1727CHAPTER 224 Malaria

A B C

D E F

FIGURE 224-4 Thin blood films of Plasmodium falciparum. A. Young trophozoite. B. Old trophozoite. C. Trophozoites in erythrocytes and pigment in polymorphonuclear cells.

D. Mature schizont. E. Female gametocyte. F. Male gametocyte. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the

World Health Organization.)

A B C

D E

FIGURE 224-5 Thin blood films of Plasmodium vivax. A. Young trophozoite. B. Old trophozoite. C. Mature schizont. D. Female gametocyte. E. Male gametocyte. (Reproduced

from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)

(Figs. 224-4 through 224-9). In general, if the blood smear is negative

when examined by an experienced microscopist, the patient does not

have malaria. If reliable microscopy is not available, a rapid test should

be performed. Malaria is not a clinical diagnosis.

■ DEMONSTRATION OF THE PARASITE

The definitive diagnosis of malaria rests on the demonstration of

asexual forms of the parasite in stained peripheral-blood smears.

Of the Romanowsky stains, Giemsa at pH 7.2 is preferred; Field’s,

Wright’s, or Leishman’s stain can also be used. Staining of parasites

with the fluorescent dye acridine orange allows more rapid diagnosis of

malaria (but not speciation of the infection) in patients with low-level

parasitemia.

Both thin (Figs. 224-4 and 224-5) and thick (Figs. 224-6, 224-7,

224-8, and 224-9) blood smears should be examined. The thin

blood smear should be air-dried, fixed in anhydrous methanol, then

1728 PART 5 Infectious Diseases

A B

FIGURE 224-6 Thick blood films of Plasmodium falciparum. A. Trophozoites.

B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria

Infections, 2nd ed, with the permission of the World Health Organization.)

A B C

FIGURE 224-7 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections,

2nd ed, with the permission of the World Health Organization.)

stained; the RBCs in the tail of the film should then be examined

under oil immersion (×1000 magnification). The density 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. Both parasites and white

blood cells (WBCs) are counted, and the number of parasites per unit

volume is calculated from the total leukocyte count. Alternatively, a

WBC count of 8000/μL is assumed. This figure is converted to the

number of parasitized erythrocytes per microliter. A minimum of 200

WBCs should be counted under oil immersion. Interpretation of blood

smears, particularly thick films, requires some experience because

artifacts are common. Before a thick smear is judged to be negative,

100–200 fields should be examined. In high-transmission areas, the

presence of up to 10,000 parasites/μL of blood may be tolerated without symptoms or signs in partially immune individuals. Thus, in these

areas, the detection of low-density malaria parasitemia is sensitive but

has low specificity in identifying malaria as the cause of illness. Because

the prevalence of asymptomatic parasitemia is often high, low-density

parasitemia is a common incidental finding in other conditions causing

fever.

Rapid, simple, sensitive, and specific antibody-based diagnostic

stick or card tests that detect P. falciparum–specific, histidine-rich

protein 2 (PfHRP2), lactate dehydrogenase, or aldolase antigens in

finger-prick blood samples are now being used widely in control

programs (Table 224-5). Some of these rapid diagnostic tests (RDTs)

carry a second antibody (either pan-malaria or P. vivax–specific) and

so distinguish falciparum malaria from the less dangerous malarias.

PfHRP2-based RDTs may remain positive for several weeks after

acute infection. This prolonged positivity is a disadvantage in hightransmission areas where infections are frequent but helps in the diagnosis of severe malaria in patients who have taken antimalarial drugs

and cleared peripheral parasitemia but who still have a strongly positive PfHRP2 test. A disadvantage of RDTs is that they do not quantify

parasitemia. Widespread use of PfHRP2 RDTs has put strong selection

pressure on P. falciparum populations in some areas, leading to an

increased prevalence of mutant parasites that are not detected by the

current generation of PfHRP2-based tests.

The relationship between parasite density and prognosis is complex and variable; in general, patients with >105

 parasites/μL are at

increased risk of dying, but nonimmune patients may die with much

lower counts, and partially immune persons may tolerate parasitemia

levels many times higher with only minor symptoms. In severe malaria,

a poor prognosis is indicated by a predominance of more mature P.

falciparum parasites (i.e., >20% of parasites with visible pigment) in

the peripheral-blood film or by the presence of phagocytosed malarial

pigment in >5% of neutrophils (an indicator of recent schizogony). In

P. falciparum infections, gametocytemia peaks 1 week after the peak of

asexual parasite densities. Because the mature gametocytes of P. falciparum (unlike those of other plasmodia) are not affected by most antimalarial drugs, their persistence does not mean there is drug resistance

or a need to re-treat if a full course of appropriate treatment has been

given. Phagocytosed malarial pigment seen inside peripheral-blood

monocytes may provide a clue to recent infection if malaria parasites

are not detectable. After parasite clearance, this intraphagocytic malarial pigment is often evident for several days in peripheral-blood films

or for longer in bone marrow aspirates or smears of fluid expressed

after intradermal puncture.

Molecular diagnosis by polymerase chain reaction (PCR) amplification of parasite nucleic acid is more sensitive than microscopy or rapid

diagnostic tests for detecting malaria parasites and defining malarial

species. While currently impractical in the standard clinical setting,

PCR is used in reference centers in endemic areas. In epidemiologic

surveys, ultrasensitive PCR detection has proved very useful in identifying asymptomatic infections as control and eradication programs

drive parasite prevalences down to very low levels. Serologic diagnosis

with either indirect fluorescent antibody or enzyme-linked immunosorbent assays is useful for screening of prospective blood donors

and may prove useful as a measure of transmission intensity in future

epidemiologic studies. Serology has no place in the diagnosis of acute

illness.

■ LABORATORY FINDINGS IN ACUTE MALARIA

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 acute infection.

The platelet count is usually reduced to ~105

/μL. The erythrocyte

sedimentation rate, plasma viscosity, and levels of C-reactive protein

and other acute-phase proteins are elevated. Severe infections may be

accompanied by prolonged prothrombin and partial thromboplastin

times and by more severe thrombocytopenia. Antithrombin III levels

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, phosphate, and albumin, together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated

and unconjugated bilirubin. Hypergammaglobulinemia is usual in

1729CHAPTER 224 Malaria

TABLE 224-5 Standard Methods for the Diagnosis of Malariaa

METHOD PROCEDURE ADVANTAGES DISADVANTAGES

Thick blood filmb Blood should be uneven in thickness but thin enough

that the hands of a watch can be read through part of

the spot. Stain dried, unfixed blood spot with Giemsa,

Field’s, or another Romanowsky stain. Count number of

asexual parasites per 200 WBCs (or per 500 WBC at low

densities). Count and report gametocytes separately.c

Sensitive (0.001% parasitemia); species

specific; inexpensive

Requires experience (artifacts may be

misinterpreted as low-level parasitemia);

underestimates true count

Thin blood filmd Stain fixed smear with Giemsa, Field’s, or another

Romanowsky stain. Count number of RBCs containing

asexual parasites per 1000 RBCs. In severe malaria,

assess stage of parasite development and count

neutrophils containing malaria pigment.e

 Count and

report gametocytes separately.c

Rapid; species specific; inexpensive;

in severe malaria, provides prognostic

informatione

Insensitive (<0.05% parasitemia); uneven

distribution of P. vivax, as enlarged

infected red cells concentrate at leading

edge

PfHRP2 dipstick or

card test

A drop of blood is placed on the stick or card, which

is then immersed in washing solutions. Monoclonal

antibody capture of parasitic antigens reads out as a

colored band.

Robust and relatively inexpensive;

rapid; sensitivity similar to or slightly

lower than that of thick films (~0.001%

parasitemia)

Detects only Plasmodium falciparum;

remains positive for weeks after highdensity infectionsf

; does not quantitate

P. falciparum parasitemia; evasion of

detection by certain strains due to

polymorphisms in HRP2 gene

Plasmodium LDH

dipstick or card test

A drop of blood is placed on the stick or card, which

is then immersed in washing solutions. Monoclonal

antibody capture of parasitic antigens reads out as two

colored bands. One band is genus specific (all malarias),

or P. vivax specific, and the other band is specific for

P. falciparum.

Rapid; sensitivity similar to or slightly

lower than that of thick films for

P. falciparum (~0.001% parasitemia)

May miss low-level parasitemia with

P. vivax, P. ovale, and P. malariae and

may not speciate these organisms; does

not quantitate P. falciparum parasitemia;

lower sensitivity for detection of

P. knowlesi, which may be misidentified as

P. falciparum

Microtube

concentration

methods with

acridine orange

staining

Blood is collected in a specialized tube containing

acridine orange, anticoagulant, and a float. After

centrifugation, which concentrates the parasitized cells

around the float, fluorescence microscopy is performed.

Sensitivity similar or superior to that

of thick films (~0.001% parasitemia);

ideal for processing large numbers of

samples rapidly

Does not speciate or quantitate; requires

fluorescence microscopy

a

Malaria cannot be diagnosed clinically with accuracy, but treatment should be started on clinical grounds if laboratory confirmation is likely to be delayed. In areas of

the world where malaria is endemic and transmission rates are high, low-level asymptomatic parasitemia is common in otherwise healthy people. Thus, malaria may not

be the cause of a fever, although in this context, the presence of >10,000 parasites/μL (~0.2% parasitemia) does indicate that malaria is likely to be the cause. Antibody

and polymerase chain reaction (PCR) tests have no role in the diagnosis of malaria except that PCR is increasingly used for genotyping and speciation in mixed infections

and for detection of low-level parasitemia in asymptomatic residents of endemic areas. b

Asexual parasites/200 WBCs × 40 = parasite count/μL (assumes a WBC count

of 8000/μL). See Figs. 224-6 through 224-9. c

P. falciparum gametocytemia may persist for days or weeks after clearance of asexual parasites. Gametocytemia without

asexual parasitemia does not indicate active infection. d

Parasitized RBCs (/1000) × hematocrit × 125.6 = parasite count/μL. See Figs. 224-4 and 224-5. e

The presence of

>100,000 parasites/μL (~2% parasitemia) is associated with an increased risk of severe malaria, but some patients have severe malaria with lower counts. At any level

of parasitemia, the finding that >50% of parasites are tiny rings (cytoplasm thickness less than half of nucleus width) carries a relatively good prognosis. In a severely ill

patient, the presence of visible pigment in >20% of parasites or of phagocytosed pigment in >5% of polymorphonuclear leukocytes (indicating massive recent schizogony)

carries a worse prognosis. f

Persistence of PfHRP2 is a disadvantage in high-transmission settings, where many asymptomatic people have positive tests, but can be used to

diagnostic advantage in low-transmission settings when a sick patient has previously received unknown treatment (which, in endemic areas, often consists of antimalarial

drugs). In this situation, a positive PfHRP2 test indicates that the illness is falciparum malaria, even if the blood smear is negative.

Abbreviations: LDH, lactate dehydrogenase; PfHRP2, P. falciparum histidine-rich protein 2; RBCs, red blood cells; WBCs, white blood cells.

A B C

FIGURE 224-8 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections,

2nd ed, with the permission of the World Health Organization.)

A B C

FIGURE 224-9 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria

Infections, 2nd ed, with the permission of the World Health Organization.)

1730 PART 5 Infectious Diseases

immune and semi-immune subjects living in malaria-endemic areas.

Urinalysis generally gives normal results. In adults and children with

cerebral malaria, the mean cerebrospinal fluid (CSF) opening pressure

at lumbar puncture is ~160 mm H2

O; usually the CSF content is normal or there is a slight elevation of total protein level (<1.0 g/L [<100

mg/dL]) and cell count (<20/μL).

TREATMENT

Malaria

Patients with severe malaria and those unable to take oral drugs

should receive parenteral antimalarial therapy immediately

(Table 224-6). Antimalarial drug susceptibility testing can be performed but is rarely available, has poor predictive value in an individual case, and yields results too slowly to influence the choice of

treatment. If there is any doubt about the resistance status of the

infecting organism, it should be considered resistant.

The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) as first-line treatment for

uncomplicated P. falciparum malaria in malaria-endemic areas.

ACT is also the recommended first-line treatment for P. knowlesi

infections, and either chloroquine or an ACT is recommended for

the other malarias. The choice of ACT partner drug depends on the

likely sensitivity of the infecting parasites. Artemisinin-based combinations are sometimes unavailable in temperate countries, where

treatment recommendations are limited to the registered available

drugs. 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 an

effective treatment for P. vivax malaria in many areas and for

P. ovale and P. malariae infections everywhere.

Artemisinin resistance in P. falciparum has emerged in Southeast

Asia over the past decade and has been followed by piperaquine and

mefloquine resistance. ACTs are failing in Cambodia, Vietnam, and

the border regions of Thailand. Significant artemisinin resistance is

TABLE 224-6 Regimens for the Treatment of Malariaa

TYPE OF DISEASE OR TREATMENT REGIMEN(S)

Uncomplicated Malaria

Known chloroquine-sensitive strains of

Plasmodium vivax, P. malariae, P. ovale,

P. falciparumb

Chloroquine (10 mg of base/kg stat followed by 5 mg/kg at 12, 24, and 36 h or by 10 mg/kg at 24 h and 5 mg/kg at 48 h)

or

Amodiaquine (10–12 mg of base/kg qd for 3 days)

Radical treatment for P. vivax or P.

ovale infection (prevention of relapse)

In addition to chloroquine or amodiaquine or ACT, primaquine (0.5 mg of base/kg qd in Southeast Asia and Oceania [total

dose 7 mg/kg] and 0.25 mg/kg elsewhere [total dose 3.5 mg/kg]) should be given for 14 days to prevent relapse.c

 In mild G6PD

deficiency, 0.75 mg of base/kg should be given once weekly for 8 weeks. Primaquine should not be given in severe G6PD

deficiency.

P. falciparum malariac Artesunated,e (4 mg/kg qd for 3 days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single dose

or

Artesunated

 (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)d,e

or

Artemether-lumefantrined

 (1.5/9 mg/kg bid for 3 days with food)

or

Artesunated

 (4 mg/kg qd for 3 days) plus mefloquine (24–25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2

and then 10 mg/kg on day 3)f

or

DHA-piperaquined

 (target dose: 4/24 mg/kg qd for 3 days in children weighing <25 kg and 4/18 mg/kg qd for 3 days in persons

weighing ≥25 kg)

or

Artesunate-pyronaridined

 (4/12 mg/kg qd for 3 days)

Second-line treatment/treatment of

imported malaria

Artesunatee

 (2 mg/kg qd for 7 days) or quinine (10 mg of salt/kg tid for 7 days) plus 1 of the following 3:

1. Tetracyclinef

 (4 mg/kg qid for 7 days)

2. Doxycyclinef

 (3 mg/kg qd for 7 days)

3. Clindamycin (10 mg/kg bid for 7 days)

or

Atovaquone-proguanil (20/8 mg/kg qd for 3 days with food)

Severe Falciparum Malariag,h

Artesunatee

 (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary; for children weighing <20 kg,

give 3 mg/kg per dose)

or, if unavailable,

Artemethere

 (3.2 mg/kg stat IM followed by 1.6 mg/kg qd)

or, if unavailable,

Quinine dihydrochloride (20 mg of salt/kgi

 infused over 4 h, followed by 10 mg of salt/kg infused over 2–8 h q8hj

)

a

In endemic areas where malaria transmission is low, except in pregnant women and infants, a single dose of primaquine (0.25 mg of base/kg) should be added as a

gametocytocide to all falciparum malaria treatments to prevent transmission. This addition is considered safe, even in G6PD deficiency. b

Very few areas now have

chloroquine-sensitive P. falciparum malaria. c

Recent large studies indicate that these total doses can be condensed into 7-day primaquine regimens. d

In areas where

the partner drug to artesunate is known to be effective. Fixed-dose co-formulated combinations are available. The World Health Organization recommends artemisinin

combination regimens as first-line therapy for falciparum malaria in all tropical countries and advocates use of fixed-dose combinations. e

Artemisinin derivatives are

not readily available in some temperate countries. f

 Tetracycline and doxycycline should not be given to pregnant women or to children <8 years of age. g

Oral treatment

should be substituted as soon as the patient recovers sufficiently to take fluids by mouth. h

Artesunate is the drug of choice when available. The data from large studies in

Southeast Asia showed a 35% lower mortality rate than with quinine, and very large studies in Africa showed a 22.5% reduction in mortality rate compared with quinine. The

doses of artesunate in children weighing <20 kg should be 3 mg/kg. i

A loading dose should not be given if therapeutic doses of quinine have definitely been administered in

the previous 24 h. j

Infusions can be given in 0.9% saline and 5–10% dextrose in water. Infusion rates for quinine should be carefully controlled.

Abbreviations: ACT, artemisinin combination therapy; DHA, dihydroartemisinin; G6PD, glucose-6-phosphate dehydrogenase.

1731CHAPTER 224 Malaria

now prevalent throughout the Greater Mekong subregion and there

is recent clear evidence for the emergence of artemisinin resistance

in East Africa (Rwanda, Uganda). Falsified or substandard antimalarial drugs are sold in many Asian and African countries and may

be the cause of treatment failures. Characteristics of antimalarial

drugs are shown in Table 224-7.

SEVERE MALARIA

In large randomized controlled clinical trials, parenteral artesunate,

a water-soluble artemisinin derivative, has reduced severe falciparum malaria mortality rates by 35% in Asian adults and children

and by 22.5% in African children compared with quinine treatment.

Artesunate therefore is now the drug of choice for all patients with

severe malaria everywhere. Artesunate is given by IV injection but

is also absorbed rapidly following IM injection. Artemether and the

closely related drug artemotil (arteether) are oil-based formulations

given by IM injection; they are erratically absorbed and do not confer the same survival benefit as artesunate. A rectal formulation of

artesunate has been developed as a community-based pre-referral

treatment for patients in the rural tropics who cannot take oral

medications. Pre-referral administration of rectal artesunate has

been shown to decrease mortality rates among severely ill children

without access to immediate parenteral treatment. IV artesunate

has been approved by the U.S. Food and Drug Administration for

emergency use in severe malaria and can be obtained through the

Centers for Disease Control and Prevention (CDC) Drug Service

(see end of chapter for contact information). The antiarrhythmic

quinidine gluconate was used to treat severe malaria in the United

States previously, but manufacturing was discontinued in 2019;

artesunate is much more effective and safer. Although parenteral quinine is steadily being replaced by parenteral artesunate in

endemic areas, it still has a role in the very few cases of artemisinin-resistant severe falciparum malaria from Southeast Asia, where

both artesunate and quinine are given together in full doses.

Severe falciparum malaria constitutes a medical emergency

requiring intensive nursing care and careful management. Frequent

evaluation of the patient’s condition is essential. Adjunctive treatments such as high-dose glucocorticoids, urea, heparin, dextran,

desferrioxamine, antibody to tumor necrosis factor α, high-dose

phenobarbital (20 mg/kg), mannitol, or large-volume fluid or albumin boluses have proved either ineffective or harmful in clinical

trials and should not be used. In acute renal failure or severe metabolic acidosis, hemofiltration or hemodialysis should be started as

early as possible.

In severe malaria, parenteral antimalarial treatment should be

started immediately. Artesunate, given by either IV or IM injection,

is simple to administer, very safe, and rapidly effective. It does not

require dose adjustments in liver dysfunction or renal failure. It

should be used in pregnant women with severe malaria. If artesunate is unavailable and artemether or quinine is used, an initial

loading dose must be given so that therapeutic concentrations are

reached as soon as possible. Quinine causes dangerous hypotension

if injected rapidly and so must be administered carefully by ratecontrolled infusion only. If this approach is not possible, quinine

may be given by deep IM injections into the anterior thigh. The

optimal therapeutic range for quinine in severe malaria is not

known with certainty, but total plasma concentrations of 8–15 mg/L

for quinine are effective and do not cause serious toxicity. The systemic clearance and apparent volume of distribution of quinine are

markedly reduced and plasma protein binding is increased in severe

malaria, so that the blood concentrations attained with a given dose

are higher. If the patient remains seriously ill or in acute renal failure for >2 days, maintenance doses of quinine should be reduced by

30–50% to prevent toxic accumulation of the drug. The initial dose

should never be reduced. Convulsions should be treated promptly

with IV (or rectal) benzodiazepines. The role of prophylactic anticonvulsants in children is uncertain. If respiratory support is not

available, a full loading dose of phenobarbital (20 mg/kg) to prevent

convulsions should not be given as it may cause respiratory arrest.

When the patient is unconscious, the blood glucose level should

be measured every 4–6 h. All patients should receive a continuous infusion of dextrose, and blood concentrations ideally should

be maintained above 4 mmol/L. Hypoglycemia (<2.2 mmol/L or

40 mg/dL) should be treated immediately with bolus glucose. The

parasite count and hematocrit should be measured every 6–12 h.

Anemia develops rapidly. There is uncertainty as to the thresholds

for transfusion as there is some evidence that moderate anemia

may be beneficial in a patient with severe malaria and vital organ

dysfunction. It has been recommended that if the hematocrit falls

to <20%, whole blood (preferably fresh) or packed cells should be

transfused slowly, with careful attention to circulatory status. In

areas with higher malaria transmission, where blood for transfusion

is in short supply, a threshold of 15% is widely used. Renal function

should be checked at least daily. Children presenting with very

severe anemia (hemoglobin <4 g/dL) and acidotic breathing require

immediate blood transfusion. Accurate assessment is vital. Management of fluid balance is difficult in severe malaria, particularly

in adults, because of the thin dividing line between overhydration

(leading to pulmonary edema) and underhydration (contributing

to renal impairment). Fluid balance management is different from

that in sepsis: fluid boluses are potentially dangerous in severe

malaria. Nasogastric feeding should be delayed in nonintubated

patients (for 60 h in adults and 36 h in children) to reduce the risk

of aspiration pneumonia. As soon as the patient can take fluids,

oral therapy should be substituted for parenteral treatment and a

full 3-day course of ACT given. Mefloquine should be avoided as

follow-on treatment for severe malaria because of the increased risk

of post-malaria neurologic syndrome.

In areas of high transmission of both P. falciparum and P. vivax

(the island of New Guinea), severe and potentially life-threatening

anemia is common among children, and both species contribute.

Elsewhere, severe vivax malaria may occur but is uncommon.

Many patients have had comorbidities contributing to vital-organ

dysfunction.

P. knowlesi can cause severe disease associated with high parasite

densities. Acute kidney injury, respiratory distress, and shock have

all been described, but cerebral malaria does not occur. Treatment

for severe vivax and knowlesi malaria should follow the recommendations given for falciparum malaria.

UNCOMPLICATED MALARIA

P. falciparum and P. knowlesi infections should be treated with an

artemisinin-based combination because of their propensity for high

parasite densities and severe disease. Infections with sensitive strains

of P. vivax, P. malariae, and P. ovale should be treated either with an

ACT or oral chloroquine (total dose, 25 mg of base/kg). The ACT

regimens now recommended are safe and effective in adults, children,

and pregnant women. The rapidly eliminated artemisinin component

is usually an artemisinin derivative (artesunate, artemether, or dihydroartemisinin) given for 3 days, and the partner drug is usually a more

slowly eliminated antimalarial to which P. falciparum in the area is

sensitive. Six ACT regimens are currently recommended by the WHO:

artemether-lumefantrine, artesunate-mefloquine, dihydroartemisininpiperaquine, artesunate-sulfadoxine-pyrimethamine, artesunateamodiaquine, and artesunate-pyronaridine. In areas of low malaria

transmission, a single dose of primaquine (0.25 mg/kg) should

be added to ACT as a P. falciparum gametocytocide to reduce the

transmissibility of the infection. This low dose of primaquine is

safe even in G6PD deficiency. Pregnant women should not be given

primaquine. Atovaquone-proguanil is highly effective everywhere,

although it is seldom used in endemic areas because of its high cost

and the propensity for rapid emergence of resistance. Recovery is

slower after atovaquone-proguanil treatment than after ACT. Of

great concern is the spread of artemisinin-resistant P. falciparum in

the Greater Mekong subregion of Southeast Asia. Infections with

these resistant parasites are cleared slowly from the blood, with parasite clearance half-lives over 5 hours and clearance times typically

exceeding 3 days. Cure rates with ACT have fallen to unacceptably

1732 PART 5 Infectious Diseases

TABLE 224-7 Properties of Antimalarial Drugs

DRUG(S)a PHARMACOKINETIC PROPERTIES ANTIMALARIAL ACTIVITY MINOR TOXICITY MAJOR TOXICITY

Quinine Good oral and IM absorption (quinine);

Cl and Vd

 reduced, but plasma

protein binding (principally to α1

acid glycoprotein) increased (90%) in

malaria; quinine t

1/2: 16 h in malaria, 11 h

in healthy persons

Acts mainly on trophozoite blood

stage; kills gametocytes of P. vivax,

P. ovale, and P. malariae (but not

P. falciparum); no action on liver

stages

Common: cinchonism (tinnitus,

high-tone hearing loss, nausea,

vomiting, dysphoria, postural

hypotension); ECG QT interval

prolongation (usually by

<10%). Rare: diarrhea, visual

disturbance, rashes. Note: very

bitter taste

Common: hypoglycemia.

Rare: hypotension, blindness,

deafness, cardiac arrhythmias,

thrombocytopenia, hemolysis,

hemolytic-uremic syndrome,

vasculitis, cholestatic hepatitis,

neuromuscular paralysis.

Chloroquine Good oral absorption, very rapid

IM and SC absorption; complex

pharmacokinetics; enormous Cl and

Vd

 (unaffected by malaria); blood

concentration profile determined by

distribution processes in malaria;

t

1/2: 1–2 months. Active desethyl

metabolite about 25% of parent drug

concentrations

As for quinine, but acts slightly

earlier in asexual cycle

Common: nausea, dysphoria,

pruritus in dark-skinned

patients, postural hypotension,

ECG QT prolongation. Rare:

accommodation difficulties,

keratopathy, hypoglycemia,

rash. Note: bitter taste but

usually well tolerated

Acute: hypotensive shock

(parenteral), cardiac arrhythmias,

neuropsychiatric reactions.

Chronic: retinopathy (cumulative

dose, >100 g), skeletal and

cardiac myopathy

Piperaquine Adequate oral absorption, may

be enhanced by fats; similar

pharmacokinetics to chloroquine; t

1/2:

21–28 days

As for chloroquine; retains activity

against multidrug-resistant

P. falciparum, but resistance has

emerged in Southeast Asia

Occasional epigastric pain,

diarrhea, ECG QT prolongation

None identified

Amodiaquine Good oral absorption; largely

converted to active metabolite

desethylamodiaquine; t

1/2: 4–5 days

As for chloroquine, but more active

against chloroquine-resistant

P. falciparum

Nausea (tastes better than

chloroquine), dysphoria,

headache, bradycardia, ECG QT

prolongation

Agranulocytosis; hepatitis, mainly

with prophylactic use; should not

be used with efavirenz

Primaquine Complete oral absorption; active

metabolite produced mainly via

CYP2D6; t

1/2: 5–7 h

Radical cure; eradicates hepatic

forms of P. vivax and P. ovale;

kills P. falciparum gametocytes

development; kills developing liver

stages of all species

Nausea, vomiting, diarrhea,

abdominal pain, hemolysis,

methemoglobinemia

Serious hemolytic anemia

in severe G6PD deficiency;

hemoglobinuria

Mefloquine Adequate oral absorption; no

parenteral preparation; t

1/2: 14–20 days

(shorter in malaria)

As for quinine Nausea, giddiness, dysphoria,

fuzzy thinking, sleeplessness,

nightmares, sense of

dissociation

Neuropsychiatric reactions,

convulsions, encephalopathy

Lumefantrine Highly variable absorption related to fat

intake; t

1/2: 3–4 days

As for quinine None identified None identified

Artemisinin

and derivatives

(artemether,

artesunate)

Good oral absorption; good

absorption of IM artesunate but

slow and variable absorption of IM

artemether; artesunate and artemether

biotransformed to active metabolite

dihydroartemisinin; all drugs eliminated

very rapidly; t

1/2: <1 h

Broader stage specificity and more

rapid than other drugs; no action on

liver stages; kills all but fully mature

gametocytes of P. falciparum

Reduction in reticulocyte count

(but not anemia); neutropenia

at high doses; in some cases,

delayed anemia after treatment

of severe malaria with

hyperparasitemia

Anaphylaxis, urticaria, fever

Pyrimethamine Good oral absorption, variable IM

absorption; t

1/2: 4 days

For blood stages, acts mainly on

mature forms; causal prophylactic

Well tolerated Megaloblastic anemia,

pancytopenia, pulmonary

infiltration

Proguanilb

(chloroguanide)

Good oral absorption; biotransformed

to active metabolite cycloguanil; t

1/2:

16 h; biotransformation reduced by oral

contraceptive use and in pregnancy

Causal prophylactic; not used alone

for treatment

Well tolerated; mouth ulcers

and rare alopecia

Megaloblastic anemia in renal

failure

Atovaquoneb Highly variable absorption related to fat

intake; t

1/2: 30–70 h

Acts mainly on trophozoite blood

stage

None identified None identified

Tetracycline,

doxycyclinec

Excellent absorption; t

1/2: 8 h for

tetracycline, 18 h for doxycycline

Weak antimalarial activity; should

not be used alone for treatment

Gastrointestinal intolerance,

deposition in growing bones

and teeth (tetracycline),

photosensitivity, moniliasis,

benign intracranial

hypertension

Renal failure in patients

with impaired renal function

(tetracycline)

Pyronaridine Rapid variable absorption, large Vd

; t

1/2:

12–14 days

Acts mainly on trophozoite blood

stage; kills gametocytes of P. vivax,

P. ovale, and P. malariae (but not

P. falciparum); no action on liver

stages

Gastrointestinal intolerance,

anemia, transient elevation

of aminotransferases,

hypoglycemia, headache

None identified

Arterolane t

1/2: 3 h Broad stage specificity; no action

on liver stages; kills all but fully

mature gametocytes of

P. falciparum

Gastrointestinal intolerance,

transient elevation of

aminotransferases

None identified

a

Several antimalarial drugs are formulated as different salts (e.g., phosphate, sulfate, hydrochloride) and are therefore prescribed as base equivalents. For example,

chloroquine phosphate 250 salt contains 155 mg base equivalent. It is very important to check when prescribing that the correct dose is being given. b

Atovaquone and

proguanil are prescribed as a fixed-dose combination. This and proguanil alone should not be given if the estimated glomerular filtration rate is <30 mL/min. c

Tetracycline

and doxycycline should not be given to pregnant women or to children <8 years of age.

Abbreviations: Cl, systemic clearance; ECG, electrocardiogram; G6PD, glucose-6-phosphate dehydrogenase; Vd

, total apparent volume of distribution.

1733CHAPTER 224 Malaria

low levels in some areas. Triple antimalarial combinations are under

evaluation with promising results to date.

The 3-day ACT regimens are all well tolerated, although mefloquine is associated with increased rates of vomiting and dizziness.

As second-line treatments for recrudescence following first-line

therapy, a different ACT regimen may be given; another alternative

is a 7-day course of either artesunate or quinine plus tetracycline,

doxycycline, or clindamycin. Tetracycline and doxycycline are not

recommended to treat pregnant women or children <8 years of age,

however evidence for doxycycline toxicity in these groups is weak.

Oral quinine is extremely bitter and regularly produces cinchonism

comprising tinnitus, high-tone deafness, nausea, vomiting, and

dysphoria. Clinical responses are slower than those following ACT.

Adherence is poor with the required 7-day regimens of quinine.

Patients should be monitored for vomiting for 1 h after the

administration of any oral antimalarial drug. If there is vomiting,

the dose should be repeated. Symptom-based treatment, with acetaminophen (paracetamol) administration, lowers fever and thereby

reduces the patient’s propensity to vomit these drugs. Minor central

nervous system reactions (nausea, dizziness, sleep disturbances)

are common. The incidence of serious adverse neuropsychiatric

reactions to mefloquine treatment is ~1 in 1000 in Asia but may be

as high as 1 in 200 among Africans and white ethnic groups. All the

antimalarial quinolines (chloroquine, amodiaquine, mefloquine,

and quinine) exacerbate the orthostatic hypotension associated

with malaria, and all are tolerated better by children than by adults.

Pregnant women, young children, patients unable to tolerate oral

therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evaluated carefully and hospitalization

considered. If there is any doubt as to the identity of the infecting

malarial species, treatment for falciparum malaria should be given.

A negative blood smear read by an experienced microscopist makes

malaria very unlikely but does not rule it out completely; thick

blood films should be checked again 1 and 2 days later to exclude

the diagnosis. Nonimmune patients receiving treatment for malaria

should have daily parasite counts performed until the thick films

are negative for asexual parasite stages. If the level of parasitemia

does not fall below 25% of the admission value in 72 h or if parasitemia has not cleared by 7 days (and adherence is assured), drug

resistance is likely and the regimen should be changed.

To eradicate persistent liver stages and prevent relapse (radical

treatment), primaquine (0.5 mg of base/kg in East Asia and Oceania

and 0.25 mg/kg elsewhere) should be given once daily for 14 days

to patients with P. vivax or P. ovale infection after laboratory tests

for G6PD deficiency have proved negative. The same total dose

may be given over 7 days. If the patient has a mild variant of G6PD

deficiency, primaquine can be given in a dose of 0.75 mg of base/kg

(maximum, 45 mg) once weekly for 8 weeks. Pregnant women with

vivax or ovale malaria should not be given primaquine but should

receive suppressive prophylaxis with chloroquine (5 mg of base/kg

per week) until delivery, after which radical treatment can be given.

The slowly eliminated 8-aminoquinoline tafenoquine has been registered in some countries. This allows radical cure to be given in a

single dose. The consequent risk of protracted hemolysis in G6PD

deficiency, including in female heterozygotes who may test as normal with current G6PD screens (which detect <30–40% of normal

enzyme activity), requires that all patients should have a quantitative test of G6PD activity before receiving tafenoquine. Only those

with >70% of normal activity should receive the drug. Radical

curative efficacy is lower than with primaquine in Southeast Asia.

MANAGEMENT OF COMPLICATIONS

Acute Renal Failure If plasma levels of BUN or creatinine

rise 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 (Chap. 310). Hemofiltration and hemodialysis are

more effective than peritoneal dialysis and are associated with lower

mortality risk. 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) This syndrome is caused by increased pulmonary

capillary permeability. Patients should be positioned with the head

of the bed at a 45° elevation and should be given oxygen and IV

diuretics. Positive-pressure ventilation should be started early if the

immediate measures fail (Chap. 305). Rarely, patients may require

extracorporeal membrane oxygenation.

Hypoglycemia An initial slow injection of 20% dextrose (2 mL/kg

over 10 min) 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. In severely ill patients,

hypoglycemia commonly occurs together with metabolic (lactic)

acidosis and carries a poor prognosis.

Sepsis Hypoglycemia or gram-negative septicemia should be

suspected when the condition of any patient suddenly deteriorates

for no obvious reason during antimalarial treatment. In malariaendemic areas where a high proportion of children are parasitemic,

it is usually impossible to distinguish severe malaria from bacterial sepsis with confidence. These children should be treated with

both antimalarials and broad-spectrum antibiotics with activity

against nontyphoidal Salmonella species from the outset. Empirical

antibiotics should also be given to adults with >20% parasitemia.

Antibiotics should be considered for severely ill patients of any age

who are not responding to antimalarial treatment or deteriorate

unexpectedly.

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.

GLOBAL CONSIDERATIONS

The goal of global eradication of malaria remains a challenge. Success

will require strong leadership, increased national commitment, and

substantial international support. The two main tools used to control

malaria are insecticide-treated bed nets (ITNs), previously shown to

reduce all-cause mortality in African children by 20%, and the ACTs.

New drugs are in development. One vaccine (the RTS,S/AS01 vaccine) which, in African children, provided 35–40% protection against

falciparum malaria over 4 years of follow-up, has recently been recommended by WHO for widespread roll-out. Challenges to malaria

eradication include the widespread distribution of Anopheles breeding

sites, the enormous number of infected persons, the emergence and

spread of resistance in P. falciparum to ACTs, increasing insecticide

resistance and behavioral changes (to avoid ITN contact) in anopheline

mosquito vectors, and inadequacies in human and material resources,

infrastructure, and control programs. Newer ITNs combine pyrethroids with piperonyl butoxide, which increases mosquito susceptibility to pyrethroids by inhibiting CYP P450. Eliminating vivax malaria is

further hindered by the lack of a simple, safe, radical curative regimen.

MALARIA PREVENTION

Malaria may be contained by judicious use of insecticides to kill

the mosquito vector, rapid diagnosis, patient management, and—

where effective and feasible—administration of intermittent preventive

treatments, seasonal malaria chemoprevention, or chemoprophylaxis to high-risk groups such as pregnant women and young children. Focal elimination of P. falciparum can be accelerated safely

by mass treatment with slowly eliminated antimalarials such as

1734 PART 5 Infectious Diseases

dihydroartemisinin-piperaquine. Despite the enormous investment

in efforts to develop a malaria vaccine, no safe, highly effective, longlasting vaccine is likely to be available for general use in the near future.

The licensed recombinant protein sporozoite-targeted adjuvanted vaccine RTS,S/AS01 was only moderately efficacious in protecting African

children from malaria in field trials, and protection wanes rapidly. The

vaccine is being deployed in Ghana, Kenya, and Malawi as part of a

large-scale pilot project and has just been approved by WHO for general deployment. An irradiated live sporozoite vaccine is in late-stage

development, and research is ongoing to develop a vaccine to protect

against placental malaria (targeting VAR2CSA). While there is great

promise for one or several malaria vaccines on the more distant horizon, prevention and control measures will continue to rely on antivector and drug-use strategies for the foreseeable future.

■ PERSONAL PROTECTION AGAINST MALARIA

Simple measures to reduce the frequency of bites by infected mosquitoes in malarious areas are very important. These measures include the

avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn) and the use of insect repellents containing 10–35%

DEET (or, if DEET is unacceptable, 7% picaridin), suitable clothing,

and ITNs or other insecticide-impregnated materials. Widespread use

of bed nets treated with residual pyrethroids reduces the incidence of

malaria in areas where vectors bite indoors at night.

■ CHEMOPROPHYLAXIS

(Table 224-8; https://wwwnc.cdc.gov/travel/yellowbook/2020/travelrelated-infectious-diseases/malaria) Recommendations for malaria prophylaxis depend on knowledge of local patterns of drug sensitivity in

TABLE 224-8 Drugs Used in the Prophylaxis of Malariaa

DRUG USAGE ADULT DOSE PEDIATRIC DOSE COMMENTS

Atovaquoneproguanil

(Malarone)

Prophylaxis in areas with

chloroquine- or mefloquineresistant Plasmodium

falciparum

1 adult tablet POb 5–8 kg: ½ pediatric tabletc

 daily

≥8–10 kg: ¾ 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

Begin 1–2 days before travel to malarious areas.

Take daily at the same time each day while in the

malarious areas and for 7 days after leaving such

areas. Atovaquone-proguanil is contraindicated in

persons with severe renal impairment (creatinine

clearance rate, <30 mL/min). In the absence of

data, it is not recommended for children weighing

<5 kg, pregnant women, or women breast-feeding

infants weighing <5 kg. Atovaquone-proguanil

should be taken with food or a milky drink.

Chloroquine

phosphate (Aralen

and generic)

Prophylaxis only in the very

few areas with chloroquinesensitive P. falciparumc

 or areas

with P. vivax only

300 mg of base

(500 mg of salt) PO

once weekly

5 mg of base/kg (8.3 mg of salt/kg)

PO once weekly, up to maximum

adult dose of 300 mg of base

Begin 1–2 weeks before travel to malarious areas.

Take weekly on the same day of the week while

in the malarious areas and for 4 weeks after

leaving such areas. Chloroquine may exacerbate

psoriasis.

Doxycycline (many

brand names and

generic)

Prophylaxis in areas with

chloroquine- or mefloquineresistant P. falciparumd

100 mg PO qd

(except in pregnant

women; see

Comments)

≥8 years of age: 2 mg/kg PO qd, up to

adult dose

Begin 1–2 days before travel to malarious areas.

Take daily at the same time each day while in the

malarious areas and for 4 weeks after leaving

such areas. Doxycycline is contraindicated in

children aged <8 years and in pregnant women.

Hydroxychloroquine

sulfate (Plaquenil)

An alternative to chloroquine

for primary prophylaxis

only in the very few areas

with chloroquine-sensitive

P. falciparumd

 or areas with

P. vivax only

310 mg of base

(400 mg of salt) PO

once weekly

5 mg of base/kg (6.5 mg of salt/kg)

PO once weekly, up to maximum

adult dose of 310 mg of base

Begin 1–2 weeks before travel to malarious areas.

Take weekly on the same day of the week while in

the malarious areas and for 4 weeks after leaving

such areas. Hydroxychloroquine may exacerbate

psoriasis.

Mefloquine (Lariam

and generic)

Prophylaxis in areas with

chloroquine-resistant

P. falciparumd

228 mg of base

(250 mg of salt) PO

once weekly

≤9 kg: 4.6 mg of base/kg (5 mg of

salt/kg) PO once weekly

10–19 kg: ¼ tablete

 once weekly

20–30 kg: ½ tablet once weekly

31–45 kg: ¾ tablet once weekly

≥46 kg: 1 tablet once weekly

Begin 1–2 weeks before travel to malarious

areas. Take weekly on the same day of the

week while in the malarious areas and for 4

weeks after leaving such areas. Mefloquine is

contraindicated in persons allergic to this drug or

related compounds (e.g., quinine and quinidine)

and in persons with active or recent depression,

generalized anxiety disorder, psychosis,

schizophrenia, other major psychiatric disorders,

or seizures. Use with caution in persons

with psychiatric disturbances or a history of

depression. Mefloquine is not recommended for

persons with cardiac conduction abnormalities.

Primaquine For prevention of malaria in

areas with mainly P. vivax

30 mg of base

(52.6 mg of salt)

PO qd

0.5 mg of base/kg (0.8 mg of salt/kg)

PO qd, up to adult dose; should be

taken with food

Begin 1–2 days before travel to malarious areas.

Take daily at the same time each day while in the

malarious areas and for 7 days after leaving such

areas. Primaquine is contraindicated in persons

with G6PD deficiency. It is also contraindicated

during pregnancy.

Primaquine Used for presumptive

antirelapse therapy (terminal

prophylaxis) to decrease risk of

relapses of P. vivax and P. ovale

30 mg of base

(52.6 mg of salt) PO

qd for 14 days after

departure from the

malarious area

0.5 mg of base/kg (0.8 mg of salt/kg),

up to adult dose, PO qd for 14 days

after departure from the malarious

area

This therapy is indicated for persons who have

had prolonged exposure to P. vivax and/or

P. ovale. It is contraindicated in persons with

G6PD deficiency as well as during pregnancy.

a

Several antimalarial drugs are formulated as different salts (e.g., phosphate, sulfate, hydrochloride) and are therefore prescribed as base equivalents. For example,

chloroquine phosphate 250 salt contains 155 mg base equivalent. It is very important to check when prescribing that the correct dose is being given. b

An adult tablet

contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride. c

A pediatric tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. d

Very few

areas now have chloroquine-sensitive falciparum malaria. e

One tablet contains 228 mg of base (250 mg of salt).

Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.

Source: Centers for Disease Control and Prevention, https://www.cdc.gov/malaria/travelers/index.html.