INFECTIONS
November 1, 2007

Malaria

Joel G. Breman, M.D.
Dr. Breman is D.T.P.H, Senior Scientific Advisor at Fogarty International Center, National Institutes of Health, Bethesda, Maryland.


Most of us think of the mosquito-borne disease malaria as ancient history, but the truth is it remains a threat in tropical areas that are home to three billion people, killing between one and three million each year. Mosquito control has eliminated malaria in the U.S. and Canada, but it survives and has even made a comeback in many parts of the world. Despite promising new research efforts, malaria continues to be a major world health problem.

How Malaria Happens
Malaria is caused by a parasite that is carried by mosquitos who transmit the parasite to people when they bite them to feed on human blood. The parasite that causes malaria belongs to the genus Plasmodium. It has four subtypes that cause nearly all malarial infections in humans. They are called P. falciparum, P. vivax, P. ovale and P. malariae.

Almost all deaths from malaria are caused by the first one on the list, falciparum malaria. Human infection occurs when a female anopheles mosquito bites a person and transmits cells called sporozoites from its salivary gland to a person's bloodstream.

The Malaria Transmission Cycle
Sporozoite cells deposited in the human bloodstream after a mosquito bite travel rapidly to the liver, where they invade liver cells; the infected liver cells swell and eventually burst, discharging cells (called merozoites) into the bloodstream. These infected cells then invade red blood cells and multiply 6- to 20-fold every 48 to 72 hours. In certain strains of malaria, P. vivax and P. ovale, infected cells (called hypnozoites) remain dormant for between 3 weeks and a year or more. These dormant infected cells are what are behind the relapses that so often characterize certain types of malaria.

The disease we call malaria is a result of the direct and indirect effects of red blood cell invasion and destruction by the parasite

After reentering the bloodstream the infected merozoites rapidly invade red blood cells. By the end of 48 hours, (72 hours for P. malariae), the parasite has grown to occupy most of the affected red blood cells. Multiple nuclear divisions then occur and the red blood cell then ruptures to release 6 to 30 daughter merozoites, each potentially capable of invading a new red blood cell.

The disease we call malaria is a result of the direct and indirect effects of red blood cell invasion and destruction by the parasite. After a series of asexual reproduction cycles (P. falciparum) or immediately after release from the liver (P. vivax, P. ovale, P. malariae), some of the parasites develop into distinct, longer-lived sexual forms (gametocytes) that continue the cycle of malaria transmissionafater ingestion of gametocytes by the mosquito.

The lifecycle of the the parasite within the mosquito continues in the following manner. After being ingested along with human blood by a biting female anopheles mosquito, male and female gametocytes form a cell called a zygote in the insect's stomach. This develops into something called an oocyst, which expands asexually, by division, until it bursts to liberate many sporozoites, which then migrate to the salivary gland of the mosquito to await transmission to another human at the next feeding.

Partial Immunity Is Not Necessarily Protection
After surviving repeated exposures to malaria, the human immune system can develop the capacity to protect the body from many of the effects of the disease, but not from further infection. As a result, a state of infection and partial immunity without illness is common among adults and older children in some areas. Despite this, the complexity of the human immune response to malaria, the sophistication of the parasites' evasion mechanisms and other factors have slowed progress toward an effective vaccine.

Where Malaria Is Found — and Why
Malaria depends on the ability of the anopheles mosquito to breed, which requires standing water, which in turn depends on rainfall. In certain regions of tropical Africa or coastal New Guinea where P. falciparum is common, people may receive many mosquito bites per day and become infected constantly throughout their lives. In these regions, infection rates and mortality from malaria are high during childhood. By adulthood, however, most people who live in these areas have developed a limited immunity to malaria; their infections are mild and cause few symptoms.

Malaria is an epidemic disease in northern India, Sri Lanka, Afghanistan, the Sahel areas of Africa, Ethiopia, the East African highlands, Burundi, Rwanda, Madagascar and Brazil. Outside of these areas, an epidemic can develop when there are heavy rains following drought or after people migrate from a non-malaria infected region to an area of high transmission. Breakdowns in malaria control and the local health care system can intensify an epidemic. Urban malaria is increasingly common, as cities grow rapidly in many malaria-infected areas.

[A]n epidemic can develop when there are heavy rains following drought or after people migrate from a non-malaria infected region to an area of high transmission.

The transmission of malaria is directly proportional to the population density of the mosquitoes that carry the disease, the number of human bites per day per mosquito and the probability of the mosquito's surviving for 1 day.

Mosquito longevity is particularly important because in order to transmit malaria, the mosquito must survive for at least seven days to accommodate the portion of the parasite's life cycle that takes place within the mosquito.

The most effective mosquito carrier of malaria is anopheles gambiae, an African mosquito that is long-lived, occurs in high densities in tropical climates, breeds readily and prefers human blood to animal blood.

Early Symptoms
The first symptoms of malaria — malaise, headache, fatigue, abdominal discomfort and muscle aches, followed by fever — are similar to those of any viral illness. Unlike meningitis, malaria causes no neck stiffness or sensitivity to light. Muscle pain from malaria is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting and low blood pressure are common.

The classic malaria attack that most people are familiar with — in which fever spikes and chills come and go in waves — is relatively unusual. The temperature of infected adults and children can exceed above 40°C or 104°F and is accompanied by increased heart rate and delirium. Although any of the types of malaria may cause childhood convulsions, seizures are specifically associated with the most common form — falciparum malaria and may indicate the development of cerebral malaria (see below).

Most victims have few physical symptoms other than fever, malaise, mild anemia and, sometimes, a swollen spleen. Splenic enlargement is found in many otherwise healthy individuals in malaria-infested areas and is a sign of repeated infections. Enlargement of the liver among young children and mild jaundice among adults are also common.

Symptoms of Severe Falciparum Malaria
When promptly treated, (24 to 48 hours after symptom onset), simple falciparum malaria carries a low mortality rate — around 0.1%. However, once vital organs are affected or the total proportion of red blood cells infected increases to more than 2%, mortality rises steeply. Some of the symptoms of severe falciparum malaria follow.

Coma and Retinal Hemorrhages
Falciparum malaria can lead to so-called cerebral malaria, which can cause coma. Coma is associated with death rates of around 20% among adults and 15% among children. The coma may come on gradually or suddenly, following a convulsion.

Retinal hemorrhages occur in 30 to 40% of those with cerebral malaria. Other eye symptoms include retinal opacification, papilledema (swelling of the eye), "cotton wool" spots and loss of color in a retinal vessel or part of a vessel.

Convulsions
Convulsions occur in as many as half of children with cerebral malaria. About 15% of children who survive cerebral malaria — especially those with hypoglycemia, severe anemia, repeated seizures and deep coma — are left with some neurologic impairment, including partial paralysis, cerebral palsy, blindness, deafness and impaired cognition and learning. They may also develop epilepsy.

Hypoglycemia
Hypoglycemia, or low blood sugar, is common in severe malaria; it indicates a poor prognosis and is particularly dangerous for children and pregnant women.

Acidosis
Acidosis, or acid buildup in the blood, is one of the main causes of death from severe malaria.

Pulmonary Edema
Adults with severe falciparum malaria may develop pulmonary edema, or fluid buildup in the lungs, even after several days of antimalarial therapy. The mortality rate for people with this symptom is 80% or higher.

Kidney Impairment
Kidney problems are common among adults with severe falciparum malaria but rare among children. Acute kidney failure may occur at the same time as other vital organ dysfunction, in which case mortality is high, or may emerge as other disease symptoms resolve.

Anemia
Anemia can develop rapidly and blood transfusions are often required. As a consequence of repeated malarial infections, children in many areas of Africa may develop chronic severe anemia along with antimalarial drug resistance.

Liver Dysfunction
When accompanied by other vital organ dysfunction (e.g., kidney impairment), liver dysfunction indicates a poor prognosis.

Other Complications
Salmonella bacteria infection often occurs with P. falciparum infections. HIV and malaria infections can increase each other's effects. The most common complications of severe falciparum malaria are summarized in Table 1.

Table 1.
Severe Falciparum Malaria Complications.

Adults Pregnant women Children
Anemia + ++ +++
Convulsions + + +++
Hypoglycemia + +++ +++
Jaundice +++ +++ +
Renal failure +++ +++ -
Pulmonary edema ++ +++ +


Key:
- = rare
+ = infrequent
++ = frequent
+++ = very frequent


Malaria and Pregnancy
In areas where malaria is extremely common, falciparum malaria causes low birth weight and increased infant and childhood mortality. HIV infection predisposes pregnant women to malaria, predisposes their newborns to malaria infection and exacerbates the reduction in birth weight associated with malaria.

In other areas, pregnant women are prone to severe infections and are particularly vulnerable to fetal distress, premature labor and stillbirth or low birth weight. P. vivax malaria in pregnancy is also associated with low birth weight.

Malaria in Children
Most of the estimated 1 to 3 million persons who die of falciparum malaria each year are young African children. Survivors are often severely anemic and suffer from labored, deep breathing. They also tend to suffer long-term cognitive and developmental deficits.

Diagnosis — Detecting the Parasite
Malaria is diagnosed by finding forms of the parasite in blood smears. Because false negatives are common, repeat smears sometimes come back positive.

Treatment
Antimalarial drug treatment should be started immediately. Several drugs are available to treat malaria. The choice of drug depends on geography, because the infecting parasites in some areas have developed resistance to particular drugs. Chloroquine remains the treatment of choice for the P. vivax, P. ovale and P. malariae, except in Indonesia and Papua New Guinea, where there are very high levels of resistance.

Those with severe malaria or those unable to take medicine orally should be given antimalarial drugs by injection or IV.

Fake or adulterated drugs, including antimalarial agents, are being sold in many developing countries.

The treatment of falciparum malaria has changed radically in recent years. In endemic areas the World Health Organization now recommends artemisinin-based combinations (ACTs) as the first line of treatment for falciparum malaria. These reliable and rapidly effective drugs are often unavailable in temperate countries such as the United States. In August 2007, the Food and Drug Administration (FDA) gave the Centers for Disease Control and Prevention (CDC) permission to provide intravenous artesunate for severe malaria. The availability of antimalarial drugs varies considerably from one country to another. Fake or adulterated drugs, including antimalarial agents, are being sold in many developing countries.

Severe Malaria
In large studies conducted in Asia, treatment with artesunate has been shown, compared to quinine, to cut the mortality of severe falciparum malaria by 35%. Artesunate is usually given by IV but can also be given by injection. An artesunate suppository has been developed in the rural tropics for people unable to take oral medications. These drugs are safer than quinine and quinidine.

Quinidine gluconate is as effective as quinine and is more readily available. Therefore it has replaced quinine for the treatment of malaria in the United States.

Uncomplicated Malaria
Infections from P. vivax, P. malariae and P. ovale should be treated with oral chloroquine. In much of the tropics, drug resistant strains of P. falciparum are spreading. Chloroquine-resistant P. falciparum is now present throughout most of the tropical world and resistance to sulfadoxine/pyrimethamine is becoming widespread.

To prevent resistance, falciparum malaria should be treated with drug combinations, particularly in endemic areas. This means simultaneous use of two or more drugs: one, usually an artemisinin derivative (artesunate, artemether or dihydroartemisinin); and the other, a slower-acting antimalarial to which P. falciparum is sensitive. Artemisinin combination treatments are now recommended as the first-line treatment for falciparum malaria.

Artesunate or quinine plus tetracycline, doxycycline or clindamycin are all effective as second-line treatments. Tetracycline and doxycycline cannot be given to pregnant women or to children younger than eight. Oral quinine is extremely bitter and has unpleasant side effects such as ringing in the ears, partial deafness, nausea, vomiting and irritability.

If there is any doubt as to the identity of the infecting malarial species, treatment for falciparum malaria should be given.

Complications
Blood glucose levels should be checked regularly after treatment, as low blood sugar is a common side effect, particularly in those taking quinine or quinidine. Spontaneous bleeding is treated with transfusions of fresh blood and IV vitamin K. Convulsions are treated with IV or rectal benzodiazepines. Pneumonia is common in unconscious victims with convulsions. Low blood sugar or super-infections such as gram-negative septicemia should be tested for when the condition of any malaria victim suddenly deteriorates for no obvious reason.

What You Can Do to Protect Yourself Against Malaria

Personal Protection
  • The first line of defense against malaria is to reduce your risk of mosquito bites in malarious areas.
  • Stay inside at peak feeding times (dusk and dawn) and throughout the night
  • Use insect repellents containing DEET or picardin
  • Wear clothing that covers as much skin as possible
  • Use insecticide-impregnated bed nets and other materials

Preventive Drugs
Which preventive drug to use depends on where you will be and the local patterns of drug sensitivity as well as your likelihood of developing malarial infection. When there is uncertainty, drugs effective against resistant P. falciparum should be used [atovaquone-proguanil (Malarone®), doxycycline, mefloquine or primaquine].

Preventive drugs are never foolproof and malaria should always be considered as a possible cause of fever in people who have traveled to areas where it is common, even if they have been taking antimalarial drugs.

Travelers should start taking antimalarial drugs at least a week before departure in case they have a bad reaction. They should then continue for four weeks after the traveler has left the endemic area...

Pregnant women traveling to malarious areas should strongly consider the potential risks. All pregnant women in endemic areas should have regular check-ups with an OB-GYN. Apart from mefloquine, the safety of preventive antimalarial drugs for pregnant women is uncertain.

Preventive antimalarial drugs have been shown to reduce mortality in children between the ages of 3 months and 4 years in malaria endemic areas but they are too expensive for many developing countries. An alternative, giving intermittent treatment doses (IPT), has shown promise in infants, young children and pregnant women. Children born to non-immune mothers in endemic areas (usually expatriates moving to malaria endemic areas) should receive preventive drugs from birth.

What Travelers Need to Know
Travelers should start taking antimalarial drugs at least a week before departure in case they have a bad reaction. They should then continue for four weeks after the traveler has left the endemic area, except if atovaquone-proguanil or primaquine has been taken — these drugs should be discontinued one week after departure.

Atovaquone-proguanil is a fixed-combination once-daily preventive treatment for both adults and children; it has fewer gastrointestinal side effects than chloroquine-proguanil and fewer central nervous system side effects than mefloquine. Atovaquone-proguanil is best taken with food or a milky drink. There are insufficient data on the safety of this treatment in pregnancy.

Mefloquine has been widely used because of its effectiveness against multidrug-resistant falciparum malaria and its relatively few side effects. Mild nausea, dizziness, fuzzy thinking, disturbed sleep patterns, vivid dreams and malaise are the most common. Approximately 1 in every 10,000 recipients develops an acute, but reversible, neuropsychiatric reaction causing confusion, psychosis and convulsions.

Doxycycline is an effective alternative to atovaquone-proguanil or mefloquine. Doxycycline is generally well tolerated but may cause thrush, diarrhea and photosensitivity and cannot be used by children under eight or by pregnant women.

Chloroquine remains the drug of choice for the prevention of infection with drug-sensitive P. falciparum and with the other human malarial species. Chloroquine has few side effects, although some are unable to take the drug because of malaise, headache, vision problems, gastrointestinal intolerance or (in dark-skinned people) itchy skin. Chloroquine is safe for pregnant women.

Primaquine has proven safe and effective in the prevention of drug-resistant falciparum and vivax malaria in adults. This drug can be considered for travelers who are intolerant to other drugs. Abdominal pain and a blood condition called oxidant hemolysis, the principal side effects, are not common as long as the drug is taken with food. Primaquine should not be given to pregnant women or newborns.

Conclusion
These are halcyon days for malaria prevention and control. Highly effective new drugs have been discovered and developed; insecticide-treated mosquito nets and insecticides for spraying inside dwellings are being purchased for endemic countries by the Global Fund for HIV/AIDS, Malaria and Tuberculosis and the President's Malaria Initiative. The Roll Back Malaria Partnership, Global Health Council and other organizations are advocating strongly for even greater efforts.

Still, the total eradication of malaria remains an elusive goal because of the widespread distribution of anopheles breeding sites; the great number of infected people; the continued use of ineffective antimalarial drugs; and the widespread lack of trained treatment and research personel, material resources, infrastructure and control programs.

Malaria may someday be contained by judicious use of insecticides to kill the mosquito; rapid diagnosis and more effective treatment; and the administration of preventive drugs to high-risk groups. Toward this end, malaria researchers are intensifying their efforts to better understand the parasite-human-mosquito cycle.

Despite the enormous current investment in efforts to develop a malaria vaccine, no safe, effective, long-lasting vaccine is likely to be available for general use in the near future. While one or more malaria vaccines may be on the distant horizon, our primary weapons against this dreadful disease remain prevention, mosquito control measures and rapid drug treatment.

Government Resources
Because of the increasing spread and intensity of antimalarial drug resistance, the Centers for Disease Control and Prevention (CDC; http://www.cdc.gov/malaria/), which recommends a daily dose of atovaquone-proguanil for all travelers, maintains an updated 24-h travel and malaria information audiotape that can be accessed by touch-tone telephone (877-FYI-TRIP).

Regional and disease-specific documents may be requested from the CDC Fax Information Service (888-232-3299). Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and local health departments and the CDC Malaria Hotline (770-488-7788) or the CDC Emergency Operations Center (770-488-7100).
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