Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children

INTRODUCTION — The clinical manifestations of malaria vary with parasite species, epidemiology, immunity, and age.

Issues related to clinical manifestations and diagnosis of malaria will be reviewed here. Technical aspects of laboratory tools for diagnosis of malaria are discussed further separately.

The epidemiology, pathogenesis, diagnosis, and treatment of malaria are discussed separately:

●(See "Malaria: Epidemiology, prevention, and control".)

●(See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

●(See "Treatment of severe malaria".)

●(See "Malaria in pregnancy: Prevention and treatment".)

●(See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

●(See "Non-falciparum malaria: Plasmodium knowlesi".)

RISK GROUPS — 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]. For this reason, it is important to consider malaria in all febrile patients with history of travel to malarious areas.

INCUBATION PERIOD — 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. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

Two primate malarias, Plasmodium knowlesi and Plasmodium simium, have been shown to infect humans in Southeast Asia and Brazil, respectively; P. knowlesi resembles P. malariae, and P. simium resembles P. vivax (via microscopy and polymerase chain reaction) [9]. There is an expanding number of Plasmodium species that typically infect nonhuman primates but could cross over to humans; however, whether they are a source of human disease is debated.

CLINICAL MANIFESTATIONS

Uncomplicated malaria

●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).

•Signs and symptoms − Malaria should be suspected in patients with febrile illness who have had exposure to a region where malaria is endemic [1,2,7]. 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. (See 'Cerebral malaria' below and "Clinical features and evaluation of febrile seizures".)

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]. (See 'Concomitant infection' below.)

•Physical findings − Physical findings may include manifestations of anemia (lethargy, pallor) and a palpable spleen in some cases; splenic enlargement supports the diagnosis if present but may also reflect other conditions. In endemic areas, anemia is common among young children and is often due to multiple causes in addition to malaria (including iron and other nutritional deficiencies as well as helminth infection) [12]. Mild jaundice may develop in patients with otherwise uncomplicated falciparum malaria. (See "Anemia in malaria".)

•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.

●Other species − Uncomplicated malaria can occur with other Plasmodium species as well. It is often not possible to determine the species of malaria infection on clinical grounds alone; there are some unique characteristics associated with each species. P. vivax, P. ovale, P. malariae, and P. knowlesi are discussed in detail separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae" and "Non-falciparum malaria: Plasmodium knowlesi".)

Severe malaria — 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). (See "Non-falciparum malaria: Plasmodium knowlesi".)

General principles — Manifestations of severe malaria are summarized in the table (table 2) [13,14].

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].

The clinical manifestations of severe malaria vary with age and geography. In areas where malaria is endemic, young children (ages two to five years) are at high risk for severe malaria, as are pregnant individuals. Older children and adults develop partial immunity to febrile malaria episodes (but not to malaria infection) after repeated infection and thus are at lower risk for severe disease [20]. Travelers to areas where malaria is endemic with no previous exposure to malaria parasites are at higher risk for progression to severe disease if infected with P. falciparum [21]. (See 'Children versus adults' below.)

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]. Those at greatest risk for severe disease include nonimmune individuals, immunocompromised patients (including asplenic individuals), children 6 to 59 months of age, and pregnant individuals [7,23]. 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. (See "Laboratory tools for diagnosis of malaria".)

Manifestations of severe malaria can portend a grave prognosis; such patients should receive a prompt and thorough evaluation and immediate treatment [24,25]. (See "Treatment of severe malaria".)

Cerebral malaria

●Definition − 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 − 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.

●Lumbar puncture findings − 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.

In one study comparing CSF findings from 12 children with cerebral malaria and 14 children with presumed viral encephalitis, lower white cell count, glucose, and protein levels were observed among patients with cerebral malaria [32]. Children with malaria had mean white cell count of 0 cells/microL (range 0 to 4 cells/microL); children with viral encephalitis had mean white cell count of 4 cells/microL (range 0 to 9 cells/microL). A CSF glucose concentration below 3.4 mmol/L (61 mg/dL) was the best discriminator of cerebral malaria from presumed viral encephalitis.

●Retinopathy − 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 − 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].

●Sequelae − 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 — Hypoglycemia is a common complication of severe malaria, although the usual signs (sweating, tachycardia, neurologic impairment) are difficult to distinguish from systemic symptoms due to severe malaria. 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 — 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.

Renal impairment — Renal impairment is common among adults with severe falciparum malaria. Historically, renal involvement has not been considered to be a major component of pediatric severe malaria. However, over the past decade, improved estimates of glomerular filtration rate and creatinine measurement have demonstrated the importance of considering renal impairment in children [40,41]. The frequency of estimated acute kidney injury (AKI) in pediatric severe malaria ranges from 24 to 59 percent [42]. Patients with AKI are at increased risk for mortality [41], chronic kidney disease [43], and postdischarge behavioral problems [44].

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 — 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. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Children with severe anemia may present with deep, labored respirations. This is usually due to metabolic acidosis (often compounded by hypovolemia).

Hematologic abnormalities — 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).

Children in endemic areas with serial episodes of malaria infection may develop severe chronic anemia. In nonimmune individuals and in areas with unstable transmission, anemia can develop acutely. 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. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Liver dysfunction — 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. Liver dysfunction together with renal impairment and other organ dysfunction portend a poor prognosis [7].

Concomitant infection — There appears to be a biological association between malaria, human immunodeficiency virus (HIV), malnutrition, and invasive bacterial infections. These conditions occur often in malarious areas, as do geohelminths; the latter contribute greatly to anemia and malnutrition, especially in children [12,48].

Bacterial infection — Septicemia may complicate severe malaria, particularly in children [48]. In endemic areas, Salmonella bacteremia has been associated with P. falciparum infections [49]. Chest infections and catheter-induced urinary tract infections are common among patients who are unconscious for ≥3 days. Aspiration pneumonia may follow generalized seizures.

HIV infection — HIV and malaria often coexist. HIV infection is associated with increased susceptibility to malaria, higher parasitemia, and increased risk for recurrent malaria infection, particularly in patients with CD4 counts <200 cells/microL [50]. HIV and malaria independently lead to anemia. Coinfection may be associated with anemia of greater severity among children P. falciparum infection in children [51]. In addition, malaria infection in patients with HIV infection has been associated with more rapid CD4 cell decline relative to patients with HIV infection in the absence of malaria [52].

In some circumstances malaria infection has been associated with a transient increase in HIV viral load; however, this does not appear to hasten progression to acquired immunodeficiency syndrome (AIDS) [53-57].

Children versus adults — Clinical manifestations of malaria vary between children and adults [58]. Seizures and severe anemia are more common in children, whereas hyperparasitemia, ARDS, and jaundice are more common in adults [58]. Cerebral malaria (with coma), shock, acidosis, renal impairment, and respiratory arrest may occur at any age [58].

It can be difficult to distinguish congenital malaria infection from malaria infection acquired as a newborn. Among infants with congenital malaria, onset of clinical manifestations usually occurs at two to eight weeks of age; signs and symptoms include poor feeding, fever, vomiting, diarrhea, and irritability. Anemia, thrombocytopenia, and hyperbilirubinemia are common [59]. Splenomegaly is more common than hepatomegaly. Issues related to vertical transmission of malaria are discussed separately. (See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome", section on 'Vertical transmission'.)

Recurrent malaria infection — 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. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Preventing relapse'.)

DIAGNOSIS — Uncomplicated falciparum malaria consists of symptomatic P. falciparum infection with a positive parasitologic test, in the absence of symptoms consistent with severe malaria (table 2). Severe malaria is defined as presence of P. falciparum parasitemia and one or more of the manifestations in the table (table 2). (See 'Severe malaria' above.)

Malaria should be suspected in the setting of fever (temperature ≥37.5°C) and relevant epidemiologic exposure (residence in or travel to an area where malaria is endemic). In nonimmune individuals, most infections due to P. falciparum become clinically apparent within one month after exposure [13]. In endemic areas with stable transmission and for areas with seasonal malaria during high-transmission season, malaria should also be suspected in children with palmar pallor or hemoglobin concentration <8 g/dL.

The diagnosis of malaria is definitively established in the setting of symptoms consistent with malaria and a positive malaria diagnostic test; diagnostic tools include light microscopy of blood smears and rapid diagnostic tests. For patients with suspected malaria, definitive diagnosis should be established [13]. 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]. (See "Laboratory tools for diagnosis of malaria", section on 'General principles'.)

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 sub-Saharan Africa (where the burden of malaria is greatest), a definitive diagnosis of malaria among patients with fever is established in less than half of cases [68-70]. One systemic review and meta-analysis including 21 studies (14 studies of endemic malaria and 7 studies of imported malaria) assessed the predictive value of clinical findings for diagnosis of malaria [71]. 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]). 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).

Individuals with acquired partial immunity due to repeated exposures in endemic settings may have asymptomatic parasitemia. There is no diagnostic test capable of distinguishing between parasitemia causing clinical malaria and febrile illness due to another cause in a patient who also has asymptomatic parasitemia. (See 'Differential diagnosis' below.)

Diagnostic tools include light microscopy and rapid diagnostic tests. Detailed discussion regarding these tools is presented separately. (See "Laboratory tools for diagnosis of malaria".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of malaria is broad due to the nonspecific nature of symptoms, physical findings, and laboratory parameters (excluding parasitemia). In nonimmune populations (including travelers to endemic areas), a single diagnosis is likely; however, in immune or partially immune populations (including individuals residing in endemic areas), it is important to consider concomitant infections.

The broad differential diagnosis includes:

●Dengue fever – 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 – Chikungunya resembles dengue but is milder and self-limiting, often with a rash. The diagnosis is established via serology. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

●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). The diagnosis of bacterial meningitis is established via lumbar puncture and culture. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

●Pneumonia – Clinical manifestations of pneumonia include fever, cough, dyspnea, and sputum production. Patients with pneumonia may have intercostal retractions and other signs of labored breathing. The diagnosis is of pneumonia established via chest radiography and sputum culture. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Community-acquired pneumonia in children: Clinical features and diagnosis".)

●Sepsis due to bacteremia – Sepsis due to bacteremia may present with fever, tachycardia, and altered mental status; diagnosis requires blood culture.

●Typhoid fever – Clinical manifestations of typhoid fever include fever, bradycardia, abdominal pain, and rash. The diagnosis is established by stool and/or blood culture. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

●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. The diagnosis is established by serologic testing. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●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. The diagnosis is established by immunoassay or nucleic acid testing. (See "Clinical manifestations and diagnosis of Ebola virus disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)

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Basics topic (see "Patient education: Malaria (The Basics)")

SUMMARY

●Risk groups – (See 'Risk groups' above.)

•Individuals in endemic areas

-In areas where malaria is endemic, groups at high risk for severe malaria and its consequences include young children (6 months to 5 years of age) and pregnant individuals. Older children and adults develop partial immunity after repeated infection and are at relatively low risk for severe disease.

-As disease incidence wanes, older age groups become more susceptible due to decreasing immunity. In addition, as areas within endemic regions (such as urban centers) reduce or eliminate transmission, residents in those areas are at increased risk when they travel to endemic areas within their own countries.

•Travelers – Travelers to areas where malaria is endemic, including individuals from nonendemic areas and individuals who have been away from endemic areas, are at very high risk for severe disease if infected with Plasmodium falciparum. (See 'Risk groups' above.)

●Incubation period – The incubation period for P. falciparum infection is usually 12 to 14 days (range 7 to 30 days). Longer incubation periods are more likely in semi-immune individuals and individuals taking inadequate malaria prophylaxis at the time of infection. The relapsing malarias (Plasmodium vivax and Plasmodium ovale) can cause clinical illness several weeks or months after the initial infection due to presence of hypnozoites in the liver. (See 'Incubation period' above.)

●Clinical manifestations – Malaria should be suspected in the setting of fever (temperature ≥37.5°C) and relevant epidemiologic exposure (residence in or travel to an area where malaria is endemic).

•Uncomplicated malaria – Uncomplicated falciparum malaria consists of symptomatic infection due to P. falciparum (established via a positive parasitologic test) in a patient who can swallow medicines, in the absence of symptoms and signs consistent with severe malaria (table 2).

•Severe malaria – Severe malaria is defined as presence of P. falciparum parasitemia and one or more of the manifestations in the table (table 2). General principles regarding diagnosis of malaria are discussed above.

•Children versus adults – Common manifestations among children with severe malaria include convulsions, coma, hypoglycemia, metabolic acidosis, severe anemia, and neurodevelopmental sequelae. Findings observed more frequently among adults than children include severe jaundice, acute respiratory distress syndrome, and acute pulmonary edema. (See 'Children versus adults' above.)

●Diagnosis – (See 'Diagnosis' above.)

•Definitive diagnosis – A definitive diagnosis of malaria is established in the setting of symptoms consistent with malaria and a positive malaria diagnostic test; diagnostic tools include light microscopy and rapid diagnostic tests. For patients with suspected malaria, definitive diagnosis should be established whenever possible. (See 'Clinical manifestations' above.)

•Presumptive diagnosis – 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.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joel Breman, MD, DTPH, who contributed to earlier versions of this topic review.