CHAPTER 1 INTRODUCTION 1.

1 Background Malaria is caused by infection with protozoan parasites belonging to the genus Plasmodium transmitted by female Anopheles species mosquitoes. Our understanding of the malaria parasites begins in 1880 with the discovery of the parasites in the blood of malaria patients by Alphonse Laveran. The sexual stages in the blood were discovered by William MacCallum in birds infected with a related haematozoan, Haemoproteus columbae, in 1897 and the whole of the transmission cycle in culicine mosquitoes and birds infected with Plasmodium relictum was elucidated by Ronald Ross in 1897. In 1898 the Italian malariologists, Giovanni Battista Grassi, Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Camillo Golgi and Ettore Marchiafava demonstrated conclusively that human malaria was also transmitted by mosquitoes, in this case anophelines. The discovery that malaria parasites developed in the liver before entering the blood stream was made by Henry Shortt and Cyril Garnham in 1948 and the final stage in the life cycle, the presence of dormant stages in the liver, was conclusively demonstrated in 1982 by Wojciech Krotoski. This article traces the main events and stresses the importance of comparative studies in that, apart from the initial discovery of parasites in the blood, every subsequent discovery has been based on studies on non-human malaria parasites and related organisms. Malaria is an ancient disease and references to what was almost certainly malaria occur in a Chinese document from about 2700 BC, clay tablets from Mesopotamia from 2000 BC, Egyptian papyri from 1570 BC and Hindu texts as far back as the sixth century BC. Such historical records must be regarded with caution but moving into later centuries we are beginning to step onto firmer ground. The early Greeks, including Homer in about 850 BC, Empedocles of Agrigentum in about 550 BC and Hippocrates in about 400 BC, were well aware of the characteristic poor health, malarial fevers and enlarged spleens seen in people living in marshy places.

Malaria may be a common illness in areas where it is transmitted and therefore the diagnosis of malaria should routinely be considered for any febrile person who has traveled to an area with known malaria transmission in the past several months preceding symptom onset. Symptoms of malaria are generally non-specific and most commonly consist of fever, malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills, and/or cough. The diagnosis of malaria should also be considered in any person with fever of unknown origin regardless of travel history. Patients suspected of having malaria infection should be urgently evaluated. Treatment for malaria should not be initiated until the diagnosis has been confirmed by laboratory investigations. "Presumptive treatment" without the benefit of laboratory confirmation should be reserved for extreme circumstances (strong clinical suspicion, severe disease, impossibility of obtaining prompt laboratory confirmation, usually by microscopy). Laboratory diagnosis of malaria can be made through microscopic examination of thick and thin blood smears. Thick blood smears are more sensitive in detecting malaria parasites because the blood is more concentrated allowing for a greater volume of blood to be examined; however, thick smears are more difficult to read. Thin smears aid in parasite species identification and quantification. Blood films need to be read immediately; off-hours, qualified personnel who can perform this function should be on-call. A negative blood smear makes the diagnosis of malaria unlikely. However, because non-immune individuals may be symptomatic at very low parasite densities that initially may be undetectable by blood smear, blood smears should be repeated every 12-24 hours for a total of 3 sets. If all 3 are negative, the diagnosis of malaria has been essentially ruled out. After malaria parasites are detected on a blood smear, the parasite density should then be estimated. The parasite density can be estimated by looking at a monolayer of red blood cells (RBCs) on the thin smear using the oil immersion

objective at 100x. The slide should be examined where the RBCs are more or less touching (approximately 400 RBCs per field). The parasite density can then be estimated from the percentage of infected RBCs, after counting 500 to 2000 RBCs. In addition to microscopy, other laboratory diagnostic tests are available. Several antigen detection tests (rapid diagnostic tests or RDTs) using a dipstick or cassette format exist, but only one is approved for general diagnostic use in the United States. RDTs can more rapidly determine that the patient is infected with malaria, but they cannot confirm the species or the parasitemia. Laboratories that do not provide in-house on-the-spot microscopy services should maintain a stock of malaria RDTs so that they will be able to perform malaria diagnostic testing when urgently needed. Parasite nucleic acid detection using polymerase chain reaction (PCR) is more sensitive and specific than microscopy but can be performed only in reference laboratories and should be reserved for specific instances (e.g., back-up or confirmation of microscopy). Serologic tests, also performed in reference laboratories, can be used to assess past malaria experience but not current infection by malaria parasites. 2.2 Objective This paper is done in order to complete the task in following the doctors professional education program in the department of pediatrics. In addition, providing knowledge to the author and readers about malaria.

CHAPTER 2 LITERATURE REVIEW 2.1 Description of the pathogen Four species of malarial parasites commonly infect humans, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. P. falciparum is the most lethal and the most drug resistant. From an evolutionary standpoint, P. falciparum is the Plasmodium species most recently acquired by humans; by genetic analysis, it is related most closely to malarial species in birds. Of the human species of Plasmodium, P. vivax was the most widely distributed geographically and best adapted to survive in temperate climates. However, successful mosquito eradication programs in the United States and Europe essentially eliminated P. vivax from these regions. P. falciparum is the most prevalent in sub-Saharan Africa. P. ovale mainly occurs in the western areas of sub-Saharan Africa. Sporozoites are inoculated into humans by the bite of an Anopheles mosquito and invade hepatic parenchymal cells within minutes. The parasites undergo asexual multiplication, or schizogony, in this tissue phase of their lifecycle, also called exo-erythrocytic schizogony. After a period of development and amplification (7 to 10 days for P. falciparum, P. ovale, and P. vivax and 10 to 14 days for P. malariae), merozoites emerge to invade erythrocytes and begin what will become the symptomatic phase of the illness. Parasites of the two relapsing species of Plasmodium, P. ovale and P. vivax, also can differentiate into a quiescent stage, the hypnozoite, which later can enter into schizogony and reemerge to invade erythrocytes. P. malariae has the potential to persist at very low levels in the circulation for decades. Each species has developed an efficient strategy for erythrocyte invasion that relies on a specific, complex interaction of certain surface proteins or glycoproteins on the erythrocyte and a specific ligand of the parasite. For example, P. vivax preferentially invades erythrocytes bearing the Duffy blood group antigen,[1] an antigen that is rarely found on erythrocytes in persons from

West and central Africa. Plasmodium falciparum most efficiently invades erythrocytes with intact glycosylated forms of the glycophorin family of proteins.
[2]

Parasitic ligands that facilitate interactions with these erythrocyte molecules

have been identified in P. falciparum and P. vivax. [2] [3] P. ovale and P. falciparum invade erythrocytes of all ages while P. vivax preferentially invade reticulocytes, and P. malariae preferentially invade mature erythrocytes. Once inside the erythrocyte, parasites can undergo either asexual schizogony or sexual differentiation to produce gametocytes. During asexual schizogony, the parasites are known as trophozoites once they are established inside the erythrocyte; the early trophozoite forms often are called rings because of their apparent lack of central cytoplasmic staining. Parasites in this stage ferment homolactate and actively digest the host cell hemoglobin, which they use as a source of amino acids and energy.[4] This activity is accomplished through a set of highly adapted proteinases in a singularly adapted organelle, the food vacuole.[5] The residue of hemoglobin degradation is an intact tetrapyrrole ring, ferriprotoporphyrin IX, which the parasites detoxify through polymerization and which can be seen microscopically as malarial pigment.[6] This polymerization step is thought to be the site of action of quinoline-containing antimalarial compounds, including chloroquine. [7] [8] The last few hours of the erythrocytic stage of the parasite's lifecycle, when the parasite is called a schizont, comprise the actual replicative phase in which the parasite undergoes mitosis and subdivides and differentiates into merozoites. It is the subsequent rupture and release of merozoites that lead to fever and other malarial symptoms. If infections are synchronized, the periodicity of symptoms is 48 hours in P. ovale and P. vivax malaria, whereas it is 72 hours in P. malariae infections. While periodicity may be every 48 hours in P. falciparum infections, it often is irregular. Indeed, the parasite's reproductive cycles often are not synchronized with any of the species and the absence of periodicity does not rule against malaria being the cause of fevers. Parasites in the erythrocytic stages also can undergo sexual differentiation, a step that is necessary for transmission. Male and female gametes, which are

produced by each Plasmodium species, remain inside the erythrocyte until they are ingested by the mosquito. At this point, they undergo further differentiation and join to form a zygote, which differentiates into an ookinete and invades the mosquito midgut to form the reproductive oocyst. Sporozoites emerge from the oocyst and migrate to the salivary gland, where they can reinfect a human during a subsequent blood meal. In general, all of the erythrocytic asexual and sexual developmental stages of P. ovale, P. vivax, and P. malariae occur in circulating blood and can be visualized in the peripheral blood smear. The late trophozoite stages of P. falciparum rarely are seen in the peripheral circulation because of the development of knobs on infected erythrocytes that lead to adherence of the parasitized erythrocytes to the capillary endothelium.[9] Sequestration of parasites in various organs is believed to be responsible for the clinical manifestations that occur with P. falciparum infections, such as central nervous system and pulmonary complications. No strict immunity develops to malaria, but rather an acquired ability to tolerate Plasmodium infections occurs, which is a selective process related to the degree of exposure to a variety of strains. [10] Most deaths from malaria occur in children younger than 5 years in areas of high transmission of P. falciparum. Although P. falciparum can cause lethal infection in young children or nonimmune individuals, asymptomatic parasitemia is common in older age groups in highly endemic areas. Rupture of a large number of erythrocytes at the same time releases a large amount of pyrogens, causing the paroxysms of malarial fever. The periodicity of malarial fever depends on the time required for the erythrocytic cycle and is definite for each species. P malariae needs 72 hours for each cycle, leading to the name quartan malaria. The other 3 species each take 48 hours for 1 cycle and cause fever on alternate days (tertian malaria). However, this periodicity requires all the parasites to be developing and releasing simultaneously; if this synchronization is absent, periodicity is not observed.

Most malaria acquired in Africa is due to P falciparum. P vivax dominates in Asia and the Americas. The bite of an infected female Anopheles mosquito transmits malaria. Species of mosquito capable of transmitting malaria are found in all 48 of the contiguous states of the United States. Malaria can also be transmitted through blood transfusion. Among people living in malarious areas, semi-immunity to malaria allows donors to have parasitemia without any fever or other clinical manifestations. The malaria transmitted is by the merozoites, which do not enter the liver cells. Because the liver stage is not present, curing the acute attack results in complete cure. Organ transplantation is another malarial transmission route. Transplacental malaria (ie, congenital malaria) can be significant in populations who are semi-immune to malaria. The mother may have placental parasitemia, peripheral parasitemia, or both, without any fever or other clinical manifestations. Vertical transmission of this infestation may be as high as 40% and is associated with anemia in the baby.

This micrograph illustrates the trophozoite form, or immature-ring form, of the malarial parasite within peripheral erythrocytes. Red blood cells infected with trophozoites do not produce sequestrins and, therefore, are able to pass through the spleen.

A mature schizont within an erythrocyte. These red blood cells (RBCs) are sequestered in the spleen when malaria proteins, called sequestrins, on the RBC surface bind to endothelial cells within that organ. Sequestrins are only on the surfaces of erythrocytes that contain the schizont form of the parasite. P falciparum The most malignant form of malaria is caused by this species. P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). In contrast, P vivax and P ovale infect only young RBCs and thus cause a lower level of parasitemia (usually < 2%). Hemoglobinuria (blackwater fever), a darkening of the urine seen with severe RBC hemolysis, results from high parasitemia and is often a sign of impending renal failure and clinical decline. Sequestration is a specific property of P falciparum. As it develops through its 48hour life cycle, the organism demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels. For this reason, only early forms are observed in the peripheral blood before the sequestration develops; this is an important diagnostic clue that a patient is infected with P falciparum. Sequestration of parasites may contribute to mental-status changes and coma, observed exclusively in P falciparum infection. In addition, cytokines and a high burden of parasites contribute to end-organ disease. End-organ disease may develop rapidly in patients with P falciparum infection, and it specifically involves the central nervous system (CNS), lungs, and kidneys. Other manifestations of P falciparum infection include hypoglycemia, lactic acidosis, severe anemia, and multiorgan dysfunction due to hypoxia. These severe manifestations may occur in travelers without immunity or in young children who live in endemic areas.

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.

2.2 Risk factors Risk factors for malaria include the following:

Residence in, or travel through, a malarious area No previous exposure to malaria (hence no immunity) No chemoprophylaxis or improper chemoprophylaxis

2.3 Epidemiology The epidemiology of malarial infections is intricately linked to the distribution and habits of the anopheline vectors in any particular region. In highly endemic areas, mosquito breeding can take place nearly year-round, and reproductive capacity in the mosquito is maximized by a tropical climate. [11] In areas of seasonal transmission its prevalence is particularly related to rainfall or other ecologic events that affect the mosquito population. Malaria also can be related to occupation when only certain segments of the population are exposed to the vectors. The estimated worldwide incidence of malaria is greater than 350500 million clinical malaria episodes per year, with more than 1 million deaths annually, most of which occur in children younger than 5 years.[12] Almost all deaths are due to P. falciparum, with more than 80% occurring in sub-Saharan Africa. Prior to the 1950s, malaria was endemic throughout the southeastern United States. During the late 1940s, a combination of improved housing and socioeconomic conditions, water management, vector-control efforts, and case management was successful at interrupting malaria transmission in the United States. In the United States today, most cases occur in persons who have traveled to or are emigrating from malarious areas,[13] although transmission also can occur congenitally or through blood transfusion or organ transplantation. Anopheline vectors are still present in most areas of the United States, and, occasionally, localized outbreaks of malaria occur because of transmission from imported human cases.[14] Malaria is a major health problem in Africa, Asia, Central America, Oceania, and South America. About 40% of the world's population lives in areas

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where malaria is common.[15] Approximately 300-500 million cases of malaria occur every year, and 1-2 million deaths occur, most of them in young children. People of all races are affected by malaria, with some exceptions. People of West African origin who do not have the Duffy blood group are not susceptible to P vivax malaria. Children of all ages living in nonmalarious areas are equally susceptible to malaria. In endemic areas, children younger than age 5 years have repeated and often serious attacks of malaria. The survivors develop partial immunity. Thus, older children and adults often have asymptomatic parasitemia (ie, the presence of plasmodia in the bloodstream without the clinical manifestations of malaria). Most deaths resulting from malaria occur in children younger than age 5 years. 2.4 Clinical Manifestations The clinical features of malaria are dependent on the malaria-specific immune status of the host and the infecting species of Plasmodium. Nonimmune people, such as those who have not resided in an endemic area or have been away from an endemic area for as little as 1 year, generally have symptomatic infection. Infections with P. falciparum are more severe than infections with the other three species that infect humans. The febrile paroxysm is the hallmark of malaria and typically lasts from 10 to 12 hours and consists of a period of severe rigors or chills, followed by high fever that can induce a febrile seizure; profuse sweating occurs with defervescence. Other nonspecific complaints at the time of fever include headache, malaise, myalgia, and arthralgia. Gastrointestinal tract symptoms, including abdominal pain, vomiting, and diarrhea can occur. Individuals are usually prostrated but can otherwise be remarkably asymptomatic between febrile episodes. Given the variable and nonspecific clinical findings and the potential for rapidly fatal disease, a high index of suspicion for malaria is necessary in ill travelers who have returned from an endemic area. Another complicating factor is that nonimmune individuals may have clinical symptoms despite low levels of

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parasitemia. Thus, both thick and thin blood smears obtained repeatedly (for example, at least once or twice daily) over a 48- to 72-hour period are needed to exclude malaria. Mortality from P. falciparum infections often is due to cerebral effects. [16] Delirium and confusion can occur with the high fever of malaria, but actual declining mental status is more ominous and indicates the need for urgent treatment. Symptoms can progress rapidly to coma. Whereas meningismus, generalized seizures, and symmetrical upper motor neuron dysfunction can be seen, focal seizures or localizing neurologic signs are uncommon in malaria. The rapid recovery of central nervous system function with treatment and the general lack of sequelae suggest metabolic encephalopathy as the probable mechanism of dysfunction. The highest risk for neurologic sequelae is in patients with multiple seizures, prolonged coma, hypoglycemia, and clinical features of intracranial hypertension. [17] [18] The combination of respiratory compromise and renal dysfunction with P. falciparum infection also is associated with increased mortality.[19] Adult respiratory distress syndrome can occur and is exacerbated by vigorous fluid resuscitation. Renal dysfunction most commonly is acute tubular necrosis, probably secondary to hypoperfusion from hypotension or hypovolemia. Although reported in children, this complication is observed more frequently in nonimmune adults. Nephrotic syndrome and glomerulonephritis have been associated with chronic infections with P. malariae in children, but are not common. Hyperparasitemia (more than 5% of red blood cells infected) with P. falciparum in nonimmune individuals frequently is associated with hypotension, metabolic acidosis, and hypoglycemia. [16] [19] These signs can all be attributed to parasitemia and associated cytokine disturbances, although gram-negative bacillary septicemia has been reported, particularly in association with severe gastrointestinal tract symptoms.[19] Hypoglycemia must be managed aggressively and monitored carefully, particularly when using quinine or quinidine for therapy.

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Anemia is an expected consequence of malaria, especially with hyperparasitemia. Hemolysis from erythrocytic parasitosis, sequestration and red cell destruction from hypersplenism, and dyserythropoiesis have been identified as mechanisms contributing to anemia.[20] Thrombocytopenia is common in malaria but rarely leads to a bleeding diathesis. Evidence of a consumptive coagulopathy is rare but can occur with P. falciparum infection in nonimmune individuals and usually develops in the setting of algid malaria, a septic shocklike syndrome. Brisk hemolysis with hemoglobinuria, called blackwater fever, can occur with hyperparasitemia in nonimmune individuals, but it is more common as an epiphenomenon in individuals residing in endemic areas and is associated with prolonged quinine intake (which is no longer recommended) or in glucose-6phosphate dehydrogenase (G6PD)-deficient patients using oxidant antimalarial drugs. 2.5 Diagnosis The most important step in making the diagnosis of malaria is consideration of the diagnosis. Many of the deaths from malaria in the United States are related to a delay in diagnosis.[21] Malaria should be considered the primary diagnosis until proven otherwise in any febrile patient who has traveled to or emigrated from an endemic area. Malaria also should be considered in patients who develop fever within days to a few months after blood transfusion. The diagnosis of malaria is made by identifying parasites in thick or thin blood films stained with common hematologic stains, most typically Giemsabased stains. The thick-film preparation is the more sensitive technique, but it is more difficult to interpret by inexperienced examiners. Speciation usually is performed with a thin smear. For initial clinical management, it is most important to identify whether P. falciparum is present. P. falciparum is strongly suggested by parasitemia exceeding 2% of red cells, erythrocytes containing multiple parasites, the exclusive presence of ring forms, and lack of schizonts. P. falciparum is identified pathognomonically by the banana-shaped gametocyte form; its presence is helpful, but its absence does not rule out the diagnosis. Late

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trophozoite stages of P. falciparum rarely are seen except in the setting of high parasitemia. A quantitative assessment of the initial parasitemia is generally helpful in establishing a treatment strategy and is useful in assessing response to therapy. Various test kits are available to detect antigens derived from malaria parasites. Such immunologic (immunochromatographic) tests most often use a dipstick or cassette format, and provide results in 2 to 10 minutes. These Rapid Diagnostic Tests (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Malaria RDTs are currently not approved by the U.S. Food and Drug Administration (FDA) for use in the United States. Parasite nucleic acids are detected using polymerase chain reaction (PCR) and may be a useful complement to microscopy, for example when species determination cannot be made by blood smear. However, it requires a specialized laboratory and is not widely available. Serology detects antibodies against malaria parasites, but because of the time required for development of antibody and also the persistence of antibodies, serologic testing is not useful for routine diagnosis of acute malaria. While no other laboratory findings are diagnostic for malaria, a number of laboratory findings support the diagnosis. Generally, patients have a normochromic, hemolytic anemia with a variable white blood cell count and differential count, but either leukopenia or leukocytosis can occur. Thrombocytopenia often is present. In the setting of cerebral malaria, lumbar puncture may reveal raised opening pressure, and cerebrospinal fluid (CSF) analysis can show mildly elevated protein levels and mild lymphocytic pleocytosis. Electrolyte disturbances are common in the setting of severe malaria and usually are multifactorial in origin, including dehydration, vomiting, renal failure, and tissue hypoxia. Hypoglycemia is common. Urinalysis generally is normal except for proteinuria during high fever. Urinalysis also can reveal hemoglobinuria in the setting of brisk hemolysis, proteinuria associated with nephrotic syndrome, or red cells with glomerulonephritis. Mildly elevated hepatic

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transaminase levels and indirect hyperbilirubinemia can be present; hepatic failure is uncommon. History Elicit any history of travel through, or immigration from, a malarious area. Even a few hours at an airport in an endemic area is significant. Obtain history of blood transfusion, organ transplantation, and (for newborns) malaria in the mother. Young children manifest this disease in many different ways, but the classic picture of malaria, with periodic fever, shivering, and sweating, is not observed. Malaria can mimic any febrile illness and should be suspected in any febrile child who has recently been in a malarious area. Older children may manifest the classic periodicity of fever with chills and shivering. After the mosquito bite, children are asymptomatic while the parasites complete the liver cycle and 1 erythrocytic cycle, which takes 8-18 days, depending on the species. Children then become restless, drowsy, apathetic, and anorexic. Older children may report aching body, headache, and nausea. Fever is usually continuous and may be very high (40C) from the first day. Many children have only flulike respiratory symptoms at presentation, with mild cough and cold. These symptoms abate in 1-2 days, with or without treatment. Vomiting is very common in children with malaria and may make oral therapy ineffective. Mild diarrhea is often observed, with dark green mucoid stools. Occasionally, profuse diarrhea with dehydration and circulatory failure is observed. Seizures are common and may occur at the onset of the disease, even before high fever has set in. Differentiating postictal impairment of consciousness from cerebral malaria is often difficult. Parasitemia in neonates within 7 days of birth implies transplacental transmission. This congenital malaria is usually associated with placental parasitemia, which sometimes persists even after adequate treatment with

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antimalarial drugs. Babies have fever, are irritable, refuse feeds, and often develop anemia, jaundice, and hepatosplenomegaly. Children living in an area where malaria is endemic have frequent infections and develop and maintain partial immunity. These children often develop only a low-grade fever, anemia, poor appetite, and malaise. Tiredness, restlessness, cough, and diarrhea are other symptoms that may occur. Depending on the species of Plasmodium involved, relapses and recrudescences vary in their effects. P vivax and P ovale both give rise to hypnozoites in the liver. P vivax malaria may relapse for up to 3 years and P ovale for 1-1.5 years. P falciparum and P malariae do not form hypnozoites, so they do not have true relapses. However, the disease recrudesces because of surviving erythrocytic forms. Although P falciparum can recrudesce for up to 1 year, P malariae may continue to cause clinical malarial attacks even 20 years after the original infection. Only the sporozoites (introduced by the mosquitoes themselves) can penetrate the liver cells. Thus, if malaria is acquired by blood transfusion or transplacentally, no infection of the liver occurs and relapses do not occur. 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.

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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. Diagnostic Considerations Conditions to consider in the differential diagnosis of malaria include the following:

Viral illness Bacteremia African trypanosomiasis Amebiasis and amebic liver abscess Brucellosis Cholera Collagen vascular disease Enteric fever Epidemic or louse-borne typhus Food-borne illness or toxin Hodgkin disease Relapsing fever Poliomyelitis Schistosomiasis (acute Katayama fever) Seizure disorder
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HIV infection Babesiosis Plague Q fever Viral hemorrhagic fevers Dengue Fever Encephalitis Gastroenteritis Giardiasis Heat exhaustion and heatstroke Hepatitis Hypothermia Leishmaniasis Mononucleosis Otitis media Pelvic inflammatory disease Pharyngitis Bacterial pneumonia Immunocompromised pneumonia Mycoplasma pneumonia Viral Pneumonia Salmonella infection Sinusitis Tetanus Toxoplasmosis Yellow fever

Physical Examination Fever can be very high from the first day. Temperatures of 40C and higher are often observed. Fever is usually continuous or irregular. Classic

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periodicity may be established after some days. High fever, poor oral intake, and vomiting all contribute to dehydration. The liver may be slightly tender. Splenomegaly takes many days, especially in the first attack in nonimmune children. In children from an endemic area, severe splenomegaly sometimes occurs. Prolonged malaria can cause anemia. Also, with heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria. Other Tests Serologic tests provide confirmation of past malaria in patients and are valuable for epidemiologic studies. These tests are also useful for screening donated blood and diagnosing hyperactive malarial splenomegaly. Among the tests used are:

Indirect fluorescent antibody test (IFAT) Indirect hemagglutination antibody (IHA) test Enzyme-linked immunosorbent assay (ELISA) Immuno-chromatographic test (ICT) for filariasis

All of these tests produce positive results several days after malarial parasites appear in the blood and so do not help in the diagnosis of the acute infection for treatment purposes. Dipstick tests based on the detection of P falciparum histidine-rich protein-2 (PfHRP-2) antigen are specific for P falciparum infections and do not detect the other 3 species. Dipstick tests based on the detection of parasite lactate dehydrogenase are now available; these tests can detect P falciparum and P vivax. These tests have high sensitivity and specificity, require no special equipment or training, and produce results rapidly. They offer an advantage where the disease is uncommon and blood smear examination expertise is not readily available. However, they remain positive for a week or more after the treatment and cure and, in this situation, can yield false-positive results.

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Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) probes and polymerase chain reaction (PCR) assays have good sensitivity and specificity but require sophisticated expensive equipment. Approach Considerations Demonstration of the parasite in a smear of the blood definitely establishes the presence of malaria. A negative finding on examination does not rule out malaria. Only 50% of children with malaria have positive smear findings, even on repeated examination. Asymptomatic parasitemia is common in children from an endemic area who have partial immunity to the disease. A positive smear for malaria parasite does not always confirm a diagnosis of malaria in these children. More importantly, a positive smear should not stop the diagnostic effort in a febrile illness. Lumbar puncture is indicated to rule out meningitis in cerebral malaria and febrile seizures with malaria. Severe P falciparum malaria is often associated with hypoglycemia. Lower blood glucose levels are associated with higher mortality rates. Blood Smear Examination Both thick and thin films are essential. If the parasitemia is light, a thin film examination may miss the diagnosis. Thick films save time in diagnosis of scanty infections but make species identification of the parasite difficult. At least 100-200 fields of a thick film should be scrutinized before a slide is reported as negative for malaria. In doubtful cases, the examination can be repeated after 4 hours. Obtaining thick and thin blood films at the bedside is important. These films may have to be taken repeatedly for diagnosis. Earlobe or finger prick is used for older children; the great toe is used in infants. Take a large drop of blood on one end of a clean slide, spread uniformly, and air-dry. A smaller drop should be spread thinly so that the end of the smear

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does not reach the end of the slide. Giemsa staining is suitable for identifying malarial parasites in these films. Various techniques to enhance the diagnostic value of the peripheral blood smear examination are in use. Fluorescent staining and microscopy, centrifugation, selective magnetic separation techniques, and other techniques have been used but have only a moderate effect. Histologic findings The appearance of the parasite varies in the thick and thin films. The thick unfixed film shows only leucocytes and parasites; erythrocytes are destroyed in the staining process. The parasites themselves are also altered. Young trophozoites appear as incomplete rings or spots of blue cytoplasm with discrete red nuclei. In mature trophozoites, the cytoplasm may be fragmented, and the various characteristics of the different species are often indistinct. Gametocytes and schizonts usually retain their characteristic appearances. Thin film examination is essential for the accurate identification of plasmodial species, which has an important bearing on treatment. 2.6 Differential Diagnoses

African Trypanosomiasis (Sleeping Sickness) Human African trypanosomiasis (HAT), also called sleeping sickness, is an illness endemic to sub-Saharan Africa. It is caused by the flagellate protozoan Trypanosoma brucei, which exists in 2 morphologically identical subspecies: Trypanosoma brucei rhodesiense (East African or Rhodesian African trypanosomiasis) and Trypanosoma brucei gambiense (West African or Gambian African trypanosomiasis). Both of these parasites are transmitted to human hosts by bites of infected tsetse flies (Glossina palpalis transmits T brucei gambiense and Glossina morsitans transmits T brucei rhodesiense), which are found only in Africa.

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Dengue Fever Dengue is the most common arthropod-borne viral (Arboviral) illness in humans. Globally, 2.5-3 billion individuals live in approximately 112 countries that experience dengue transmission. Annually, approximately 50-100 million individuals are infected. It is caused by infection with 1 of the 4 serotypes of dengue virus, which is a Flavivirus (a genus of single-stranded nonsegmented RNA viruses). Infection with one dengue serotype confers lifelong homotypic immunity to that serotype and a very brief period of partial heterotypic immunity to other serotypes, but a person can eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic. Dengue hemorrhagic fever has also been termed dengue vasculopathy. Vascular leakage in these patients results in hemoconcentration and serous effusions and can lead to circulatory collapse. This, in conjunction with severe hemorrhagic complications, can lead to dengue shock syndrome, which poses a greater fatality risk than bleeding. Dengue virus transmission follows 2 general patterns: epidemic dengue and hyperendemic dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region as an isolated event that involves a single viral strain. If the number of vectors and susceptible pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection incidence of 25-50%. Mosquito-control efforts, changes in weather, and herd immunity contribute to the control of these epidemics. Transmission appears to begin in urban centers and then spreads to the rest of the country. This is the current pattern of transmission in parts of Africa and South America, areas of Asia where the virus has reemerged, and small island nations. Travelers to these areas are at increased risk of acquiring dengue during these periods of epidemic transmission.

22

Infective Endocarditis Infective endocarditis (IE) is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect. Its intracardiac effects include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.

Influenza Influenza virus infection, one of the most common infectious diseases, is a highly contagious airborne disease that causes an acute febrile illness and results in variable degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and death. These symptoms contribute to significant loss of workdays, human suffering, mortality, and significant morbidity. Although the usual strains of influenza that circulate in the annual influenza cycle constitute a substantial public health concern, far more lethal influenza strains than these have emerged periodically. These deadly strains produced 3 global pandemics in the last century, the worst of which occurred in 1918. Called the Spanish flu (although cases appeared earlier in the United States and elsewhere in Europe), this pandemic killed an estimated 20-50 million persons, with 549,000 deaths in the United States alone.

Leptospirosis Leptospirosis is a disease that is caused by pathogenic spirochetes of the genus Leptospira. It is considered the most common zoonosis in the world. Leptospirosis has recently been recognized as a re-emerging infectious disease among animals and humans and has the potential to

23

become even more prevalent with anticipated global warming. Leptospirosis is distributed worldwide (sparing the polar regions) but is most common in the tropics. Humans and a wide range of animals, including mammals, birds, amphibians, and reptiles can develop Leptospira infection. However, humans are rarely chronic carriers and are therefore considered accidental hosts. Leptospirosis is transmitted via direct contact with the body fluid of an acutely infected animal or by exposure to soil or fresh water contaminated with the urine of an animal that is a chronic carrier.

Meningitis Infections of the central nervous system (CNS) can be divided into 2 broad categories: those primarily involving the meninges (meningitis) and those primarily confined to the parenchyma (encephalitis).

Typhoid Fever Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella typhi. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications. S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War. The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly

24

reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries. 2.7 Prevention Travelers to endemic areas should prevent malaria through the use of chemoprophylaxis and personal protective measures. The risk of acquiring malaria is highest in sub-Saharan Africa and Oceania and is more variable for other regions. The evolving picture of drug resistance complicates recommendations for chemoprophylaxis. Breastfed infants should receive appropriate malaria prophylaxis since they will not receive enough drug in the mother's milk to protect them. Chloroquine is the drug of choice for prophylaxis in areas where chloroquine-resistant P. falciparum has not been reported or where nonfalciparum malaria is the only risk[22] ( Table 1 ). Chloroquine is available only in tablet form in the United States, and the taste is bitter when crushed. Reported side effects include gastrointestinal disturbance, headache, dizziness, blurred vision, insomnia, and pruritus, but often these effects do not require that the drug be discontinued. Chloroquine has been reported to exacerbate psoriasis. TABLE 1. -- Drugs used in the prophylaxis of malaria Adult Drug oguanil (Malarone) Usage areas resistant mefloquineresistant falciparum. Dose with tablets contain or 250 mg atovaquon P. e and 100 mg proguanil Pediatric Dose Comments Pediatric tablets contain 62.5 mg atovaquon e and 25 mg proguanil Begin 12 days before travel to malarious areas. Take daily at the same time each day while in the malarious area and for 7 days Atovaquone/pr Prophylaxis in Adult chloroquine-

25

Adult Drug Usage Dose hydrochlor ide. adult tablet orally, daily 1 Pediatric Dose Comments hydrochlor ide. 5-7 kg: pediatric tablet daily 8-10 kg: pediatric tablet daily 11-20 kg: 1 pediatric tablet daily 21-30 kg: 2 pediatric tablets daily 31 -40 kg: 3 pediatric tablets daily 41 kg or more: daily 1 adult tablet after leaving

such areas. Atovaquone/pro guanil contraindicated in persons with severe impairment (creatinine clearance < 30 mL/min). Atovaquone/pro guanil should be taken with food or a milky drink. Atovaquone/pro guanil recommended for children 5 kg, women, women breastfeeding infants weighing < 5 kg. pregnant and is renal is

Chloroquine phosphate (Aralen and

Prophyla xis only

26

Adult Drug generic) Usage in with chloroqui nesensitive P. falciparu m. Doxycycline (Many names generic formulations) brand and Prophyla xis areas with chloroqui neresistant or mefloqui neresistant P. falciparu m. Mefloquine (Lariam generic formulations) and Prophyla xis areas with 228 mg orally, once/week mg salt) 9 kg and under: 4.6 mg/kg base (5 mg/kg 100 daily mg 8 years of age Begin or older: up 2 before mg/kg 12 travel days to areas Dose Pediatric Dose Comments

in orally,

to malarious areas. Take time each day while in the malarious area and for 4 weeks after leaving such areas. Doxycycline contraindicated is in

adult dose of daily at the same 100 mg/day.

children < 8 years of age and in pregnant women.

in base (250

27

Adult Drug Usage chloroqui neresistant P. falciparu m. Dose Pediatric Dose Comments salt) orally, once/week 10-19 kg: 1/4 tablet once/week 20-30 kg: 1/2 tablet once/week 31-45 kg: 3/4 tablet once/week 46 kg and over: tablet once/week Primaquine An option for 30 special mg daily mg 0.5 mg/kg base Begin 12 travel days to 1

prophylaxis in base (52.6 (0.8 mg/kg salt) before circumstances. orally, orally, daily

salt) up to adult dose malarious areas. Take daily at the same time each day while in the malarious area and for 7 days after leaving such areas.

28

Adult Drug Usage Dose Pediatric Dose Comments Contraindicated deficiency. contraindicated during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level. Use in consultation with malaria experts. in Also persons with G6PD

Atovaquone-proguanil, doxycycline, and mefloquine are all recommended prophylactic options for persons traveling to areas where chloroquine-resistant P. falciparum has been reported ( Table 1 ). The most common adverse effects reported in persons using atovaquone-proguanil for prophylaxis include abdominal pain, nausea, vomiting, and headache. Atovaquone-proguanil should not be used in children weighing < 5 kg, pregnant women, women breastfeeding infants weighing < 5 kg, or patients with severe renal impairment (creatinine clearance < 30 mL/min). Atovaquone-proguanil should be given with food. Because atovaquone-proguanil is considered a causal prophylactic agent (i.e., it kills the initial hepatic stage of malaria parasites), it needs to be given for only 7 days after leaving a malarious area. Daily doxycycline is another option for children who are > 8 years old. Gastrointestinal complaints, photosensitivity, and candidal vaginitis are reported adverse effects. Photosensitivity associated with the use of doxycycline may be lessened with sunscreens that protect against ultraviolet A radiation. Doxycycline

29

is contraindicated during pregnancy. Doxycycline should be taken with an ample amount of fluid and should not be taken prior to sleep to minimize the risk of esophagitis. Mefloquine can be used in children of any weight ( Table 1 ). Nausea and vomiting have been problematic in children. Other reported side effects include headache, insomnia, abnormal dreams, visual disturbances, depression, anxiety disorder, and dizziness. Rare serious adverse reactions include acute reversible severe neuropsychiatric reaction, seizures, and cardiac conduction abnormalities. Mefloquine is safe to use in pregnancy although data on use in the first trimester is limited. Mefloquine is contraindicated in persons with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures (but not including typical febrile seizures). It should be used with caution in persons with prior psychiatric disturbances or a previous history of depression. It is not recommended for persons with cardiac conduction abnormalities. Resistance to mefloquine has been reported in the border areas of Thailand with Myanmar and Cambodia, where doxycycline or atovaquone-proguanil should be used for prophylaxis. Several studies have shown that daily primaquine provides effective prophylaxis against chloroquine-resistant P. falciparum, but it is only recommended when other options are not appropriate[22] While malaria chemoprophylaxis is recommended for travel to malarious areas, if travelers elect not to take prophylaxis, do not choose an optimal regimen, cannot take an optimal regimen (for example, because of contraindications), or are traveling to very remote areas, they may choose to carry a 3-day course of atovaquone-proguanil for self-treatment of a febrile illness if medical care is not readily available. The treatment dose is the same as that listed for treatment in Table 1. This self-treatment of possible malaria infection is only a temporary measure and prompt medical evaluation must be sought. Atovaquone-proguanil is not recommended for standby treatment in persons already taking atovaquoneproguanil for chemoprophylaxis.

30

Avoidance of mosquitoes and barrier protection are critical aspects of malaria prophylaxis given that no chemoprophylaxis guarantees complete protection. Anopheline mosquitoes feed from dusk to dawn. Avoiding nighttime exposure by staying in screened-in areas, using protective clothing, sleeping under insecticide-treated bed nets, and using repellents are all helpful. Topical mosquito repellents that contain N-N-diethyl-m-toluamide (DEET) are the most effective in preventing malaria.[22] Permethrin-impregnated bed nets are effective, and permethrin sprays are available for use on clothing. Pyrethrum-containing sprays are also effective as residual insecticides for use in nonscreened areas. None of these measures is 100% effective, and therefore the diagnosis of malaria should be considered in anyone with a fever who has been in an endemic area. Most travelers in whom malaria is diagnosed manifest symptoms within a few weeks to months of return from the malarious area, particularly with P. falciparum infection. Infections with the other species of malaria can appear months later. For persons emigrating from malarious areas, manifestations of P. falciparum infection would rarely occur beyond 1 year, whereas those with the other species of Plasmodium could occur years later. Pregnancy increases the risk of complications from malaria in both nonimmune and partially immune women. Their clinical course can be more severe, and malaria during pregnancy carries an increased risk of premature birth or pregnancy loss. Pregnant women should avoid travel to malarious areas. If they must travel, chloroquine prophylaxis can be used during pregnancy for travel to areas where chloroquine-resistant P. falciparum has not been reported or where nonfalciparum malaria is the only risk. Mefloquine prophylaxis is safe and effective in all trimesters, although data on first trimester use are limited, [22] and should be recommended for all women who cannot defer travel to areas where chloroquine-resistant P. falciparum has been reported. Doxycycline and atovaquone-proguanil are not recommended for use during pregnancy. Traveling with children requires special preparation. In the United States, antimalarial drugs are available only in tablet form and most taste bitter. Compounding pharmacies can pulverize tablets, weigh out the precise dose, and

31

place the dose in a gelatin capsule; sufficient time will be needed before travel to allow preparation of appropriate dosages. The capsule can be opened at the time of administration and the medication mixed with sweet food items, such as applesauce, chocolate syrup or jelly, to disguise the taste. [22] [23] 2.8 Treatment Once the diagnosis of malaria is made, multiple factors must be assessed to establish an appropriate strategy for treatment. The first factor to consider is whether the patient has uncomplicated or severe malaria ( Tabel 2 ). Other factors that affect therapy are the geographic region in which the malaria was acquired and the use of antimalarial chemoprophylaxis. Tabel 2 MANIFESTATIONS OF SEVERE MALARIA Cerebral malaria, defined as unarousable coma not attributable to any other cause in a patient with P. falciparum malaria Repeated generalized convulsions Severe normocytic anemia with hematocrit < 15% Hypoglycemia Metabolic acidosis with respiratory distress Fluid and electrolyte disturbances Acute renal failure Respiratory compromise, acute pulmonary edema, or adult respiratory distress syndrome Circulatory collapse, shock, septicemia (algid malaria) Abnormal bleeding Jaundice Hemoglobinuria Hyperparasitemia (> 5% of red blood cells infected)

Patients with P. falciparum malaria and those in whom P. falciparum cannot be excluded should be hospitalized for therapy and monitoring because of the rapid clinical deterioration that can occur even if the patient initially appears

32

stable ( Tabel 3 ). Therapy should be started immediately and supportive care given as necessary. If the patient has severe malaria or is unable to tolerate oral therapy, intravenous quinidine in combination with doxycycline, tetracycline or clindamycin should be used in a setting where cardiovascular status and hypoglycemia can be monitored closely ( Table 4 ). As newer anti-arrhythmic drugs have replaced quinidine for many cardiac indications, some hospitals and other healthcare facilities have dropped quinidine gluconate from their formularies. Tabel 3 MANAGEMENT OF INDIVIDUALS WITH SEVERE MALARIA Initiate antimalarial therapy immediately Correct fluid balance and electrolyte abnormalities cautiously Monitor, prevent, and correct hypoglycemia Correct anemia as needed Provide antipyretic therapy Protect the airway in patients with altered mental status Consider exchange transfusion for parasitemia > 10% or end organ complications Avoid harmful adjuvant therapies

TABLE 4 -- Guidelines for the Treatment of Malaria in the United States Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose Severe malaria All regions Quinidine gluconate plus one of the following: Doxycycline, Tetracycline, or Clindamycin Quinidine gluconate plus one of the following: Doxycycline, Tetracyclinea, or Clindamycin

33

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose Quinidine gluconate: 6.25 mg base/kg (= 10 mg salt/kg) loading dose IV over 12 hrs, then 0.0125 mg base/kg/min (= 0.02 mg salt/kg/min) continuous infusion for at least 24 hours. An alternative regimen is 15 mg base/kg (=24 mg salt/kg) loading dose IV infused over 4 hours, followed by 7.5 mg base/kg (= 12 mg salt/kg) infused over 4 hours every 8 hours, starting 8 hours after the loading dose. Once parasite density is < 1% and patient can take oral medication, complete treatment with oral quinine, dosed as below. Quinidine/quini ne course = 7 days in Quinidine gluconate: Same mg/kg dosing and recommendatio ns as for adults Doxycyclinea: 4 mg/kg/day po divided bid 7 days. Can be used in children > 8 years old. If patient is not able to take oral medication, may give IV For children < 45 kg, give 2.2 mg/kg IV every 12 hours and then give oral doxycycline (dose as above) as soon as patient can take oral medication. For children > 45 kg, use same dosing as for adults. Tetracyclinea: 25 mg/kg/day po divided qid 7 days Clindamycin: 20 mg

34

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose southeast Asia; = 3 days in Africa or South America. Doxycycline: 100 mg po bid 7 days. If patient is not able to take oral medication, give 100 mg IV every 12 hours and then give oral doxycycline as soon as patient can take oral medication. Treatment course = 7 days. Tetracycline: 250 mg po qid 7 days Clindamycin: 20 mg kg/day po divided tid 7 days. If patient is not able to take oral medication, give 10 mg base/kg loading dose IV followed by 5 mg base/kg IV every 8 hours. Give oral clindamycin base/kg/day po divided tid 7 days. If patient is not able to take oral medication, give 10 mg/kg loading dose IV followed by 5 mg/kg IV every 8 hours. Switch to oral clindamycin (oral dose as above) as soon as patient can take oral medication.

35

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose (oral dose as above) as soon as patient can take oral medication. Treatment course = 7 days. Uncomplicated malaria/P. falciparum or Species not identified If species not identified is subsequently diagnosed as P. vivax or P. ovale: see P. vivax and P. ovale (below) re treatment with primaquine Chloroquine Chloroquine Chloroquine sensitive (Central phosphate phosphate America west of (Aralen(tm) and (Aralen(tm) and Panama Canal; generic generic Haiti; the formulations) 600 formulations) 10 Dominican mg base (=1000 mg mg base/kg po Republic; and salt) po immediately, immediately, most of the followed by 300 mg followed by 5 mg Middle East) base (=500 mg salt) base/kg po at 6, 24, po at 6, 24, and 48 and 48 hours Total hours Total dose: dose: 25 mg base/kg 1500 mg base (=2500 mg salt) Chloroquine resistant or unknown resistance[b](All malarious regions except those specified as chloroquine sensitive listed in the box above. Middle eastern countries with chloroquine resistant P. falciparum include Iran, Oman, Saudi A. Quinine sulfate plus one of the following: Doxycycline, Tetracycline, or Clindamycin Quinine sulfate: 542 mg base (= 650 mg salt) po tid 3 to 7 days Doxycycline: Treatment as above A. Quinine [c] sulfate plus one of the following: Doxycyclinea, Tetracyclinea or Clindamycin Quinine sulfate[c] 8.3 mg base/kg (= 10 mg salt/kg) po tid 3 to 7 days Doxycyclinea Treatment as

36

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose Arabia, and Yemen. Of note, infections acquired in the Newly Independent States of the former Soviet Union and Korea to date have been uniformly caused by P. vivax and should therefore be treated as chloroquinesensitive infections.) Tetracycline: Treatment as above Clindamycin: Treatment as above above Tetracyclinea Treatment as above Clindamycin Treatment as above B. Atovaquoneproguanil (Malarone(tm) ) Adult tablet = 250 mg atovaquone/10 0 mg proguanil Pediatric tablet = 62.5 mg atovaquone/25 mg proguanil 58 kg: 2 pediatric tablets po qd 3 days 910 kg: 3 pediatric tablets po qd 3 days 1120 kg: 1 adult tablet po qd 3 days 2130 kg: 2 adult tablets po qd 3 days

B. Atovaquoneproguanil (Malarone(tm) ) Adult tablet = 250 mg atovaquone/10 0 mg proguanil 4 adult tablets po qd 3 days

37

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose 3140 kg: 3 adult tablets po qd 3 days > 40 kg: 4 adult tablets po qd 3 days C. Mefloquine (Lariam(tm) and generic formulations) 684 mg base (= 750 mg salt) po as initial dose, followed by 456 mg base (= 500 mg salt) po given 612 hours after initial dose Total dose = 1250 mg salt Uncomplicated malaria P. malariae Uncomplicate d malaria P. vivax or P. ovale All regions C. Mefloquine (Lariam(tm) and generics) 13.7 mg base/kg (= 15 mg salt/kg) po as initial dose, followed by 9.1 mg base/kg (= 10 mg salt/kg) po given 612 hours after initial dose Total dose = 25 mg salt/kg

Chloroquine Chloroquine phosphate: phosphate: Treatment as above Treatment as above Chloroquine phosphate plus Primaquine phosphate Chloroquine phosphate: Treatment as above Primaquine Chloroquine phosphate plus Primaquine phosphate Chloroquine phosphate: Treatment as above

All regions'[1] Note: for suspected chloroquine resistant P. vivax, see below

38

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose phosphate: 30 mg base po qd x 14 days Primaquine phosphate: 0.6 mg base/kg po qd x 14 days A. Quinine sulfate[c] plus either Doxycycline[a] or Tetracycline,[a] plus Primaquine phosphate Quinine sulfate[c]: Treatment above

Uncomplicate d malaria P. vivax

Chloroquin e-resistant[d] (Papua New Guinea and Indonesia)

A. Quinine sulfate[c] plus either Doxycycline or Tetracycline, plus Primaquine phosphate Quinine sulfate: Treatment above

as

as

Doxycycline or Tetracycline: Treatment as above Primaquine phosphate: Treatment as above

Doxycycline[a] or Tetracycline[a]: Treatment as above Primaquine phosphate: Treatment as above B. Mefloquine plus Primaquine phosphate Mefloquine: Treatment as above Primaquine

B. Mefloquine plus Primaquine phosphate Mefloquine: Treatment as above Primaquine

39

Recommended Drug and Pediatric Clinical Recommended Dose Pediatric dose Diagnosis/Plasmodi Region Infection Drug and Adult should NEVER um species Acquired Dose exceed adult dose phosphate: Treatment as above phosphate: Treatment as above

Patients with severe malaria should be given an intravenous loading dose of quinidine unless they have received more than 40 mg/kg of quinine in the preceding 48 hours or if they have received mefloquine within the preceding 12 hours. Consultation with a cardiologist and a physician with experience treating malaria is advised when treating patients with malaria using quinidine. During administration of quinidine, monitoring of blood pressure (for hypotension) and continuous cardiac monitoring (for widening of the QRS complex and/or lengthening of the QTc interval) is needed and blood glucose (for hypoglycemia) should be evaluated periodically.[27] Cardiac complications, if severe, may warrant temporary discontinuation of the drug or slowing of the intravenous infusion. Exchange transfusion should be strongly considered if the initial parasitemia is greater than 10% or if altered mental status, non-volume overload pulmonary edema, or renal complications are present. [26] [27] [28] The parasite density can be estimated from the percentage of infected RBCs and should be monitored every 12 hours. Because of sequestration in the micro- vasculature of mature erythrocyte forms of P. falciparum, density of parasitemia can be underestimated or diagnosis missed on examination of a single blood smear. Exchange transfusion should be continued until the parasite density is < 1% (usually requires replacement of 1 to 2 blood volumes). Intravenous quinidine administration should not be delayed for an exchange transfusion and can be given concurrently throughout the exchange transfusion. Clinical deterioration can occur in the first 24 hours of therapy, particularly in patients with high parasitemia. Supportive care during this period is

40

critical and should include careful monitoring for hypoglycemia and anemia, careful management of fluid and electrolyte disturbances, monitoring for respiratory and renal compromise, and protection of the patient's airway if declining mental status is evident. Adjunctive therapies such as corticosteroids, heparin, epinephrine, desferrioxamine, cyclosporin A, prostacyclin, or osmotic agents for cerebral edema have not proven effective for severe malaria, and considerable evidence suggests potential harm from some of these treatments. Cerebral edema or increased intracranial pressure is rarely a problem, even with patients in coma, except as terminal events. Complications of malaria generally are limited to the acute illness; prolonged convalescence is common. In general, full recovery from any pulmonary, renal, or central nervous system compromise is the rule. The exception occurs in children with cerebral malaria where up to 10% may have residual neurologic deficits.[19] Parasitemia should decrease substantially within the first 48 hours of therapy. Parasites generally clear by 72 hours and their persistence should prompt evaluation of possible causes, including inadequate dosage or possible drug resistance. Follow-up blood smears should also be performed at the end of therapy to ensure that parasitemia has cleared. Gametocytes of P. falciparum are not killed by most therapies used and can be seen for weeks after the initiation of therapy; this finding should not be considered a sign of drug failure and no additional antimalarial therapy is required. Individuals with uncomplicated malaria due to P. falciparum can use oral chloroquine if infection was acquired in the Caribbean basin, northern Middle East region, or west of the Panama Canal Zone in Central America and if the patient is able to take oral medication ( Table 4 ). Individuals with falciparum malaria acquired in all other geographic areas should be treated with atovaquoneproguanil or with oral quinine sulfate plus either tetracycline, doxycycline or clindamycin, depending on the age of the patient, because of the high risk of chloroquine resistance. In southeast Asia there is evidence for the declining efficacy of quinine, and treatment should be continued for 7 days. Doxycycline,

41

tetracycline, or clindamycin should not be used alone for malaria therapy in nonimmune hosts because of the delayed onset (48 hours) of action of these drugs. Mefloquine is an alternative treatment for P. falciparum infections acquired in areas with chloroquine-resistance if neither atovaquone-proguanil nor quinine-based regimens can be used. Its use is limited by the higher rate of neuropsychiatric reactions seen at treatment doses and thus is considered second line therapy. It should not be given at the same time as quinine or quinidine due to concern for cardiotoxicity. Moreover, mefloquine should not be used in patients who have acquired infection in the region of Burma, Thailand or Cambodia due to high levels of resistance reported. Halofantrine is a drug similar to mefloquine and though it is FDA approved, it is not marketed in the United States. Halofantrine is not recommended for treatment as it has been reported to cause ventricular dysrhythmias, which can be fatal, in persons with and without pre-existing cardiac disease.[29] Another group of compounds initially identified in China as derivatives of the qinghao plant, is widely used outside the United States but currently is not available in the United States. Qinghaosu, or artemisinin, a sesquiterpine endoperoxide, is the active agent.[30] This class of compounds are rapidly malariocidal and highly effective in areas where drug resistance is a major problem, including in pediatric-aged patients. [31] [32] All patients who do not have P. falciparum infection can be treated with chloroquine as outpatients, depending on their overall clinical status, and monitored for symptomatic improvement ( Table 4 ). Chloroquine treatment failure rates are high among P. vivax infections acquired in Papua New Guinea and Indonesia, and thus P. vivax infections acquired in these areas should be treated with mefloquine or a combination of quinine plus doxycycline. If the patient cannot take oral medication, intravenous quinidine is the drug of choice. Sporadic reports of P. vivax with decreased susceptibility to chloroquine have appeared in other areas, including Brazil, Myanmar, India, Guyana, and Colombia. The potential for decreased susceptibility must be considered if infection was acquired in one of these latter regions.[33] If the patient does not

42

respond to treatment with chloroquine, then the treatment should be changed to a regimen effective against chloroquine-resistant P. vivax. If the infecting species is identified as P. vivax or P. ovale, treatment with primaquine is also necessary to prevent relapse from latent hypnozoite forms in the liver ( Table 4 ). Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be ruled out prior to giving primaquine. Primaquine therapy should be initiated concomitantly with the blood schizonticide as there is evidence that this results in greater efficacy in eradicating hypnozoites. Primaquine treatment of a confirmed P. vivax or P. ovale infection in a known G6PD-deficient individual should only be used after a careful assessment of risk and benefit and under strict medical supervision. Individuals with G6PD deficiency who are not able to take primaquine should be retreated with chloroquine if relapses occur. The recommended course of primaquine is 0.6 mg/kg daily for 14 days with a target total dose of > 6 mg/kg. Failure of primaquine to eradicate hypnozoites is very unusual if this dose is attained. However, in many cases adherence cannot be assured. If relapse occurs, the patient should be retreated with chloroquine and primaquine. Primaquine should not be used during pregnancy.

43

CHAPTER 3 MEDICAL RECORD MALARIA 3.1 Objective The aim of doing this paper is to report a case of Malaria of 12 years old boy that was admitted at Pediatrics Department of Haji Adam Malik General Hospital. 3.2 Case Name Age Sex Adress Date of Admission :W : 12 years and 11 mounth old : Male : Padang Sidempuan : October, 2nd 2012

Chief Complaint History

: Fever : This problem has already been occurring to this patient for

8 days. Fever was high, fluctuate and decrease with antipyretic. Fever often appearing at night started by shivering, high fever and profuse sweating. Seizure was not found. Nausea and vomiting was found, this complaint since 8 days ago, frequency + 2 times a day, the contents of the vomit what is eaten. History of the black colored vomit not found. Malaise was found since 2 weeks ago and patient also complained headache since 1 week ago. Cough was not found. History of bleeding such as petichiae, bleeding gums, nosebleeds, and melena not found. History of constipation was found since 8 days ago and 3 days before these, patient was given fluids through the anus and finally the patient defecated 1 time, after that the patient did not defecate until now. History of travel to areas endemic

44

for malaria for this patient is not necessary because patient has already lived in endemic area. History of blood transfusion was not found. Normal urination positive. Family history of suffering from the same thing not found. History of previous illness : Patient was referred from Padang Sidimpuan Regional General Hospital with differential diagnostic Typhoid fever + malaria History of previous medication Physical Examination Presense Status : Sensorium: compos mentis Temperature 39.8oC Anemic (+), Icteric (-), Dyspnea (-), Cyanotic (-), Edema (-). Weight: 28 kg Head Length: 133 cm BW/BL: 100% : Eye: Light reflexes (+/+), isochoric pupil, pale conjunctiva palpebra inferior (+/+) Ear nose and mouth: within normal limit Neck Thorax : Lymph node enlargement (-) : Simetrical fusiform, retraction (-) HR: 100 bpm, regular, murmur (-) RR: 30 x/minute, regular, ronchi (-/-) Abdomen : Soepel, peristaltic (+) Normal Hepar: palpable 2 cm below arcus costae (d) Lien: non palpable Genitalia Extrimities : male, within normal limit : pulse: 100 bpm, regular, adequate pressure/volume, CRT<3, warm, edema (-). : Suldox,. Ceftriaxone

45

Laboratory Finding Padang Sedimpuan Regional General 25/09/2012 Test IgG Dengue IgM Dengue Widal test Result Non reactive Non reactive H 1/80 O AO 1/640 1/80 1/160 1/40

Hospital:

Normal value

AH 1/40

BH 1/160 BO CH 1/80 CO

Laboratory Finding Adam Malik General Hospital: 02/10/2012 Test CBC Renal Ureum Creatinin 131 mEq/L 4.5 mEq/L 135-155 mEq/L 3.5-5.5 mEq/L Sodium Hb RBC Ht WBC PLT MCV MCH MCHC Blood random) 35.90 mg/dl 0.89 mg/dl <50 mg/dl 0.53-0.79 mg/dl glucose 9.00 g% 3.37 x 106/mm3 26.60% 5.85 x 103/mm3 93 x 103/mm3 78.90 fL 26.70 pg 33.80 g% (ad 83.40 mg/dl 12.0-14.4 g% 4.75-4.85 x 106/mm3 36-42% 4.5-11.0 x 103/mm3 150-450 x 103/mm3 75-87 fL 25-31 pg 33-35 g% <200 mg/dl Result Normal value

Carbohydrate Metabolism

Electrolite

46

Phosphate Clor

103 mEq/L Leu (+) / Nit (-) / Uro (-) / Prot (-) / pH (6.0) / Blood (-) / SG (1.010) / Ket (+) / Bil (+) / Glu (-)

96-106 mEq/L

Dipstick urine:

Differential Diagnosis: Typhoid Fever Malaria Dengue Hemorrhagic Fever

Working Diagnosis: Typhoid Fever + malaria Treatment: IVFD D5% NaCl 0,45% 40 40 drips/minute Paracetamol tab 3 x 300 mg (k/p) Diet MII1660 ccal & 56 gr protein

Planning: Blood Smears Tubex TF test Consul Division of Tropical infections

Follow Up

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October 3rd 2012 S Fever (+), Shiver (+), Diarhoea (+) 1x O Sens: CM. Temp: 40.30C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 84 bpm, regular, murmur (-) RR: 32 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normo peristaltic. Liver palpable 2 cm below arcus costae spleen unpalpable. Extrimities: Pulse 84 bpm, regular, adequate p/v, warm, CRT < 3. BP: 100/70 mmHg Laboratory findings: Peripheral blood: Plasmodium vivax Stadium: Tropozoid 11.160/L Schizon (-) Gametosit 2.280/L Consul Division of Tropical Infection Diagnosis Treatment : Tertian Malaria : Artesunate 1x125 mg (2 tablet) for 3 days Amodiaquine 1x280 mg (2 tablet) for 3 days A P Primaquine 1x7 mg (1/2 tablet) for 14 days Typhoid Fever + Malaria - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Check G6PD before treat with primaquine - Iron profile

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- Blood smear 1, 2, 3, 7, 14, 28, 42 day treatment October 4th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 36.80C Head : Pale conjunctiva palpebra inferior Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 80 bpm, regular, murmur (-) RR: 20 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 2 cm below arcus costae spleen unpalpable. Extrimities: Pulse 80 bpm, regular, adequate p/v, warm, CRT < 3. BP: 110/70 mmHg Laboratory finding: Immunoserology Tubex TF: negative Iron Profile: - Ferritin432.40 ng/mL - Besi 58 mg/dL A P - TIBC 235 g/dL Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Dalprex 1 x 2 tab (H1) - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Check G6PD (9/10/12) - Blood smear 1st day treatment October 5th 2012 (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit

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S O

Fever (-), Shiver (-) Sens: CM. Temp: 36.80C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 88 bpm, regular, murmur (-) RR: 22 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 2 cm below arcus costae spleen unpalpable. Extrimities: Pulse 88 bpm, regular, adequate p/v, warm, CRT < 3. BP: 120/80 mmHg Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Dalprex 1 x 2 tab (H2) - Paracetamol tab 3 x 300 mg (k/p) - Diet MII 1660 ccal with 56 gr protein - Check G6PD (9/10/12) - Peripheral blood 2nd day start treatment

A P

October 6th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 36.70C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 98 bpm, regular, murmur (-) RR: 22 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 2 cm below arcus costae spleen unpalpable. Extrimities: Pulse 98 bpm, regular, adequate p/v, warm, CRT < 3. BP: 110/80 mmHg

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Laboratory finding: A P Malaria: Negative Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Dalprex 1 x 2 tab (H3) - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Check G6PD (9/10/12) - Peripheral blood 3rd day start treatment October 7th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 36.80C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 96 bpm, regular, murmur (-) RR: 24 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 2 cm below arcus costae spleen unpalpable. Extrimities: Pulse 96 bpm, regular, adequate p/v, warm, CRT < 3. BP: 110/70 mmHg Laboratory finding: A P Plasmodium vivax: Negative Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Check G6PD (9/10/12)

October 8th 2012

51

S O

Fever (-), Shiver (-) Sens: CM. Temp: 37.00C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 90 bpm, regular, murmur (-) RR: 22 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 1 cm below arcus costae spleen unpalpable. Extrimities: Pulse 92 bpm, regular, adequate p/v, warm, CRT < 3. BP: 110/70 mmHg Laboratory finding: Hb: 8.3 gr% Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Paracetamol tab 3 x 300 mg (k/p) - Diet MII 1660 ccal with 56 gr protein - Check G6PD (9/10/12) - Transfussion PRC 302.4 ml

A P

October 9th 2012 S Fever (+), Shiver (-) O Sens: CM. Temp: 40.20C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 120 bpm, regular, murmur (-) RR: 22 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 1 cm below arcus costae spleen unpalpable. Extrimities: Pulse 120 bpm, regular, adequate p/v, warm, CRT < 3. BP:

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100/60 mmHg Laboratory finding: A P G6PD 7.9 U/gHb (N: 7.0 - 20.4) Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Primaquin - Transfussion PRC I 175 ml October 10th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 37.20C Head : Pale conjunctiva palpebra inferior (+/+), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 108 bpm, regular, murmur (-) RR: 24 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 1 cm below arcus costae spleen unpalpable. Extrimities: Pulse 108 bpm, regular, adequate p/v, warm, CRT < 3. BP: A P 110/60 mmHg Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Primaquin 1 x 7 mg (1/2 tablet) for 14 days - Paracetamol tab 3 x 300 mg (k/p) R - Diet MII 1660 ccal with 56 gr protein - Transfusion PRC II 125 ml

October 11th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 37.00C Head : Pale conjunctiva palpebra inferior (-/-), Light reflex (+/+), Isochoric
53

pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-) Thorax : SF. Retraction (-) HR: 92 bpm, regular, murmur (-) RR: 24 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 1 cm below arcus costae spleen unpalpable. Extrimities: Pulse 92 bpm, regular, adequate p/v, warm, CRT < 3. BP: 110/70 mmHg Laboratory finding: Hb Ht PLT 11.80 g% 32.80% 432 x 103/mm3 RBC 4.11 x 106/mm3 WBC 13.20 x 103/mm3 MCV 79.80 fL MCH 28.70 pg MCHC36.00 g% Hitung jenis A P E/B/N/L/M 0/0/69/19/11 Malaria Tertiana (P. vivax) - IVFD D5% NaCl 0.45% 40 gtt/i (micro) - Primaquin 1 x 7 mg (H2) - Paracetamol tab 3 x 300 mg (k/p) - Diet MII 1660 ccal with 56 gr protein October 12th 2012 S Fever (-), Shiver (-) O Sens: CM. Temp: 36.90C Head : Pale conjunctiva palpebra inferior (-/-), Light reflex (+/+), Isochoric pupil. Ear/Nose/Mouth: within normal limit Neck : Lymph node enlargement (-)

54

Thorax : SF. Retraction (-) HR: 102 bpm, regular, murmur (-) RR: 24 x/i, regular, ronchi (-/-) Abdomen: Soepel. Normoperistaltic. Liver palpable 1 cm below arcus costae spleen unpalpable. Extrimities: Pulse 102 bpm, regular, adequate p/v, warm, CRT < 3. BP: A P R 110/60 mmHg Malaria Tertiana (P. vivax) - Paracetamol tab 3 x 300 mg (k/p) - Primaquin 1 x 7 mg (H3) Scheduled to be an outpatient

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CHAPTER 4 DISCUSSION AND SUMMARY 4.1 Disscussion W, male, 12 years and 11 mounth old was admitted to Pediatrics Department of Haji Adam Malik General Hospital and was diagnosed with malaria. The diagnosis was established based on history taking, clinical manifestations, physical examination and laboratory finding. From history taking and clinical manifestations patient experienced periodic fever which started by shivering, high fever and profuse sweating, nausea and vomiting, malaise, and the patient live in areas that is endemic for malaria which is mean that the patient has no immunity for malaria. Risk factors for malaria include the following; Residence in, or travel through, a malarious area, no previous exposure to malaria (hence no immunity), no chemoprophylaxis or improper chemoprophylaxis. The clinical features of malaria are dependent on the malaria-specific immune status of the host and the infecting species of Plasmodium. Nonimmune people, such as those who have not resided in an endemic area or have been away from an endemic area for as little as 1 year, generally have symptomatic infection. Fever can be very high from the first day. Temperatures of 40C and higher are often observed. Fever is usually continuous or irregular. Classic periodicity may be established after some days. High fever, poor oral intake, and vomiting all contribute to dehydration. From physical examination in this patient were found anemic and liver was palpable 2 cm below arcus costae. Laboratory result for this patient was

56

anemia normokrom normositer and trombositopenia. From blood smear in the patient was found p. vivax. Of patients infected with P vivax, 50% experience a relapse within a few weeks to 5 years after the initial illness. The liver may be slightly tender. Splenomegaly takes many days, especially in the first attack in nonimmune children. In children from an endemic area, severe splenomegaly sometimes occurs. Prolonged malaria can cause anemia. Also, with heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria. 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. The degree of parasitemia hadnt reached until 5 % which mean that this patient is categorized for moderate malaria. Both thick and thin films are essential. If the parasitemia is light, a thin film examination may miss the diagnosis. Thick films save time in diagnosis of scanty infections but make species identification of the parasite difficult. At least 100-200 fields of a thick film should be scrutinized before a slide is reported as negative for malaria. In doubtful cases, the examination can be repeated after 4 hours. Obtaining thick and thin blood films at the bedside is important. These films may have to be taken repeatedly for diagnosis. Earlobe or finger prick is used for older children; the great toe is used in infants. The patient is admitted to the hospital on 2nd October with hemoglobin 9 gr % and the status for iron is normal based on finding of serum iron, TIbc and serum ferritin. On 8th October patients hemoglobin is 8,3 gr% and we gave the patient packed red cell transfusion. On the 11th October patients hemoglobin was increased until 11,8 gr%. The laboratory result for G6PD is negative. The treatment given were IVFD D5% NaCl 0.45% 40 gtt/i (micro), Paracetamol tab 3 x 300 mg (k/p), Dalprex 1 x 2 tab for 3 days, Primaquin 1 x 7 mg for 14 days, Transfussion PRC 302.4 ml. If the infecting species is identified as P. vivax or P. ovale, treatment with primaquine is also necessary to prevent relapse from latent hypnozoite forms in

57

the liver ( Table 4 ). Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be ruled out prior to giving primaquine. Primaquine therapy should be initiated concomitantly with the blood schizonticide as there is evidence that this results in greater efficacy in eradicating hypnozoites. Primaquine treatment of a confirmed P. vivax or P. ovale infection in a known G6PD-deficient individual should only be used after a careful assessment of risk and benefit and under strict medical supervision. Individuals with G6PD deficiency who are not able to take primaquine should be retreated with chloroquine if relapses occur. The recommended course of primaquine is 0.6 mg/kg daily for 14 days with a target total dose of > 6 mg/kg. Failure of primaquine to eradicate hypnozoites is very unusual if this dose is attained. However, in many cases adherence cannot be assured. If relapse occurs, the patient should be retreated with chloroquine and primaquine. Primaquine should not be used during pregnancy. 4.2 Summary The patient is stated negative for malaria on 6th October but primaquin is still be given until 12th October. This will helped to prevent the parasites for being dormant in the liver. This patient was discharged from the hospital after the clinical condition was improved, patient has an appetite

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information for international travel 20052006 Atlanta: US Department of 23. Stauffer WM, Kamat D, Magill AJ: Traveling with infants and children. Part IV: insect avoidance and malaria prevention. J Travel Med 2003; 10(4):225-240.

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