Attack & Defense
Week 8
(Block 2 – Week 8/8)
Clinical Topic: Malaria
Facilitator Introduction:
The case for this week takes place in the eighth and final week of the Attack & Defense module. The
theme for this week is “Mycology and Parasitology”. This is the final week of new content in this
module. The students have their Language of Medicine (anatomy) final written and practical exams
on the afternoon of Friday, December 6, and the Attack & Defense final exam on Friday December 13.
The case for the week involves Jack Newman, a 25-year-old man who is dating Juanita Goldman (the
meningitis case patient from earlier in this module). Mr. Newman presents with the acute
manifestations of severe falciparum malaria. The content of this case will cover presenting signs and
symptoms of malaria and their relationship to the life cycle of the causative organisms, diagnostic
testing, pharmacologic and supportive treatment, and global epidemiology of malaria.
Part I Monday Case Information
Students will see:
Develop a differential diagnosis for a patient presenting with the above symptoms.
Although the signs and symptoms Mr. Newman is presenting with are relatively nonspecific, he has the
notable historical factor of recent travel in Zambia, a country that the CDC Malaria Map Application
(http://www.cdc.gov/malaria/map/) categorizes as “Malaria everywhere”.
Access Medicine’s “Diagnosaurus”: Fever in a Returning Traveler
Typhoid fever
Prodrome of hepatitis A, B, or E
Amebiasis or amebic liver abscess
Rickettsial spotted fever
Visceral leishmaniasis
Acute HIV infection
Acute schistosomiasis
Yellow fever
Scrub typhus
African trypanosomiasis
“The first symptoms of malaria are nonspecific; the lack of a sense of well-being, headache, fatigue,
abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor
viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, arthralgia,
myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, there
is not neck stiffness or photophobia as occurs in meningitis. While myalgia may be prominent, it is not
usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus.
Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which
fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with
P. vivax or P. ovale. The fever is irregular at first (that of falciparum malaria may never become regular);
the temperature of nonimmune individuals and children often rises above 40°C in conjunction with
tachycardia and sometimes delirium… Malaria is not associated with a rash like those seen in
meningococcal septicemia, typhus, enteric fever, viral exanthems, and drug reactions. Petechial
hemorrhages in the skin or mucous membranes—features of viral hemorrhagic fevers and leptospirosis—
develop only rarely in severe falciparum malaria.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
2. List the clinical findings of severe falciparum malaria, and describe their relationship to the mechanism
of action of the parasite.
Harrison’s TABLE 210-2 Manifestations of Severe Falciparum Malaria
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
“Ischemia due to poor perfusion causes the manifestations of cerebral malaria”
Kumar , Vinay. Robbins and Cotran Pathologic Basis of Disease, 8th Edition. W.B. Saunders Company, 062009. <vbk:978-1-4160-31215#outline(>.
“P. falciparum assembles cytoadherence proteins (PfEMP1s, encoded by a highly variable family of var
genes) into structures called knobs that are presented on the erythrocyte surface. Knobs allow the P.
falciparum-parasitized erythrocyte to bind to postcapillary vascular endothelium, so as to avoid spleenmediated clearance and allow the parasite to grow in a low oxygen, high carbon dioxide
microenvironment. For the patient, the consequences are microvascular blockage in the brain and organ
beds, and local release of cytokines and direct vascular intermediates such as nitric oxide. These lead to
severe complications such as cerebral malaria, pulmonary edema, acute renal failure, and placental
Brunton. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 12th Edition. McGraw-Hill Higher Education.
“Hypoglycemia in malaria results from a failure of hepatic gluconeogenesis and an increase in the
consumption of glucose by both host and, to a much lesser extent, the malaria parasites. To compound
the situation, quinine (and quinidine), which is still widely used for the treatment of both severe and
uncomplicated falciparum malaria, is a powerful stimulant of pancreatic insulin secretion… Acidosis, an
important cause of death from severe malaria, results from accumulation of organic acids…
Hyperlactatemia commonly coexists with hypoglycemia… Other still-unidentified organic acids are major
contributors to acidosis… Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues
where sequestered parasites interfere with microcirculatory flow, hypovolemia, lactate production by the
parasites, and a failure of hepatic and renal lactate clearance… The pathogenesis of renal failure is unclear
but may be related to erythrocyte sequestration and agglutination interfering with renal microcirculatory
flow and metabolism… Anemia results from accelerated RBC removal by the spleen, obligatory RBC
destruction at parasite schizogony, and ineffective erythropoiesis.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
Jawetz Microbiology Fig 46-9: Life Cycle of Malaria Parasites
3. Identify the appropriate diagnostic test for malaria and recognize common laboratory findings.
“The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained
peripheral-blood smears… Both thin and thick blood smears should be examined. The thin blood
smear should be rapidly air-dried, fixed in anhydrous methanol, and stained; the RBCs in the tail of
the film should then be examined under oil immersion (×1000 magnification). The level of
parasitemia is expressed as the number of parasitized erythrocytes per 1000 RBCs. The thick blood
film should be of uneven thickness. The smear should be dried thoroughly and stained without fixing.
As many layers of erythrocytes overlie one another and are lysed during the staining procedure, the
thick film has the advantage of concentrating the parasites (by 40- to 100-fold compared with a thin
blood film) and thus increasing diagnostic sensitivity.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
“Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it
may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia,
with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte
sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins
are high. The platelet count is usually reduced to ∼105/µL. Severe infections may be accompanied by
prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia.
Levels of antithrombin III are reduced even in mild infection. In uncomplicated malaria, plasma
concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal. Findings
in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium,
bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine,
urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin… Urinalysis generally
gives normal results. In adults and children with cerebral malaria, the mean opening pressure at
lumbar puncture is ∼160 mm of cerebrospinal fluid (CSF); usually the CSF is normal or has a slightly
elevated total protein level [<1.0 g/L (<100 mg/dL)] and cell count (<20/µL).”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
Part I Formative Assessment
Four multiple-choice questions pertaining to the case details and learning objectives.
Part II Wednesday Case Continuation
Students will see:
1. Differentiate between the treatment of falciparum and non-falciparum malaria.
“Despite increasing evidence of chloroquine resistance in P. vivax (from parts of Indonesia, Oceania,
eastern and southern Asia, and Central and South America), chloroquine remains the treatment of
choice for the non-falciparum malarias (P. vivax, P. ovale, P. malariae, P. knowlesi) except in
Indonesia and Papua New Guinea, where high levels of resistance in P. vivax are prevalent.
The treatment of falciparum malaria has changed radically in recent years. In all endemic areas, the
World Health Organization (WHO) now recommends artemisinin-based combinations as first-line
treatment for uncomplicated falciparum malaria…
“Infections due to P. vivax, P. knowlesi, P. malariae, and P. ovale should be treated with oral
chloroquine (total dose, 25 mg of base/kg). In much of the tropics, drug-resistant P. falciparum has
been increasing in distribution, frequency, and intensity. It is now accepted that, to prevent
resistance, falciparum malaria should be treated with drug combinations and not with single drugs in
endemic areas... This combination strategy is based on simultaneous use of two or more drugs with
different modes of action. Artemisinin combination treatment (ACT) regimens are now recommended
as first-line treatment for falciparum malaria throughout the malaria-affected world. The artemisinin
component is usually an artemisinin derivative (artesunate, artemether, or dihydroartemisinin) given
for 3 days, and the partner drug is usually a slower-acting antimalarial to which P. falciparum is
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
“As a class, the artemisinins are very potent and fast-acting antimalarials, inducing more rapid
parasite clearance and fever resolution than any other currently licensed antimalarial drug. They are
particularly well suited for the treatment of severe P. falciparum malaria and are also effective
against the asexual erythrocytic stages of P. vivax. Increasingly, the standard treatment of malaria
employs artemisinin-based combination therapies (ACTs) to increase treatment efficacy and reduce
selection pressure for the emergence of drug resistance. Artemisinins cause a significant reduction of
the parasite burden, with a four-log10 reduction in the parasite population for each 48-hour cycle of
intraerythrocytic invasion, replication, and egress. As such, only three to four cycles (6–8 days) of
treatment are required to remove all the parasites from the blood (White, 2008).”
Brunton. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 12th Edition. McGraw-Hill Higher Education.
2. Identify the drug of choice for the treatment of severe malaria.
“In large studies conducted in Asia, parenteral artesunate, a water-soluble artemisinin derivative, has
been shown to reduce mortality rates in severe falciparum malaria among adults by 35% from rates
obtained with quinine. Recently, the largest trial ever in severe malaria showed that parenteral
artesunate reduced the mortality rate among African children by 22.5% compared with that obtained
with quinine. Artesunate has, therefore, become the drug of choice for all patients with severe
malaria everywhere.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
3. Understand the basis for the additional agents needed in treating P. vivax and P. ovale malaria.
“Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from
its salivary gland during a blood meal… These microscopic motile forms of the malarial parasite are
carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and
begin a period of asexual reproduction… The swollen infected liver cell eventually bursts, discharging
motile merozoites into the bloodstream. These merozoites then invade the red blood cells (RBCs) and
multiply six- to twentyfold every 48–72 h… In 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 or longer before reproduction begins. These dormant forms, or hypnozoites, are the cause
of the relapses that characterize infection with these two species.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
“To eradicate persistent liver stages and prevent relapse (radical treatment), primaquine (0.5 mg of
base/kg, adult dose) should be given daily for 14 days to patients with P. vivax or P. ovale infections
after laboratory tests for G6PD deficiency have proved negative. If the patient has a mild variant of
G6PD deficiency, primaquine can be given in a dose of 0.75 mg of base/kg (45 mg maximum) once
weekly for 6 weeks.”
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
4. Understand the complications of malaria and their key management principles.
Acute Renal Failure If the level of BUN or creatinine rises despite adequate rehydration, fluid
administration should be restricted to prevent volume overload. As in other forms of hypercatabolic
acute renal failure, renal replacement therapy is best performed early. Hemofiltration and
hemodialysis are more effective than peritoneal dialysis and are associated with lower mortality.
Some patients with renal impairment pass small volumes of urine sufficient to allow control of fluid
balance; these cases can be managed conservatively if other indications for dialysis do not arise.
Renal function usually improves within days, but full recovery may take weeks.
Acute Pulmonary Edema (Acute Respiratory Distress Syndrome) Patients should be positioned with
the head of the bed at a 45° elevation and given oxygen and IV diuretics. Pulmonary artery occlusion
pressures may be normal, indicating increased pulmonary capillary permeability. Positive-pressure
ventilation should be started early if the immediate measures fail.
Hypoglycemia An initial slow injection of 50% dextrose (0.5 g/kg) should be followed by an infusion
of 10% dextrose (0.10 g/kg per hour). The blood glucose level should be checked regularly thereafter
as recurrent hypoglycemia is common, particularly among patients receiving quinine or quinidine. In
severely ill patients, hypoglycemia commonly occurs together with metabolic (lactic) acidosis and
carries a poor prognosis.
Other Complications Patients who develop spontaneous bleeding should be given fresh blood and
IV vitamin K. Convulsions should be treated with IV or rectal benzodiazepines and, if necessary,
respiratory support. Aspiration pneumonia should be suspected in any unconscious patient with
convulsions, particularly with persistent hyperventilation; IV antimicrobial agents and oxygen should
be administered, and pulmonary toilet should be undertaken. Hypoglycemia or gram-negative
septicemia should be suspected when the condition of any patient suddenly deteriorates for no
obvious reason during antimalarial treatment… Antibiotics should be considered for severely ill
patients of any age who are not responding to antimalarial treatment.
Fauci, Anthony. Harrison's Principles of Internal Medicine, 18th Edition. McGraw-Hill Professional Publishing, 07/2011.
--------------------------------------------------------------------------------------------------------------------------------------Part III Friday Activities
Learning Objectives Part III: (for release on Blackboard at noon on Friday December 6, 2013)
Upon completion of this activity, students will be able to:
1. Understand the life cycle of Plasmodium species and how this impacts diagnosis and treatment of
2. Understand how knowledge of global epidemiology affects decisions regarding prophylaxis and
3. Differentiate between different prophylactic regimens for malaria and select a regimen for a
4. Choose an effective treatment regimen for malaria based on infecting Plasmodium species.
Friday Morning Timeline
Facilitators meet in LIB 2.010, then released to prepare rooms
Activity 1: Plasmodium Life Cycle
Activity 2: Epidemiology of Malaria Affects Treatment
Activity 3: Selecting a Treatment Regimen for Malaria
Activity 4: Malaria Prophylaxis
Activity 1: Plasmodium Life Cycle (0900-0915)
Instruct the students as follows: “Find a resource that will help you answer this question.”
Display the following from the slide set:
“Match the following stages of the Plasmodium life cycle with the locations where they occur:
1. Merozoite  Trophozoite  Gametocyte OR Schizont  Merozoite
2. Sporozoite  Schizont  Merozoite
3. Gametocyte  Sporozoite
a. Mosquito gut
b. Human erythrocyte/blood
c. Human liver”
(ANSWERS: 1b, 2c, 3a)
Allow the teams to cross-report, and consider using this graphic aid.
Harrison’s Fig 210-1: The Malaria Transmission Cycle (slide set)
Additional questions:
What is the name of the dormant stage that can be seen with P. vivax and P. ovale? Where do
these dormant organisms reside? How does this affect treatment? (Hypnozoites In the liver,
add primaquine to regimen to prevent recurrent disease)
When making a diagnosis by blood smear, which stages can be seen? (Trophozoite,
gametocyte, schizont)
Activity 2: Epidemiology of Malaria Affects Treatment (0915-0945)
Pose the following problem to the teams (slide set):
“Jack’s mother said she had contracted malaria last year while on an ecotour of Panama, but says she
wasn’t as sick as Jack. She asks you if all malaria is the same.
How would you answer her? (Role play opportunity)
What is the likely difference between Jack’s mother’s case of malaria and Jack’s?”
The underlying principle is that you need to know where someone contracted malaria in order to best
treat it. This concept is alluded to in the textbook readings, but the CDC malaria map tool
(http://www.cdc.gov/malaria/map/) gives the detailed information needed to answer these
questions. (Malaria in Panama is overwhelmingly P. vivax that is choroquine-resistant.)
Query the students for places they have traveled or have plans to travel. Is malaria prevalent there?
What types? (These may include Haiti, India, Central American countries) Capture these for use in
Activity 4 as well.
How close to the US does malaria reach? (Mexico, though no reports at US-Mexico border)
--------------------------------------------------------------------------------------------------------------------------------------Activity 3: Selecting a Treatment Regimen for Malaria (0945-1015)
Teams will choose an effective treatment regimen for Jack’s malaria based on his diagnosis of severe
falciparum malaria. You can tell them to assume he weighs 70 kg. (His dose of artesunate at 2.4
mg/kg – this dose is immediately and every 12 hours for a total of at least three doses (i.e. time 0, 12
hours, 24 hours), then daily as needed.)
**How do you get this medication?
You can also go through the exercise of writing all the admission orders, time permitting (level of
care, fluids, serial labs, additional medication, etc).
FILLER QUESTIONS for this activity: 1) What if the infection was due to P. vivax? 2) What if the patient
(not Jack!) was pregnant?
Goodman & Gilman’s Pharmacology Table 49-3: Regimens for the Treatment of Malaria
--------------------------------------------------------------------------------------------------------------------------------------Activity 4: Malaria Prophylaxis (1015-1045)
Display the following from the slide set:
“Mr. Newman’s parents show you a nearly-full prescription bottle of doxycycline that they found in
his luggage after his return.
What medications are used to prevent malaria in people traveling to endemic areas?
(They should come up with: Atovoquone/proguanil, doxycycline, mefloquine, chloroquine
List the advantages and disadvantages of each of these key agents”
Prophylaxis for chloroquineresistant P. falciparum
GI side effects
Once-a-day dosing
Not for pregnant women or
Treatment for 7 days after leaving
endemic area
Prophylaxis for chloroquineresistant P. falciparum
Not for pregnant women or
young children
Once-a-day dosing
Treatment for 4 weeks
after leaving endemic area
GI side effects, Risk of
Prophylaxis for chloroquineresistant P. falciparum
Treatment for 4 weeks
after leaving endemic area
Once-a-week dosing
GI side effects
May exacerbate psychiatric
Once-a-week dosing
Can be used in pregnancy
Treatment for 4 weeks
after leaving endemic area
(Table will be in slide set)
Using this table and the CDC Malaria map tool, pose some prophylaxis problems:
A pregnant woman traveling to the Congo
A 24-year-old man traveling to Haiti.
A woman with a history of severe depression going to stay with her ailing mother in a rural
area of India.
Each of the countries students have traveled to from Activity 2
You can also discuss potential reasons why Jack was not compliant with his prophylaxis (side effects,
needing to take it for so long after return, daily dosing, lack of understanding of its importance)

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