Management of Severe Malaria

Abstract

Imported malaria is the principal, preventable, life-threatening infection among US travelers. Using a base case scenario, we will discuss the most recent information on the management and treatment for Severe Malaria.

Case Presentation

A 25-year-old male presented to the emergency department with a history of abdominal pain in the right hypochondrium, jaundice, fever, and a decrease in consciousness. He was businessman who had recently returned from Nigeria, where he had spent 3 weeks. Laboratory tests at presentation showed WBC: 20,650 Neu:88 Lymph:12 Platelets: 38,000 SGOT: 88 SGPT: 120 Billirubins: T: 4.3 mg/dl I: 29 mg/dl, severe metabolic acidosis, thrombocytopenia, a creatinine of 5.6 mg/dl, and dark urine (macroscopic hemoglobinuria see Fig. 57.1). His APACHE II score was 37, with an estimated risk of death of 88 %. The patient was admitted to the intensive care unit with septic shock. A thick blood smear revealed P. falciparum malaria. The patient was initiated with anti-malaria IV drugs: quinidine gluconate plus doxycycline. Despite antimalarial drug administration and supportive care the patient developed acute respiratory distress syndrome, acute renal failure requiring renal replacement therapy, and an Important Thrombocytopenia (Fig. 57.2).

Fig. 57.1

“Blackwater Fever” – Urine sample showing dark urine due to hemoglobinuria (right tube)

Fig. 57.2

(a, b) Ecchymosis from thrombocytopenia

Question

What are the challenges in the diagnosis and management of the returning traveller with severe malaria?

Answer

People now move across the world with great facility, whether on vacation or business. Endemic diseases, such as malaria, can affect the travelers upon return to home. Malaria.com maps the regions of the world where Plasmodium falciparum, the type intensivists might encounter, may be transmitted [1].

In a returning traveler, fever can be a benign and self-limiting infection, but initially must be considered seriously. Table 57.1 displays the top illnesses encountered in returning travelers. In order to make a diagnosis a comprehensive history with details regarding places visited, duration, purpose, activities undertaken, any chemoprophylaxis taken before or while traveling is critical for the initial work-Up. Knowledge of incubation period and disease risk by geographic are helps in making a differential diagnosis. Table 57.2 displays various diseases potentially encountered by the returning traveler by the duration of incubation period.

Table 57.1 Top illnesses in returning travelers

Table 57.2 Incubation period of various diseases potentially encountered in returning travelers

Principles of Management in Severe Falciparum Malaria

Patients with severe malaria usually present with a high level of parasitemia and/or major signs of organ dysfunction. Populations at greatest risk for severe falciparum malaria are young children, pregnant women and travelers to endemic areas. In endemic areas, elder children and adults develop partial immunity after repeated infections and are at relatively low risk for severe disease. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and are at high risk for severe disease. Pregnant women are more likely to develop severe P. falciparum malaria than other adults, particularly in the second and third trimesters. Complications such as hypoglycemia and pulmonary edema are more common than in non-pregnant individuals. Maternal mortality can approach 50 %, and fetal death and premature labor are common [2].

Patients with severe malaria represent a clinical challenge for the clinician given the complex pathophysiology of the infection involving multiple organ systems. Seizures and severe anemia are relatively more common in children, whereas hyperparasitemia, acute renal failure, and jaundice are more common in adults. Cerebral malaria (with coma), shock, acidosis, and respiratory arrest may occur at any age [2–4].

Definition of Severe Malaria

Severe malaria is generally defined as acute malaria with high levels of parasitemia (>5 %) and/or major signs of organ dysfunction

• 1. Altered consciousness with or without convulsions

• 2. Use of accessory muscles, nasal alar flaring, Tachypnea.

• 3. Metabolic acidosis (plasma bicarbonate M 15 mmol/L or whole blood lactate >5 mmol/L)

• 4. Circulatory collapse

• 5. Pulmonary edema or acute respiratory distress syndrome (ARDS)

• 6. Renal failure, hemoglobinuria (“Blackwater Fever”)

• 7. Jaundice

• 8. Disseminated Intravascular coagulation

• 9. Severe Anemia

• 10. Hypoglycemia

Diagnosis

The clinician must have a high index of suspicion for malaria in travelers presenting with fever and a history of travel to malaria endemic regions within the previous year and especially in the prior 3 months. In uncomplicated malaria apart from fever, patients usually present with nonspecific clinical features. If the diagnosis of falciparum malaria has been delayed, a seemingly well-appearing patient may rapidly deteriorate and present with jaundice, confusion, or seizures and have a high fatality rate. Hence, it is critical to make a rapid and accurate diagnosis when malaria is suspected clinically [3, 4].

Microscopy is the gold standard and preferred option for the diagnosis of malaria. In most cases the examination of thin and thick blood films will reveal Malaria parasites (Figs. 57.3 and 57.4).

Fig. 57.3

P falciparum on thick smear (From: Centers for Disease Control and Prevention (CDC) [23])

Fig. 57.4

P. falciparum on thin smear (From: Centers for Disease Control and Prevention (CDC) [23])

Thick films are more sensitive to detect low levels of parasitemia. In general the greater the parasite density in the peripheral blood, the higher likelihood that severe disease is present or will develop, especially in immunocompromised patients. Thick smears are more sensitive diagnostically but the thin smear subsequently helps in determining the malaria species and the level of parasitemia (the percentage of a patient’s red blood cells that are infected with malaria parasites).

Clinical Management

General Principles

Most of the time uncomplicated malaria have a good prognosis with a fatality case less 0.1 %. Uncomplicated malaria caused by P. ovale, P. vivax, and P. malariae can usually be managed with oral drugs on an outpatient basis, unless a patient has other comorbidities or is unable to take drugs orally [4, 5].

Due to little immunity against these infections, P. falciparum infections in travelers can rapidly progress to severe illness or death in as little as 1–2 days, so prompt assessment and initiation of antimalarial therapy is essential. Patients should be evaluated with attention to findings consistent with malaria as well as additional and/or alternative causes of presenting symptoms. Of primary importance in the treatment of malaria is the provision of prompt, effective therapy and concurrent supportive care to manage life-threatening complications of the disease. Supportive measures, such as fluid management, oxygen, ventilatory support, cardiac monitoring, and pulse oximetry, should be instituted as needed. During this time, intravenous access should be obtained immediately. Point-of-care testing can be used for rapid determination of hematocrit [packed cell volume (PCV) or hemoglobin (HemoCue)], glucose, and lactate. Parasitemia can also be determined quickly but requires a microscope. Additional tests can be done if/when indicated: electrolytes, full blood count, type and cross, blood culture, and clotting studies. Unconscious patients should have a lumbar puncture to rule out concomitant bacterial meningitis in the absence of contraindications (i.e., papilledema). These tasks should overlap with institution of antimalarial treatment as well as other ancillary therapies as needed (including anticonvulsants, intravenous glucose and fluids, antipyretics, antibiotics, and blood transfusion) [6, 7].

Repeat clinical assessments should be performed every 2–4 h for prompt detection and management of complications in an intensive care setting, if possible. If the Glasgow Coma Score (or in children the Blantyre coma score [see Table 57.3]) decreases after initiation of treatment, investigation should focus on the possibility of seizures, hypoglycemia, or worsening anemia. Repeat laboratory assessments of parasitemia, hemoglobin/hematocrit, glucose, and lactate should be performed in 6-h intervals. A flow chart summarizing the vital information may be used to guide management decisions [6–8].

Table 57.3 Blantyre coma score

Important independent predictors for fatality among African children with severe malaria include acidosis, impaired consciousness (coma and/or convulsions), elevated blood urea nitrogen, and signs of chronic disease (lymphadenopathy, malnutrition, candidiasis, severe visible wasting, and desquamation). Clinical features previously identified as being poor prognostic features that did not correlate with mortality in this study included age, glucose level, axillary temperature, parasite density, and Blackwater Fever [9–11].

Careful observation and thoughtful responses to changes in clinical status are the most important elements in looking after patients with severe malaria. Patients can make remarkable recoveries, and the time and effort to address the components of clinical care described in the following sections can reap tangible rewards in a relatively short period of time.

Clinical evaluation includes full physical exam, a complete neurologic examination, calculation of Glasgow or Blantyre coma score (Table 57.3), and funduscopic evaluation. Malarial retinopathy is pathognomonic for cerebral malaria in patients who satisfy the standard clinical case definition (Fig. 57.5).

Fig. 57.5

Photograph of the retina in patient with malaria, which shows exudates (arrowheads), hemorrhages (thick arrows) and changes in the color of the blood vessels (thin arrows) (From Mishra and Newton [24]. Reprinted with permission from Nature Publishing Group)

Patients with altered sensorium should undergo lumbar puncture (in the absence of contraindications) to exclude concomitant bacterial meningitis. If clinical instability or papilledema on ocular fundus examination preclude lumbar puncture, presumptive antibiotic therapy for bacterial meningitis should be initiated. Usual findings are: mean opening pressure about 16 cm of CSF, slightly elevated total protein level and cell count.

Antimalarial Therapy (See Treatment Table 57.4)

Table 57.4 Treatment of malaria

Monitoring Parasite Density

Parasitemia should be monitored during treatment to confirm adequate response to therapy. The CDC recommends daily repeat blood smear to document declining parasite density until negative or until treatment day 7 (if discharged prior to complete parasitemia clearance). During treatment of severe malaria, parasite density should be monitored every 12 h during the first 2–3 days or until negative; some recommendations suggest switching from parenteral to oral therapy as tolerated after parasitemia falls below 1 % [10, 11].

Respiratory System

Hypoxemia and rales are not common in the setting of severe malaria; the presence of either should raise suspicion for a concomitant lower respiratory tract infection. Pulmonary edema may develop, particularly in the settings of renal impairment or severe malarial anemia. Acute respiratory distress syndrome (ARDS) can also complicate severe malaria.

Deep breathing (Kussmaul respirations) is a clinical indicator of metabolic acidosis and is associated with a worse outcome in patients with falciparum malaria [10, 11].

Neurologic Involvement

The standard clinical case definition of cerebral malaria includes the following criteria:

• 1. Blantyre coma score ≤2

• 2. P. falciparum parasitemia (any density)

• 3. No other identifiable cause of coma (e.g., hypoglycemia, meningitis, or a post-ictal state)

The histologic hallmark of cerebral malaria is cerebral sequestration of parasitized erythrocytes.

Establishing whether retinopathy is present is an important marker for cerebral malaria. In the absence of this finding, alternative causes for coma (such as bacterial infection) should be pursued and treated, even in the presence of established malaria infection [11, 12].

Seizure Management

Seizures occur in up to 70 % of children with severe malaria; subclinical seizures occur in 15–20 % of cases. Seizures may be generalized or focal, and the clinical signs may be subtle (nystagmus, irregular respirations, hypoventilation, or a drop in the Blantyre coma score). It is also important to evaluate for causes of seizure besides cerebral malaria (e.g., hypoglycemia, fever) and to treat accordingly as outlined in the following sections.

Benzodiazepines are useful first-line agents for seizure treatment. Diazepam (0.4 mg/kg) can be administered intravenously or per rectum; lorazepam (0.1 mg/kg) can be administered intravenously or intraosseously. These doses can be repeated once if seizures do not cease within five minutes of the initial dose. Benzodiazepines should not be combined due to risk of respiratory depression. If seizures are not controllable with benzodiazepines, other options include phenobarbitone (phenobarbital 15–20 mg/kg, slow IV push) or phenytoin (18 mg/kg diluted in 100 mL normal saline, infused over 20 min).

If seizures recur, repeat single doses of benzodiazepine may be administered. Alternatively, maintenance doses of phenobarbital (5–15 mg/kg/day, administered orally, via NG tube, or via slow IV push in divided doses every 12 h) or phenytoin (10 mg/kg/day IV in divided doses every 12 h) may be initiated.

Paraldehyde was used as an intramuscular injection to treat seizures in the setting of severe malaria (0.2–0.4 mL/kg); its chief advantage is that it does not cause respiratory suppression. The cost of this agent has increased dramatically, and it is therefore out of reach for many formularies in malaria-endemic areas.

Patients with severe malaria should not receive routine seizure prophylaxis in the absence of clinical seizure activity [12–14].

Anemia and Coagulopathy

Severe hemolysis, which is mainly extravascular, occurs in hyperparasitemic falciparum malaria. Removal of both infected and uninfected erythrocytes from the circulation, mainly by the spleen, is associated with rapid development of anemia. Patients with severe anemia may present with or without altered consciousness; in addition, severe anemia has been associated with long-term neurocognitive impairment. In endemic areas hemoglobin concentration may decrease gradually over the course of repeated malaria infections. As a result, patients can be fully alert with hemoglobin concentrations of 2–3 g/dL (hematocrit <10 %). Evaluation for pallor of the conjunctivae, nail beds, and palms can provide a rough estimate of the degree of anemia, since blood vessels in these areas are close to the surface.

Hemoglobin concentration and hematocrit are routinely measured components of complete blood counts, but this may not be available in resource-limited settings or the results may not be available in a timely manner. In such circumstances the hematocrit can be measured on a fingerprick sample of blood collected into a heparinized capillary tube and centrifuged using a mechanical device. Alternatively, the hemoglobin concentration can be determined from fingerprick samples of blood collected into cuvettes. This method is more expensive than manually spinning a hematocrit, but can be performed readily near the bedside.

Clinically evident disseminated intravascular coagulation in the setting of severe malaria is rare (<5 %), but profound thrombocytopenia is common, and the microcirculation in many organs is occluded by fibrin thrombi [15, 16].

Blood Products

Blood products should be administered in patients with dire prognoses, i.e., patients with altered consciousness, high output heart failure, respiratory distress, a cool periphery, hyperlactatemia, and/or high density parasitemia. Laboratory parameters of concern include low hemoglobin concentration (≤4–5 g/dL) or low hematocrit (≤10–15 %). The degree of anemia and the level of parasitemia may be useful parameters for predicting the need for a blood transfusion and for determining the volume of blood to transfuse. In general, 10 mL/kg of packed red blood cells or 20 mL/kg of whole blood transfused over 2–4 h is appropriate. Blood should be typed and crossmatched prior to infusion.

Blood transfusions are generally well-tolerated in the setting of severe malaria, since patients are relatively hypovolemic; diuretics are rarely needed. Monitoring of hemoglobin concentration or hematocrit should continue until the parasitemia clears, since repeat transfusion may be required [16].

Hypoglycemia

Defined as blood glucose <40 mg/dL or <2.2 mmol/L), hypoglycemia is a common complication of malaria and a marker of severe disease. It should be suspected in any patient who is comatose or who deteriorates suddenly.

The pathogenesis of hypoglycemia is not fully understood; it may be related to parasite glucose consumption and/or impaired host gluconeogenesis. Malnutrition, adrenal insufficiency, and hyperinsulinemia are not likely causes of hypoglycemia. In addition to primary hypoglycemia, administration of quinine or quinidine (insulin secretagogues) can cause iatrogenic hypoglycemia. Hypoglycemia with artesunate therapy is less common than with quinine or quinidine.

Patients presenting with normoglycemia can develop hypoglycemia during the course of treatment. When determining maintenance intravenous fluids, the clinician should consider the possibility of hypoglycemia and use glucose containing solutions. In addition, those managed promptly for hypoglycemia at presentation can have subsequent recurrent hypoglycemia. Therefore, blood glucose should be monitored closely during the course of illness with prompt management as outlined above. Patients with recurrent hypoglycemia should receive 10 % dextrose. Ten percent dextrose can be prepared quickly by withdrawing 100 mL from a one liter bag of a 5 % dextrose solution and replacing it with 100 mL of a 50 % dextrose solution [15–17].

Volume Management

Adults with malaria appear to be more vulnerable to fluid overload than children. There is a fine line between under hydration, and thus worsening renal impairment, and over hydration, risking pulmonary and cerebral edema. Hence, fluid requirements should be assessed on an individual basis, using commonly employed tools such as delayed capillary refill, low central venous pressure, and low urine output. Deep breathing, reflecting lactic acidosis, may also be a reasonable indicator of hypovolemia [16, 17].

Nutrition

Nutritional supplementation should be provided by nasogastric tube (NG) for patients with prolonged coma who are unable to eat and drink within 24–48 h.

Fever

High fevers (>38.5 °C) are common in the setting of malaria infection and may reflect the host response to endogenous pyrogens released at the time of schizont rupture. The optimal approach to treatment of fever is uncertain, although use of antipyretics in patients with high fever is appropriate given the association between high fever and convulsions. Aggressive temperature control may help reduce long-term neurologic outcomes in pediatric patients with retinopathy-positive cerebral malaria.

Paracetamol (acetaminophen); 15 mg/kg every 6 h; maximum dose 1000 mg) is a reasonable antipyretic agent; oral therapy can be used for patients able to swallow. Otherwise, suppository formulations are acceptable. If fever persists, ibuprofen (10 mg/kg every 6 hours; maximum dose 1,200 mg per day) can be administered (orally, via nasogastric tube, or intravenously) alone or on an alternating schedule with paracetamol every 3 h [17–19].

Bacterial Infection

Concomitant bacterial infection is an important contributor to morbidity and mortality in the setting of severe malaria, and severe anemia has been implicated as a primary risk factor for non-typhoidal Salmonella septicemia. Bacterial infection should be suspected in patients with severe anemia together with signs or symptoms of sepsis (hypotension, cool extremities, delayed capillary refill, hyperlactatemia). In such cases, blood cultures should be obtained and broad spectrum antibiotic therapy with activity against gram-negative bacilli should be initiated [18, 19].

Evidence Contour

Other Diagnostic Modalities

A major drawback of light microscopy is that the efficiency of the test depends on the type and quality of the smear, skill of the technician, parasite density, and time spent on examining the smear. In addition, mixed infections with P. malariae or P. ovale are often missed, because their densities are often low in comparison to that of P falciparum. These problems may occur more frequently in non-endemic areas where malaria microscopy is performed infrequently.

Quantitative Buffy Coat

Quantitative buffy coat (QBC) is fluorescent microscopy based on the principle of concentrating the red blood cell-containing parasites within a narrow zone by centrifugation of blood in capillary tubes and staining of malarial parasite nucleic acid with acridine dyes. The sensitivity of QBC almost equals that of Giemsa-stained films. The advantage of QBC is ease of interpretation and rapidity. Species identification and quantification are difficult, however, with this technique and, therefore, thick and thin blood film examination is still required. This technique requires the use of expensive fluorescent microscopy equipment for the interpretation of results. This is an important limitation especially in the poor resource countries [19].

Antigen Rapid Detection Test (RDT)

Antigen detection RDTs detect malaria antigen in blood by immunochromatographic test with monoclonal antibodies directed against the target parasite antigen, which is impregnated on a test strip. The result is usually obtained in 5–20 min. Currently, different combinations of immunochromatographic tests are commercially available, targeting different genus specific or species-specific antigen for malaria diagnosis. Some of the commonly used antigens in RDTs are HRP-2 (P. falciparum specific), aldolase (pan-specific), plasmodium lactate dehydrogenase (pLDH) (P. falciparum specific), pLDH (P. vivax- specific), and pLDH (panspecific) [19, 20].

Serology

Serology detection of antibodies against malaria parasites, using either indirect immunofluorescence assay or ELISA, does not indicate current infection but rather measures past exposure. Therefore, it has no role in diagnosis of acute infections. Serology may be used to screen donors to prevent transfusion-related malaria, however, and to confirm the diagnosis of malaria in recently treated cases in which the diagnosis could not be confirmed previously [19–21].

Molecular Methods

Molecular technologies have been developed to improve the diagnosis of malaria by detecting specific parasite nucleic acid. The advantage of molecular methods is their exquisite sensitivity down to the level of 5 parasites/mL or 0.0001 % parasitemia [20, 21].

Exchange Transfusion

Exchange transfusion has been proposed as a means of removing infected red blood cells from the circulation, thereby lowering the parasite burden and replacing with unparasitized cells. There is no evidence supporting efficacy of exchange transfusion as adjunctive therapy in severe malaria, and there is no consensus on the indications, approach, benefits, or risks of this procedure.

The CDC no longer recommends exchange transfusion for treatment of severe malaria, based on a review that demonstrated no differences in outcome among patients who underwent exchange transfusion; previously, the CDC recommended exchange transfusion for patients with parasite density of >10 % with end organ complications. The WHO guidelines indicate that it is not possible to make any recommendations regarding the use of exchange transfusion based on the available evidence. The American Society for Apheresis (ASFA) supports exchange transfusion as an adjunctive therapy for patients with >10 % parasitemia, although its consideration of adverse events associated with exchange transfusion for malaria is limited [19–21].