Malaria (www.cdc.gov)

Disease

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Incubation Period | Uncomplicated Malaria | Severe Malaria | Malaria Relapses | Other Manifestations of Malaria

Infection with malaria parasites may result in a wide variety of symptoms, ranging from absent or very mild symptoms to severe disease and even death. Malaria disease can be categorized as uncomplicated or severe (complicated) . In general, malaria is a curable disease if diagnosed and treated promptly and correctly.

Patient with symptoms of malaria seen at the Moronacocha Health Center in the outskirts of Iquitos, on the Peruvian Amazon. A blood smear confirmed that he had malaria. (Image contributed by Dr. Jaime Chang, USAID/Peru)

Incubation Period

Following the infective bite by the Anopheles mosquito, a period of time (the "incubation period") goes by before the first symptoms appear. The incubation period in most cases varies from 7 to 30 days. The shorter periods are observed most frequently with P. falciparum and the longer ones with P. malariae.

Antimalarial drugs taken for prophylaxis by travelers can delay the appearance of malaria symptoms by weeks or months, long after the traveler has left the malaria-endemic area. (This can happen particularly with P. vivax and P. ovale, both of which can produce dormant liver stage parasites; the liver stages may reactivate and cause disease months after the infective mosquito bite.)

Such long delays between exposure and development of symptoms can result in misdiagnosis or delayed diagnosis because of reduced clinical suspicion by the health-care provider. Returned travelers should always remind their health-care providers of any travel in malaria-risk areas during the past 12 months.

Uncomplicated Malaria

The classical (but rarely observed) malaria attack lasts 6-10 hours. It consists of:

• a cold stage (sensation of cold, shivering)
• a hot stage (fever, headaches, vomiting; seizures in young children)
• and finally a sweating stage (sweats, return to normal temperature, tiredness)

Classically (but infrequently observed) the attacks occur every second day with the "tertian" parasites (P. falciparum, P. vivax, and P. ovale) and every third day with the "quartan" parasite (P. malariae).

More commonly, the patient presents with a combination of the following symptoms:

• Fever
• Chills
• Sweats
• Headaches
• Nausea and vomiting
• Body aches
• General malaise.

In countries where cases of malaria are infrequent, these symptoms may be attributed to influenza, a cold, or other common infections, especially if malaria is not suspected. Conversely, in countries where malaria is frequent, residents often recognize the symptoms as malaria and treat themselves without seeking diagnostic confirmation ("presumptive treatment").

Physical findings may include:

• Elevated temperature
• Perspiration
• Weakness
• Enlarged spleen.

In P. falciparum malaria, additional findings may include:

• Mild jaundice
• Enlargement of the liver
• Increased respiratory rate.

Diagnosis of malaria depends on the demonstration of parasites on a blood smear examined under a microscope. In P. falciparum malaria, additional laboratory findings may include mild anemia, mild decrease in blood platelets (thrombocytopenia), elevation of bilirubin, elevation of aminotransferases, albuminuria, and the presence of abnormal bodies in the urine (urinary "casts").

Severe Malaria

Severe malaria occurs when P. falciparum infections are complicated by serious organ failures or abnormalities in the patient's blood or metabolism. The manifestations of severe malaria include:

• Cerebral malaria, with abnormal behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities
• Severe anemia due to hemolysis (destruction of the red blood cells)
• Hemoglobinuria (hemoglobin in the urine) due to hemolysis
• Pulmonary edema (fluid buildup in the lungs) or acute respiratory distress syndrome (ARDS), which may occur even after the parasite counts have decreased in response to treatment
• Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets)
• Cardiovascular collapse and shock

Other manifestations that should raise concern are:

• Acute kidney failure
• Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites
• Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia
• Hypoglycemia (low blood glucose). Hypoglycaemia may also occur in pregnant women with uncomplicated malaria, or after treatment with quinine.

Severe malaria occurs most often in persons who have no immunity to malaria or whose immunity has decreased. These include all residents of areas with low or no malaria transmission, and young children and pregnant women in areas with high transmission.

In all areas, severe malaria is a medical emergency and should be treated urgently and aggressively.

Malaria Relapses

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ("hypnozoites") that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack.

Other Manifestations of Malaria

• Neurologic defects may occasionally persist following cerebral malaria, especially in children. Such defects include troubles with movements (ataxia), palsies, speech difficulties, deafness, and blindness.
• Recurrent infections with P. falciparum may result in severe anemia. This occurs especially in young children in tropical Africa with frequent infections that are inadequately treated.
• Malaria during pregnancy (especially P. falciparum) may cause severe disease in the mother, and may lead to premature delivery or delivery of a low-birth-weight baby.
• On rare occasions, P. vivax malaria can cause rupture of the spleen or acute respiratory distress syndrome (ARDS).
• Nephrotic syndrome (a chronic, severe kidney disease) can result from chronic or repeated infections with P. malariae.
• Hyperreactive malarial splenomegaly (also called "tropical splenomegaly syndrome") occurs infrequently and is attributed to an abnormal immune response to repeated malarial infections. The disease is marked by a very enlarged spleen and liver, abnormal immunologic findings, anemia, and a susceptibility to other infections (such as skin or respiratory infections).
  

See also: Diagnosis

The History of Malaria, an Ancient Disease (Copy From www.cdc.gov)

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Malaria or a disease resembling malaria has been noted for more than 4,000 years. From the Italian for "bad air," mal'aria has probably influenced to a great extent human populations and human history.

Ancient History (2700 BCE-340 CE)

The symptoms of malaria were described in ancient Chinese medical writings. In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching, The Canon of Medicine). Nei Ching was edited by Emperor Huang Ti. Malaria became widely recognized in Greece by the 4th century BCE, and it was responsible for the decline of many of the city-state populations. Hippocrates noted the principal symptoms. By the age of Pericles, there were extensive references to malaria in the literature and depopulation of rural areas was recorded. In the Susruta, a Sanskrit medical treatise, the symptoms of malarial fever were described and attributed to the bites of certain insects. A number of Roman writers attributed malarial diseases to the swamps.

In China, during the second century BCE, the Qinghao plant (Artemisia annua L) was described in the medical treatise, 52 Remedies, found in the Mawangdui Tomb. In the United States, this plant is known as the annual or sweet wormwood.) In 340 CE, the anti-fever properties of Qinghao were first described by Ge Hong of the East Yin Dynasty. The active ingredient of Qinghao was isolated by Chinese scientists in 1971. Known as artemisinin, it is today a very potent and effective antimalarial drug, especially in combination with other medicines.

Quinine (Early 17th Century)

Plate from "Quinologie", Paris, 1854, showing bark of Quinquina calisaya (from Bolivia).

Following their arrival in the New World, the Spanish learned of a medicine used for the treatment of fevers. Spanish Jesuit missionaries in South America learned of a medicinal bark from indigenous Indian tribes. With this bark, the Countess of Chinchón, the wife of the Viceroy of Peru, was cured of her fever. The bark from the tree was then called Peruvian bark and the tree was named Cinchona after the countess. The medicine from the bark is now known as the antimalarial, quinine. Along with artemisinin, quinine is one of the most effective antimalarial drugs available today.

Alphonse Laveran was the first to notice parasites in the blood of a patient suffering from malaria.

Discovery of the Malaria Parasite (1880)

Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria. This occurred on the 6th of November 1880. For his discovery, Laveran was awarded the Nobel Prize in 1907.

More: Laveran and the Discovery of the Malaria Parasite

Differentiation of Species of Malaria (1886)

Camillo Golgi, an Italian neurophysiologist, established that there were at least two forms of the disease, one with tertian periodicity (fever every other day) and one with quartan periodicity (fever every third day). He also observed that the forms produced differing numbers of merozoites (new parasites) upon maturity and that fever coincided with the rupture and release of merozoites into the blood stream. He was awarded a Nobel Prize in Medicine for his discoveries in neurophysiology in 1906.

Naming of Human Malaria Parasites (1890,1897)

The Italian investigators Giovanni Batista Grassi and Raimondo Filetti first introduced the names Plasmodium vivax and P. malariae for two of the malaria parasites that affect humans in 1890. Laveran had believed that there was only one species, Oscillaria malariae. An American, William H. Welch, reviewed the subject and, in 1897, he named the malignant tertian malaria parasite, P. falciparum. There were many arguments against the use of this name, however, the use was so extensive in the literature that a change back to the name given by Laveran was no longer thought possible. In 1922, John William Watson Stephens described the fourth human malaria parasite, P. ovale.

Ronald Ross was the first to demonstrate that a mosquito could transmit a (bird) malaria parasite.

Discovery That Mosquitoes Transmit Malaria Parasites (1897-1898)

On August 20th, 1897, Ronald Ross, a British officer in the Indian Medical Service, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes. In further work with bird malaria, Ross showed that mosquitoes could transmit malaria parasites from bird to bird. This necessitated a sporogonic cycle (the time interval during which the parasite developed in the mosquito). Thus, the problem of malaria transmission was solved. For his discovery, Ross was awarded the Nobel Prize in 1902.

More: Ross and the Discovery that Mosquitoes Transmit Malaria Parasites

Discovery of the Transmission of the Human Malaria Parasites Plasmodium (1898-1899)

Led by Giovanni Batista Grassi, a team of Italian investigators, which included Amico Bignami and Giuseppe Bastianelli, collected Anopheles claviger mosquitoes and fed them on malarial patients. The complete sporogonic cycle of Plasmodium falciparum, P. vivax, and P. malariae was demonstrated. In 1899, mosquitoes infected by feeding on a patient in Rome were sent to London where they fed on two volunteers, both of whom developed benign tertian malaria.

The Panama Canal (1905-1910)

The construction of the Panama Canal was made possible only after yellow fever and malaria were controlled in the area. These two diseases were a major cause of death and disease among workers in the area. In 1906, there were over 26,000 employees working on the Canal. Of these, over 21,000 were hospitalized for malaria at some time during their work. By 1912, there were over 50,000 employees, and the number of hospitalized workers had decreased to approximately 5,600. Through the leadership and efforts of William Crawford Gorgas, Joseph Augustin LePrince, and Samuel Taylor Darling, yellow fever was eliminated and malaria incidence markedly reduced through an integrated program of insect and malaria control.

More: The Panama Canal

The U.S. Public Health Service (USPHS) and Malaria (1914-1942)

During the U.S. military occupation of Cuba and the construction of the Panama Canal at the turn of the 20th century, U.S. officials made great strides in the control of malaria and yellow fever. In 1914 Henry Rose Carter and Rudolph H. von Ezdorf of the USPHS requested and received funds from the U.S. Congress to control malaria in the United States. Various activities to investigate and combat malaria in the United States followed from this initial request and reduced the number of malaria cases in the United States. The USPHS established malaria control activities around military bases in the malarious regions of the southern United States to allow soldiers to train year round.

The U.S. Tennessee Valley Authority (TVA) - The Integration of Malaria Control with Economic Development (1933)

U.S. President Franklin D. Roosevelt signed a bill that created the TVA on May 18, 1933. The law gave the federal government a centralized body to control the Tennessee river's potential for hydroelectric power and improve the land and waterways for development of the region. An organized and effective malaria control program stemmed from this new authority in the Tennessee River valley. Malaria affected 30 percent of the population in the region when the TVA was incorporated in 1933. The Public Health Service played a vital role in the research and control operations and by 1947, the disease was essentially eliminated. Mosquito breeding sites were reduced by controlling water levels and insecticide applications.

Chloroquine (Resochin) (1934, 1946)

Chloroquine was discovered by a German, Hans Andersag, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. He named his compound resochin. Through a series of lapses and confusion brought about during the war, chloroquine was finally recognized and established as an effective and safe antimalarial in 1946 by British and U.S. scientists.

Dichloro-diphenyl-trichloroethane (DDT) (1939)

A German chemistry student, Othmer Zeidler, synthesized DDT in 1874, for his thesis. The insecticidal property of DDT was not discovered until 1939 by Paul Müller in Switzerland. Various militaries in WWII utilized the new insecticide initially for louse-borne typhus. DDT was used for malaria control at the end of WWII after it had proven effective against malaria-carrying mosquitoes by British, Italian, and American scientists. Müller won the Nobel Prize for Medicine in 1948.

Malaria Control in War Areas (MCWA) (1942-1945)

MCWA was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic. Many of the bases were established in areas where mosquitoes were abundant. MCWA aimed to prevent reintroduction of malaria into the civilian population by mosquitoes that would have fed on malaria-infected soldiers, in training or returning from endemic areas. During these activities, MCWA also trained state and local health department officials in malaria control techniques and strategies.

Cover of a MCWA booklet (1945).

CDC and Malaria (1946-present)

CDC's mission to combat malaria began at its inception on July 1, 1946. The Communicable Disease Center, as CDC was first known, stemmed from MCWA. Thus, much of the early work done by CDC was concentrated on the control and eradication of malaria in the United States. With the successful reduction of malaria in the United States, the CDC switched its malaria focus from eradication efforts to prevention, surveillance, and technical support both domestically and internationally. This is still the focus of CDC's Malaria Branch today.

More: CDC's Origins and Malaria

Eradication of Malaria in the United States (1947-1951)

The National Malaria Eradication Program, a cooperative undertaking by state and local health agencies of 13 Southeastern states and the CDC, originally proposed by Louis Laval Williams, commenced operations on July 1, 1947. By the end of 1949, over 4,650,000 housespray applications had been made. In 1947, 15,000 malaria cases were reported. By 1950, only 2,000 cases were reported. By 1951, malaria was considered eradicated from the United States.

More: Eradication of Malaria in the United States

Eradication Efforts Worldwide: Success and Failure (1955-1978)

Stamps highlighting malaria eradication

With the success of DDT, the advent of less toxic, more effective synthetic antimalarials, and the enthusiastic and urgent belief that time and money were of the essence, the World Health Organization (WHO) submitted at the World Health Assembly in 1955 an ambitious proposal for the eradication of malaria worldwide. Eradication efforts began and focused on house spraying with residual insecticides, antimalarial drug treatment, and surveillance, and would be carried out in 4 successive steps: preparation, attack, consolidation, and maintenance. Successes included eradication in nations with temperate climates and seasonal malaria transmission. Some countries such as India and Sri Lanka had sharp reductions in the number of cases, followed by increases to substantial levels after efforts ceased. Other nations had negligible progress (such as Indonesia, Afghanistan, Haiti, and Nicaragua). Some nations were excluded completely from the eradication campaign (most of sub-Saharan Africa). The emergence of drug resistance, widespread resistance to available insecticides, wars and massive population movements, difficulties in obtaining sustained funding from donor countries, and lack of community participation made the long-term maintenance of the effort untenable. Completion of the eradication campaign was eventually abandoned to one of control.