on 10-Jun-2023 (Sat)

In areas where malaria is highly endemic, groups at highest risk include young children (6 to 59 months), who can develop severe illness, and pregnant individuals, who are at risk for anemia and delivering low birthweight newborns.

In areas where malaria is transmitted throughout the year, older children and adults develop partial immunity after repeated infections and are at relatively low risk for severe disease.

Travelers to malarious areas generally have had no previous exposure to malaria parasites or have lost their immunity if they left the endemic area; they are at very high risk for severe disease if infected with Plasmodium falciparum [1,2].

Following the bite of an infected female Anopheles mosquito, the inoculated sporozoites migrate to the liver within one to two hours (figure 1). Individuals are generally asymptomatic for 12 to 35 days after infection, but symptoms can commence as early as 7 days (depending on parasite species).

Symptoms begin during the erythrocytic stage of the parasite life cycle, when infected red cells rupture and release merozoites, leading to fever and other symptoms.

In most cases, infections due to P. falciparum become clinically apparent within one month after exposure [3-5]. Longer incubation periods are more likely in semi-immune individuals and individuals taking incompletely effective malaria prophylaxis.

The incubation period for the relapsing species, Plasmodium vivax and Plasmodium ovale, is also about two weeks; however, illness can occur months after initial infection due to activation of residual hypnozoites in the liver [3,6,7]. Relapses generally occur within two to three years of infection; with even longer periods of dormancy being reported [8].

The incubation period for Plasmodium malariae is about 18 days; however, low-grade asymptomatic infections can very rarely persist for years (table 1). P. falciparum and P. malariae have no dormant (hypnozoite) phase, hence do not relapse.

Uncomplicated falciparum malaria − Uncomplicated falciparum malaria consists of symptomatic infection due to P. falciparum (established via a positive parasitologic test), in the absence of symptoms and signs consistent with severe malaria (table 2).

The initial symptoms are nonspecific and may also include tachycardia, tachypnea, chills, malaise, fatigue, diaphoresis, headache, cough, anorexia, nausea, vomiting, abdominal pain, diarrhea, arthralgias, and myalgias [2,7]. Individuals with uncomplicated disease are generally able to swallow antimalarial drugs.

Fever − Early in the course of malaria infection, febrile paroxysms occur at irregular intervals each day. In children and nonimmune adults, the temperature may rise above 40°C and may occur in conjunction with tachycardia and/or delirium. Febrile seizures may occur among children in the setting of malaria due to any species. However, generalized seizures are associated with P. falciparum infection and may herald the development of cerebral malaria.

Later in the course of infection, rupture of infected red cells can become synchronous following concurrent schizont rupture and release of merozoites from erythrocytes (figure 1). Febrile paroxysms may occur every other day for P. vivax, P. ovale, and P. falciparum and every third day for P. malariae.

Paroxysms occurring at regular intervals are more common in the setting of infection due to P. vivax or P. ovale than P. falciparum. With improvements in early diagnosis and treatment, this traditional description of cyclic fever is seen infrequently.

Febrile illness may reflect concomitant infection. The lower the parasitemia, the greater the chance of a lower respiratory tract, intestinal, or bloodstream bacterial or viral infection [10,11].

Laboratory findings − Laboratory evaluation may demonstrate parasitemia (usually <5000 parasites/microL of blood, <0.1 percent parasitized red blood cells [RBCs]), anemia, thrombocytopenia, elevated transaminases, mild coagulopathy, and elevated blood urea nitrogen (BUN) and creatinine.

Severe malaria is defined as presence of P. falciparum parasitemia and one or more of the manifestations in the table (table 2). P. knowlesi, which is restricted to Southeast Asia, can also cause severe disease. It is acquired in forested regions as a predominately zoonotic infection via mosquito transmission from simian hosts (Macaca fascicularis and Macaca nemestrina).

Many of the clinical findings are the result of the parasitized RBCs adhering to the endothelial cells lining small blood vessels ("cytoadherence") causing small infarcts, capillary leakage, and organ dysfunction. These include the following [7,15,16]:

● Altered consciousness

● Seizures

● Severe anemia (eg massive intravascular hemolysis)

● Hypoglycemia

● Respiratory distress or acute respiratory distress syndrome (ARDS)

● Coagulopathy, with or without disseminated intravascular coagulation

● Metabolic acidosis

● Circulatory collapse

● Renal failure, hemoglobinuria ("blackwater fever")

● Hepatic failure

Physical findings may include pallor, petechiae, jaundice, hepatomegaly, and/or splenomegaly. Splenic rupture has been described. Diagnostic evaluation may demonstrate the following: parasitemia ≥4 to 10 percent, anemia, thrombocytopenia, coagulopathy, elevated transaminases, elevated BUN/creatinine, acidosis, and hypoglycemia [7,17,18].

Thrombocytopenia has been associated with increased risk of death from falciparum or vivax malaria, particularly in the setting of concurrent severe anemia [ 19].

While most severe malaria is usually due to P. falciparum, patients with severe malaria due to P. vivax have also been described. Patients with severe P. vivax may manifest pulmonary complications and ARDS [22].

Increasing parasitemia is associated with increasing disease severity. Semi-immune individuals may have substantial parasitemia with few or no clinical manifestations. However, some severely ill or inadequately treated patients may have a low but rising parasitemia when first seen by a clinician.

Cerebral malaria is an encephalopathy that presents with impaired consciousness, delirium, and/or seizures; focal neurologic signs are unusual. The onset may be gradual or sudden, following a convulsion. The severity depends on a combination of factors including parasite virulence and host immune response.

Risk factors for cerebral malaria include age (children and older adults), pregnancy, poor nutritional status, host genetic susceptibility, and history of splenectomy [26-29]. Among adults, cerebral malaria occurs more commonly among nonimmune individuals than among those living in highly endemic areas.

In children with cerebral malaria, the mean opening pressure is about 22 cm H₂O; approximately 80 percent of patients having elevated opening pressure [30,31]. Laboratory examination of cerebrospinal fluid (CSF) is generally normal.

Retinal hemorrhages may be observed in 30 to 40 percent of cases via pupillary dilation and indirect ophthalmoscopy; without pupillary dilation, this finding may be seen in approximately 15 percent of cases. Other funduscopic abnormalities include discrete spots of retinal opacification (30 to 60 percent), cotton wool spots (<5 percent), and decolorization of a retinal vessel or segment of vessel (picture 1 and picture 2 and picture 3) [33].

Inclusion of malarial retinopathy in the World Health Organization clinical definition of cerebral malaria increases the diagnostic sensitivity and specificity to 90 and 95 percent, respectively (with presence of parasites in the brain on autopsy as the ‘gold standard’) [ 34].

Cerebral edema and elevated intracranial pressure may contribute to a fatal outcome (picture 4). In one study including 164 children with cerebral malaria, approximately 84 percent of deaths occurred among individuals with evidence of severe brain swelling on magnetic resonance imaging at admission (picture 4); such swelling was noted among 27 percent of survivors [35].

Among survivors of cerebral malaria, neurologic sequelae are more common among children than adults (about 50 versus 3 percent, respectively) [36]. Residual deficits may include hemiplegia, cerebral palsy, cortical blindness, deafness, epilepsy, language deficit, and impaired cognition [37,38]. Such sequelae are more likely among patients with other grave prognostic indicators including hypoglycemia, acidosis, severe anemia, repeated seizures, and deep coma.

Postmalaria neurologic syndrome is an autoimmune encephalitis that manifests within two months of treatment and resolution of cerebral malaria. The condition is rare, presents often with seizures, and responds to parenteral steroids [39].

Hypoglycemia occurs as a result of the following factors:

● Diminished hepatic gluconeogenesis

● Depletion of liver glycogen stores

● Increase in the consumption of glucose by the host (and, to a much lesser extent, the parasite)

● Quinine-induced hyperinsulinemia

Hypoglycemia is associated with a poor prognosis, particularly in children and pregnant individuals.

Acidosis is an important clinical finding in severe malaria and must be corrected quickly. It is caused by several factors, including:

● Anaerobic glycolysis in host tissues where sequestered parasites interfere with microcirculatory flow

● Parasite lactate production

● Hypovolemia

● Insufficient hepatic and renal lactate clearance

The prognosis of severe acidosis is poor.

The pathogenesis of renal failure is uncertain but may be related to erythrocyte sequestration interfering with renal microcirculatory flow and metabolism. Other potential factors include hypovolemia and hemolysis [45]. Large amounts of hemoglobin and malarial pigments may be present in the urine secondary to intravascular hemolysis. This uncommonly manifests in very dark urine following several attacks of falciparum malaria; mortality is high. Renal impairment can manifest as acute tubular necrosis (both clinically and pathologically), although renal cortical necrosis does not occur.

Noncardiogenic pulmonary edema (eg, acute respiratory distress syndrome) may be observed in adults with severe falciparum malaria [46]. The pathogenesis is uncertain but may be related to sequestration of parasitized red cells in the lungs and/or cytokine-induced leakage from the pulmonary vasculature. This complication may develop even after several days of antimalarial therapy and can be aggravated by overly vigorous administration of intravenous fluid [24].

Noncardiogenic pulmonary edema can also develop in otherwise uncomplicated vivax malaria.

Anemia is usually mild to moderate, though severe anemia may occur in the setting of P. falciparum malaria. In one series including 100 Canadian travelers, patients with malaria presented with anemia in 41 percent of cases [47]. White blood cell counts were elevated above 9.8 x 10⁹/L in 3 percent of patients but were less than 5.0 x 10⁹/L in 48 percent. Platelets were low in 83 percent of P. vivax-infected patients (mean 102 x 10⁹/L) and in 62 percent of P. falciparum-infected patients (mean 137 x 10⁹/L).

Anemia in the setting of malaria occurs as a result of the following factors:

● Hemolysis of parasitized red cells

● Increased splenic sequestration and clearance of erythrocytes with diminished deformability

● Cytokine suppression of hematopoiesis

● Shortened erythrocyte survival

● Repeated infections and ineffective treatments

Additional information regarding these mechanisms is presented separately. (See "Anemia in malaria".)

Coagulopathy can occur in the setting of falciparum malaria; bleeding with evidence of disseminated intravascular coagulation occurs in <5 percent of patients with severe malaria.

Mild jaundice due to hemolysis in malaria is common in adults. Severe jaundice due to hemolysis, hepatocyte injury, and cholestasis may occur in the setting of P. falciparum infection; this manifestation is more common among adults than children.

There appears to be a biological association between malaria, human immunodeficiency virus (HIV), malnutrition, and invasive bacterial infections.

Recurrence of malaria can occur as a result of treatment failure (recrudescence), relapse, or reinfection; these may be difficult to distinguish. Both recrudescent and relapsing infections manifest as return of disease after its apparent cessation

Recrudescence occurs most often within days or weeks; relapse occurs within weeks or months. In recrudescence, parasites remain in the bloodstream undetected due to ineffective treatment or host immunological response (or both). In relapse, new blood stage parasites are released from dormant parasite stages (hypnozoites) in liver cells, causing a repeat episode of peripheral parasitemia.

P. falciparum is the usual cause of recrudescent infection, although P. malariae can remain present at low levels of parasitemia for years prior to clinical presentation [60]. P. vivax and P. ovale may cause relapse months after the primary blood stage infection is cured, as these species have hypnozoite forms; the likelihood of relapse is decreased if the patient took presumptive anti-relapse therapy to eradicate the dormant hypnozoite liver stages.

Definition of severe malaria^[1,2]

Manifestations	Definitions
Impaired consciousness	Glasgow coma score <11 in adults or Blantyre coma score <3 in children; inability to swallow
Prostration	Generalized weakness so that a person is unable to sit, stand, or walk without assistance
Multiple convulsions	More than two episodes within 24 hours
Acidosis	A base deficit of >8 mEq/L, a plasma bicarbonate level of <15 mmol/L, or venous plasma lactate ≥5 mmol/L. Clinical indicators of acidosis include rapid, deep, labored breathing.
Hypoglycemia	Blood or plasma glucose <40 mg/dL (<2.2 mmol/L) for children ≥5 years and adults; blood or plasma glucose <54 mg/dL (<3 mmol/L) for children <5 years
Severe anemia	Hemoglobin concentration ≤5 g/dL or hematocrit ≤15% in children <12 years of age (<7 g/dL and <20%, respectively, in adults) with parasite count >10,000 parasites/uL
Renal impairment	Plasma or serum creatinine >3 mg/dL (265 umol/L) or blood urea >20 mmol/L
Jaundice	Plasma or serum bilirubin >50 umol/L (3 mg/dL) with one of the following: Plasmodium falciparum parasite count >2.5% parasitemia Plasmodium knowlesi parasite count >20,000 parasites/uL
Pulmonary edema	Radiographically confirmed or oxygen saturation <92% on room air with respiratory rate >30/minute, often with chest indrawing and crepitation on auscultation
Significant bleeding	Including recurrent or prolonged bleeding (from the nose, gums, or venipuncture sites), hematemesis, or melena
Shock	Compensated shock is defined as capillary refill ≥3 seconds or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure <70 mmHg in children or <80 mmHg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
Hyperparasitemia	P. falciparum: In non-immune travelers: parasitemia ≥5%[3] All patients: parasitemia >10% P. knowlesi: Parasite density >100,000 parasites/uL Plasmodium vivax: No established parasite density thresholds

Severe malaria is defined as one or more of the above criteria, occurring in the presence of malaria infection and in the absence of an identified alternative cause.

If initial diagnostic evaluation is negative and clinical suspicion for malaria persists, follow-up testing should be performed each day for two more days [61].

If diagnostic tools are not readily available and there is clinical suspicion for P. falciparum infection, it may be reasonable to make a presumptive diagnosis (and treat empirically), given the potential severity of infection. Making a presumptive diagnosis depends on individual patient circumstances including epidemiologic exposure, clinical manifestations such as fever, and suggestive laboratory findings including anemia, in the absence of a clear alternative diagnosis. However, the clinical presentation of malaria overlaps with many other causes, and even in endemic areas, clinical diagnosis of malaria is frequently incorrect [62-67]. Furthermore, empiric therapy may negatively affect the accuracy of subsequent diagnostic testing.

In returning travelers, presence of splenomegaly (LR 6.5, 95% CI 3.9-11.0), jaundice or icterus (LR 4.5, 95% CI 1.7-12.0), or pallor (LR 2.8, 95% CI 1.7-4.6) were associated with increased the likelihood of malaria. In addition, malaria was more likely in the setting of thrombocytopenia and hyperbilirubinemia (odds ratios 74.0 [95% CI 9.2-601.0] and 11 [95% CI 8-15], respectively).

In endemic areas, presence of splenomegaly and hepatomegaly were associated with increased likelihood of malaria (likelihood ratios [LRs] 3.3 [95% CI 2.0-4.7] and 2.4 [95% CI 1.6-3.6, respectively]).

Dengue fever can cause malaise, headache, fatigue, abdominal discomfort, and muscle aches in association with fever. Myalgia due to dengue fever is usually more severe than myalgia due to malaria. The diagnosis is established with serology. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

Chikungunya resembles dengue but is milder and self-limiting, often with a rash. The diagnosis is established via serology.

Meningitis – The headache of malaria may be severe, although there is no neck stiffness or photophobia as seen with bacterial or viral meningitis. Malaria is not associated with a rash (unlike meningococcal septicemia).

Typhoid fever – Clinical manifestations of typhoid fever include fever, bradycardia, abdominal pain, and rash.

Leptospirosis – Leptospirosis is associated with fever, rigors, myalgia, and headache. Myalgia due to leptospirosis is usually more severe than in malaria; leptospirosis may also be associated with petechial hemorrhages in the skin or mucous membranes.

Viral hemorrhagic fever – Viral hemorrhagic fever is associated with fever, malaise, and systemic symptoms. It may be associated with petechial hemorrhages in the skin or mucous membranes; this occurs in severe malaria only rarely.