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Fatigue
Malaise
Shaking chills
Arthralgia
Myalgia
Paroxysm of fever, shaking chills, and sweats (every 48 or 72 hours,
depending on species)
Less common symptoms include the following:
Anorexia and lethargy
Nausea and vomiting
Diarrhea
Jaundice
Most patients with malaria have no specific physical findings, but splenomegaly
may be present. Severe malaria manifests as the following:
Cerebral malaria (sometimes with coma)
Severe anemia
Respiratory abnormalities: Include metabolic acidosis, associated respiratory
distress, and pulmonary edema; signs of malarial hyperpneic syndrome
include alar flaring, chest retraction, use of accessory muscles for
respiration, and abnormally deep breathing
Renal failure (typically reversible)
See Clinical Presentation for more detail.
Diagnosis
Plasmodium falciparum
P vivax
P ovale
P malariae
P knowlesi
In the United States, patients with P falciparum infection are often treated on an
inpatient basis to allow observation for complications. Patients with non P
falciparum malaria who are well can usually be treated on an outpatient basis.
General recommendations for pharmacologic treatment of malaria are as follows:
P falciparum malaria: Quinine-based therapy is with quinine (or quinidine)
sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine;
alternative therapies are artemether-lumefantrine, atovaquone-proguanil, or
mefloquine
P falciparum malaria with known chloroquine susceptibility (only a few
areas in Central America and the Middle East): Chloroquine
P vivax, P ovale malaria: Chloroquine plus primaquine
P malariae malaria: Chloroquine
P knowlesi malaria: Same recommendations as for P falciparum malaria
Pregnant women (especially primigravidas) are up to 10 times more likely to
contract malaria than nongravid women and have a greater tendency to develop
severe malaria. Medications that can be used for the treatment of malaria in
pregnancy include the following:
Chloroquine
Quinine
Atovaquone-proguanil
Clindamycin
Mefloquine (avoid in first trimester)
Sulfadoxine-pyrimethamine (avoid in first trimester)
Artemether-lumefantrine[2]
Artesunate and other antimalarials[3]
See Treatment and Medication for more detail.
Image library
blood cells infected with trophozoites do not produce sequestrins and, therefore,
P vivax
If this kind of infection goes untreated, it usually lasts for 2-3 months with
diminishing frequency and intensity of paroxysms. Of patients infected with P
vivax, 50% experience a relapse within a few weeks to 5 years after the initial
illness. Splenic rupture may be associated with P vivax infection secondary to
splenomegaly resulting from RBC sequestration. P vivax infects only immature
RBCs, leading to limited parasitemia.
P ovale
These infections are similar to P vivax infections, although they are usually less
severe. P ovale infection often resolves without treatment. Similar to P vivax, P
ovale infects only immature RBCs, and parasitemia is usually less than that seen in
P falciparum.
P malariae
Persons infected with this species of Plasmodium remain asymptomatic for a much
longer period of time than do those infected with P vivax or P ovale.
Recrudescence is common in persons infected with P malariae. It often is
associated with a nephrotic syndrome, possibly resulting from deposition of
antibody-antigen complex on the glomeruli.
P knowlesi
Autochthonous cases have been documented in Malaysian Borneo, Thailand,
Myanmar, Singapore, the Philippines, and other neighboring countries. It is
thought that simian malaria cases probably also occur in Central America and
South America. Patients infected with this, or other simian species, should be
treated as aggressively as those infected with falciparum malaria, as P knowlesi
may cause fatal disease.[4]
Epidemiology
Occurrence in the United States
Malaria was endemic in the southern United States until the 19th and early 20th
centuries, but it has since been eradicated. Almost all US cases of malaria are
imported from patients traveling from endemic areas. In very rare cases, infections
in individuals who have not traveled have occurred near airports (so-called airport
Individuals who are heterozygotic for RBC band 3 ovalocytosis are at reduced risk
of infection with P falciparum, P knowlesi, and, especially, P vivax malaria. West
African populations lacking RBC Duffy antigen are completely refractory to
infection by P vivax. Polymorphisms in a hosts TNF (tumor necrosis factor) gene
can also be protective against malaria.
Persons living in areas of malaria endemicity may develop partial immunity to
infection with time and repeated exposure. This limited immunity reduces the
frequency of symptomatic malaria and also reduces the severity of infection.
Immunity to malaria infection can be lost over long periods of time spent away
from endemic areas with limited exposure. As a result, those individuals born in
malaria-endemic regions who move abroad for work or study and then return home
may be at increased risk for developing severe malaria and complications of
infection.
History
In patients with suspected malaria, obtaining a history of recent or remote travel to
an endemic area is critical. Asking explicitly if they traveled to a tropical area at
anytime in their life may enhance recall. Maintain a high index of suspicion for
malaria in any patient exhibiting any malarial symptoms and having a history of
travel to endemic areas.
Also determine the patient's immune status, age, and pregnancy status; allergies or
other medical conditions that he or she may have; and medications that he or she
may be using.
Patients with malaria typically become symptomatic a few weeks after infection,
although the host's previous exposure or immunity to malaria affects the
symptomatology and incubation period. In addition, each Plasmodium species has
a typical incubation period. Importantly, virtually all patients with malaria present
with headache. Clinical symptoms also include the following:
Cough
Fatigue
Malaise
Shaking chills
Arthralgia
Myalgia
Paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on
species)
The classic paroxysm begins with a period of shivering and chills, which lasts for
approximately 1-2 hours and is followed by a high fever. Finally, the patient
experiences excessive diaphoresis, and the body temperature of the patient drops to
normal or below normal.
Many patients, particularly early in infection, do not present the classic paroxysm
but may have several small fever spikes a day. Indeed, the periodicity of fever
associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale [or
tertian fever] ; 72 h for P malariae [or quartan fever]) is not apparent during initial
infection because of multiple broods emerging in the bloodstream. In addition, the
periodicity is often not observed in P falciparum infections. Patients with longstanding, synchronous infections are more likely to present with classic fever
patterns. In general, however, the occurrence of periodicity of fever is not a reliable
clue to the diagnosis of malaria.
Less common malarial symptoms include the following:
Anorexia and lethargy
Nausea and vomiting
Diarrhea
Jaundice
Notably, infection with P vivax, particularly in temperate areas of India, may cause
symptoms up to 6-12 months after the host leaves the endemic area. In addition,
patients infected with P vivax or P ovale may relapse after longer periods, because
of the hypnozoite stage in the liver.
P malariae does not have a hypnozoite stage, but patients infected with P malariae
may have a prolonged, asymptomatic erythrocytic infection that becomes
symptomatic years after leaving the endemic area.
Tertian and quartan fevers are due to the cyclic lysis of red blood cells that occurs
as trophozoites complete their cycle in erythrocytes every 2 or 3 days, respectively.
P malariae causes quartan fever; P vivax and P ovale cause the benign form of
tertian fever, and P falciparum causes the malignant form. The cyclic pattern of
fever is very rare.
Travelers to forested areas of Southeast Asia and South America have become
infected by Plasmodium knowlesi, a dangerous species normally found only in
long-tailed and pigtail macaque monkeys (Macaca fascicularis and M nemestrina,
respectively). This species can cause severe illness and death in humans, but, under
the microscope, the parasite looks similar to the more benign P malariae and has
sometimes been misdiagnosed.
Because P malariae infection is typically relatively mild, Plasmodium knowlesi
infection should be suspected in persons residing or traveling in the above
geographical areas who are severely ill and have microscopic evidence of P
malariae infection. Diagnosis may be confirmed via polymerase chain reaction
(PCR) assay test methods.
Physical Examination
Most patients with malaria have no specific physical findings, but splenomegaly
may be present. Symptoms of malarial infection are nonspecific and may manifest
as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some
patients with malaria present with diarrhea and other gastrointestinal (GI)
symptoms. Immune individuals may be completely asymptomatic or may present
with mild anemia. Nonimmune patients may quickly become very ill.
Severe malaria primarily involves P falciparum infection, although death due to
splenic rupture has been reported in patients with non P falciparum malaria.
Severe malaria manifests as cerebral malaria, severe anemia, respiratory
symptoms, and renal failure.
In children, malaria has a shorter course, often rapidly progressing to severe
malaria. Children are more likely to present with hypoglycemia, seizures, severe
anemia, and sudden death, but they are much less likely to develop renal failure,
pulmonary edema, or jaundice.
Cerebral malaria
This feature is almost always caused by P falciparum infection. Coma may occur;
coma can usually be distinguished from a postictal state secondary to generalized
seizure if the patient does not regain consciousness after 30 minutes. When
evaluating comatose patients with malaria, hypoglycemia and CNS infections
should be excluded.
Severe anemia
The anemia associated with malaria is multifactorial and is usually associated with
P falciparum infection. In nonimmune patients, anemia may be secondary to
erythrocyte infection and a loss of infected RBCs. In addition, uninfected RBCs
are inappropriately cleared, and bone marrow suppression may be involved.
Renal failure
This is a rare complication of malarial infection. Infected erythrocytes adhere to
the microvasculature in the renal cortex, often resulting in oliguric renal failure.
Renal failure is typically reversible, although supportive dialysis is often needed
until kidney function recovers. In rare cases, chronic P malariae infection results in
nephrotic syndrome.
Respiratory symptoms
Patients with malaria may develop metabolic acidosis and associated respiratory
distress. In addition, pulmonary edema can occur. Signs of malarial hyperpneic
syndrome include alar flaring, chest retraction (intercostals or subcostal), use of
accessory muscles for respiration, or abnormally deep breathing
Approach Considerations
In returning travelers from endemic areas, malaria is suggested by the triad of
thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical
lymphocytes. These findings should prompt obtaining malarial smears.
In general, blood cultures should be drawn in a febrile patient. Patients from
tropical areas may have more than 1 infection; maintaining a high suspicion for
additional infections should be considered when patients do not respond to
antimalarials.
Assess hemoglobin (decreased in 25% of patients, often profoundly in young
children), platelet counts (thrombocytopenia in 50-68% of patients), and liver
Alternative diagnostic methods typically are used if the laboratory does not have
sufficient expertise in detecting parasites in blood smears.
Rapid diagnostic tests (RDT)
Immunochromatographic tests based on antibody to histidine-rich protein-2
(PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very
sensitive and specific.[11, 12] Some RDTs may be able to detect P falciparum in
parasitemias that are below the threshold of reliable microscopic species
identification. Only one RDT (BinaxNOW) has been approved to date for the
diagnosis of malaria in the United State.[13]
In one study, RDTs were found to perform better than microscopy under routine
conditions. RDTs performed by the health facility staff were 91.7% sensitive and
96.7% specific. Microscopy was 52.5% sensitive and 77% specific.[14] A recent
sudy using loop-mediated amplification technique (LAMP)also suggests that RDTs
have accuracy similar to that of nested PCR, with a greatly reduced time to result,
and was superior to expert microscopy.[15]
In a study from Tanzania, d'Acremont et al reported that antimalarials could be
safely withheld from febrile children (< 5 y) who had negative results from an
RDT based on PfHRP2.[16]
RDTs are less effective when parasite levels are below 100 parasites/mL of blood,
and, in rare instances, an RDT test is negative in patients with high parasitemias.
For these reasons, confirm RDT test results with a second type of screening test
when possible. A false-positive result from an RDT may occur up to 2 weeks or
more after treatment due to persistence of circulating antigens.
Other tests
In addition to the RDT listed above, new molecular techniques, such as PCR assay
testing and nucleic acid sequence-based amplification (NASBA), are also available
for diagnosis. They are more sensitive than thick smears but are expensive and
unavailable in most developing countries.[17]
The quantitative buffy coat (QBC) is a technique that is as sensitive as thick
smears. Because results cannot be used to speciate Plasmodium, a thin smear must
be examined.
small advantage for mefloquine in terms of efficacy, although the incidence of side
effects was higher with mefloquine than with sulfadoxine-pyrimethamine.[31, 32]
In addition to mefloquine and sulfadoxine-pyrimethamine, other medications have
been used in the treatment of the pregnant patient with malaria. In a recent study in
African patients, artemether-lumefantrine was as efficacious and as well tolerated
as oral quinine in treating uncomplicated falciparum malaria during the second and
third trimesters of pregnancy.[2]
Artesunate and other antimalarials also appear to be effective and safe in the first
trimester of pregnancy, when development of malaria carries a high risk of
miscarriage.[3]
Inpatient Care
Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or
otherwise severe symptoms and those with P falciparum infection should be
considered for inpatient treatment to ensure that medicines are tolerated.
Obtain blood smears every day to demonstrate a response to treatment. The sexual
stage of the protozoan, the gametocyte, does not respond to most standard
medications (eg, chloroquine, quinine), but gametocytes eventually die and do not
pose a threat to the individual's health or cause any symptoms.
Deterrence and Prevention
Avoid mosquitoes by limiting exposure during times of typical blood meals (ie,
dawn, dusk). Wearing long-sleeved clothing and using insect repellants may also
prevent infection. Avoid wearing perfumes and colognes.
Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In
children, use concentrations of less than 35% DEET. Use sparingly and only on
exposed skin. Remove DEET when the skin is no longer exposed to potential
mosquito bite. Consider using bed nets that are treated with permethrin. While this
is an effective method for prevention of malaria transmission in endemic areas, an
increasing incidence of pyretrhoid resistance in Anopheles spp has been reported.
[33]
Seek out medical attention immediately upon contracting any tropical fever or
flulike illness.
Consider chemoprophylaxis with antimalarials in patients traveling to endemic
areas. Chemoprophylaxis is available in many different forms. The drug of choice
is determined by the destination of the traveler and any medical conditions the
traveler may have that contraindicate the use of a specific drug.
Before traveling, people should consult their physician and the Malaria and
Traveler's Web site of the CDC to determine the most appropriate
chemoprophylaxis.[34] Travel Medicine clinics are also a useful source of
information and advice.
Investigational malaria vaccine
Interim phase 3 trial results have been reported for the malaria vaccine
RTS,S/AS01. The results included 6000 African children aged 5-17 months who
received the malaria vaccine or a comparator vaccine and were followed for 12
months. The incidence of malaria was 0.44 case per person-year in the
RTS,S/AS01 group, compared with 0.83 case per person-year in the comparator
vaccine group. The vaccine efficacy rate was calculated to be 55.8%.[35, 36]
Consultations
Consider consulting an infectious disease specialist for assistance with malaria
diagnosis, treatment, and disease management. The CDC is an excellent resource if
no local resources are available. To obtain the latest recommendations for malaria
prophylaxis and treatment from the CDC, call the CDC Malaria Hotline at (770)
488-7788 or (855) 856-4713 (M-F, 9 am-5 pm, Eastern time). For emergency
consultation after hours, call (770) 488-7100 and ask to talk with a CDC Malaria
Branch clinician.[37]
Pregnant patients with malaria are at increased risk of morbidity and mortality.[38]
In addition, nonimmune mothers and immune primigravidas may be at an
increased risk of low birth weight, fetal loss, and prematurity. Consult an expert in
malaria to determine the safest and most effective prophylaxis or treatment in a
pregnant woman
Medication Summary
The 4 major drug classes currently used to treat malaria include quinoline-related
compounds, antifolates, artemisinin derivatives, and antimicrobials. No single
drug that can eradicate all forms of the parasite's life cycle has been discovered or
manufactured yet. Therefore, 1 or more classes of drugs often are given at the
same time to combat malarial infection synergistically. Treatment regimens are
Chloroquine phosphate is effective against P vivax, P ovale, P malariae, and drugsensitive P falciparum. It can be used for prophylaxis or treatment. This is the
prophylactic drug of choice for sensitive malaria.
View full drug information
Quinine (Qualaquin)
Quinine is used for malaria treatment only; it has no role in prophylaxis. It is used
with a second agent in drug-resistant P falciparum. For drug-resistant parasites, the
second agent is doxycycline, tetracycline, pyrimethamine sulfadoxine, or
clindamycin.
View full drug information
Quinidine gluconate
Atovaquone may inhibit metabolic enzymes, which in turn inhibits the growth of
microorganisms.
Used for pediatric patients, this combination should be administered for
uncomplicated P falciparum; can also be used in combination with chloroquine.
This agent is approved in the United States for the prophylaxis and treatment of
mild chloroquine-resistant malaria. It may be a good prophylactic option for
patients who are visiting areas with chloroquine-resistant malaria and who cannot
tolerate mefloquine. Each tab combines 250 mg of atovaquone and 100 mg of
proguanil hydrochloride. The dosage for children is based on body weight; in
children 40 kg (88 lb) or less, a lower-dose pediatric tablet (62.5 mg of atovaquone
and 25 mg of proguanil hydrochloride) is available.
Primaquine is not used to treat the erythrocytic stage of malaria. Administer the
drug for the hypnozoite stage of P vivax and P ovale to prevent relapse.
View full drug information
Artemether and lumefantrine (Coartem)