Malaria and Other Tropical Infections in the Intensive Care Unit

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143 Malaria and Other Tropical Infections in the Intensive Care Unit

Although the spectrum of possible “tropical” infections in a patient with exposures overseas may initially seem daunting, a detailed history of the travel itinerary, activities, and exposures can often significantly narrow the differential diagnosis (Table 143-1). This must include more than simply recording the countries to which the patient traveled. Exposures of a business traveler staying at hotels and dining in fine restaurants in a major city may differ drastically from those of a student back-packing through rural areas of the same country. General knowledge of the diseases endemic in a given area and their incubation periods and drug resistance patterns is vital (Figure 143-1 and Table 143-2). In addition, most “non-tropical” infections are also common in developing countries. Thus, although the differential diagnosis must be expanded to include tropical pathogens, common illnesses seen in developing as well as industrialized countries must be considered.

TABLE 143-1 Some Tropical Diseases Which May Merit Management in an Intensive Care Unit*

Figure 143-1 Malaria-endemic countries in the Western and Eastern Hemispheres. The risk of malaria may vary within specific regions of each country.

(From Health information for international travel 2010. Atlanta: Centers for Disease Control and Prevention; 2010. Available at: http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria.aspx.)

TABLE 143-2 Features of the Five Species of Malaria Known to Cause Disease in Humans

Patients prone to tropical infections can be divided into three groups: (1) nonimmune persons who have no history of exposure to tropical pathogens, primarily tourists and young children, regardless of geographic origin, after the waning of maternal antibodies (around age 6 months); (2) immune or semi-immune persons residing in tropical countries who are repeatedly exposed; (3) those originally from tropical countries but now residing elsewhere who, in the absence of continued exposure, have waning immunity. The degree of immunity may exert profound effects on the presentation and severity of illness. For example, a returning traveler may develop severe malaria at a relatively low parasitemic load, whearas a resident of sub-Saharan Africa with the same degree of parasitemia may be asymptomatic. Genetic differences in susceptibility may also exist, such as resistance to Plasmodium vivax in blacks due to the absence of Duffy factor, which serves as the receptor, or the relative protection from severe malaria of any species afforded to those carrying the sickle cell trait.^1,^2,³

In returning travelers, knowledge of pre-travel vaccinations as well as prescribed and taken chemoprophylaxis (which often turn out not to be the same) is imperative. Nevertheless, these preventive measures do not confer 100% protection and should not be used to completely discard a given entity from the differential diagnosis. Both physicians and patients frequently err in the prescribing of and adherence to appropriate prophylactic regimens.^4,⁵ Chemotherapy, complete or partial, may prolong the incubation period or alter the presentation of the illness. Those initially from tropical countries are often less likely to seek pre-travel medical advice before making a visit home and also often have considerably more exposures to tropical pathogens during their visit than do short-term travelers from industrialized countries.⁶

People living in resource-poor tropical countries may be more likely to have complicating health problems but less likely to have them previously diagnosed or controlled. Underlying diabetes, hypertension, malnutrition, chronic anemia, intestinal parasites, tuberculosis, HIV, or hepatitis virus infection may be discovered at the time of the acute illness.⁷ Infection with multiple tropical pathogens is common in those living in endemic areas. Thus the finding of a given pathogen cannot automatically be assumed to be the cause of the patient’s current illness.

Epidemiology

Malaria parasites are spread to humans by the bite of anopheline mosquitoes. Four species of Plasmodia commonly cause malaria in humans: Plasmodium falciparum, P. vivax, Plasmodium ovale, and Plasmodium malariae (see Table 143-2). A fifth species, Plasmodium knowlesi, is a zoonotic parasite of monkeys recently found to also cause disease in humans with exposure in forests of Southeast Asia.^8,⁹ Furthermore, recent evidence suggests that there may be distinct species of P. vivax.¹⁰

Malaria is the most common serious infection in most tropical countries as well as in returning travelers, and it should therefore be considered in any patient reporting travel in malaria-endemic areas or with exposure to unscreened blood products (“transfusion malaria”) or blood-contaminated needles. Increased travel and immigration over the past several decades have resulted in increases in imported malaria in most industrialized countries.^11,¹² The risk of acquiring P. falciparum, the cause of most severe disease, is highest for those traveling to sub-Saharan Africa and New Guinea, moderate in India, and comparatively low in Southeast Asia and Latin America.^13,¹⁴ Malaria is occasionally reported in individuals without reported travel, usually resulting from the carriage of malaria-infected passengers (who may be asymptomatic) or anopheline mosquitoes on aircraft arriving from endemic areas.¹⁵ The parasite may then be secondarily transmitted by anopheline mosquitoes endemic in some industrialized countries, including the United States.

Pathophysiology

P. falciparum accounts for the vast majority of severe malaria because of (1) its ability to infect red blood cells (RBCs) of all ages, resulting in overwhelming parasitemia (up to 70% of RBCs); (2) its induction of adherence of parasitized RBCs to the microvascular wall, with consequent obstruction; (3) its induction of severe metabolic derangements directly through glucose consumption and lactate production and indirectly through the induction of cytokines; and (4) the high prevalence of chloroquine resistance to P. falciparum in many parts of the world (see Table 143-2). Nonimmune persons and pregnant women are at greatest risk. Human genetic as well as parasite strain differences probably play roles in the ultimate course of any given malaria infection.

Unlike the other species of malaria, P. falciparum causes decreased RBC deformability and the production of small protrusions or “knobs” on parasitized RBC membranes that mediate their adhesion to the venular endothelium (Figure 143-2). The rupture of schizont-stage parasites exposes glycosylphosphatidylinositol anchors on the parasite and RBC surface that induce macrophages and other inflammatory cells to release a host of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin-1, TNF-β, and various kinins and reactive nitrogen intermediates.¹⁶^–¹⁸ These cytokines play a role in up-regulation and activation of endothelial adhesion molecules such as ICAM-1 and E-selectin, enhancing cytoadherence of parasitized cells as well as mediating pathologic processes such as hypoglycemia, lactic acidemia, shock, gut mucosal damage, and increased permeability and neutrophil aggregation in the lung. The sum total of this cascade is sequestration of parasitized RBCs in the microvasculature where they are not only sheltered from removal but cause sluggish flow and obstruction, resulting in impaired oxygen delivery and organ dysfunction.^16,¹⁹ The most profound effects are usually on the cerebral capillaries, although a host of tissues may be affected, including the kidney, liver, spleen, placenta, intestine, lung, bone marrow, heart, and retina. Histopathologic changes are usually minimal, but ring hemorrhages and perivascular infiltrates sometimes develop at the sites of obstructed vessels, perhaps facilitated by thrombocytopenia due to splenic sequestration of platelets. Although subendocardial and epicardial hemorrhages have been noted at autopsy, myocarditis does not occur, and primary cardiac events are relatively rare in malaria.

Figure 143-2 Pathogenesis of severe and complicated Plasmodium falciparum malaria. GPI, glycosylphosphatidylinositol; RBC, red blood cell; TNF, tumor necrosis factor.

(Modified from Krogstad D. Plasmodium species (malaria). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000).

Clinical Presentation

Malaria infections are classified broadly into three clinical categories: (1) asymptomatic parasitemia, which generally does not require treatment; (2) uncomplicated malaria, defined as parasitemia and fever without evidence of end-organ damage or other signs of severe disease (these patients may often be treated as outpatients with oral antimalarials); and (3) severe and complicated malaria, defined as parasitemia and the presence of vital organ damage or other signs of severe disease. Patients with severe and complicated malaria require hospitalization, often in an intensive care unit (ICU), and parenteral antimalarials. This third category is the focus of this chapter.

Malaria classically produces three stages of symptoms which progress over an 8- to 12-hour period, comprising a “paroxysm.” These correspond and are attributable to the period of schizont rupture and appearance of ring forms (merozoites) in the blood, accompanied by the release of numerous host inflammatory mediators. The paroxysm classically begins suddenly with a “cold stage” in which the patient experiences rigors and chills, often accompanied by headache, nausea, and vomiting. Intense peripheral vasoconstriction may result in pale, goose-pimpled skin and cyanosis of the lips and nail beds. Within a few hours, the “hot stage” ensues, with high fever, flushed skin, throbbing headache, and palpitations. The paroxysm concludes with the “defervescent stage,” consisting of a drenching sweat and resolution of the fever. The exhausted patient often then sleeps. Clinical deterioration with P. falciparum usually appears 3 to 7 days after onset of fever.

Although a classic periodicity is described for the different malaria species (see Table 143-2), this occurs only when the infection has persisted untreated long enough to allow for synchronization of schizont rupture. Furthermore, schizont rupture tends to be asynchronous in P. falciparum and in most primary infections of any plasmodium species. Therefore, malaria may often result in persistently spiking fevers difficult to distinguish from fever produced by many other infections. The absence of a classic paroxysm and periodicity therefore should not be used to exclude the diagnosis. Paroxysms may be accompanied by cough, sore throat, myalgias, back pain, postural hypotension, abdominal pain, nausea, vomiting, diarrhea, and weakness. These are more common in children and may lead to misdiagnoses. Rash and lymphadenopathy are not typical of malaria and suggest another diagnosis.

Severe and Complicated Malaria

Although all species of malaria may produce severe consequences in a debilitated patient, potentially fatal malaria which merits attention in an ICU can be grouped into three categories: (1) severe complications of P. falciparum in nonimmune children and adults, responsible for the vast majority of severe disease worldwide (Table 143-3); (2) splenic rupture, which occurs most frequently with P. vivax; and (3) chronic nephrotic syndrome due to immune-complex nephritis associated with P. malariae, usually seen in children and often complicated by overwhelming bacterial infection. There is emerging evidence that P. knowlesi can also cause severe fatal malaria and should be treated in an ICU setting.⁸

TABLE 143-3 Clinical and Laboratory Features That Classify a Patient as Suffering from Severe Plasmodium falciparum Malaria According to the World Health Organization

Laboratory Findings

Hypoglycemia (blood glucose <2.2 mmol/L or <40 mg/dL)

Metabolic acidosis (plasma bicarbonate <15 mmol/L)

Severe normocytic anemia (hemoglobin <5 g/dL, packed cell volume <15%)

Hemoglobinuria

Hyperparasitemia (>2% or 100,000/µL in low-intensity transmission areas or > 5% or 250,000/µL in areas of high stable malaria transmission intensity)

Hyperlactatemia (lactate >5 mmol/L)

Renal impairment (serum creatinine >265 µmol/L).

Modified from Guidelines for the treatment of malaria 2010. Geneva: World Health Organization; 2010. Available at: http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf.

Cerebral Malaria

This is the most frequent severe complication of plasmodium infection, accounting for most fatalities as well as chronic sequelae. It is most frequent in children of 3 to 5 years of age. Strictly defined, cerebral malaria implies unarousable coma due to P. falciparum.^20,²¹ Hyperpyrexia and febrile convulsions in young children may produce transiently altered mental status without true involvement of the cerebral microvasculature and thus technically do not constitute cerebral malaria. However, in clinical practice, seizures or persistent changes in sensorium which cannot be attributed to other disease processes should be considered cerebral malaria until proven otherwise. Although cerebral malaria is classically attributed to cytoadhesion and microvascular obstruction in the brain, other ongoing processes including hypoglycemia, metabolic acidosis, and impaired oxygenation due to anemia and pulmonary edema likely contribute.

The altered sensorium of cerebral malaria may develop gradually within a few days of onset of illness or manifest as persistent coma after a generalized convulsion. Compared to adults, children with cerebral malaria have a shorter history of fever before progressing to coma (average about 2 days). The most common neurologic picture is of a symmetrical upper motor neuron lesion with hypertonia, hyperreflexia, clonus, absent abdominal reflexes, and extensor Babinski responses. Hypotonia and acute cerebellar ataxia are sometimes seen as well, especially in India and Sri Lanka. There is usually a diffuse symmetric encephalopathy, sometimes with signs of frontal lobe release such as a pout reflex or bruxism. There is usually no grasp reflex, and the gag reflex is normally maintained. Both decorticate as well as decerebrate posturing may occur.²¹ Meningismus, opisthotonos, and disconjugate gaze are frequently seen. Nystagmus and a sixth nerve palsy are rare. Pupils are usually symmetric with intact pupillary, corneal, oculocephalic, and oculovestibular reflexes. Photophobia, severe neck rigidity, and papilledema are almost never seen.

Convulsions may occur in up to 50% of cases of cerebral malaria. As a child ages above 3 to 4 years, seizures become more likely to represent cerebral malaria rather than febrile convulsions.²² Although generalized seizures are classically reported, partial motor seizures, with or without secondary generalization, may occur. ²⁰ Although often showing only diffuse cortical dysfunction, EEG studies may sometimes reveal underlying status epilepticus even when it is not clinically evident.²¹

Pulmonary Edema and Acute Respiratory Distress Syndrome

Pulmonary edema, which may progress to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), is frequent and typically the most lethal of the complications of malaria. Recent evidence suggests that the mechanism may involve acute pulmonary hypertension precipitated by nitric oxide consumption by free plasma hemoglobin released from intravascular hemolysis.[Janka et al., in press] Endothelial injury leading to increased alveolar permeability and noncardiogenic pulmonary edema may also contribute. Interstitial edema and inflammatory cell infiltrates are seen at autopsy, but sequestration of parasitized RBCs in the lung is uncommon.²³ Pulmonary complications occur in 5% to 30% of patients with severe malaria, especially pregnant women, nonimmune persons, and patients already suffering from other complications.²³ The onset may be any time during the course of illness, even if the patient appears to be improving and parasitemia has decreased. Symptoms include dyspnea and cough, with rapid progression to hypoxia and respiratory distress.

Anemia and Hematologic Perturbations

Although some degree of anemia is common in all types of malaria, severe anemia (hemoglobin less than 5 g/100 mL) occurs almost exclusively with P. falciparum infections, owing to their high parasitemias. It is most common and often severe in pregnant women and young children (<1 year), in whom it may be the presenting sign.²⁴ In addition to the acute hemolytic destruction of parasitized RBCs, the more chronic processes of removal of parasitized cells from circulation by the spleen and cytokine inhibition of erythropoiesis may contribute.²⁵ Nonimmune subjects may develop anemia within days after infection, whereas anemia usually develops more slowly in those who are semi-immune. The degree of anemia generally correlates with bilirubin level and level of parasitemia. It may be exacerbated by underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency in the setting of administration of oxidant antimalarial drugs (e.g., quinine, sulfadoxine) and iron-deficiency anemia due to malnutrition. Significant jaundice and hemoglobinuria may result. Thrombocytopenia, although frequent, is not usually associated with bleeding or correlated with disease severity. Disseminated intravascular coagulation (DIC) is seen in less than 10% of severe cases.

Acute Renal Failure

Acute renal failure (ARF) is seen in about 30% of adult patients with cerebral malaria but is uncommon in children. For unclear reasons, ARF is rare in semi-immune persons. ARF is usually due to acute tubular necrosis, is oliguric in nature (<400 mL urine/24 h for adults), and is most often reversible. Renal ischemia due to hypovolemia, renal vasoconstriction, microvascular obstruction, and pigment nephropathy from hemolysis may all contribute. Electrolyte abnormalities such as hyponatremia, hypocalcemia (usually related to albumin loss), hypophosphatemia, and metabolic acidemia, as well as fluid overload with pulmonary edema, may result.

Blackwater fever refers to a severe syndrome characterized by low or absent parasitemia, intravascular hemolysis, hemoglobinuria, and ARF. It is classically seen in people of northern European descent chronically exposed to P. falciparum and irregularly taking the quinoline antimalarial drugs, quinine or quinidine, which together are known as the cinchona alkaloids. The syndrome virtually disappeared after 1950 when chloroquine superseded quinine. However, it is now said to be resurgent, albeit with lower mortality, in relation to mounting chloroquine resistance and consequent increased use of quinine and the newer quinolines, such as mefloquine and halofantrine.²⁶

Hypoglycemia, Lactic Acidosis, and Other Metabolic Perturbations

Severe metabolic derangements are frequent, especially in pregnant women and young children. Although sometimes asymptomatic in pregnancy, hypoglycemia often causes impaired consciousness, extensor posturing, and convulsions and may be confused with cerebral malaria. In addition to direct glucose consumption by the malaria parasite, decreased oral intake, depletion of liver glycogen, cytokine inhibition of gluconeogenesis, and insulin release stimulated by quinine or quinidine may contribute to hypoglycemia. Serum insulin levels are low, and lactate, alanine, and counter-regulatory hormones are appropriately elevated. Although rarely clinically significant, mild hepatocellular damage may occur and be manifested by elevated hepatic transaminases and jaundice. At least theoretically, such hepatic dysfunction could result in impaired metabolic clearance of antimalarial medications and lactate and deficits in the production of coagulation factors and albumin.

Shock and Bacterial and Other Suprainfection

So-called algid malaria, referring to hypotension and shock, may resemble and indeed sometimes be due to gram-negative sepsis from impaired flow in intestinal capillaries, with resultant mucosal erosion. Non-typhoidal salmonella septicemia is specifically associated with P. falciparum.²⁷ Algid malaria is often seen in the setting of hyperparasitemia, with concomitant hypoglycemia and lactic acidemia, and may progress to multiorgan system failure and death. As with most malaria complications, severe hemodynamic derangements are most often seen in nonimmune persons.²⁸ Whether bacteria are isolated or not, a classic septic shock picture is typical, with elevated cardiac index and decreased systemic vascular resistance.²⁹ Hemodynamic decompensation due to splenic rupture may mimic algid malaria.

A host of other infectious complications, including aspiration pneumonia and parvovirus infection, may be related to falciparum malaria. Malaria occurs with increasing frequency and severity in those who are human immunodeficiency virus (HIV) infected, especially during pregnancy, and can also transiently up-regulate HIV replication.³⁰^–³⁴ An association between severe malaria infection and hepatitis B surface antigen carriage has also been noted.³⁵

Tropical Splenomegaly and Splenic Rupture

Splenomegaly is common in infection with all species of malaria. The tropical splenomegaly syndrome, also sometimes termed hyperreactive malarial syndrome (HMS), refers to a condition of massive splenomegaly, high titers of total serum IgM and malaria-specific antibodies, and scanty or absent parasitemia. It is seen in individuals with a history of residence in an endemic area and can be associated with any malaria species. Host genetic factors appear to play a role.³⁶

Unlike virtually all the other complications of malaria that are most often associated with P. falciparum, acute splenic complications occur most commonly in P. vivax, especially with the first infection. Although the term spontaneous splenic rupture has traditionally been used, in reality a range of hematomas or tears of varying severity may occur. The rupture or tear usually occurs 2 to 3 months after infection, presumably due to increased intrasplenic tension, often precipitated by trauma of varying degrees or mechanical ventilation.³⁷ Over-eager examiners have been suggested to play a role, although no cases of clear palpation-induced rupture have been reported. Fever, tachycardia, vomiting, prostration, abdominal pain or guarding, tender splenomegaly, hypovolemia, and rapidly worsening anemia are common presenting features. Abdominal pain may be localized or diffuse, mild or severe. Shock may ensue. Diaphragmatic irritation after rupture may cause referred pain to the left shoulder, supraclavicular, or scapular regions (“Kehr’s sign”). This is present in about one-half of cases and is said to have good specificity for rupture.

Malaria in Pregnancy and Children

In addition to being more susceptible to infection, malaria is particularly dangerous in pregnant women and their fetuses, with increased risk of pulmonary edema, hypoglycemia, severe anemia, premature delivery, low birth weight, and maternal and fetal death. Malaria parasites can often be found in the placenta and may impair oxygen and nutrient transport to the fetus. Disease is most severe in primiparae, especially if nonimmune. In contrast, women from endemic areas are usually asymptomatic, with the exception of the effects of anemia, again more severe in primiparae. Congenital malaria is rare except in those infants born to nonimmune mothers.³⁸

Diagnosis

Clinical

Malaria often presents with nonspecific signs and symptoms, so making a clinical diagnosis may be difficult. Although almost all patients have a history of fever, they may frequently be afebrile at the time of examination.³⁹ Physicians in industrialized countries who are unfamiliar with the disease may not initially include malaria in the differential diagnosis. Delayed diagnosis is frequent and associated with a poor outcome.^6,⁴⁰ Although patients with other species of malaria parasite may not present for months or even years after infection, the vast majority of those with P. falciparum will present within 6 months of exposure.⁴ The differential diagnosis includes most febrile illnesses found in the tropics (see Table 143-1). Babesiosis may present both clinically and microscopically similar to malaria in patients without travel to malaria-endemic areas. Cerebral malaria must be distinguished from bacterial meningitis, the viral meningoencephalitides, metabolic coma, and intoxications by lumbar puncture.⁴¹ In cerebral malaria, the cerebrospinal fluid (CSF) opening pressure is usually normal, although a few lymphocytes and moderate elevation of protein may be seen. High CSF lactate and low glucose indicate a poor prognosis.

Conventional Microscopy

Laboratory diagnosis has traditionally been made via the examination of thick and thin Giemsa-stained smears. Thick smears are more sensitive in diagnosing malaria, whereas thin smears allow identification of the specific parasite. Either smear can be used to quantify the level of parasitemia, but thick smears are theoretically more sensitive for this purpose.^42,⁴³ Simultaneous infections with multiple strains of P. falciparum are common in some areas of sub-Saharan Africa and also may occur with P. vivax in Southeast Asia and Latin America.^44,⁴⁵ Blood obtained by pricking a fingertip or earlobe is preferred because parasite densities are higher in these capillary-rich areas, although blood obtained by venipuncture collected in heparin or EDTA anticoagulant-coated tubes is acceptable if used shortly after being drawn (to prevent alteration in the morphology of white blood cells and malaria parasites).⁴⁶ Smears should be taken as soon as the diagnosis of malaria is considered, without waiting for manifestation of a classic paroxysm. Parasitemia may be undetectable in the early stages of the illness, in those with partial immunity, and in those who have previously self-administered antimalarials, a common practice in malaria-endemic areas.⁴⁷ Levels of parasitemia may fluctuate over time, necessitating repeated smears for diagnosis. Furthermore, P. falciparum–parasitized red blood cells may be sequestered in the deep capillaries of the spleen, liver, and bone marrow. Although a blood film is unlikely to be falsely negative in a patient with severe disease, negative smears should not prevent prompt administration of antimalarial therapy if the diagnosis is strongly suspected.¹⁴ Conversely, asymptomatic parasitemia is common in children from endemic areas, and thus a positive smear does not necessarily signify a clinical case under these circumstances.

Considerable expertise at reading malaria smears may be necessary to detect and distinguish the parasites (see Table 143-2). The most important point is to distinguish P. falciparum, with its concomitant risk of severe complications, from the other plasmodia. Superimposed platelets, particles of stain, pits in the slide, RBC inclusions such as Howell-Jolly bodies and those seen in siderocytes, and other intracellular pathogens such as Bartonella and Babesia must be distinguished from malaria parasites. Furthermore, alterations in parasite morphology may occur related to strain variation, drug pressure, and blood collection method.

Newer Laboratory Methods

Various new diagnostic techniques for malaria have been developed in recent years, including microscopy with fluorescent stains, dipstick antigen detection, DNA probes, polymerase chain reaction (PCR) assays, and automated blood cell analysis.^42,^43,⁴⁸^–⁵² Use of one of these new diagnostic modalities should be considered when a high suspicion of malaria remains despite repeatedly negative blood smears, especially if the microscopist has limited experience with reading malaria smears.⁴³ Each technique has unique advantages and disadvantages, but the sensitivity and specificity for P. falciparum is generally similar or better than conventional microscopy. Because of its greater sensitivity (as low as 5 parasites/µL), PCR may be a particularly valuable tool in nonimmune persons. PCR also allows evaluation for possible infection with multiple malaria strains and determination of drug resistance. The U.S. Food and Drug Administration (FDA) recently approved a rapid diagnostic test—the BinaxNOW malaria test (Binax/Alere Inc., Scarborough, Maine)—that detects the HRP-2 protein of P. falciparum as well as an aldolase common to all plasmodia, with sensitivities of 100% and 97%, respectively.⁴² However, the sensitivity of this and other dipstick antigen tests is diminished when the parasitemia is less than 100 parasites/µL. Furthermore, the HRP-2 protein may persist in the bloodstream and give a false-positive test result for up to 4 weeks after successful treatment of malaria. Hence, it is still important to confirm the rapid diagnostic test with microscopy when possible.

Imaging

Computed tomography (CT) or magnetic resonance imaging (MRI) scanning of the abdomen is the usual diagnostic modality when splenic rupture is considered, although ultrasonography, arteriography, bleeding scans, or exploratory laparotomy may sometimes be needed. Findings such as increased brain volume and occasionally brain swelling have been noted in CT and MRI studies in cerebral malaria, but these tests are generally unhelpful clinically and are indicated only to rule out suspected mass lesions when the diagnosis of cerebral malaria is uncertain.⁵³

Clinical Management

Indications for Admission to the Intensive Care Unit and General Management

Features that indicate severe disease meriting admission to an ICU and urgent IV therapy are noted in Table 143-3. In these critically ill patients, chloroquine-resistant P. falciparum should be assumed until proven otherwise. As per routine ICU management, the patient’s breathing and circulatory status should first be rapidly assessed, the airway secured, and the neurologic status scored on the Glasgow Coma Scale or other appropriate scoring system.⁵⁴ For patients in profound shock, blood cultures should be drawn and broad-spectrum antibiotics begun unless the diagnosis of severe malaria has already been confirmed or if bacterial suprainfection is suspected. Unconscious patients should have a lumbar puncture to rule out bacterial meningitis.

Careful attention to fluid balance is imperative, especially considering the very poor prognosis once pulmonary edema or ARDS develops. Measurements of urine output and daily weights should be routinely performed. Monitoring of central venous pressure should be considered in delicate cases, such as those with respiratory distress or compromised renal function. Considering that the prognosis associated with pulmonary failure is considerably poorer than that of ARF, some authors recommend early use of inotropes rather than excessive fluids in the setting of hypotension, although a beneficial effect on the overall hemodynamic profile has yet to be conclusively demonstrated.^39,⁵⁵ Dialysis is indicated for ARF and may aid not only through improved fluid balance and control of acidemia but also via removal of circulating cytokine mediators of inflammation. Although observations are limited, the quinolines appear not to be dialyzed.⁵⁶ Cautious transfusion of packed cells is usually indicated when the hematocrit falls below 20%. In addition to improved oxygen transport, blood transfusion may reduce the parasite load and cytokine mediators of inflammation.^39,⁵⁷ Concurrent administration of diuretics or low-dose dopamine may be warranted to avoid fluid overload.

Increasing respiratory distress may indicate the onset of ALI or ARDS. Arterial blood gas measurements may reveal hypoxemia, and chest x-rays bilateral infiltrates. Supplemental oxygen and mechanical ventilation may be required. In accordance with the NIH ARDS Network Trial, lung-protective ventilation, with tidal volume of 6 mL/kg predicted body weight and plateau pressures less than 30 cm H₂O are indicated for improved survival.²³ Extracorporeal oxygenation has also been employed.⁵⁸ Metabolic acidosis should be treated by improving pulmonary gas exchange, correcting hypovolemia and hypoglycemia, and treating associated septicemia. Blood glucose should be checked frequently, especially in pregnant patients, and 50% dextrose administered when needed. Results of studies on the efficacy of continuous IV infusion of 5% dextrose have been mixed.^59,⁶⁰ Quinoline-induced hypoglycemia may be prevented by administering somatostatin analogs followed by glucagons.⁶¹ Acute seizures may be treated with benzodiazepines or paraldehyde, and prolonged seizures terminated with phenytoin.²¹ However, prophylactic anticonvulsants are not recommended and may be harmful.⁵⁴ Although the risk of bleeding is low, aspirin should be avoided in the presence of thrombocytopenia. Many patients with splenic rupture can be managed conservatively with supportive therapy, although splenectomy may be necessary.³⁶

In late pregnancy, fetal monitoring should be begun prior to initiation of quinoline therapy so that the effects of the disease can be distinguished from those of drug toxicity. Early obstetric intervention should be considered for the benefit of both mother and fetus. Although fetal distress is usually the result of placental insufficiency, it may sometimes be related to high maternal temperature and hypoglycemia. Thus these parameters should be carefully monitored and treated accordingly. Fluid balance is particularly crucial in pregnant patients; the sudden increase in peripheral vascular resistance postpartum may precipitate pulmonary edema. In young children prone to febrile convulsions, extra efforts should be made to control fever by the use of acetaminophen, cooling blankets, and baths.

Antimalarial Chemotherapy

Because delay of therapy is associated with increased mortality, empirical parental treatment should be implemented immediately in all suspected cases of severe malaria after obtaining appropriate blood specimens. Infection with chloroquine-resistant P. falciparum should be assumed unless specifically ruled out. Treatment regimens for severe P. falciparum are also effective for the more infrequent cases of severe malaria due to other species.

Two classes of medicines are indicated for parenteral treatment: the artemisinin derivatives (artesunate, artemether, and others) and the cinchona alkaloids (Table 143-4). Randomized trials in Southeast Asia show artesunate to be superior to quinine for severe malaria in adults, although there is currently insufficient evidence to support this conclusion in children.^54,⁶² Despite its use throughout much of the world, in the United States, intravenous (IV) artesunate has “investigational new drug” status and is only available through request to the Centers for Disease Control and Prevention (CDC).^63,⁶⁴ Because IV quinine is also unavailable in the United States, quinidine gluconate is often used.⁶⁵ Cinchona alkaloids may also be considered for first-line treatment of patients infected in Southeast Asia, where resistance to artemisinin compounds has been documented, or if the patient has already received but not responded to an artemisinin-based therapy.^66,⁶⁷

TABLE 143-4 Treatment Guidelines for Severe Plasmodium falciparum Malaria

Drug	Dose	Comments
Artemisinin Compound Regimens*
Artesunate	2.4 mg/kg IV daily × 3 days, followed by one of the following: 1 Doxycycline, 100 mg PO BID × 7 days 2 Clindamycin, 20 mg base/kg/d PO, divided TID × 7 days 3 Atovaquone/proguanil: — Adults: 4 adult tabs PO daily × 7 days — Children: PO daily × 7 days as follows: 5-8 kg: 2 pediatric tabs 9-10 kg: 3 pediatric tabs 11-20 kg: 1 adult tab 21-30 kg: 2 adult tabs 31-40 kg: 3 adult tabs >40 kg: 4 adult tabs 1 Mefloquine: — Adults: 684 mg base (=750 mg salt) PO as initial dose, followed by 456 mg base (=500 mg salt) PO given 6-12 hours later (total dose = 1250 mg salt) — Children: 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 6-12 hours later (total dose = 25 mg salt/kg)

Artesunate has “investigational new drug” status in the United States and is only available on request to the CDC (770-488-7788). Eligibility requirements include inability to take oral medications, high levels of parasitemia, clinical evidence of severe malaria, intolerance of or contraindication to quinidine, failure of quinidine therapy, and lack of rapid access to quinidine.⁶⁴ Where available, artesunate rectal suppositories (10 mg/kg) may be used in children < 5 years of age if IV or IM administration is not possible. Doxycycline is contraindicated in children < 8 years of age and in pregnancy. Atovaquone/proguanil is packaged in the United States in fixed-dose combination tablets of 250 mg atovaquone/100 mg proguanil for adults and 62.5 mg atovaquone/25 mg proguanil for children. Safety of atovaquone/proguanil in pregnancy has not been established. Cinchona Alkaloid Regimens Quinine dihydrochloride

20 mg salt/kg IV or IM on admission, then 10 mg/kg q 8 h. Can be given IM if IV administration is not possible. One of the following drugs should also be given concurrently:

1 Doxycycline as above. If patient unable to take PO, give 100 mg IV q 12 h and switch to PO when possible. Avoid rapid IV administration.

2 Clindamycin as above. If patient unable to take PO, give 10 mg base/kg loading dose IV followed by 5 mg base/kg IV q 8 h and switch to PO when possible. Avoid rapid IV administration.

The infusion rate of IV quinine should be rate controlled and not exceed 5 mg salt/kg/h. The drug is usually diluted in 5% dextrose and infused over 4 hours. IV quinine is not available in the United States. When administering IM, the dose should be split and diluted to a concentration of 60-100 mg/kg delivered to each thigh. Reduce the quinine dose by one-third after 48 hours in patients with severe renal and/or hepatic dysfunction. Doxycycline is contraindicated in children <8 years old and in pregnancy. Quinidine gluconate 6.25 mg base/kg (=10 mg salt/kg) IV on admission, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion. 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 q 8 h, starting 8 hours after the loading dose. A second drug should be given concurrently as listed above for quinine. The loading dose should be omitted if the patient received >40 mg/kg quinine in the preceding 48 hours or mefloquine in the previous 12 hours. Reduce the dose by one-third after 48 hours in patients with severe renal and/or hepatic dysfunction. Quinidine should be given for 7 days in infections in southeast Asia and 3 days in Africa or South America.

* Various other artemisinin combined therapy regimens are in use around the world depending upon drug availability, national policy, and personal preference, including artesunate plus amodiaquine, artemether plus lumefantrine, dihydroartemisinin plus piperaquine.

According to CDC recommendations, the patient should receive at least 24 hours of parenteral therapy with quinidine gluconate even if there is immediate dramatic improvement.⁶⁴ After 24 hours, patients may be transitioned to oral quinine only if they are able to tolerate oral medications and the parasite density is less than 1%. The IV quinidine/oral quinine treatment course is 7 days total if malaria was contracted in Southeast Asia and 3 days if in South America or Africa.

The patient should be given a 7-day oral course of second drug in addition to the IV artesunate or IV quinidine/oral quinine therapy (see Table 143-3). Artemisinin compounds should be followed by oral doxycycline, clindamycin, atovaquone/proguanil, or mefloquine, whereas either doxycycline or clindamycin are given concurrently with the cinchona alkaloids. Doxycycline is preferred to other tetracyclines because it can be given once daily and does not accumulate in renal failure. Mefloquine should be avoided if the patient presented initially with impaired consciousness; an increased incidence of neuropsychiatric complications associated with mefloquine following cerebral malaria has been documented. Chloroquine is no longer recommended for the treatment of severe malaria because of widespread resistance. Intramuscular sulfadoxine/pyrimethamine is no longer recommended.

Adverse Effects of Therapy

Side effects associated with artemisinin compounds are infrequent and generally mild and include abdominal pain, diarrhea, contact dermatitis, decreases in reticulocyte and neutrophil counts, and elevated hepatic transaminases.⁶⁸ Severe allergic reactions and cerebellar dysfunction have been rarely reported.⁶⁹

Side effects of quinine and quinidine, known as cinchonism, are common and typically include nausea, vomiting, headache, dysphoria, vasodilation, tinnitus, and changes in auditory and visual acuity. These alterations are dose related and reversible. Less common side effects include rash, urticaria, angioedema of the face, pruritus, agranulocytosis, hepatitis, blackwater fever, and psychiatric disorders. Overdoses are associated with depressed respiration, circulatory collapse, and CNS alterations including seizures and coma, which may be difficult to distinguish from cerebral malaria.⁷⁰ Simultaneous use of two quinolines or retreatment with the same quinoline within a short period of time may predispose to severe side effects.⁷¹ The cinchona alkaloids are metabolized in the liver and excreted in the urine. Monitoring blood levels is recommended for persons with impaired renal or hepatic function, and dose reduction is necessary in those with severe renal impairment. Quinine metabolism appears to be decreased in children with kwashiorkor but increased in those with marasmus.⁷²

Although rarely clinically significant, prolongation of the electrocardiographic QT interval with IV quinoline therapy is common.⁷³ Severe conduction abnormalities may occur along with hypotension, blindness, and deafness.^54,^63,^64,⁷³ Dysrhythmias and hypotension may also result from overly rapid infusion. Coma may result when serum quinoline levels exceed 20 mg/L. Cardiac monitoring should be performed with IV quinoline use, especially with quinidine, which although more potent against the malaria parasite is also generally more toxic.⁷³ Infusion rates of quinidine should be decreased if the QT interval increases by more than 25% of its baseline level.

Quinoline-induced stimulation of insulin release may elicit significant hypoglycemia, especially in pregnancy.^60,⁷⁴ Hypophosphatemia may also be precipitated by both quinoline and IV dextrose, causing CNS dysfunction.³⁹ Levels of digoxin, mefloquine, neuromuscular blocking agents, and oral anticoagulants may all be increased with quinoline administration. Quinine can cause hemolysis in patients with G6PD deficiency. Because of their curare-like effect on skeletal muscle, quinolines are contraindicated in patients with myasthenia gravis.

Atovaquone/proguanil is usually well tolerated. Gastrointestinal symptoms, skin rash, headache, insomnia, and (rarely) hematologic and renal effects have been reported, especially at high levels.^75,⁷⁶

Ancillary Therapies

Various ancillary therapies have been proposed for severe malaria. In most cases, controlled data are not available to judge their efficacy. Exchange transfusion and erythrocytapheresis have been employed with apparent benefit in cases of severe disease with high parasitemia (>15%) and should be considered in such situations, especially if the patient’s condition is worsening despite adequate chemotherapy.⁷⁷^–⁸⁰ The rationale for this form of therapy is based on (1) rapid reduction in parasite load; (2) removal of toxic substances; and (3) reducing microcirculatory sludging.⁷⁷ In some studies, iron chelators such as desferrioxamine have been demonstrated to hasten malaria parasite clearance and shorten the duration of cerebral malaria coma.^81,⁸² Proposed mechanisms include depriving the parasite of necessary iron, enhancing the T-helper immune response, and protecting against iron-mediated peroxidant cerebral tissue damage.⁵⁸ Antioxidants such as pentoxifylline and inhaled nitric oxide have been used, but attempts to attenuate the immune response in malaria have generally met with mixed results.⁸³^–⁸⁵ Monoclonal antibodies directed against TNF-α had no impact on mortality and may increase morbidity (neurologic sequelae), probably reflecting the participation of multiple cytokines in the pathogenesis of severe and complicated malaria.^86,⁸⁷ Dichloroacetate to counter lactic acidosis is also under study.⁸⁸ Corticosteroids are detrimental in severe malaria and should not be used.⁸⁹

Laboratory Monitoring

Findings in severe malaria may include profound hemolytic anemia and thrombocytopenia, leukocytosis with a left shift (although milder cases may show leukopenia), prolonged coagulation times (with increased fibrin split products and diminished fibrinogen reflecting DIC), hyponatremia, hypoalbuminemia, hypophosphatemia, hypoglycemia, lactic acidemia, and elevated hepatic enzymes, LDH, bilirubin, BUN, and creatinine. Urinalysis may reveal proteinuria, RBCs and RBC casts, and hemoglobinuria. Coagulation defects and thrombocytopenia often correlate with the degree of parasitemia. The level of parasitemia should be monitored via blood smear every 12 hours after initiation of therapy. A decrease of 75% should be noted within 48 hours. If this does not occur, drug resistance should be suspected, and the regimen should be changed accordingly (see Table 143-4).

Prognosis

Case fatality rates in severe malaria range from 2% to 50%.^20,^21,⁹⁰^–⁹² Factors which correlate with a poor prognosis include the infecting species and resistance profile, CNS involvement, pulmonary edema, hypoglycemia, lactic acidosis, renal failure, severe anemia, younger age, pregnancy, and treatment in a rural health facility as opposed to an ICU.^39,⁹³^–¹⁰⁰ There is a semiquantitative relationship between level of parasitemia and risk of death, especially in nonimmune patients. Although less than 10% of adults with cerebral malaria have persistent neurologic sequelae, this number may be as high as 40% in children, especially if associated with hypoglycemia.^59,⁹⁰ Commonly seen sequelae include psychosis, hemiparesis, cerebellar ataxia, and extrapyramidal rigidity.^20,²¹ Children who survive without obvious neurologic sequelae appear to then develop normally neuropsychologically.¹⁰¹ A postmalarial neurologic syndrome, usually associated with mefloquine use, of an acute confusional state, psychosis, convulsions, and tremors has been described but is usually self-limited.²¹