1718 PART 5 Infectious Diseases

stools with few neutrophils, correct diagnosis requires bacterial cultures, microscopic examination of stools, and amebic serologic testing.

As has been mentioned, amebiasis must be ruled out in any patient

thought to have inflammatory bowel disease.

Because of the variety of presenting signs and symptoms, amebic

liver abscess can easily be confused with pulmonary or gallbladder disease or with any febrile illness with few localizing signs, such as malaria

(Chap. 224) or typhoid fever (Chap. 165). The diagnosis should be

considered in members of high-risk groups who have recently traveled

outside the United States (Chap. 124) and in inmates of institutions.

Once radiographic studies have identified an abscess in the liver, the

most important differential diagnosis is between amebic and pyogenic

abscess. Patients with pyogenic abscess typically are older and have a

history of underlying bowel disease or recent surgery. Amebic serology

is helpful, but aspiration of the abscess, with Gram’s staining and culture

of the material, may be required for differentiation of the two diseases.

TREATMENT

Amebiasis

INTESTINAL DISEASE (TABLE 223-1)

The drugs used to treat amebiasis can be classified according

to their primary site of action. Luminal amebicides are poorly

absorbed and reach high concentrations in the bowel, but their

activity is limited to cysts and trophozoites close to the mucosa. Only

two luminal drugs are available in the United States: iodoquinol and

paromomycin. Indications for the use of luminal agents include

eradication of cysts in patients with colitis or a liver abscess and

treatment of asymptomatic carriers. The majority of asymptomatic

individuals who pass cysts are colonized with E. dispar, which does

not warrant specific therapy. However, it is prudent to treat asymptomatic individuals who pass cysts unless E. dispar colonization

can be definitively demonstrated by specific antigen-detection tests.

Tissue amebicides reach high concentrations in the blood and

tissue after oral or parenteral administration. The development of

nitroimidazole compounds, especially metronidazole, was a major

advance in the treatment of invasive amebiasis. Patients with amebic colitis should be treated with IV or oral metronidazole. Side

effects include nausea, vomiting, abdominal discomfort, and a

disulfiram-like reaction. Another, longer-acting imidazole compound, tinidazole, is likewise effective and is available in the United

States. All patients should also receive a full course of therapy with

a luminal agent, since metronidazole does not eradicate cysts. Resistance to metronidazole has been selected in the laboratory but has

not been found in clinical isolates. Relapses are not uncommon and

probably represent reinfection or failure to eradicate amebae from

the bowel because of an inadequate dosage or duration of therapy.

AMEBIC LIVER ABSCESS

Metronidazole is the drug of choice for amebic liver abscess.

Longer-acting nitroimidazoles (tinidazole and ornidazole) have

been effective as single-dose therapy in developing countries. With

early diagnosis and therapy, mortality rates from uncomplicated

amebic liver abscess are <1%. There is no evidence that combined

therapy with two drugs is more effective than the single-drug regimen. Studies of South Africans with liver abscesses demonstrated

that 72% of patients without intestinal symptoms had bowel infection with E. histolytica; thus, all treatment regimens should include

a luminal agent to eradicate cysts and prevent further transmission.

Amebic liver abscess recurs rarely.

More than 90% of patients respond dramatically to metronidazole therapy with decreases in both pain and fever within

72 h. Indications for aspiration of liver abscesses are (1) the need

to rule out a pyogenic abscess, particularly in patients with multiple lesions; (2) the lack of a clinical response in 3–5 days; (3) the

threat of imminent rupture; and (4) the need to prevent rupture of

left-lobe abscesses into the pericardium. There is no evidence that

aspiration, even of large abscesses (up to 10 cm), accelerates healing.

Percutaneous drainage may be successful even if the liver abscess

has already ruptured. Surgery should be reserved for instances of

bowel perforation and rupture into the pericardium.

■ PREVENTION

Amebic infection is spread by ingestion of food or water contaminated

with cysts. Since an asymptomatic carrier may excrete up to 15 million

cysts per day, prevention of infection requires adequate sanitation and

eradication of cyst carriage. In high-risk areas, infection can be minimized by the avoidance of unpeeled fruits and vegetables and the use

of bottled water. Because cysts are resistant to readily attainable levels

of chlorine, disinfection by iodination (tetraglycine hydroperiodide) is

recommended. There is no effective prophylaxis.

INFECTION WITH FREE-LIVING AMEBAE

■ EPIDEMIOLOGY

There are multiple genera of free-living amebae, but the major human

pathogens are Acanthamoeba, Naegleria, and Balamuthia. All of these

parasites can cause serious central nervous system (CNS) infections,

which are almost always fatal. Acanthamoeba and Naegleria are distributed throughout the world and have been isolated from a wide

variety of fresh and brackish water, including water from taps, lakes,

hot springs, swimming pools, heating and air-conditioning units, and

hospital water networks, and even from the nasal passages of healthy

children. Encystation may protect these protozoa from desiccation and

food deprivation. The persistence of Legionella pneumophila in water

supplies is attributable in part to chronic infection of free-living amebae, particularly Acanthamoeba. Recent in vitro studies have suggested

that several pathogens that can resist phagosome-mediated killing may

be able to survive within water systems in free-living amebae. These

pathogens include Pseudomonas aeruginosa, nontuberculous Mycobacteria (both slow-growing species—e.g., those in the Mycobacterium

avium complex, M. kansasii, and M. gordonae—and rapid-growing

species—e.g., M. chelonae and M. abscessus), and viruses such as adenoviruses and echoviruses.

In contrast, the environmental niche of free-living amebae of the

genus Balamuthia appears to be soil. A soil sample from a flowerpot

was linked to a fatal infection in a child. Cases have been reported from

all continents except Africa, but the majority of cases are from warm,

dry areas of the southwestern United States and Latin America.

With better recognition of these pathogens, additional risk factors

have been identified. Since 2010, five cases of Naegleria fowleri infection have been reported in northern U.S. states and have been associated with exposure to piped water, which represents a new ecologic

niche. Since 2009, three clusters of Balamuthia mandrillaris infections

have been associated with organ transplantation. Acanthamoeba species have caused large outbreaks of microbial keratitis associated with

contact lens wear.

■ NAEGLERIA INFECTIONS

Primary amebic meningoencephalitis (PAM) is a fulminant CNS

infection caused by the free-living ameba N. fowleri, which thrives in

TABLE 223-1 Drug Therapy for Amebiasis

INDICATION THERAPY

Asymptomatic carriage Luminal agent: iodoquinol (650-mg tablets), 650 mg

tid for 20 days; or paromomycin (250-mg tablets),

500 mg tid for 10 days

Acute colitis Metronidazole (250- or 500-mg tablets), 750 mg PO or

IV tid for 5–10 days; or tinidazole, 2 g/d PO for 3 days

plus

Luminal agent as above

Amebic liver abscess Metronidazole, 750 mg PO or IV for 5–10 days; or

tinidazole, 2 g PO once; or ornidazole,a

 2 g PO once

plus

Luminal agent as above

a

Not available in the United States.

1719CHAPTER 223 Amebiasis and Infection with Free-Living Amebae

warm freshwater of lakes and rivers. In the United States, 138 cases of

PAM were reported from 1962 through 2015. Although the number of

infections reported annually has remained stable (0–8), recent changes

in the epidemiology of PAM are a cause of concern. In 2010–2015, 24

cases of PAM were reported and confirmed by the Centers for Disease

Control and Prevention (CDC). In 2010, a PAM case was reported for

the first time from the northern state of Minnesota; this case was followed by additional cases from Minnesota, Indiana, and Kansas in 2011

and 2012. With climate change, other areas may be at risk because of

higher temperatures. The remaining cases were reported mostly from

southern states. Sixty-three percent of cases affected female patients,

and the median age of patients was 11 years (range, 4–56 years). The

majority of patients (19, or 79%) were exposed to recreational freshwater from lakes, reservoirs, rivers, streams, or ditches. The remaining

five cases (21%) were due to tap-water exposure through nasal irrigation with a neti pot, playing on a backyard waterslide, and swimming

in a poorly maintained pool.

PAM follows the aspiration of water contaminated with trophozoites

or cysts or the inhalation of contaminated dust leading to invasion of

the olfactory neuroepithelium. Infection is most common in otherwise healthy children or young adults, who often report swimming in

lakes or heated swimming pools. In rare instances, cases occur when

contaminated water is used for nasal irrigation. After an incubation

period of 2–15 days, severe headache, high fever, nausea, vomiting, and

meningismus develop. Photophobia and palsies of the third, fourth,

and sixth cranial nerves are common. Rapid progression to seizures

and coma may follow. The prognosis is uniformly poor: most patients

die within a week.

The diagnosis of Naegleria infection should be considered in any

patient who has purulent meningitis without evidence of bacteria on

Gram’s staining, antigen detection assay, and culture. Other laboratory findings resemble those for fulminant bacterial meningitis, with

elevated intracranial pressure, high white blood cell counts (up to

20,000/μL), and elevated protein concentrations and low glucose levels

in cerebrospinal fluid (CSF). Diagnosis depends on the detection of

motile trophozoites in wet mounts of fresh spinal fluid. Antibodies to

Naegleria species have been detected in healthy adults; thus, serologic

testing is not useful in the diagnosis of acute infection. Diagnostic PCR

and histochemical staining of biopsies are available through the CDC.

A number of antimicrobial agents have in vitro activity against N.

fowleri, but the prognosis remains poor. The few survivors have been

treated with different combinations of amphotericin B, azoles, azithromycin, and rifampin. The new antiparasitic agent miltefosine—an

alkylphosphocholine compound used to treat breast cancer and visceral leishmaniasis—is active in vitro against Naegleria, Acanthamoeba,

and Balamuthia and is available from the CDC. Of three patients who

received miltefosine for Naegleria infection, one recovered completely,

one survived with significant neurologic deficits, and one died. Since

2013, when miltefosine became available through the CDC, this drug

has been administered to both of two surviving U.S. patients with PAM

and to three (33%) of nine patients who died of PAM (CDC, unpublished data). Early diagnosis, prompt combination therapy including

miltefosine, and aggressive management of neurologic complications,

including therapeutic hypothermia, are important factors in better

outcomes. A clinician whose patient may have PAM should contact the

CDC Emergency Operations Center at (770) 488-7100 for assistance

in diagnosis by PCR and treatment recommendations (which should

include miltefosine).

■ ACANTHAMOEBA INFECTIONS

Granulomatous Amebic Encephalitis Infection with Acanthamoeba species follows a more indolent course than Naegleria

infection and typically occurs in chronically ill or debilitated patients.

Risk factors include lymphoproliferative disorders, chemotherapy,

glucocorticoid therapy, lupus erythematosus, and AIDS. Infection

usually reaches the CNS hematogenously from a primary focus in the

sinuses, skin, or lungs. In the CNS, the onset is insidious, and the syndrome often mimics a space-occupying lesion. Altered mental status,

headache, and stiff neck may be accompanied by focal findings such as

cranial nerve palsies, ataxia, and hemiparesis. Cutaneous ulcers or hard

nodules containing amebae are frequently detected in AIDS patients

with disseminated Acanthamoeba infection.

Examination of the CSF for trophozoites may be diagnostically helpful, but lumbar puncture may be contraindicated because of increased

intracerebral pressure. CT frequently reveals cortical and subcortical

lesions of decreased density consistent with embolic infarcts. In other

patients, multiple enhancing lesions with edema may mimic the CT

appearance of toxoplasmosis (Chap. 228). Demonstration of the

trophozoites and cysts of Acanthamoeba on wet mounts or in biopsy

specimens establishes the diagnosis. Culture on nonnutrient agar plates

seeded with Escherichia coli also may be helpful. Fluorescein-labeled

antiserum is available from the CDC for the detection of protozoa

in biopsy specimens. Granulomatous amebic encephalitis in patients

with AIDS may have an accelerated course (with survival for only

3–40 days) because of the difficulty these individuals have in forming

granulomas. Various antimicrobial agents have been used to treat

Acanthamoeba infection, but miltefosine from the CDC should be

included in combination therapy.

Keratitis The incidence of keratitis caused by Acanthamoeba has

increased in the past 20 years, in part as a result of improved diagnosis. Earlier infections were associated with trauma to the eye and

exposure to contaminated water. At present, most infections are linked

to extended-wear contact lenses, and rare cases are associated with

laser-assisted in situ keratomileusis (LASIK). Risk factors include the

use of homemade saline, the wearing of lenses while swimming, and

inadequate disinfection. Since contact lenses presumably cause microscopic trauma, early corneal findings may be nonspecific. The first

symptoms usually include tearing and the painful sensation of a foreign

body. Once infection is established, progression is rapid. The characteristic clinical sign is an annular, paracentral corneal ring representing a

corneal abscess. Deeper corneal invasion and loss of vision may follow.

The differential diagnosis includes bacterial, mycobacterial, and

herpetic infection. The irregular polygonal cysts of Acanthamoeba

(Fig. 223-4) may be identified in corneal scrapings or biopsy material,

and trophozoites can be grown on special media. Cysts are resistant

to available drugs, and the results of medical therapy have been

disappointing. Some reports have suggested partial responses to

propamidine isethionate eyedrops. Severe infections usually require

keratoplasty.

■ BALAMUTHIA INFECTIONS

Balamuthia mandrillaris is a free-living ameba that was first identified

in 1986 as the cause of a fatal infection in a mandrill baboon at the Wild

Animal Park in San Diego, California. The parasite has been isolated

from soil and dust and is probably widespread in the environment. It is an

important etiologic agent of granulomatous amebic encephalitis, cutaneous lesions, and sinus infections in humans. The potential risk factors for

FIGURE 223-4 Double-walled cyst of Acanthamoeba castellani, as seen by phasecontrast microscopy. (From DJ Krogstad et al, in A Balows et al [eds]: Manual of

Clinical Microbiology, 5th ed. Washington, DC, American Society for Microbiology,

1991.)

1720 PART 5 Infectious Diseases

FIGURE 223-5 Brain MRI of amebic meningoencephalitis due to Balamuthia

mandrillaris. A large lesion in the parieto-occipital lobe and other smaller lesions

are seen. (Courtesy of the Department of Radiology, UCSD Medical Center,

San Diego.)

granulomatous amebic encephalitis identified by the California Encephalitis Project include young age, immunocompromising conditions,

and Hispanic ethnicity. The infection likely starts with percutaneous

or mucous membrane exposure and then spreads hematogenously to

the brain and other organs—a pattern that explains the risk for transmission through organ transplantation. In 2009–2010, two clusters of

organ transplant–transmitted B. mandrillaris infections were detected

by recognition of severe unexpected illness in multiple recipients from

the same donor after an incubation period of 17–24 days.

Frequently, Balamuthia affects immunocompetent individuals, in

whom the course is typically subacute, with focal neurologic signs,

fever, seizures, and headaches leading to death within 1 week to several months after onset. Skin lesions may occur on the face, trunk, or

extremities. In addition to dust inhalation, inoculation of trophozoites

or cysts from stagnant water may occur through open wounds or

mucous membranes. Diagnosis relies on examination of CSF, which

reveals mononuclear or neutrophilic pleocytosis, elevated protein levels, and normal to low glucose concentrations. Amebae are rarely isolated from CSF. Multiple hypodense lesions are usually detected with

imaging studies (Fig. 223-5). Fluorescent antibody and PCR assays are

available from the CDC.

The five surviving patients in the United States have been treated

with a variety of drugs, including pentamidine, flucytosine, sulfadiazine, and macrolides. The CDC recommends that miltefosine now be

included, as for treatment of other free-living amebae. The differential

diagnosis includes tuberculomas (Chap. 178) and neurocysticercosis

(Chap. 235).

■ FURTHER READING

Amebiasis

Burgess SL et al: Gut microbiome communication with bone marrow

regulates susceptibility to amebiasis. J Clin Invest 130:4019, 2020.

Debnath A et al: A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nat Med 18:956, 2012.

Gilchrist CA et al: Role of the gut microbiota of children in diarrhea

due to the protozoan parasite Entamoeba histolytica. J Infect Dis

213:1579, 2016.

Ngobeni R et al: Entamoeba species in South Africa: Correlations

with the host microbiome, parasite burdens, and first description of

Entamoeba bangladeshi outside of Asia. J Infect Dis 216:1592, 2017.

Shirley DAT et al: A review of the global burden, new diagnostics, and

current therapeutics for amebiasis. Open Forum Infect Dis 5:1, 2018.

Wojcik GL et al: Genome-wide association study reveals genetic link

between diarrhea-associated Entamoeba histolytica infection and

inflammatory bowel disease. mBio 9:e01668, 2018.

Free-Living Amebae

Bellini NK et al: The therapeutic strategies against Naegleria fowleri.

Exp Parasitol 187:1, 2018.

Capewell LG et al: Diagnosis, clinical course, and treatment of primary amoebic meningoencephalitis in the United States, 1937–2013.

J Pediatr Infect Dis Soc 4:e68, 2015.

Farnon EC et al: Transmission of Balamuthia mandrillaris by organ

transplantation. Clin Infect Dis 63:878, 2016.

Humanity has but three great enemies: Fever, famine, and war; of these by

far the greatest, by far the most terrible, is fever.

—William Osler, 1896

Malaria is a protozoan disease transmitted by the bite of infected

female Anopheles mosquitoes. The most important of the parasitic

diseases of humans, malaria is transmitted in 87 countries containing

3 billion people. In 2019, it was estimated that there were 229 million

cases and 409,000 deaths (i.e., ~1100 deaths each day). Mortality rates

decreased dramatically between 2000 and 2015 as a result of highly

effective control programs in several countries, but since then, progress

has reversed and estimated global case numbers have risen steadily.

Malaria was eliminated from the United States, Canada, Europe, and

Russia >50 years ago, but its prevalence rose in many parts of the

tropics between 1970 and 2000. In response to this rise, there has been

substantial investment aimed at increasing access to accurate diagnosis,

effective treatments, and insecticide-treated bed nets. An increasing

number of countries that had low malaria transmission are now targeting malaria elimination. This ambitious goal is threatened by increasing resistance to antimalarial drugs and insecticides.

Malaria remains today, as it has been for centuries, a heavy burden

on tropical communities, a threat to nonendemic countries, and a

danger to travelers.

ETIOLOGY AND PATHOGENESIS

Six species of the genus Plasmodium cause nearly all malarial infections

in humans. These are P. falciparum, P. vivax, two morphologically

identical sympatric species of P. ovale (curtisi and wallikeri), P. malariae, and—in Southeast Asia—the monkey malaria parasite P. knowlesi

(Table 224-1). Occasionally humans are also infected with the monkey

parasites P. simium (South America) and P. cynomolgi (Southeast Asia).

While almost all deaths are caused by falciparum malaria, P. knowlesi

and P. vivax can also cause severe illness. Human infection begins when

a female anopheline mosquito inoculates plasmodial sporozoites from

its salivary glands during a blood meal (Fig. 224-1). These microscopic

motile forms of the malaria parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and

begin a period of asexual reproduction. By this amplification process

(known as intrahepatic or preerythrocytic schizogony), a single sporozoite may produce from 10,000 to >30,000 daughter merozoites. These

few swollen infected liver cells eventually burst, discharging motile

224 Malaria

Nicholas J. White, Elizabeth A. Ashley

1721CHAPTER 224 Malaria

Most West Africans and people with origins in that region are the

Duffy-negative FyFy phenotype and are generally resistant to P. vivax

malaria. P. knowlesi also invades Duffy-positive human RBCs preferentially. During the first few hours of intraerythrocytic development,

the small “ring forms” of the different malaria species appear similar

under light microscopy. As the trophozoites enlarge, species-specific

characteristics become evident, malaria pigment (hemozoin) becomes

visible, and the parasite assumes an irregular or ameboid shape. By the

end of the intraerythrocytic life cycle, the parasite has consumed twothirds of the RBC’s hemoglobin and has grown to occupy most of the

cell. It is now called a schizont. Multiple nuclear divisions have taken

place (schizogony or merogony). The infected RBC then ruptures to

release 6–30 daughter merozoites, each potentially capable of invading

a new RBC and repeating the cycle. The disease in human beings is

caused by the direct effects of the asexual parasite—RBC invasion and

destruction—and by the host’s reaction. Some of the blood-stage parasites develop into morphologically distinct, longer-lived sexual forms

(gametocytes) that can transmit malaria. In falciparum malaria, a delay

of several asexual cycles precedes this switch to gametocytogenesis.

Female gametocytes typically outnumber males by 4:1.

After being ingested in the blood

meal of a biting female anopheline mosquito, the male gametocyte exflagellates

and divides rapidly into eight motile

male gametes. These fuse with female

gametocytes, undergoing two rounds

of sexual division (meiosis) to form

a zygote in the insect’s midgut. This

zygote matures into an ookinete, which

penetrates and encysts in the mosquito’s

gut wall. The resulting oocyst expands

by asexual division until it bursts to liberate myriad motile sporozoites, which

then migrate in the hemolymph to the

salivary gland of the mosquito to await

inoculation into another human at the

next feed, thus completing the life cycle.

EPIDEMIOLOGY

Malaria occurs throughout most

of the tropical regions of the world

(Fig. 224-2). P. falciparum predominates

in Africa, New Guinea, and Hispaniola

(i.e., the Dominican Republic and Haiti);

P. vivax is more common in Central and

TABLE 224-1 Characteristics of Plasmodium Species Infecting Humans

CHARACTERISTIC 

FINDING FOR INDICATED SPECIES

P. FALCIPARUM P. VIVAX P. OVALEa P. MALARIAE P. KNOWLESI

Duration of intrahepatic

phase (days)

5.5 8 9 15 5.5

Number of merozoites

released per infected

hepatocyte

30,000 10,000 15,000 15,000 20,000

Approximate duration of

erythrocytic cycle (hours)

48 48 50 72 24

Red cell preference Younger cells (but can

invade cells of all ages)

Reticulocytes and cells up

to 2 weeks old

Reticulocytes Older cells Younger cells

Morphology Usually only ring

forms; banana-shaped

gametocytes

Irregularly shaped large

rings and trophozoites;

enlarged erythrocytes;

Schüffner’s dots

Infected erythrocytes,

enlarged and oval with

tufted ends; Schüffner’s

dots

Band or rectangular

forms of trophozoites

common

Resembles P. falciparum

(early trophozoites)

or P. malariae (later

trophozoites, including

band forms)

Pigment color Black Yellow-brown Dark brown Brown-black Dark brown

Ability to cause relapses No Yes Yes No No

a

Genomic studies have revealed P. ovale to be two sympatric species: P. ovale curtisi and P. ovale wallikeri. which are morphologically very similar but may have different

incubation periods and latencies.

Antibodies to sporozoites

block invasion of hepatocytes

Pre-erythrocytic

Asexual

erythrocytic Transmission

Antibodies block fertilization,

development, and invasion

Sporozoites

Schizont

Liver

Merozoites

RBC

Gametocytes

In mosquito

gut

Ookinete

Zygote

Gamete

CD4+ and CD8+ T cells

kill intrahepatic parasites

Antibodies to merozoites

block invasion of RBCs

Antibodies to malaria “toxins”

Antibodies to parasite antigens

on infected RBCs block

cytoadherence to endothelium

and augment splenic clearance

Cell-mediated immunity and

antibody-dependent cytotoxicity

kill intraerythocytic parasites

FIGURE 224-1 The malaria transmission cycle from mosquito to human and targets of immunity. In P. vivax and P. ovale

infections some liver stage parasites remain dormant (“hypnozoites”), and awake weeks or months later to cause

relapses. RBC, red blood cell.

merozoites into the bloodstream. The merozoites then invade red blood

cells (RBCs) to become trophozoites and, in non-immune subjects, multiply six- to twentyfold every 48 h (P. knowlesi, 24 h; P. malariae, 72 h).

When the parasites reach densities of ~50/μL of blood (~100 million

parasites in total in the blood of an adult), the symptomatic stage of

the infection begins. In P. vivax and P. ovale infections, a proportion

of the intrahepatic forms do not divide immediately but remain inert

for a period ranging from 2 weeks to ≥1 year. These dormant forms,

or hypnozoites, are the cause of the relapses that characterize infection

with these species.

Attachment of merozoites to erythrocytes is mediated via a complex

interaction with several different binding ligands and specific erythrocyte surface receptors. P. falciparum merozoites bind via erythrocyte

binding antigen 175 to glycophorin A and via EBL140 to glycophorin

C. The other glycophorins (B and D) also contribute.

The merozoite reticulocyte-binding protein homologue 5 (PfRh5)

plays a critical role binding to red cell basigin (CD147, EMMPRIN).

P. vivax binds to receptors on developing erythrocytes. The Duffy

blood-group antigen Fya

 or Fyb

 plays an important role in invasion.

1722 PART 5 Infectious Diseases

P. faIciparum

P. knowlesi

P. vivax

P. falciparum + P. vivax

Predominant species

circulating

FIGURE 224-2 Malaria-endemic countries showing predominant Plasmodium species. Plasmodium vivax is common in the Horn of Africa and in Mauritania but relatively

unusual elsewhere in the continent

South America and Southeast Asia. The prevalence of these two species

is approximately equal on the Indian subcontinent and in Oceania. P.

malariae is found in most endemic areas, especially throughout sub-Saharan Africa, but is much less common. P. ovale is relatively unusual

outside of Africa and, where it is found, comprises <1% of isolates. P.

knowlesi causes human infections commonly on the island of Borneo

and, to a lesser extent, elsewhere in Southeast Asia, where the main

hosts, long-tailed and pig-tailed macaques, are found.

The epidemiology of malaria is complex and may vary considerably

even within relatively small geographic areas. Endemicity traditionally

has been defined in terms of rates of microscopy-detected parasitemia

or palpable spleens in children 2–9 years of age and has been classified as hypoendemic (<10%), mesoendemic (11–50%), hyperendemic

(51–75%), and holoendemic (>75%). In holo- and hyperendemic areas

(e.g., certain regions of tropical Africa or coastal New Guinea) where

there is intense P. falciparum transmission, people may sustain one or

more infectious mosquito bites per week and are infected repeatedly

throughout their lives. In such settings, malaria morbidity and mortality are substantial during early childhood. Immunity against disease

is hard won in these areas following repeated symptomatic infections

in childhood, but, if the child survives, infections become increasingly

likely to be asymptomatic. These asymptomatic older children and

adults are a major source of malaria transmission. As control measures

progress and urbanization expands, environmental conditions become

less conducive to malaria transmission, and all age groups may lose

protective immunity and become susceptible to illness. Constant,

frequent, year-round infection is termed stable transmission. In areas

where transmission is low, erratic, or focal, full protective immunity is

not acquired, and symptomatic disease may occur at all ages. This situation usually exists in hypoendemic areas and is termed unstable transmission. Even in stable transmission areas, there is often an increased

incidence of symptomatic malaria during the rainy season coinciding

with increased mosquito breeding and transmission. Malaria can

behave like an epidemic disease in some areas, particularly those with

unstable malaria, such as northern India (the Punjab region), the

Horn of Africa, Rwanda, Burundi, southern Africa, and Madagascar.

Epidemics may occur when changes in environmental, economic, or

social conditions (e.g., heavy rains following drought or migration—

usually of refugees or workers—from a nonmalarious region to an area

of high transmission) are compounded by failure to invest in national

programs or by a breakdown in malaria control and prevention services caused by war or civil disorder. The recent socioeconomic and

political crisis in Venezuela has led to a resurgence of malaria. Epidemics often result in high mortality rates among all age groups. The

principal determinants of the epidemiology of malaria are the number

(density), the human-biting habits, and the longevity of the anopheline

mosquito vectors. More than 100 of the >400 anopheline species can

transmit malaria, but the ~40 species that do so commonly vary considerably in their efficiency as malaria vectors. More specifically, the

transmission of malaria is directly proportional to the density of the

vector, the square of the number of human bites per day per mosquito,

and the tenth power of the probability of the mosquito’s surviving for

1 day. Mosquito longevity is particularly important as a determinant of

malaria transmissibility because the portion of the parasite’s life cycle

that takes place within the mosquito—from gametocyte ingestion

to subsequent inoculation (sporogony)—lasts 8–30 days, depending

on ambient temperature. In order to transmit malaria, the mosquito

must therefore survive for >7 days. Sporogony is not completed at

cooler temperatures—i.e., <16°C (<60.8°F) for P. vivax and <21°C

(<69.8°F) for P. falciparum; thus, transmission does not occur below

these temperatures or at high altitudes, although malaria outbreaks

and transmission have occurred in the highlands (>1500 m) of eastern Africa, which were previously free of vectors. The most effective

mosquito vectors of malaria are those, such as the Anopheles gambiae

species complex in Africa, that are long-lived, occur in high densities

in tropical climates, breed readily, and bite humans in preference to

other animals. The entomologic inoculation rate (i.e., the number of

sporozoite-positive mosquito bites per person per year) is the most

common measure of malaria transmission and varies from <1 in some

parts of Latin America and Southeast Asia to >300 in parts of tropical

Africa.

PATHOPHYSIOLOGY

■ ERYTHROCYTE CHANGES

After invading an erythrocyte, the growing malarial parasite progressively

consumes and degrades intracellular proteins, principally hemoglobin.

The potentially toxic heme is detoxified by lipid-mediated crystallization to biologically inert hemozoin (malaria pigment). The parasite also

alters the RBC membrane by changing its transport properties, exposing

1723CHAPTER 224 Malaria

cryptic surface antigens, and inserting new parasite-derived proteins.

The RBC becomes more irregular in shape, more antigenic, and less

deformable.

In P. falciparum infections, membrane protuberances appear on the

erythrocyte’s surface 12–15 h after cell invasion. These “knobs” extrude

a high-molecular-weight, antigenically variant, strain-specific erythrocyte membrane adhesive protein (PfEMP1) that mediates attachment

to receptors on venular and capillary endothelium (cytoadherence).

Several vascular receptors have been identified; intercellular adhesion

molecule 1 and endothelial protein C receptor are important in the

brain, chondroitin sulfate B predominates in the placenta, and CD36

binds parasitized RBCs in most other organs. Erythrocytes containing

more mature parasites stick inside and eventually block capillaries and

venules. These infected RBCs may also adhere to uninfected RBCs

(to form rosettes) and to other parasitized erythrocytes (agglutination). The processes of cytoadherence, rosetting, and agglutination

are central to the pathogenesis of falciparum malaria. They result in

the sequestration of infected RBCs in vital organs (particularly the

brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the

principal host defense mechanism: splenic processing and filtration.

As a consequence, only the younger ring forms of the asexual parasites

circulate in the peripheral blood in falciparum malaria, and the level of

peripheral parasitemia variably underestimates the true number of parasites within the body. In severe malaria, uninfected erythrocytes also

become less deformable, which compromises their passage through the

partially obstructed capillaries and venules and shortens their survival.

In the other human malarias, significant sequestration does not

occur, and all stages of the parasite’s development are evident on

peripheral-blood smears. P. vivax and P. ovale show a marked predilection for young RBCs and P. malariae for old cells; these species produce

a level of parasitemia that seldom exceeds 2%. In contrast, P. falciparum

can invade erythrocytes of all ages and may be associated with very

high parasite densities. Dangerously high parasite densities may also

occur in P. knowlesi infections, with rapid increases as a result of the

shorter (24-h) asexual life cycle.

■ HOST RESPONSE

Initially, the host responds to malaria infection by activating nonspecific defense mechanisms. Splenic immunologic and filtrative clearance

functions are augmented, and the removal of both parasitized and

uninfected erythrocytes is accelerated. The spleen also removes damaged ring-form parasites (a process known as “pitting”) from within

the red cell and returns the once-infected cells back to the circulation,

where their survival is shortened. The parasitized cells escaping splenic

removal are destroyed when the schizont ruptures. The material

released induces monocyte/macrophage activation and the release of

proinflammatory cytokines, which cause fever and other pathologic

effects. Temperatures of ≥40°C (≥104°F) damage mature parasites;

in untreated infections, the effect of such temperatures is to further

synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally characterized the different

malarias. These regular fever patterns (quotidian, daily; tertian, every

2 days; quartan, every 3 days) are seldom seen today as patients receive

prompt and effective antimalarial treatment.

The geographic distributions of the thalassemias, sickle cell disease, hemoglobins C and E, hereditary ovalocytosis, and glucose-6-

phosphate dehydrogenase (G6PD) deficiency closely resemble that

of falciparum malaria before the introduction of control measures.

This similarity suggests that these genetic disorders confer protection

against death from falciparum malaria. HbA/S heterozygotes (sickle

cell trait) have a sixfold reduction in the risk of dying from severe falciparum malaria and are correspondingly protected from the bacterial

infections that complicate malaria. Hemoglobin S–containing RBCs

impair parasite growth at low oxygen tensions, and P. falciparum–

infected RBCs containing hemoglobin S or C exhibit reduced cytoadherence because of reduced surface presentation of the adhesin

PfEMP1. Parasite multiplication in HbA/E heterozygotes is reduced at

high parasite densities. In Melanesia, children with α-thalassemia have

more frequent malaria (both vivax and falciparum) in the early years of

life, and this pattern of infection appears to protect them against severe

disease. In Melanesian ovalocytosis, rigid erythrocytes resist merozoite

invasion, and the intraerythrocytic milieu is hostile. G6PD deficiency

provides some protection against severe P. falciparum infections but

has a much stronger protective effect against P. vivax infections.

Nonspecific host defense mechanisms stop the infection’s expansion, and the subsequent strain-specific immune response then controls the infection. Eventually, exposure to sufficient strains confers

protection from high-level parasitemia and disease but not from infection. As a result of this state of infection without illness (premunition),

asymptomatic parasitemia is very common among adults and older

children living in regions with stable and intense transmission (i.e.,

holo- or hyperendemic areas) and also in parts of low-transmission

areas. Parasitemia in asymptomatic infections fluctuates in density

but often averages ~5000/mL—just below the level of microscopy

detection but sufficient to generate transmissible densities of gametocytes. Immunity is mainly specific for both the species and the strain

of infecting malarial parasite. Both humoral immunity and cellular

immunity are necessary for protection, but the mechanisms of each

are incompletely understood (Fig. 224-1). Immune individuals have

a polyclonal increase in serum levels of IgM, IgG, and IgA, although

much of this antibody is unrelated to protection. Antibodies to a

variety of parasite antigens presumably act in concert to limit in vivo

replication of the parasite. In P. falciparum infections, the variant surface adhesin PfEMP1 is the most important of these antigens. Passive

transfer of maternal antibody contributes to the partial protection of

infants from severe malaria in the first months of life. This complex

immunity to disease declines when a person lives outside an endemic

area for several months or longer.

Several factors retard the development of cellular immunity to

malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct

T cell recognition; malaria antigen–specific immune unresponsiveness;

and the enormous strain diversity of malarial parasites, along with the

ability of the parasites to express variant immunodominant antigens

on the erythrocyte surface that change during the course of infection.

Parasites may persist in the blood for months or years (or, in the case

of P. malariae, for decades) if treatment is not given. The complexity

of the immune response in malaria, the sophistication of the parasites’

evasion mechanisms, and the lack of a good in vitro correlate with

clinical immunity have all slowed progress toward an effective vaccine.

CLINICAL FEATURES

Malaria is a common cause of fever in tropical countries. Clinical

diagnosis is notoriously unreliable. 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, cough, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although

headache may be severe in malaria, the neck stiffness and photophobia

seen in meningitis do not occur. 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 unusual

and at presentation suggest infection (often relapse) with P. vivax or P.

ovale. The fever is usually irregular at first (that of falciparum malaria

may never become regular). The temperature of nonimmune individuals and children often rises above 40°C (104°F), with accompanying

tachycardia and sometimes delirium. Although childhood febrile

convulsions may occur with any of the malarias, generalized seizures

are associated specifically with falciparum malaria and may herald

the development of encephalopathy (cerebral malaria). Many clinical

abnormalities have been described in acute malaria, but most patients

with uncomplicated infections have few abnormal physical findings

other than fever, malaise, mild anemia, and (in some cases) a palpable

spleen. Anemia is common among young children living in areas with

1724 PART 5 Infectious Diseases

stable transmission (e.g., much of West Africa), and increases in prevalence where resistance has compromised the efficacy of antimalarial

drugs. Frequent vivax malaria relapse is an important cause of anemia

in young children in some areas (e.g., on the island of New Guinea).

In nonimmune individuals with acute malaria, the spleen takes several

days to become palpable, but splenic enlargement is found in a high

proportion of otherwise healthy individuals in malaria-endemic areas

and reflects repeated infections. Slight enlargement of the liver is also

common, particularly among young children. Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated malaria and usually resolves over 1–3 weeks. Malaria is not

associated with a rash. Petechial hemorrhages in the skin or mucous

membranes—features of viral hemorrhagic fevers and leptospirosis—

develop only very rarely in severe falciparum malaria.

■ SEVERE FALCIPARUM MALARIA

Appropriately and promptly treated, uncomplicated falciparum malaria

(i.e., that in which the patient can sit or stand unaided and can swallow

medicines and food) carries a mortality rate of <0.1%. However, once

vital-organ dysfunction occurs or the total proportion of erythrocytes

infected increases to >2% (a level corresponding to >1012 parasites in an

adult), mortality risk rises steeply, depending on the immunity of the

host. The major manifestations of severe falciparum malaria are shown

in Table 224-2, and features indicating a poor prognosis are listed in

Table 224-3.

Cerebral Malaria Coma is a characteristic and ominous feature

of falciparum malaria and, even with treatment, has been associated

with death rates of ~20% among adults and 15% among children. Any

obtundation, delirium, or abnormal behavior in falciparum malaria

should be taken very seriously. The onset of coma may be gradual or

sudden following a convulsion.

Cerebral malaria manifests as a diffuse symmetric encephalopathy;

focal neurologic signs are unusual. Although some passive resistance to

head flexion may be detected, signs of meningeal irritation are absent.

The eyes may be divergent, and bruxism and a pout reflex are common,

but other primitive reflexes are usually absent. 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. On routine funduscopy, ~15% of patients have retinal hemorrhages; with pupillary

dilation and indirect ophthalmoscopy, this figure increases to 30–40%.

Other funduscopic abnormalities (Fig. 224-3) include discrete spots of

retinal opacification (30–60%), papilledema (8% among children, rare

among adults), cotton wool spots (<5%), and decolorization of a retinal

vessel or segment of vessel (occasional cases). Convulsions, which are

usually generalized and often repeated, occur in ~10% of adults and up

to 50% of children with cerebral malaria. More covert seizure activity is

common, particularly among children, and may manifest as repetitive

tonic–clonic eye movements or even hypersalivation. Whereas adults

rarely (<3% of cases) suffer neurologic sequelae, ~10% of children

surviving cerebral malaria—especially those with hypoglycemia, severe

anemia, repeated seizures, and deep coma—have residual neurologic

deficits when they regain consciousness; hemiplegia, cerebral palsy,

cortical blindness, deafness, and impaired cognition may all occur.

The majority of these deficits improve markedly or resolve completely

within 6 months. However, the prevalence of some other deficits

increases over time; ~10% of children surviving cerebral malaria have

a persistent language deficit. There may also be deficits in learning,

planning and executive functions, attention, memory, and nonverbal

functioning. The incidence of epilepsy is increased and life expectancy

decreased among these children.

Hypoglycemia Hypoglycemia, an important and common complication of severe malaria, is associated with a poor prognosis and is

particularly problematic in children and pregnant women. Hypoglycemia in malaria results from both a failure of hepatic gluconeogenesis

and an increase in the consumption of glucose by the host and, to a

much lesser extent, the malaria parasites. This may be compounded by

quinine, a powerful stimulant of pancreatic insulin secretion, which is

still widely used for the treatment of both severe and uncomplicated

falciparum malaria. Hyperinsulinemic hypoglycemia is especially

troublesome in pregnant women receiving quinine treatment. In

severe disease, the clinical diagnosis of hypoglycemia is difficult: the

usual physical signs (sweating, gooseflesh, tachycardia) are absent, and

the neurologic impairment caused by hypoglycemia cannot be distinguished from that caused by malaria.

Acidosis Acidosis, resulting from accumulation of organic acids,

is an important cause of death from severe malaria, which in adults is

often compounded by coexisting renal impairment. Hyperlactatemia

commonly coexists with hypoglycemia. In children, ketoacidosis may

contribute. Hydroxyphenyllactic acid, α-hydroxybutyric acid, and

β-hydroxybutyric acid concentrations are elevated. Acidotic breathing,

sometimes called “respiratory distress,” is a sign of poor prognosis. It is

followed often by circulatory failure refractory to volume expansion or

inotropic drug treatment and ultimately by respiratory arrest. Plasma

concentrations of bicarbonate or lactate are the best biochemical prognosticators in severe malaria. Hypovolemia is not a major contributor

to acidosis. Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues where sequestered parasites interfere with

TABLE 224-2 Manifestations of Severe Falciparum Malaria

SIGNS MANIFESTATIONS

Major

Unarousable coma/

cerebral malaria

Failure to localize or respond appropriately to noxious

stimuli; coma persisting for >30 min after generalized

convulsion

Acidemia/acidosis Arterial pH of <7.25, base deficit >8 meq/L, or plasma

bicarbonate level of <15 mmol/L; venous lactate level of

>5 mmol/L; manifests as labored deep breathing, often

termed “respiratory distress”

Severe

normochromic,

normocytic anemia

Hematocrit of <15% or hemoglobin level of <50 g/L

(<5 g/dL) with parasitemia level of >10,000/μLa

Renal failure Serum or plasma creatinine level of >265 μmol/L (>3 mg/

dL); urine output (24 h) of <400 mL for adults or <12 mL/kg

for children; no improvement with rehydrationb

Pulmonary edema/

adult respiratory

distress syndrome

Noncardiogenic pulmonary edema, often aggravated by

overhydration

Hypoglycemia Plasma glucose level of <2.2 mmol/L (<40 mg/dL)

Hypotension/shock Systolic blood pressure of <50 mmHg in children

1–5 years or <80 mmHg in adults; core/skin temperature

difference of >10°C; capillary refill >2 s

Bleeding/

disseminated

intravascular

coagulation

Significant bleeding and hemorrhage from the gums,

nose, and gastrointestinal tract and/or evidence of

disseminated intravascular coagulation

Convulsions More than two generalized seizures in 24 h; signs of

continued seizure activity, sometimes subtle (e.g., tonicclonic eye movements without limb or face movement)

Other

Hemoglobinuriac Macroscopic black, brown, or red urine; not associated

with effects of oxidant drugs and red blood cell enzyme

defects (such as G6PD deficiency)

Extreme weakness Prostration; inability to sit unaidedd

Hyperparasitemia Parasitemia level of >5% in nonimmune patients (>10%

in any patient)

Jaundice Serum bilirubin level of >50 mmol/L (>3 mg/dL) if

combined with a parasite density of 100,000/μL or other

evidence of vital-organ dysfunction

a

This is nonspecific and may include patients with chronic anemia; a parasitemia

threshold of 100,000/μL is more specific for acute malarial anemia. b

In practice,

urine output information is usually unavailable, so the plasma or serum creatinine

alone is used. c

Hemoglobinuria may also occur in uncomplicated malaria and

in patients with G6PD deficiency, particularly if they take oxidant drugs such as

primaquine. d

In children who are normally able to sit.

Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.

1725CHAPTER 224 Malaria

TABLE 224-3 Features Indicating a Poor Prognosis in Severe

Falciparum Malaria

Clinical

Marked agitation

Hyperventilation (respiratory distress)

Low core temperature (<36.5°C; <97.7°F)

Bleeding

Deep coma

Repeated convulsions

Anuria

Shock

Laboratory

Biochemistry

Hypoglycemia (<2.2 mmol/L)

Hyperlactatemia (>5 mmol/L)

Acidemia (arterial pH <7.25, base deficit >8 meq/L, or serum HCO3

 <15 mmol/L)

Elevated serum creatinine (>265 μmol/L)

Elevated total bilirubin (>50 μmol/L)

Elevated liver enzymes (AST/ALT 3 times upper limit of normal)

Elevated muscle enzymes (CPK ↑, myoglobin ↑)

Elevated urate (>600 μmol/L)

Hematology

Leukocytosis (>12,000/μL)

Severe anemia (PCV <15%)

Coagulopathy

 Low platelet count (<50,000/μL)

 Prolonged prothrombin time (>3 s)

 Prolonged partial thromboplastin time

 Decreased fibrinogen (<200 mg/dL)

Parasitology

Hyperparasitemia

 Increased mortality at >100,000/μL

 High mortality at >500,000/μL

 >20% of parasites identified as pigment-containing trophozoites and

schizonts

 >5% of neutrophils contain visible malaria pigment

Note: Increased risk of concomitant bacteremia in adults if >20% parasitemia.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase;

CPK, creatine phosphokinase; PCV, packed cell volume.

FIGURE 224-3 The eye in cerebral malaria: perimacular whitening and palecentered retinal hemorrhages. (Courtesy of N. Beare, T. Taylor, S. Harding,

S. Lewallen, and M. Molyneux; with permission.)

microcirculatory flow, lactate production by the parasites, and a failure

of hepatic and renal lactate clearance.

Noncardiogenic Pulmonary Edema Adults with severe falciparum malaria may develop noncardiogenic pulmonary edema even

after several days of antimalarial therapy. The pathogenesis of this variant

of the adult respiratory distress syndrome is unclear. The mortality rate is

>80%. Pulmonary edema can be precipitated by overly vigorous administration of IV fluid. Noncardiogenic pulmonary edema can also develop

in otherwise uncomplicated vivax malaria, where recovery is usual.

Renal Impairment Acute kidney injury is common in severe falciparum malaria. The pathogenesis of renal failure is unclear but may be

related to erythrocyte sequestration and agglutination interfering with

renal microcirculatory flow and metabolism. Clinically and pathologically, this syndrome manifests as acute tubular necrosis. Acute renal

failure may occur simultaneously with other vital-organ dysfunction

(in which case the mortality risk is high) or may progress as other

disease manifestations resolve. In survivors, urine flow resumes in a

median of 4 days, and serum creatinine levels return to normal in a

mean of 17 days (Chap. 310). Early dialysis or hemofiltration considerably improves the chances of survival, particularly in acute hypercatabolic renal failure. Oliguric renal failure is rare among children.

Hematologic Abnormalities Anemia results from accelerated

RBC removal by the spleen, obligatory RBC destruction at parasite

schizogony, and ineffective erythropoiesis. In severe malaria, the deformability of both infected and uninfected RBCs is reduced. The degree of

reduced deformability correlates with prognosis and with the development of anemia. Splenic clearance of all RBCs is increased. In nonimmune individuals and in areas with unstable transmission, anemia

can develop rapidly and transfusion is often required. A hemoglobin

of ≤3g/dL on presentation is associated with increased mortality.

Acute hemolytic anemia with massive hemoglobinuria (“blackwater

fever”) may occur. Hemoglobinuria may contribute to renal injury.

Some patients with blackwater fever have G6PD deficiency, but in the

majority of cases, it is unclear why massive hemolysis has occurred. In

non-immune patients sudden hemolysis may follow many days after

artesunate treatment of hyperparasitemia, usually as a result of relatively synchronous loss of once-parasitized “pitted” RBCs. As a consequence of repeated malarial infections, children in high-transmission

areas are usually anemic and often develop severe anemia. This results

from both shortened survival of uninfected RBCs and marked dyserythropoiesis. Anemia is a common consequence of antimalarial drug

resistance, which results in repeated or continued infection.

Slight coagulation abnormalities are common in falciparum malaria,

and mild thrombocytopenia is usual (a normal platelet count should

question the diagnosis of malaria). Fewer than 5% of patients with

severe malaria have significant bleeding with evidence of disseminated

intravascular coagulation. Hematemesis from stress ulceration or acute

gastric erosions also may occur rarely.

Liver Dysfunction Mild hemolytic jaundice is common in

malaria. Severe jaundice is associated with P. falciparum infections; is

more common among adults than among children; and results from

hemolysis, hepatocyte injury, and cholestasis. Liver failure does not

occur. When accompanied by other vital-organ dysfunction (often

renal impairment), liver dysfunction carries a poor prognosis. Hepatic

dysfunction contributes to hypoglycemia, lactic acidosis, and impaired

drug metabolism. Occasional patients with falciparum malaria may

develop deep jaundice (with hemolytic, hepatic, and cholestatic components) without evidence of other vital-organ dysfunction, in which

case the prognosis is good.

Other Complications HIV/AIDS and malnutrition predispose

to more severe malaria in nonimmune individuals. Malaria anemia is worsened by concurrent infections with intestinal helminths,

1726 PART 5 Infectious Diseases

hookworm in particular. Approximately 6% of children diagnosed

with severe malaria have concomitant bacteremia. In adults, the

proportion is lower (<1%), except in those with very high parasite

counts (>20% parasitemia). In areas of moderate and high malaria

transmission, differentiating severe malaria from sepsis with incidental parasitemia in childhood is very difficult. In endemic areas,

Salmonella spp. 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. Aspiration pneumonia may follow generalized convulsions.

The frequencies of complications of severe falciparum malaria are

summarized in Table 224-4.

■ MALARIA IN PREGNANCY

Malaria in early pregnancy causes fetal loss. In areas of high malaria

transmission, falciparum malaria in primi- and secundigravid women

is associated with low birth weight (average reduction, ~170 g) and consequently increased infant mortality rates. In general, infected mothers

in areas of stable transmission remain asymptomatic despite intense

accumulation of parasitized erythrocytes in the placental microcirculation. Maternal HIV infection predisposes pregnant women to more

frequent and higher-density malaria infections, predisposes their newborns to congenital malarial infection, and exacerbates the reduction

in birth weight associated with malaria.

In areas with unstable transmission of malaria, pregnant women are

prone to severe infections and are particularly likely to develop high

P. falciparum parasitemias complicated by anemia, hypoglycemia, and

acute pulmonary edema. Fetal distress, premature labor, and stillbirth

or low birth weight are common results. Fetal death is usual in severe

malaria. Congenital malaria occurs in <5% of newborns of infected

mothers; its frequency and the level of parasitemia are related directly

to the timing of maternal infection and the parasite density in maternal

blood and in the placenta. P. vivax malaria in pregnancy is also associated with a reduction in birth weight (average, 110 g), but in contrast

to falciparum malaria, this effect is more pronounced in multigravid

than in primigravid women. About 300,000 women die in childbirth

yearly, with most deaths occurring in low-income countries; maternal death from hemorrhage at childbirth is correlated with malariainduced anemia.

■ MALARIA IN CHILDREN

Most of the >400,000 deaths from falciparum malaria each year are in

young African children. Convulsions, coma, hypoglycemia, metabolic

acidosis, and severe anemia are relatively common among children

with severe malaria, whereas deep jaundice, oliguric acute kidney

injury, and acute pulmonary edema are unusual. Severely anemic children may present with labored deep breathing, which in the past has

been attributed incorrectly to “anemic congestive cardiac failure” but in

fact is usually caused by metabolic acidosis, sometimes compounded

by hypovolemia. In general, children tolerate antimalarial drugs well

and respond rapidly to treatment.

■ TRANSFUSION MALARIA

Malaria can be transmitted by blood transfusion, needlestick injury, or

organ transplantation. The incubation period in these settings is often

short because there is no preerythrocytic stage of development, and

thus there are no relapses of P. vivax and P. ovale infections. The clinical

features and management of these cases are the same as for naturally

acquired infections although primaquine is not needed for vivax or

ovale malaria as there are no liver stages.

CHRONIC COMPLICATIONS OF MALARIA

■ HYPERREACTIVE MALARIAL SPLENOMEGALY

Chronic or repeated malarial infections produce hypergammaglobulinemia; normochromic, normocytic anemia; and, in certain situations,

splenomegaly. Some residents of malaria-endemic areas in tropical

countries exhibit an abnormal immunologic response to repeated

infections that is characterized by massive splenomegaly, hepatomegaly, marked elevations in serum IgM and malarial antibody titers,

hepatic sinusoidal lymphocytosis, and (in Africa) peripheral B-cell

lymphocytosis. This syndrome has been associated with the production of cytotoxic IgM antibodies to CD8+ T lymphocytes, antibodies to

CD5+ T lymphocytes, and an increase in the ratio of CD4+ to CD8+

T cells. These events may lead to uninhibited B cell production of IgM

and the formation of cryoglobulins (IgM aggregates and immune complexes). This immunologic process stimulates lymphoid hyperplasia

and clearance activity and eventually produces splenomegaly. Patients

with hyperreactive malarial splenomegaly present with an abdominal

mass or a dragging sensation in the abdomen and occasional sharp

abdominal pains suggesting perisplenitis. There is usually anemia and

some degree of pancytopenia (hypersplenism). In some cases, malaria

parasites cannot be found in peripheral-blood smears by microscopy.

Respiratory and skin infections are common and many patients die of

overwhelming sepsis. Persons with hyperreactive malarial splenomegaly living in endemic areas should receive antimalarial chemoprophylaxis; the results are usually good. In nonendemic areas, antimalarial

treatment is advised. Some cases have been mistaken for hematologic

malignancy. However, in other cases refractory to therapy, clonal

lymphoproliferation may develop and this can evolve into a malignant

lymphoproliferative disorder.

■ QUARTAN MALARIAL NEPHROPATHY

Chronic or repeated infections with P. malariae (and possibly with

other malarial species) may cause soluble immune complex injury

to the renal glomeruli, resulting in the nephrotic syndrome. Other

unidentified factors must contribute to this process since only a very

small proportion of infected patients develop renal disease. The histologic appearance is that of focal or segmental glomerulonephritis with

splitting of the capillary basement membrane. Subendothelial dense

deposits are seen on electron microscopy, and immunofluorescence

reveals deposits of complement and immunoglobulins and P. malariae antigens are often visible. A coarse-granular pattern of basement

membrane immunofluorescent deposits (predominantly IgG3) with

selective proteinuria carries a better prognosis than a fine-granular,

predominantly IgG2 pattern with nonselective proteinuria. Quartan

nephropathy is rarely reported nowadays. It usually responds poorly

to treatment with either antimalarial agents or glucocorticoids and

cytotoxic drugs.

■ BURKITT’S LYMPHOMA AND EPSTEIN-BARR

VIRUS INFECTION

It is possible that malaria-related immune dysregulation provokes

infection with lymphoma viruses. Childhood Burkitt’s lymphoma

is strongly associated with Epstein-Barr virus (EBV) and with high

transmission of P. falciparum. Chronic P. falciparum malaria drives

large numbers of EBV-infected cells through the lymph node germinal

centers and deregulates activation-induced cytidine deaminase, resulting in DNA damage, c-myc translocations, and sometimes lymphoma.

DIAGNOSIS OF MALARIA

When a patient in or from a malarious area presents with fever, thick

and thin blood smears should be prepared and examined immediately

to confirm the diagnosis and identify the species of infecting parasite

TABLE 224-4 Relative Incidence of Severe Complications of

Falciparum Malaria

COMPLICATION

NONPREGNANT

ADULTS

PREGNANT

WOMEN CHILDREN

Anemia + ++ +++

Convulsions + + +++

Hypoglycemia + +++ +++

Jaundice +++ +++ +

Renal failure +++ +++ –

Pulmonary edema ++ +++ +

Note: –, rare; +, infrequent; ++, frequent; +++, very frequent.