBC removal by the spleen
– obligatory RBC destruction at parasite schizogony
– ineffective erythropoiesis
• Infected and uninfected RBCs show reduced
deformability
• Increased splenic clearance of RBCs
• Repeated malarial infections:
– development of severe anemia resulting from both
shortened RBC survival and marked dyserythropoiesis
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Hematologic Abnormalities
• Slight coagulation abnormalities are common,
• Mild thrombocytopenia is usual.
• <5% of malaria patients have significant
bleeding with evidence of DIC.
• Hematemesis may occur
– stress ulceration
– acute gastric erosions
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Liver Dysfunction
• Severe jaundice
– associated with P. falciparum infections
– more common in adults
– results from hemolysis, hepatocyte injury, and
cholestasis
• When accompanied by other vital-organ
dysfunction (often renal impairment), liver
dysfunction carries a poor prognosis.
– Hepatic dysfunction contributes to:
– Hypoglycemia
– lactic acidosis
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Other Complications…
• Septicemia may complicate severe malaria,
particularly in children
• In endemic areas, Salmonella bacteremia has
been associated specifically with P. falciparum
infections
• Chest infections and catheter-induced urinary
tract infections are common among patients
who are unconscious for >3 days
Reference: Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA
Treatment of Complicated
Malaria
• Any patient with complicated or severe falciparum malaria
must be considered as a medical emergency and managed at
the highest possible level of clinical care appropriate.
• All patients with any form of complicated or severe disease
should be treated parenterally.
Quinine
• Quinine is given by slow intravenous infusion but in an
emergency may be given intramuscularly in split doses as has
been done in children.
• Quinine and Quinidine, are potent stimulants of insulin
secretion, glucose should be carefully monitored especially in
pregnant women.
• Once the parasitemia is less than 1% and the patient is able to
take drugs by mouth, treatment may be completed with oral
quinine.
• Complete the treatment with a course of oral Doxycycline, or
in pregnant women and children, Clindamycin to prevent
recrudescent infection which is common after monotherapy.
Artemisinin and its derivatives
• Artemisinin derivatives are increasingly being used in the
treatment of malaria of all degrees of severity.
• Result in more rapid parasite clearance (being active on the
immature parasite forms.
• Safer and simpler to administer.
Recommendations for
Prevention of Malaria
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
MOSQUITO AVOIDANCE MEASURES
• remain in well-screened areas
• Use of mosquito nets (preferably insecticide-treated
nets)
• Using a pyrethroid-containing flying-insect spray in
living and sleeping areas during evening and
nighttime hours
• Wearing clothes that cover most of the body
• Use of effective mosquito repellent
http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter2/malaria.aspx
DEET (N,N-diethylmetatoluamide)
• The most effective repellent against a wide
range of vectors
• DEET formulations
– 50% are recommended for both adults and
children older than 2 months of age
– should be applied to the exposed parts of the skin
• Permethrin-containing product may be
applied to bed nets and clothing for additional
protection.
http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria.aspx
Chemoprophylaxis
• Primary chemoprophylaxis regimens
– taking medicine before travel, during travel, and for a period of time after
leaving the malaria endemic area.
– Beginning the drug before travel allows the antimalarial agent to be in the
blood before the traveler is exposed to malaria parasites.
• Presumptive antirelapse therapy (terminal prophylaxis)
– medication taken towards the end of the exposure period
– generally indicated only for prolonged exposure in malaria-endemic areas
– most malarious areas of the world (except the Caribbean) have at least one
species of relapsing malaria
– Prevent relapses or delayed-onset clinical presentations of malaria caused by
hypnozoites (dormant liver stages)
• P. vivax or P. ovale.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
• Choosing the appropriate chemoprophylactic
agent
– Country of travel
– Significant reports of antimalarial drug resistance
in that location
– medical conditions, medications being taken, cost
of the medicines, potential side effects
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Medications Used for
Chemoprophylaxis
• Atovaquone/Proguanil (Malarone)
• Chloroquine (Aralen) and
Hydroxychloroquine (Plaquenil)
• Doxycycline (Many Brand Names and
Generic)
• Mefloquine
• Primaquine
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Drugs used for Prophylaxis
Drug
Atovaquone/proguanil
(Malarone)
Usage
Prophylaxis in all
areas
Adult Dose
Adult tablets contain 250 mg
atovaquone and 100 mg
proguanil hydrochloride. 1
adult tablet orally, daily
Prophylaxis only in
Chloroquine phosphate areas with
(Aralen and generic)
chloroquinesensitive malaria
300 mg base (500 mg salt)
orally, once/week
Doxycycline (many
brand names and
generic)
100 mg orally, daily
Prophylaxis in all
areas
Pediatric Dose
Pediatric tablets contain
62.5 mg atovaquone and
25 mg proguanil
hydrochloride.
5–8 kg: 1/2 pediatric
tablet daily;
>8–10 kg: 3/4 pediatric
tablet daily;
>10–20 kg: 1 pediatric
tablet daily;
>20–30 kg: 2 pediatric
tablets daily;
>30–40 kg: 3 pediatric
tablets daily;
>40 kg: 1 adult tablet
daily
Comments
Begin 1–2 days before travel to malarious
areas. Take daily at the same time each
day while in the malarious area and for 7
days after leaving such areas.
Contraindicated in persons with severe
renal impairment (creatinine clearance
<30 mL/min). Atovaquone/proguanil
should be taken with food or a milky
drink. Not recommended for prophylaxis
for children <5 kg, pregnant women, and
women breastfeeding infants weighing <5
kg. Partial tablet dosages may need to be
prepared by a pharmacist and dispensed
in individual capsules, as described in the
text.
Begin 1–2 weeks before travel to
5 mg/kg base (8.3 mg/ kg
malarious areas. Take weekly on the same
salt) orally, once/week,
day of the week while in the malarious
up to maximum adult
area and for 4 weeks after leaving such
dose of 300 mg base
areas. May exacerbate psoriasis.
Begin 1–2 days before travel to malarious
areas. Take daily at the same time each
≥8 years of age: 2 mg/ kg
day while in the malarious area and for 4
up to adult dose of 100
weeks after leaving such areas.
mg/day
Contraindicated in children <8 years of
age and pregnant women.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Drugs used for Prophylaxis
An alternative to
5 mg/kg base (6.5 mg/ kg salt) Begin 1–2 weeks before travel to malarious areas.
chloroquine for
310 mg base (400
Hydroxychloroquine
orally, once/week, up to
Take weekly on the same day of the week while in
prophylaxis only in areas mg salt) orally,
sulfate (Plaquenil)
maximum adult dose of 310 mg the malarious area and for 4 weeks after leaving
with chloroquineonce/week
base
such areas.
sensitive malaria
Mefloquine
Begin 1-2 weeks before travel to malarious areas.
Take weekly on the same day of the week while in
≤9 kg: 4.6 mg/kg base (5 mg/kg
the malarious area and for 4 weeks after leaving
salt) orally, once/week;
such areas. Contraindicated in persons allergic to
>9–19 kg: 1/4 tablet
mefloquine or related compounds (e.g., quinine,
Prophylaxis in areas with 228 mg base (250
once/week;
quinidine) and in persons with active depression, a
mefloquine-sensitive
mg salt) orally,
>19–30 kg: 1/2 tablet
recent history of depression, generalized anxiety
malaria
once/week
once/week;
disorder, psychosis, schizophrenia, other major
>31–45 kg: 3/4 tablet
psychiatric disorders, or seizures. Use with caution
once/week;
in persons with psychiatric disturbances or a
≥45 kg: 1 tablet once/ week
previous history of depression. Not recommended
for persons with cardiac conduction abnormalities.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Drugs used for Prophylaxis
Begin 1–2 days before travel to malarious areas. Take
daily at the same time each day while in the malarious
area and for 7 days after leaving such areas.
Primaquine
Prophylaxis for shortduration travel to areas with
principally P.vivax
0.5 mg/kg base (0.8
30 mg base (52.6 mg salt) orally,
mg/kg salt) up to adult
daily
dose orally, daily
Contraindicated in persons with G6PD1 deficiency. Also
contraindicated during pregnancy and lactation unless
the infant being breastfed has a documented normal
G6PD level.
Primaquine
Used for presumptive
antirelapse therapy (terminal
prophylaxis) to decrease the
risk for relapses of P. vivax
and P. ovale
30 mg base (52.6 mg salt) orally,
once/day for 14 days after
departure from the malarious
area.
0.5 mg/kg base (0.8
mg/kg salt) up to adult
dose orally, once/day
for 14 days after
departure from the
malarious area
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Indicated for persons who have had prolonged exposure
to P. vivax and P. ovale or both. Contraindicated in
persons with G6PD1 deficiency. Also contraindicated
during pregnancy and lactation unless the infant being
breastfed has a documented normal G6PD level.
Travel to Areas with Limited Malaria
Transmission
• mosquito avoidance measures only, and no
chemoprophylaxis should be prescribed
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Travel to Areas with Mainly P. vivax
Malaria
• mosquito avoidance measures
• primaquine - primary prophylaxis for travelers
who are not G6PD-deficient
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Travel to Areas with ChloroquineSensitive Malaria
• mosquito avoidance measures
• chemoprophylaxis alternatives:
– chloroquine, atovaquone/proguanil, doxycycline,
mefloquine,
– primaquine for travelers who are not G6PDdeficient
• Longer-term travelers - weekly chloroquine
• shorter-term travelers - atovaquone/proguanil
or primaquine.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Travel to Areas with ChloroquineResistant Malaria
• to mosquito avoidance measures
• chemoprophylaxis limited to
atovaquone/proguanil, doxycycline, and
mefloquine.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Travel to Areas with MefloquineResistant Malaria
• mosquito avoidance measures
• chemoprophylaxis options are reduced to
either atovaquone/proguanil or doxycycline
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Chemoprophylaxis for Infants,
Children, and Adolescents
• All children traveling to malaria-risk areas should take an
antimalarial drug.
• Pediatric dosages should be calculated according to body weight
but should never exceed adult dosage.
• Chloroquine and mefloquine
• Primaquine can be used for children who are not G6PD-deficient
traveling to areas with principally P. vivax.
• Doxycycline may be used for children who are at least 8 years of
age.
• Atovaquone/proguanil may be used for prophylaxis for infants
and children weighing at least 5 kg (11 lbs).
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx
Chemoprophylaxis during Pregnancy
and Breastfeeding
• Malaria can increase the risk for adverse pregnancy outcomes, including
prematurity, abortion, and stillbirth.
• Women who are pregnant or likely to become pregnant should be advised
to avoid travel to areas with malaria transmission if possible.
• If travel to a malarious area cannot be deferred, use of an effective
chemoprophylaxis regimen is essential.
• Chloroquine
– to areas where chloroquine-resistant P. falciparum has not been reported
– has not been found to have any harmful effects on the fetus
– pregnancy is not a contraindication for malaria prophylaxis
• If Chloroquine resistance is present:
– mefloquine is currently the only medication recommended for malaria
chemoprophylaxis during pregnancy.
http://wwwnc.cdc.gov/travel/yellowbook/
2010/chapter-2/malaria.aspx