This is a 10 year old male who presents to the ER with a two-month history of fever. The fever occurs every 48 hours, reaching up to 40 degrees centigrade (104 degrees F), and is often associated with a headache. Before the onset of fever, he experiences chills, nausea and vomiting. The fever resolves in two hours, followed by diaphoresis and fatigue. In between these episodes he feels well. He denies any abdominal pain, hematuria or any neurological symptoms such as a change in consciousness or seizure activity. His travel history is significant for a one month trip to Africa with his family eight months ago. His vaccinations are up-to-date, and his father states that he took prophylactic chloroquine before, during and after his trip, as well as avoiding mosquito bites at night.
Exam: VS T 38.0, P 89, RR 16, BP 100/60. Height and weight are at the 25th percentile. He is alert and active in no distress. Skin exam shows no jaundice. HEENT, neck, heart, lung and neurologic exams are normal. His abdomen exam is notable for moderate splenomegaly.
Labs: WBC 10,000, 68% segs, 20% lymphs, Hgb 10, Hct 29, platelet count 140,000, reticulocyte count 1.8%. A blood smear shows mature trophozoites and schizonts, enlarged erythrocytes and Schuffner dots, with no banana shaped gametocytes. Parasitemia is estimated at 7%.
He is hospitalized for malaria. During the night he develops a fever of 40.5 degrees. Blood cultures are negative. Anti-malarial treatment is begun with mefloquine. He responds clinically in 24 hours to treatment, with a drop in parasitemia to 5%. Primaquine is also begun for the suspected hepatic source of presumed Plasmodium vivax.
Malaria is an infectious disease caused by a protozoa (single-celled eukaryotes). It impacts an incredible toll on humanity, with an estimated 300 to 500 million world-wide cases occurring annually (1). There are an estimated 1 million deaths, most of which occur in children (2,3) between the ages of 1 and 5 years (1,4) in Africa (5). In the United States, 1000 cases of malaria are diagnosed each year with 5 to 10 deaths (6). Patients usually have traveled to endemic areas, or they are recent immigrants from these areas. In addition, physicians are often asked for advice on prophylaxis for travelers visiting malaria endemic countries.
There are four Plasmodium species of malaria in humans: P. falciparum, P. vivax, P. malariae, and P. ovale. P. vivax is the most common. P. falciparum is the most dangerous being associated with cerebral malaria. P. falciparum is different from other species in that it can cause infected red blood cells to adhere to the capillary endothelium, enabling it to evade destruction by the spleen and also causing microvascular obstructive disease.
The malaria life cycle begins when the Anopheles mosquito vector takes a blood meal (a vector transfers the infectious agent from one host to another). By doing so it releases malarial sporozoites from its salivary gland into the blood of the human host. In the pre-erythrocytic phase of the cycle, these sporozoites travel in the blood and invade hepatocytes in the liver. Here the sporozoites can take two paths. One path for sporozoites in the liver is to form trophozoites, which then undergo nuclear division to form into schizonts. Schizonts are factories of merozoites, with each schizont producing 10,000-30,000 merozoites for each infected hepatocyte. This amplifies the infectious process. The liver cells become overloaded with merozoites and burst, with merozoites spilling over into the blood stream. Merozoites then infect erythrocytes once they are released into the circulation. Hypnozoites, the other path that sporozoites can take in the liver, are found in only P. vivax and P. ovale. Hypnozoites can remain dormant in the liver for 6-11 months. When hypnozoites subsequently mature into schizonts, they produce a delayed infection and will also release merozoites into the blood to infect erythrocytes. Thus, travelers who have taken prophylactic malarial agents, as in the case above, can still become infected with malaria if the dormant liver stage is not treated for these two species. This occurs because prophylactic agents such as chloroquine or mefloquine are ineffective against the hypnozoites.
After the merozoite leaves the hepatocyte, the erythrocytic cycle begins as merozoites invade erythrocytes. The merozoite also forms into a schizont in the erythrocyte. The schizont undergoes nuclear division and merozoites are formed from this RBC schizont. The erythrocyte lyses, with merozoites released into the blood stream ready to infect other erythrocytes. The process of red blood cell invasion, merozoite formation, and erythrocyte rupture takes two to three days depending on the malarial species.
In addition, some intraerythrocytic parasites develop into sexual (gametocyte) forms, which is necessary for the completion of the sexual phase of the life cycle in the mosquito. The cycle is completed when the male and female gametocytes are taken up by the female anopheline mosquito during a blood meal from an infected individual. Fertilization takes place in the stomach of the mosquito by the formation of a zygote. This zygote divides until a oocyst develops, which eventually ruptures and releases sporozoites which find their way to the salivary glands of the mosquito. Here the sporozoites remain, ready to reinfect another human and begin the cycle once again.
P. falciparum is the most severe infection of the different plasmodium species, and it produces a microvascular disease, unlike the other species which do not. Erythrocytes infected with P. falciparum adhere to the endothelial lining of small blood vessels, causing blockage and a decrease in tissue perfusion with a resulting metabolic acidosis. Lysis of erythrocytes and the release of merozoites causes an immune response with the production of cytokines (TNF-alpha), giving rise to the characteristic fever of malaria. The anemia is caused by the lysis of red blood cells as well as by the suppressive effect that TNF- alpha has on erythropoiesis. Hypoglycemia is often seen in patients with P. falciparum. This is caused by the depletion of liver glycogen from decreased intake, glucose consumption by the parasites, and increased levels of TNF- alpha. The main organs involved include the brain, kidneys, liver, spleen, lung and GI tract, although any organ can be affected. The brain in cerebral malaria is edematous and hyperemic, with small blood vessels filled with parasitized erythrocytes (7), giving rise to the impaired consciousness and seizures of cerebral malaria. Renal failure secondary to tubular necrosis is due to increased circulating free hemoglobin (hemoglobinuria), as well as due to hypovolemia and microvascular disease. Excess hemoglobin that is spilled into the urine gives malaria one of its names: blackwater fever. The spleen, which is responsible for filtering out the deformed erythrocytes, is enlarged, congested, and at times may rupture. The liver also enlarges, as it too has reticuloendothelial function. Parasitized RBCs sequestered in the pulmonary vasculature can cause cough, respiratory distress and pulmonary edema. In the gastrointestinal tract, it can cause gastroenteritis.
Infected erythrocytes in the placenta can cause increased mortality, premature delivery and low birth weight. Congenital infections in newborns are also seen if erythrocytes cross the placenta. Anemia in the mother is further worsened by malaria. P. vivax, P. ovale and P. malariae do not cause a microvascular disease because they do not cause erythrocytes to adhere to vascular endothelial cells. They do cause hemolysis and an inflammatory response, giving rise to a less severe form of the disease than that seen with P. falciparum. Sickle-cell anemia, beta-thalassemia and glucose-6-dehydrogenase deficiency are thought to offer resistance to malaria in the heterozygote forms. This protection is believed to come from the shortened RBC life-span with increased RBC susceptibility to lysis from oxidative stress (interrupting the Plasmodium reproductive cycle) and the fact that the hemoglobin with these genetic variants denatures preferentially with malaria infection, releasing toxic forms of heme that damage the parasites. In addition, P. vivax requires the Duffy blood group antigen to bind to the RBC and cause an infection. West Africans and many Americans of African descent are often missing this blood group antigen, rendering them resistant to this species. Acquired resistance comes about with IgG and IgM, with IgG giving protection against merozoites, preventing them from invading susceptible erythrocytes. This immune response renders individuals resistant to symptomatic disease. They are not however immune, as their body still can harbor parasites even though they are non-symptomatic.
The clinical manifestations of fever coincide with the rupture of the red blood cells and the release of merozoites, stimulating the production of TNF-alpha. Different malarial species have different patterns of growth, with erythrocytic schizogony and the release of a brood of merozoites occurring approximately every 48 hours (called tertian malaria) for P. falciparum, P. vivax, and P. ovale, and 72 hours (called quartan malaria) for P. malariae. If there is more than one brood of parasites developing in the blood at one time, then the fever can occur daily, obscuring the diagnosis. P. falciparum in particular is known for causing any pattern of fever. The pre-erythrocytic phase is asymptomatic, as sporozoites are released from the mosquito and pass to the hepatocytes.
An attack classically starts with the "cold stage", with chills lasting from minutes to an hour. Nausea, vomiting and frequent micturition are often seen during this phase. Following the cold stage, the "hot stage" begins with fevers between 40 (104 F) to 41 (106 F) degrees C lasting between 2 to 6 hours, associated with a severe headache, tachycardia, delirium, epigastric pain, nausea, vomiting and diarrhea. Despite the high fever, there is minimal diaphoresis. After the hot stage, the third "sweating phase" is entered lasting 2 to 3 hours, with diaphoresis, resolution of the fever, and fatigue that gives way to sleep. In children less than 5 years of age, the signs may be non-specific: fever, vomiting, abdominal pain and diarrhea. Older children may only complain of fever, headache and joint pain. For these reasons, fever in a child that has visited or lives in a malaria endemic area is considered to be due to malaria until proven otherwise.
The clinical manifestations of cerebral malaria include altered consciousness, seizures, symptoms of raised intracranial pressure, opisthotonos, decorticate or decerebrate posturing, hypotonia and conjugate eye movements. It has a high case fatality rate (8). On physical exam, signs of anemia should be sought. Respiratory distress and splenomegaly may be present. Dehydration due to decreased PO intake and increased losses from diaphoresis or diarrhea can give rise to hypotension, tachycardia and shock.
Besides having 4 different species of malaria, there are also many strains of malaria, (except for P. malariae which has only one). This diversity makes vaccine development for malaria very difficult. As stated above, in areas where malaria is endemic, repeated infections cause the development of acquired immunity from symptomatic disease (they are still susceptible to asymptomatic parasitemia). For this reason, most cases of fatal malaria occur in the first 5 years of age in these areas. In contrast, in areas with no endemic infection (such as the United States), acquired immunity is not developed and fatal malaria can occur at any age.
Laboratory findings include a decreased hemoglobin, hematocrit, thrombocytopenia and increased bilirubin due to the lysis of red blood cells. Hyponatremia, hypokalemia, and hypercalcemia may be seen. Acute renal failure with increased creatinine, proteinuria and hemoglobinuria may be present. Diagnosis is made by examination of the thick and thin smears. Thick smears allow the detection of the parasite in small numbers, while the thin smear allows one to identify the species. Classically the ring form of P. falciparum is seen. Microscopic examination can give a quantitative value to the parasitemia, with more than 5% to 10% of erythrocytes being infected associated with high mortality rate. Following the percentage of infected erythrocytes serially, is useful to evaluate treatment. PCR and ELISA can also be used in the diagnosis.
P. falciparum differs from P. vivax and P. ovale in several ways (9):
The correct diagnosis of P. falciparum is important. Looking at the table above, you would expect the more severe infection of P. falciparum to have multiple infected erythrocytes, with the more mild infection of P. vivax and P. ovale to have rare infected erythrocytes. Mature trophozoites and schizonts are not seen with P. falciparum because they are sequestered in the peripheral microvasculature. P. vivax preferentially infects a reticulocyte, so infections with P. vivax show large erythrocytes. Schüffner dots are due to pigment accumulation in infected erythrocytes, and appear blue on microscopic examination. They are characteristic of P. vivax and P. ovale infections. P. falciparum can be distinguished by its early trophozoites called ring forms (signet-ring appearance), and by the sausage or banana shape of its gametocytes.
The differential diagnosis of malaria is broad, including leptospirosis, yellow fever, juvenile rheumatoid arthritis, Hodgkin's disease, brucellosis, borreliosis, pneumonia, meningitis, tuberculosis, influenza and bacteremia (9).
Uncomplicated malaria is defined as a child with fever and a positive blood smear, but without evidence of altered consciousness, hypoglycemia, respiratory problems, jaundice or severe anemia. Severe malaria includes the fever and positive blood smear as above, but also involves mental status changes, convulsions, hypoglycemia, acidosis, jaundice, weakness or parasitemia greater than 15%. Uncomplicated malaria can be managed on an outpatient basis for a child who has lived in an endemic area all of their life. The management of an infected patient who has visited an endemic area for the first time, or a patient with severe malaria, involves hospital admission. Patients suspected of having P. falciparum should always be hospitalized, with early initiation of therapy. Conventional treatment of dehydration, hypoglycemia, anemia, seizures, pulmonary edema and renal failure is required. The selection of an antimalarial depends on the species identified or suspected, the possibility of resistance, and the ability of the patient to take oral medications. Chloroquine is the drug of choice for plasmodia sensitive to this drug. For chloroquine-resistant P. falciparum, oral therapy includes quinine with pyrimethamine-sulfadoxine, tetracycline, doxycycline or clindamycin. Mefloquine is another alternative. Chloroquine-resistant P. vivax should be treated with mefloquine. Primaquine is effective against the liver forms of P. vivax and P. ovale. A new anti-malarial drug with fewer side effects than mefloquine is atovaquone/proguanil (Malarone). Exchange transfusion can be considered in patients with severe disease. Most patients treated with chloroquine respond within 24 hours, and usually recover by the third or fourth day (12). The case fatality rate for cerebral malaria even with optimal therapy, is 15-30%, with 10% of survivors of cerebral malaria having residual signs of ataxia, hemiparesis and spasticity.
Prevention involves an assessment of the risk of the country one is visiting, along with chemoprophylaxis and methods to limit mosquito bites by Anopheles (which feed primarily from dusk to dawn). Permethrin-impregnated mosquito nets, long-sleeve shirts, and 35% DEET repellant sprays, limit exposure to Anopheles. Chloroquine can be taken on a weekly basis for chemoprophylaxis. It is taken 2 weeks before departure (to monitor for side effects), continued for the duration of the trip, and 4 weeks after leaving the endemic area. It is the drug of choice for chemoprophylaxis because it is safe for all ages and during pregnancy. Mefloquine (taken once weekly) is used for areas suspected of having chloroquine-resistant P. falciparum (Southeast Asia, the Amazon region of South America, and sub-Saharan Africa). In patients weighing less than 15 kg or for pregnant women, chloroquine combined with proguanil can be used. Doxycycline is an alternative for those older than 8 years (10,11). A newer alternative is atovaquone/proguanil, but this must be taken daily.
Questions
1. The species of malaria associated with adherence to endothelial walls, cerebral malaria, and a high mortality rate is:
. . . . . a. P. falciparum
. . . . . b. P. vivax
. . . . . c. P. malariae
. . . . . d. P. ovale
2. The fever of malaria:
. . . . . a. can be tertian (occurring every 48 hours).
. . . . . b. can be quartan (occurring every 72 hours).
. . . . . c. occur with no pattern at all.
. . . . . d. all of the above.
3. The clinical manifestations of the cyclic fever of malaria are caused by the:
. . . . . a. pre-erythrocytic phase
. . . . . b. hepatic stage
. . . . . c. erythrocytic stage
. . . . . d. sexual stage
4. Liver hypnozoites (dormant form) can be effectively treated with:
. . . . . a. chloroquine
. . . . . b. mefloquine
. . . . . c. primaquine
. . . . . d. doxycycline
5. The pathogenesis of malaria can affect which of the following organ systems:
. . . . . a. liver
. . . . . b. brain
. . . . . c. lungs
. . . . . d. kidneys
. . . . . e. spleen
. . . . . f. GI tract
. . . . . g. all of the above
6. Prophylaxis for malaria includes all of the following except:
. . . . . a. chloroquine
. . . . . b. mefloquine
. . . . . c. permethrin impregnated mosquito nets
. . . . . d. 35% DEET
. . . . . e. avoiding mosquitoes during the day
References
1. World malaria situation in 1992, Part I. Weekly Epidemiol Rec 1994;69:309-314.
2. Snow RW, Craig M, Deichman U, Marsh K. Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population. Bull World Health Org 1999;77:624-640.
3. Breman JG. The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Am J Trop Med Hyg 2001;64 (Suppl.):1-11.
4. Gilles HM. Malaria: An overview. J Infect 1989;18:11-23.
5. Newton C, Krishna S. Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Parmacol Ther 1998;79(1):1-53.
6. Barat LM, Zucker JR. Chapter 225 - Malaria. In: McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB (eds). Oski's Pediatrics, third edition. 1999, Philadelphia: Lippincott Williams and Wilkins, pp. 1177-1184.
7. Fitch CD. Chapter 217 - Malaria. In: Feigin RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, Vol. 2, fourth edition. 1998, Philadelphia: W.B. Saunders Company, pp. 2437-2451.
8. Molyneux E. Chapter 4.27 - Malaria. In: Southall D, Coulter B, Ronald C, Nicholson S, Parke S (eds). International Child Health Care: A practical manual for hospitals worldwide. 2002, London: BMJ Books, pp. 473-476.
9. Weinberg A, Levin MJ. Chapter 37 - Infections: Parasitic and Mycotic. In: Hay WH, Hayward AR, Levin MJ. Sondheimer JM (eds). Current Pediatric Diagnosis and Treatment, 15th edition. 2001, New York: Lange Medical Books/McGraw-Hill, pp. 1091-1094.
10. Krogstad DJ. Chapter 264 - Plasmodium Species (Malaria). In: Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases, vol. 2, 5th edition. 2000, Philadelphia: Churchill Livingston, pp. 2817-2831.
11. Jucket G. Malaria Prevention in Travelers. Am Fam Phys 1999;59(9):2523-2430.
12. Mandi A. Index of Suspicion. Pediatr Rev 1999;20(11):391-394.
Answers to questions
1. a. P. falciparum is unique among malarial species in that it has mechanisms to adhere to vascular endothelial walls. This produces a microvascular disease, leading to poor perfusion and metabolic acidosis. This hypoperfusion can affect almost any organ in the body, but this is of greatest significance in that it can cause cerebral malaria, which can cause a change in consciousness and seizures. Long-term affects due to cerebral malaria can also be seen. P. vivax is the most common form of malaria, but produces a more milder form of the disease.
2. d. The fever of malaria can produce any pattern of fever, with P. falciparum most known for its lack of recognizable fever patterns. Classically, the release of merozoites from red blood cells all in one group at similar times causes an inflammatory response, the production of TNF-alpha, and a characteristic pattern of fever depending on the particular species. The fever occurs approximately every 48 hours (called tertian malaria) for P. falciparum, P. vivax, and P. ovale, and 72 hours (called quartan malaria) for P. malariae.
3. c. The life cycle of malaria is very complex. It starts with malarial sporozoites being released from the anopheles mosquito. In the pre-erythrocytic stage sporozoites travel to the liver, with the patient being asymptomatic during this time. Sporozoites form schizonts, which eventually produce thousands of merozoites. These merozoites are released from hepatocytes, and infect red blood cells, giving rise to the erythrocytic stage of the life cycle. The erythrocytes burst after infection, releasing merozoites, which is the major cause of the cyclical fever. These merozoites can infect new blood cells, or form gametocytes. Male and female gametocytes are taken up by the mosquito, where they reproduce and form new sporozoites, completing the life-cycle during the mosquito's next blood meal.
4. c. Sporozoites infecting the liver can form into schizonts and can also form hypnozoites. These can remain dormant in the liver, causing an infection months later. The dormant liver-stage of the malarial life cycle, seen in P. vivax and P. ovale, is effectively treated with primaquine.
5. g. The microvascular disease of P. falciparum can affect almost any tissue of the body, giving rise to the many clinical features of malaria.
6. e. Prophylaxis for malaria includes using permethrin impregnated mosquito nets, avoiding mosquito bites using 35% DEET, and chemoprophylaxis most commonly with chloroquine or mefloquine. The anopheles mosquito usually bites from dusk to dawn, not during the day, and it is during these times that travelers should be particularly careful.