The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained peripheral-blood smears. After a negative blood smear, repeat smears should be made if there is a high degree of suspicion. Of the Romanowsky stains, Giemsa at pH 7.2 is preferred; Field’s, Wright’s, or Leishman’s stain can also be used. Both thin (Figs. 248-4 and 248-5; see also Figs. 250e-3 and 250e-4) and thick (Figs. 248-6, 248-7, 248-8, and 248-9) blood smears should be examined. The thin blood smear should be rapidly air-dried, fixed in anhydrous methanol, and stained; the RBCs in the tail of the film should then be examined under oil immersion (×1000 magnification). The level of parasitemia is expressed as the number of parasitized erythrocytes per 1000 RBCs. The thick blood film should be of uneven thickness. The smear should be dried thoroughly and stained without fixing. As many layers of erythrocytes overlie one another and are lysed during the staining procedure, the thick film has the advantage of concentrating the parasites (by 40- to 100-fold compared with a thin blood film) and thus increasing diagnostic sensitivity. Both parasites and white blood cells (WBCs) are counted, and the number of parasites per unit volume is calculated from the total leukocyte count. Alternatively, a WBC count of 8000/μL is assumed. This figure is converted to the number of parasitized erythrocytes per microliter. A minimum of 200 WBCs should be counted under oil immersion. Interpretation of blood smear films requires some experience because artifacts are common. Before a thick smear is judged to be negative, 100–200 fields should be examined under oil immersion. In high-transmission areas, the presence of up to 10,000 parasites/μL of blood may be tolerated without symptoms or signs in partially immune individuals. Thus in these areas the detection of malaria parasites is sensitive but has low specificity in identifying malaria as the cause of illness. Low-density parasitemia is common in other conditions causing fever.
Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high. The platelet count is usually reduced to ~105/μL. Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia. Levels of antithrombin III are reduced even in mild infection. In uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal. Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin. Hypergammaglobulinemia is usual in immune and semi-immune subjects. Urinalysis generally gives normal results. In adults and children with cerebral malaria, the mean cerebrospinal fluid (CSF) opening pressure at lumbar puncture is ~160 mm; usually the CSF content is normal or there is a slight elevation of total protein level (<1.0 g/L [<100 mg/dL]) and cell count (<20/μL).
(Table 248-6) When a patient in or from a malarious area presents with fever, thick and thin blood smears should be prepared and examined immediately to confirm the diagnosis and identify the species of infecting parasite (Figs. 248-4,248-5,248-6,248-7,248-8, and 248-9). Repeat blood smears should be performed at least every 12–24 h for 2 days if the first smears are negative and malaria is strongly suspected. Alternatively, a rapid antigen detection card or stick test should be performed. Patients with severe malaria or those unable to take oral drugs should receive parenteral antimalarial therapy. If there is any doubt about the resistance status of the infecting organism, it should be considered resistant. Antimalarial drug susceptibility testing can be performed but is rarely available, has poor predictive value in an individual case, and yields results too slowly to influence the choice of treatment. Several drugs are available for oral treatment. The choice of drug depends on the likely sensitivity of the infecting parasites. Despite increasing evidence of chloroquine resistance in P. vivax (from parts of Indonesia, Oceania, eastern and southern Asia, and Central and South America), chloroquine remains a first-line treatment for the non-falciparum malarias (P. vivax, P. ovale, P. malariae, P. knowlesi) except in Indonesia and Papua New Guinea, where high levels of resistance in P. vivax are prevalent.
The treatment of falciparum malaria has changed radically in recent years. In all endemic areas, the World Health Organization (WHO) now recommends artemisinin-based combinations (ACTs) as first-line treatment for uncomplicated falciparum malaria. These combinations are also highly effective for the other malarias. These rapidly and reliably effective drugs are sometimes unavailable in temperate countries, where treatment recommendations are limited by the registered available drugs. Fake or substandard antimalarials are commonly sold in many Asian and African countries. Thus, careful attention is required at the time of purchase and later, especially if the patient fails to respond as expected. Characteristics of antimalarial drugs are shown in Table 248-7. SEVERE MALARIA
In large studies, parenteral artesunate, a water-soluble artemisinin derivative, has reduced mortality rates in severe falciparum malaria among Asian adults and children by 35% and among African children by 22.5% compared with mortality rates with quinine treatment. Artesunate has therefore become the drug of choice for all patients with severe malaria everywhere. Artesunate is given by IV injection but can also be given by IM injection. Artemether and the closely related drug artemotil (arteether) are oil-based formulations given by IM injection; they are erratically absorbed and do not confer the same survival benefit as artesunate. A rectal formulation of artesunate has been developed as a community-based pre-referral treatment for patients in the rural tropics who cannot take oral medications. Pre-referral administration of rectal artesunate has been shown to decrease mortality risk among severely ill children in communities without access to immediate parenteral treatment. Although the artemisinin compounds are safer than quinine and considerably safer than quinidine, only one formulation is available in the United States. IV artesunate has been approved by the U.S. Food and Drug Administration for emergency use against severe malaria and can be obtained through the Centers for Disease Control and Prevention (CDC) Drug Service (see end of chapter for contact information). The antiarrhythmic quinidine gluconate is as effective as quinine and, as it was more readily available, replaced quinine for the treatment of malaria in the United States. The administration of quinidine must be closely monitored if dysrhythmias and hypotension are to be avoided. If total plasma levels exceed 8 μg/mL or the QTc interval exceeds 0.6 s or the QRS complex widens by more than 25% of baseline, then infusion rates should be slowed or infusion stopped temporarily. If arrhythmia or saline-unresponsive hypotension develops, treatment with this drug should be discontinued. Quinine is safer than quinidine; cardiovascular monitoring is not required except when the recipient has cardiac disease.
Severe falciparum malaria constitutes a medical emergency requiring intensive nursing care and careful management. The patient should be weighed and, if comatose, placed on his or her side. Frequent evaluation of the patient’s condition is essential. Adjunctive treatments such as high-dose glucocorticoids, urea, heparin, dextran, desferrioxamine, antibody to tumor necrosis factor α, high-dose phenobarbital (20 mg/kg), mannitol, or large-volume fluid or albumin boluses have proved either ineffective or harmful in clinical trials and should not be used. In acute renal failure or severe metabolic acidosis, hemofiltration or hemodialysis should be started as early as possible.
In severe malaria, parenteral antimalarial treatment should be started immediately. Artesunate, given by either IV or IM injection, is the agent of choice; it is simple to administer, safe, and rapidly effective. It does not require dose adjustments in liver dysfunction or renal failure, and it should be used in pregnant women with severe malaria. If artesunate is unavailable and artemether, quinine, or quinidine is used, an initial loading dose must be given so that therapeutic concentrations are reached as soon as possible. Both quinine and quinidine will cause dangerous hypotension if injected rapidly; when given IV, they must be administered carefully by rate-controlled infusion only. If this approach is not possible, quinine may be given by deep IM injections into the anterior thigh. The optimal therapeutic range for quinine and quinidine in severe malaria is not known with certainty, but total plasma concentrations of 8–15 mg/L for quinine and 3.5–8.0 mg/L for quinidine are effective and do not cause serious toxicity. The systemic clearance and apparent volume of distribution of these alkaloids are markedly reduced and plasma protein binding is increased in severe malaria, so that the blood concentrations attained with a given dose are higher. If the patient remains seriously ill or in acute renal failure for >2 days, maintenance doses of quinine or quinidine should be reduced by 30–50% to prevent toxic accumulation of the drug. The initial doses should never be reduced. If safe and feasible, exchange transfusion may be considered for patients with severe malaria, although the precise indications for this procedure have not been agreed upon and there is no clear evidence that this measure is beneficial, particularly with artesunate treatment. Convulsions should be treated promptly with IV (or rectal) benzodiazepines. The role of prophylactic anticonvulsants in children is uncertain. If respiratory support is not available, then a full loading dose of phenobarbital (20 mg/kg) to prevent convulsions should not be given as it may cause respiratory arrest.
When the patient is unconscious, the blood glucose level should be measured every 4–6 h. All patients should receive a continuous infusion of dextrose, and blood concentrations ideally should be maintained above 4 mmol/L. Hypoglycemia (<2.2 mmol/L or 40 mg/dL) should be treated immediately with bolus glucose. The parasite count and hematocrit level should be measured every 6–12 h. Anemia develops rapidly; if the hematocrit falls to <20%, then whole blood (preferably fresh) or packed cells should be transfused slowly, with careful attention to circulatory status. Renal function should be checked daily. Children presenting with severe anemia and acidotic breathing require immediate blood transfusion. Accurate assessment is vital. Management of fluid balance is difficult in severe malaria, particularly in adults, because of the thin dividing line between overhydration (leading to pulmonary edema) and underhydration (contributing to renal impairment). As soon as the patient can take fluids, oral therapy should be substituted for parenteral treatment. UNCOMPLICATED MALARIA
Infections due to sensitive strains of P. vivax, P. knowlesi, P. malariae, and P. ovale should be treated with oral chloroquine (total dose, 25 mg of base/kg) or with an ATC known to be efficacious. In much of the tropics, drug-resistant P. falciparum has been increasing in distribution, frequency, and intensity. It is now accepted that, to prevent resistance, falciparum malaria should be treated with drug combinations and not with single drugs in endemic areas; the same rationale has been applied successfully to the treatment of tuberculosis, HIV/AIDS, and cancers. This combination strategy is based on simultaneous use of two or more drugs with different modes of action. ACT regimens are now recommended as first-line treatment for falciparum malaria throughout the malaria-affected world. These regimens are safe and effective in adults, children, and after the first trimester of pregnancy (uncertainty regarding safety currently precludes their use in the first trimester). The rapidly eliminated artemisinin component is usually an artemisinin derivative (artesunate, artemether, or dihydroartemisinin) given for 3 days, and the partner drug is usually a more slowly eliminated antimalarial to which P. falciparum is sensitive. Five ACT regimens are currently recommended by the WHO. In areas with multidrug-resistant falciparum malaria (parts of Asia and South America, including those with mefloquine-resistant parasites; Fig. 248-10), artemether-lumefantrine, artesunate-mefloquine, or dihydroartemisinin-piperaquine should be used; these regimens provide cure rates of >90%. In areas with sensitive parasites, the aforementioned combinations, artesunate-sulfadoxine-pyrimethamine, or artesunate-amodiaquine also may be used. Pyronaridine-artesunate is still under evaluation. Atovaquone-proguanil is highly effective everywhere, although it is seldom used in endemic areas because of its high cost and the propensity for rapid emergence of resistance. Of great concern is the emergence of artemisinin-resistant P. falciparum in western Cambodia and eastern Myanmar. Infections with these parasites are cleared slowly from the blood, with clearance times typically exceeding 3 days, and cure rates with ACTs are reduced.
The 3-day ACT regimens are all well tolerated, although mefloquine is associated with increased rates of vomiting and dizziness. As second-line treatments for recrudescence following first-line therapy, a different ACT regimen may be given; another alternative is a 7-day course of either artesunate or quinine plus tetracycline, doxycycline, or clindamycin. Tetracycline and doxycycline cannot be given to pregnant women or to children <8 years of age. Oral quinine is extremely bitter and regularly produces cinchonism comprising tinnitus, high-tone deafness, nausea, vomiting, and dysphoria. Adherence is poor with the required 7-day regimens of quinine.
Patients should be monitored for vomiting for 1 h after the administration of any oral antimalarial drug. If there is vomiting, the dose should be repeated. Symptom-based treatment, with tepid sponging and acetaminophen administration, lowers fever and thereby reduces the patient’s propensity to vomit these drugs. Minor central nervous system reactions (nausea, dizziness, sleep disturbances) are common. The incidence of serious adverse neuropsychiatric reactions to mefloquine treatment is ~1 in 1000 in Asia but may be as high as 1 in 200 among Africans and Caucasians. All the antimalarial quinolines (chloroquine, mefloquine, and quinine) exacerbate the orthostatic hypotension associated with malaria, and all are tolerated better by children than by adults. Pregnant women, young children, patients unable to tolerate oral therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evaluated carefully and hospitalization considered. If there is any doubt as to the identity of the infecting malarial species, treatment for falciparum malaria should be given. A negative blood smear makes malaria unlikely but does not rule it out completely; thick blood films should be checked again 1 and 2 days later to exclude the diagnosis. Nonimmune patients receiving treatment for malaria should have daily parasite counts performed until the thick films are negative. If the level of parasitemia does not fall below 25% of the admission value in 48 h or if parasitemia has not cleared by 7 days (and adherence is assured), drug resistance is likely and the regimen should be changed.
To eradicate persistent liver stages and prevent relapse (radical treatment), primaquine (0.5 mg of base/kg or, in infections acquired in temperate areas, 0.25 mg/kg) should be given daily for 14 days to patients with P. vivax or P. ovale infections after laboratory tests for G6PD deficiency have proved negative. If the patient has a mild variant of G6PD deficiency, primaquine can be given in a dose of 0.75 mg of base/kg (45 mg maximum) once weekly for 8 weeks. Pregnant women with vivax or ovale malaria should not be given primaquine but should receive suppressive prophylaxis with chloroquine (5 mg of base/kg per week) until delivery, after which radical treatment can be given. COMPLICATIONS Acute Renal Failure
If the plasma level of BUN or creatinine rises despite adequate rehydration, fluid administration should be restricted to prevent volume overload. As in other forms of hypercatabolic acute renal failure, renal replacement therapy is best performed early (Chap. 334). Hemofiltration and hemodialysis are more effective than peritoneal dialysis and are associated with lower mortality risk. Some patients with renal impairment pass small volumes of urine sufficient to allow control of fluid balance; these cases can be managed conservatively if other indications for dialysis do not arise. Renal function usually improves within days, but full recovery may take weeks. Acute Pulmonary Edema (Acute Respiratory Distress Syndrome)
Patients should be positioned with the head of the bed at a 45° elevation and given oxygen and IV diuretics. Pulmonary artery occlusion pressures may be normal, indicating increased pulmonary capillary permeability. Positive-pressure ventilation should be started early if the immediate measures fail (Chap. 326). Hypoglycemia
An initial slow injection of 50% dextrose (0.5 g/kg) should be followed by an infusion of 10% dextrose (0.10 g/kg per hour). The blood glucose level should be checked regularly thereafter as recurrent hypoglycemia is common, particularly among patients receiving quinine or quinidine. In severely ill patients, hypoglycemia commonly occurs together with metabolic (lactic) acidosis and carries a poor prognosis. Other Complications
Patients who develop spontaneous bleeding should be given fresh blood and IV vitamin K. Convulsions should be treated with IV or rectal benzodiazepines and, if necessary, respiratory support. Aspiration pneumonia should be suspected in any unconscious patient with convulsions, particularly with persistent hyperventilation; IV antimicrobial agents and oxygen should be administered, and pulmonary toilet should be undertaken. Hypoglycemia or gram-negative septicemia should be suspected when the condition of any patient suddenly deteriorates for no obvious reason during antimalarial treatment. In malaria-endemic areas where a high proportion of children are parasitemic, it is usually impossible to distinguish severe malaria from bacterial sepsis with confidence. These children should be treated with both antimalarials and broad-spectrum antibiotics from the outset. Because nontyphoidal Salmonella infections are particularly common, empirical antibiotics should be selected to cover these organisms. Antibiotics should be considered for severely ill patients of any age who are not responding to antimalarial treatment.