Navy Medical Department Guide to Malaria Prevention and Control

Chapter 3: Diagnosis

Department of the Navy
Bureau of Medicine and Surgery

The definitive diagnosis of malaria is made by the identification of malaria parasites in a peripheral blood film. However, U.S. medical professionals are inexperienced in malaria diagnosis and treatment because they rarely encounter the disease. When confronted with malaria, Navy medical personnel have misdiagnosed it as "viral illness", "gastroenteritis", or "flu." Malaria also may not be considered because it shares signs and symptoms with other tropical illnesses including typhoid fever, rheumatic fever, and bacterial meningitis. Therefore, diagnosis of malaria requires a raised level of suspicion and diligent screening.

Screening. Screen all febrile patients possibly exposed to malaria transmission. This includes personnel who took malaria chemoprophylaxis medication while deployed to endemic areas, or air crew or travelers briefly exposed at airports in malaria endemic zones.

The screening tool of choice for malaria diagnosis is microscopic examination of thick and thin blood smears. Thick smear examination detects the presence of any organisms; thin smear examination identifies the specific infecting Plasmodium species. Thick and thin smears can be prepared on the same microscope slide; see Appendix 3 for description of this technique and further information on preparing and interpreting peripheral blood smears.

Timing of Screening. Symptoms often precede detectable parasitemia by 1-2 days. Therefore, screen blood obtained through fingersticks or other techniques several times a day (frequency is more important than timing) until a diagnosis of malaria is made or ruled out. Thin smear diagnosis for causal species is crucial, as P. falciparum infections are life threatening and require specific treatment. After diagnosis, blood smears should continue to be monitored for response to therapy. Decreasing parasite count (concentration) signifies favorable response to therapy; frequency of testing depends on therapeutic response and severity of illness. For example, seriously ill patients should be tested 2-3 times daily until they significantly improve, then daily until parasite level is zero.

Early diagnosis and treatment is lifesaving; falciparum malaria kills 25% of non-immune adults within 2 weeks if treatment is not started early in the infection. If the diagnosis of malaria is suspected, treat, then arrange for definitive diagnosis. The rest of this chapter describes the clinical manifestations of malaria to aid in early diagnosis and understanding of disease processes.

Clinical Manifestations

Symptoms (Table 3.1). Patients present with a variety of symptoms depending on the stage of infection and the infecting species. Fever is virtually always present, and fever plus any other symptom might be malaria if exposure occurred. Common complaints include mild to moderate malaise, fatigue, muscle aches, back pain, headache, dizziness, loss of appetite, nausea, vomiting, abdominal pain, and diarrhea. Dry cough and shortness of breath have been reported in some patients. Gastrointestinal complaints can be considerable, suggesting a diagnosis of gastroenteritis. Young children and semi-immune individuals may complain of fever and headache as their only symptoms.

Signs. Physical examination usually demonstrates an increased temperature, tachycardia, and warm flushed skin. The spleen is often palpable in initial infection, but this is more likely in subsequent attacks. It is usually soft and may be tender. The liver is often enlarged and may be tender; jaundice is not unusual. Orthostatic hypotension often occurs during initial infections. Mental confusion and cyanosis are sometimes encountered.

Laboratory Findings (Table 3.2). Abnormal laboratory findings reflect the severity of hemolysis. Blood. A normocytic, normochromic anemia with leukopenia and thrombocytopenia is sometimes present on initial screening, but is almost always present following medication therapy with the resultant clearing of parasitemia. Massive P. falciparum infections cause acute decreases in hemoglobin, hematocrit, and an increase in reticulocyte count. Kidneys. Trace to moderate protein, urobilinogen, and conjugated bilirubin may be found on urinalysis. In severe P. falciparum infections, massive hemolysis combined with circulating immune complexes produces acute renal insufficiency or failure ("blackwater fever") with laboratory findings of hemoglobinuria, proteinuria, and an elevated serum creatinine. Fever and dehydration may cause an increase in BUN and creatinine, but if serum creatinine rises disproportionately higher than BUN (BUN to creatinine ratio is normally 10 or 12 to 1), renal failure must be considered.

Table 3-1. Malaria Clinical Findings

Liver. Liver impairment may occur, though hyperbilirubinemia normally results from hemolysis. Abnormalities in liver function tests, increased ALT, AST, and prolonged prothrombin time, sometimes occur causing diagnostic confusion with viral hepatitis. Serum albumin is usually decreased.

Hypoglycemia, commonly seen in P. falciparum infections and pregnancy, is due to the 75-fold increase in glucose consumption by parasitized red blood cells. In addition, quinidine or quinine may stimulate insulin secretion, causing clinically significant hypoglycemia when used for treatment, especially when given intravenously. If a patient deteriorates during convalescence, especially with a deterioration in neurologic function, hypoglycemia should be considered as a possible cause.

False positive serologic tests may be present, including syphilis (VDRL, RPR), rheumatoid factor, heterophil agglutinins, and cold agglutinins. These result from a polyclonal increase in both IgG and IgM immunoglobulins, which are associated with appearance of specific malarial antibodies and reduced complement levels. Malaria does not cause eosinophilia.

Table 3-2. Malaria Laboratory Findings

Hyperparasitemia. Patients with P. falciparum infections that are hyperparasitemic have a higher risk of death. Hyperparasitemia is defined as a parasite count of greater than 250,000 per microliter (>250,000/_l), or as having greater than 5% of red blood cells parasitized. Risk of death is due to extensive microvascular disease, and severe metabolic effects from the parasite load.

Pathophysiology and Clinical Presentation

Clinical symptoms and signs of malaria occur shortly before or at the time of red blood cells lysis. Fever is caused by the release of merozoites, malarial pigment, parasite proteins and cellular debris. Chills or rigor, followed by high fever occur in a cyclical pattern in infections due to P. vivax, P. ovale, and P. malariae, but not P. falciparum, which is more likely to show continuous fever with intermittent temperature spikes. Clinical signs and symptoms described are those experienced by non-immune patients, such as will be seen in most U.S. military personnel. Clinical manifestations are not as severe in persons living in endemic areas. They are infected intermittently and develop partial immunity.

The malaria paroxysm is the defining clinical feature of the disease. That being said, it is often not present. Fever caused by malaria can have any pattern, and falciparum infections often present with a constant fever. The classic paroxysm typically has three stages, and is preceded in some patients by an initial period of nonspecific symptoms. Those symptoms include fatigue, muscle aches, loss of appetite, headache, and a slight fever of 2-3 day's duration.

A paroxysm begins with the "cold" or "chilling" stage lasting 15 minutes to several hours during which the patient feels cold and has shaking chills. The second "hot" stage lasts several hours and coincides with red blood cell rupture and merozoite release. During the second stage temperatures rise to 40OC (104OF) or higher. There is minimal sweating and the patient is at risk of febrile seizures or hyperthermic brain damage. Clinical signs and symptoms include tachycardia, hypotension, cough, headache, backache, nausea, abdominal pain, vomiting, diarrhea, and altered consciousness. Within 2-6 hours, the patient enters the third "sweating" stage of the paroxysm with generalized sweating, resolution of fever, and marked exhaustion, usually giving way to sleep. Paroxysms occur in regular intervals, but take several days to emerge.

As previously stated, the classic paroxysm described above is generally not how P. falciparum infections present. P. falciparum malaria is more severe and qualitatively different from the other plasmodia that infect humans, and is the only type that causes microvascular disease. For those reasons, it will be discussed separately and in more detail.

Malaria due to Plasmodium falciparum Infection

Plasmodium falciparum malaria is a microvascular disease with a substantial metabolic element that damages tissue in the following manner: P. falciparum parasites mature in red blood cells causing knobs to form on their surface in effect making them "sticky". This stickiness causes parasitized red blood cells to adhere to endothelial cells, lining capillaries and postcapillary venules of brain, kidneys, and other organs, obstructing blood flow. In addition to being "sticky," infected red blood cells are less flexible, adding to their obstructive potential. In obstructed capillaries and postcapillary venules, parasites consume glucose and produce lactate-causing acidemia and release of tissue necrosis factor-_ (a cytokine produced by the immune system). Lack of oxygen and increased concentrations of toxic metabolites cause capillaries to become more permeable, allowing leakage of protein and fluids. This results in tissue edema and further anoxia due to the edema, leading to organ damage and death. In some cases, diagnosis of P. falciparum infection is made difficult because no parasites are seen on peripheral blood smears, as they are sequestered in the host's microvasculature.

Cerebral Malaria. The principal manifestations of cerebral malaria are seizures and impaired consciousness, usually preceded by a severe headache. Neurologic examination may be unremarkable, or have findings that include contracted or unequal pupils, a Babinski sign, and absent or exaggerated deep tendon reflexes. Cerebrospinal fluid examination shows increased pressure, increased protein, and minimal or no pleocytosis. High fever, 410 to 420C (1060 to 1080F), with hot, dry skin as seen in heat stroke can occur.

Manifestations of cerebral malaria are caused by microvascular obstruction that prevents the exchange of glucose and oxygen at the capillary level, hypoglycemia, lactic acidosis, and high-grade fever. These effects impair brain function, yet cause little tissue damage in most cases, as rapid and full recovery follows prompt treatment. Ten to twelve percent of patients surviving cerebral malaria have persistent neurologic abnormalities upon hospital discharge.

Renal Failure. Renal failure, due to acute tubular necrosis, is a common complication of severe P. falciparum infections in non-immune persons. Acute tubular necrosis in severe P. falciparum infections is caused by two mechanisms: renal tubules become clogged with hemoglobin and malarial pigment released during massive hemolysis, and microvascular obstruction causes anoxia and glucose deprivation at the renal capillary or tissue level. Failure of urine production is a poor prognostic sign, requiring peritoneal or hemodialysis.

Pulmonary Edema. Often fatal, acute pulmonary edema can develop rapidly and is associated with excessive intravenous fluid therapy. Fast, labored respiration, with shortness of breath, a non-productive cough, and physical findings of moist rales and rhonchi are usually present. Chest X-rays usually show increased bronchovascular markings. It is thought that the pulmonary edema is more related to release of tissue necrosis factor-, than to the effects of microvascular obstruction.

Gastroenteritis. Most patients with falciparum malaria complain of loss of appetite and nausea. However, in some patients (especially young children), additional symptoms including vomiting, abdominal pain, watery diarrhea, and jaundice are present leading to misdiagnosis of viral gastroenteritis or hepatitis. Clinical manifestations are associated with the adherence of parasitized red blood cells in the microvasculature of the gastrointestinal tract.

Anemia. Destruction of red blood cells upon merozoite release, and inhibition of hematopoesis by tissue necrosis factor-_ cause the severe anemia often seen in P. falciparum infections. Also, P. falciparum parasites can infect red blood cells of all ages, which theoretically allows infection of all circulating red blood cells. Whereas, P. vivax and P. ovale require young red blood cells (reticulocytes) and P. malariae requires mature blood cells for infection.

Severe anemia is defined as a hematocrit of less than 21%, and clinical manifestations may include dark brown or red urine (hemoglobinuria), decrease in urine production, and jaundice. Renal failure, as previously discussed, may be a complication. Another cause of hemolysis and hemoglobinuria in patients with malaria is destruction of G-6-PD deficient red blood cells by oxidant anti-malarial drugs such as primaquine.

Malaria due to P. vivax (or P. ovale) Infection

Infections due to P. vivax and P. ovale are virtually the same. Both are less severe than falciparum malaria, and parasite blood levels are lower. Parasitized red blood cells do not develop knobs, therefore no microvascular obstruction with resultant brain, kidney, lung, or other organ complications occur in malaria due to P. vivax or P. ovale.

P. vivax and P. ovale form a dormant stage in liver cells called hypnozoites. These parasites activate and cause delayed infections or a relapse (Table 3-3). A relapse usually occurs within 6 months of an acute attack. Some hypnozoites remain dormant much longer, and are virtually undetectable. If there is any suspicion that P. vivax or P. ovale are endemic in the area of exposure, presumptive treatment must be given to prevent illness. Currently, the only available treatment is primaquine; dosages are listed in Chapters 4, 5, and Appendix 4.

As previously stated, fever is virtually always present, and fever plus any other symptom might be malaria. P. vivax or P. ovale fevers may be erratic or continuous in the initial phase of illness. After 3 to 4 days, if not treated, the fever then develops into a synchronous cycle of afternoon temperature increases every 48 hours. The fever can be as high as 40OC (104OF), and symptoms during this stage have been described as worse than falciparum malaria. Physical findings usually include an enlarged, tender spleen, and a palpable liver present by the second week of infection. Deaths have been reported due to rupture of an enlarged spleen.

Parasitemia levels are less for P. vivax or P. ovale because they infect only young red blood cells, unlike P. falciparum which can infect red blood cells of all ages. Fewer red blood cells are hemolyzed, but their loss stimulates replacement. This increases the number of young red blood cells (reticulocytes), which are susceptible to infection, leading to parasitemia levels greater than 1 to 2% in P. vivax or P. ovale infections.

Malaria due to P. malariae Infection

P. malariae infection is the mildest and most chronic of all the human malaria infections. Invasion of red blood cells builds up slowly, so blood parasite levels are low, and symptoms are usually mild. Patients may have several febrile paroxysms before parasites are seen in the peripheral blood. As in P. vivax and P. ovale infections, febrile paroxysms develop in the afternoon, but cycle every 72 hours. P. malariae and P. falciparum do not have the hypnozoite stage, therefore relapses do not occur in infections with these species. Recrudescence can be seen with P. malariae infections many years after the initial infection. This is due to an increase in parasites after a chronic, low level of parasitemia in infected red blood cells that have persisted in tissue microcapillary circulation. Low-grade infections can persist up to 20-30 years. Splenomegaly is a common complication in those patients with low-grade infections of long duration.

P. malariae infection may produce a unique immune complex glomerulonephritis . Low-level parasitemia causes continuous antigen stimulation of host antibodies and formation of immune complexes, causing an immune complex glomerulonephritis. This manifestation usually presents 3-6 months after malaria transmission season, and can lead to nephrotic syndrome. Half the people who develop nephrotic syndrome had their first symptoms before the age of 15. Classic findings include persistent proteinuria, hypoalbuminemia, edema, and ascites. Patients who develop this complication do not respond to anti-malarial therapy, and response to corticosteroids is variable.

Table 3-3. Characteristics of malaria relapse and recrudescence.

Malaria in Pregnancy

Because of the immune suppression associated with pregnancy, recrudescence and relapse are frequent in the second and third trimester. Malaria can potentiate the anemia of pregnancy, and cause acute renal insufficiency and hypoglycemia in P. falciparum infections. It is associated with increased numbers of abortions, miscarriages, stillbirths, and neonatal deaths.

Malaria in Children

In non-immune children, the initial attack can vary widely. Common symptoms include drowsiness, anorexia, thirst, headache, nausea, vomiting, and diarrhea. Common early signs include increased temperature (may be greater than 40OC), pallor, and cyanosis; enlarged liver and spleen occur later. Convulsions are frequent, and cerebral malaria is the most frequent complication. Anemia is a complication with repeated infections.

Children living in endemic areas develop limited immunity. Symptoms are milder and more difficult to detect. They include low-grade anemia, restlessness, loss of appetite, weariness, sweating, and intermittent fever.

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Operational Medicine 2001

Health Care in Military Settings

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