Blood-stage malaria parasites are responsible for the clinical manifestations of infection. The incubation period (from sporozoite inoculation to symptoms) may be as short as a few days to a week (P. falciparum), as long as months (P. vivax, P. ovale), or even years (P. malariae). The average range, however, is between 8 and 20 days.9,10 Clinical manifestations may commence with a brief flu-like prodrome of headache and malaise, myalgias and arthralgias, mild diarrhea, and low-grade fever. This is typically followed by intermittent episodes of high fever, coincident with the release of merozoites from RBCs. Depending on the species, merozoite release occurs at fairly specific intervals. For P. falciparum, P. vivax and P. ovale, this typically occurs every 48 hours and for P. malariae, every 72 hours. However, in practice, temperature spikes may be irregular, and may not necessarily be diagnostic of any particular species. This clinical syndrome of mild-to-moderate symptoms without signs of severity or vital organ dysfunction is termed uncomplicated malaria.11 This is how most children who have acquired malaria elsewhere will present in clinics in the Western world. However, without prompt and/or appropriate treatment at this point, the risk of complications may rise, and the child may develop severe disease (see P. falciparum in section “Species Variation” and also see section “Other Complications”).
A child with uncomplicated malaria will present as one with an acute febrile illness, often with no localizing signs. Most of the time, there will be history of recent travel to an endemic area, although there are rare reports of local US transmission.4 Ninety-eight percent of US returned travelers with P. falciparum malaria experience their first symptoms within 3 months of arrival.4 They most likely will present with or will have a history of fever, and may have associated chills, headache, cough, tachypnea, nausea, vomiting, diarrhea, anorexia, or fatigue/weakness. Vital signs may show tachypnea and/or tachycardia (caused by fever and/or anemia), blood pressure is usually normal. Rarely, hypotension is seen with malaria (“algid malaria”). In many cases, this may be caused by concurrent bacteremia and sepsis.10 Jaundice is not typical in young children,12 but if present, may reflect an underlying hematologic disorder such as sickle cell disease, thalassemia, or glucose-6-phosphate dehydrogenase (G6PD) deficiency. Jaundice is also seen in more severe disease. Splenomegaly and/or hepatomegaly may be present, depending on the duration or severity of illness. Skin examination may reveal pallor, especially in the palms, soles, and conjunctivae of dark-skinned children. Skin rashes are not typically present in malaria manifestations.
The majority of children with uncomplicated malaria (no signs of severe disease or vital organ dysfunction) will respond to oral antimalarial chemotherapy, but for reasons that are not entirely clear, a proportion may progress to severe/complicated malaria.10 Neurologically, the child may have had or may be having seizures, but hypoglycemia and dehydration should be ruled out before a diagnosis of cerebral malaria is entertained (see P. falciparum in section “Species Variation”). If cerebral malaria is also ruled out, a diagnosis of febrile seizures should be considered. Seizures are common in children with malaria who are admitted to hospitals in developing countries, but they are generally not associated with significantly increased mortality or other adverse outcomes in the absence of impaired consciousness.13Table 66–1 lists the signs and symptoms of malaria in children.
Table 66–1. Signs and Symptoms Associated with Malaria in Children ||Download (.pdf)
Table 66–1. Signs and Symptoms Associated with Malaria in Children
Infants/children younger than 5 y
P. falciparum produces the most severe forms of malarial infection. Severe malaria in children in endemic areas depends on age and level of transmission. In these regions, infection and clinical symptoms in infants younger than 6 months are rare and/or mild, possibly as a result of passive immunity from transferred maternal antibodies. Children in endemic areas of high transmission are generally susceptible to severe disease between 6 months and 6 years of age13–15; in low transmission areas, the incidence of severe disease may continue to young adulthood and beyond.15,16
Severe malaria may manifest as one or all of three overlapping syndromes: cerebral malaria, severe malarial anemia, and respiratory distress.12,17P. falciparum is responsible for the overwhelming majority of severe malaria cases. Unlike the other three species, P. falciparum infects RBCs of all ages, resulting in higher levels of parasitemia, severe anemia, and poorer prognosis. In contrast, P. vivax and P. ovale infect young RBCs, and P. malariae infects more mature RBCs.
P. falciparum is the only human species that causes cerebral malaria, a serious complication of infection that has significant morbidity and mortality (Figure 66–3). The World Health Organization defines cerebral malaria as the presence of P. falciparum asexual parasitemia and coma, with no other cause of coma identified.12 The peak incidence of CM by age varies according to transmission level and geographic area, with younger children (age 1–10 years) typically affected in sub-Saharan Africa14,15,18 and other children and young adults often affected in southeast Asia and Papua New Guinea.10,12 Mortality from cerebral malaria is estimated at between 15% and 40% in endemic areas.19,20 Ten to twenty percent of cerebral malaria survivors will suffer acute neurological sequelae such as ataxia, hemiparesis, and cortical blindness, most of which resolve over time.20–22 A significant proportion may have seizures/epilepsy, and >20% show long-term cognitive impairment after cerebral malaria.23 The histopathological hallmark of cerebral malaria is the engorgement of cerebral blood microvessels with parasitized and nonparasitized RBCs.16,18 This results in mechanical obstruction and presumably cerebral hypoxia. In addition, the presence of parasite antigens triggers cytokine production, particularly IFN-γ and TNF-α.14 In relatively lower concentrations, TNF-α and IFN-γ inhibit growth of malaria parasites, however, excessive production of these proinflammatory cytokines may be deleterious to the host.7,8,24 Proinflammatory cytokine excess may worsen hypoxia and hypoglycemia, and promote sequestration,18,24 thereby contributing to the development and progression of cerebral malaria.
(A) Gambian child with cerebral malaria (note severe extensor posturing); (B) Dysconjugate gaze in comatose Gambian child with cerebral malaria. (With permission from the World Health Organization.)
A child with cerebral malaria will present with a febrile illness and coma while living in or after traveling to an endemic area. They may have anorexia and vomiting, and neurologically may exhibit seizures, coma, and/or brainstem abnormalities.16 Duration of symptoms preceding the coma may be brief, typically 1 or 2 days. The Blantyre Coma Scale (Table 66–2) is a modified form of the Glasgow Coma Scale that was developed to objectively assess neurological status in children younger than 5 years. A Blantyre coma score of less than 3 denotes a state of unarousable coma and is required for a diagnosis of cerebral malaria.10,12 Once coma is confirmed, and there is evidence of asexual forms of P. falciparum on blood smear (Figure 66–4), antimalarial and supportive treatment should not be delayed. Obtaining a lumbar puncture for cerebrospinal fluid (CSF) analysis will depend on how stable the patient is for the procedure. Unless there are signs of increased intracranial pressure, indicating that a lumbar puncture is unsafe, CSF should be obtained to rule out meningitis or encephalitis as a cause of coma. If there are signs of increased intracranial pressure, lumbar puncture should be deferred, and consideration given to empiric therapy for meningitis until CSF can be obtained. Children with cerebral malaria should have normal CSF values (<5 leukocytes/μL, no erythrocytes, normal protein and glucose level).10,25 However, patients with hypoglycemia may have low or undetectable glucose levels in the CSF. Plasmodium forms are not seen on CSF staining, since these organisms sequester in the cerebral microvasculature. If the CSF examination points to another diagnosis, such as bacterial meningitis, further investigation and appropriate management should be initiated. A number of children present with P. falciparum parasitemia and impaired consciousness, but do not meet the strict definition of cerebral malaria (P. falciparum parasitemia plus coma). These children have increased mortality,13 and likely have a slightly less severe manifestation of the same pathophysiologic process as children with cerebral malaria. They should be evaluated and treated in the same way as children with strictly defined cerebral malaria.
Table 66–2. The Blantyre Coma Scale for Children* ||Download (.pdf)
Table 66–2. The Blantyre Coma Scale for Children*
A. Best motor response
Nonspecific or no response
Withdraws limb from pain
Localizes painful stimulus
B. Best verbal response
Moan or inappropriate cry
C. Eye movements
Does not follow a moving object
Does follow a moving object
(A) Giemsa-stained thin blood smear showing P. falciparum ring trophozoites (note that some RBCs are multiply infected); (B) Typical “banana”-shaped P. falciparum gametocyte on thin blood smear. (With permission from the Centers for Disease Control and Prevention.)
Severe malarial anemia is defined as P. falciparum asexual parasitemia associated with a hemoglobin concentration of <5 g/dL or a hematocrit of <15%.12 Severe malarial anemia affects many more children than cerebral malaria; however, the mortality rate of severe malarial anemia is much lower than that of cerebral malaria. The peak incidence of severe malarial anemia is in children younger than 3 years.17 The severity of anemia roughly correlates with the level of parasitemia, but there is great individual variation. Children with severe malarial anemia may develop respiratory distress as a result of metabolic acidosis from reduced oxygen-carrying capacity and supply. Severe malarial anemia may occur alone or in combination with other complications of falciparum malaria. The presence of severe anemia in association with P. falciparum parasitemia does not necessarily mean that the latter is the only cause of the former. Particularly in children at risk, or in developing countries, other causes for anemia, such as nutritional/vitamin deficiencies, should be ruled out if possible.
Respiratory distress is more common in children than adults, and is usually secondary to metabolic acidosis from poor perfusion rather than to pulmonary edema.10,12,25 Children may be tachypneic or have a low respiratory rate. If they have severe metabolic acidosis, they may exhibit Kussmaul's respirations. Respiratory distress is a poor prognostic sign of severe malaria in children,26,27 and the acid/base status and volume status of all children with respiratory distress should be evaluated immediately. Since children with pneumonia may present similarly, correlations should be made with clinical presentation and appropriate lab tests (including chest radiograph) in order to arrive at a correct diagnosis.
P. vivax (Figure 66–5) is a relatively infrequent cause of mortality, altough in some areas of Oceania, mortality from P. vivax rivals that from P. falciparum.28–30 It is a major cause of morbidity in areas where it is common (Indian subcontinent, southeast Asia, Oceania, South America). It is one of two human Plasmodium strains (the other being P. ovale) responsible for “relapsing” malaria infection. After liver invasion, P. vivax sporozoites may develop into either tissue schizonts or hypnozoites, which are responsible for clinical relapses. The hypnozoites remain dormant in the liver while tissue schizonts develop and continue the cycle, mounting a primary attack. The P vivax asexual blood stage cycle is typically “tertian,” that is, merozoite release from RBCs occurs every 48 hours, or every third day (the first day is counted as day one). After a certain period, typically within weeks to months of the initial attack, the latent hypnozoites activate, develop into tissue schizonts, and reestablish the blood stage cycle, causing clinical symptoms. It is imperative, therefore, that any patient diagnosed with P. ovale or P. vivax infection be treated not only for the initial attack, but also for the hypnozoites that lie dormant in the liver.
Large, ameboid trophozoite of P. vivax on thin blood smear (note the fine stippling caused by Schuffner's dots, and enlargement and distortion of the RBC). (With permission from Dr. Jon Rosenblatt, Mayo Clinic Laboratories.)
P. ovale infection occurs in West Africa, the Phillipines, Indonesia, and Papua New Guinea. The clinical course and fever pattern for P. ovale is similar to that of P. vivax infection; however, clinical symptoms are milder, and there is less likelihood of relapse.10
P. malariae infection (Figure 66–6) has patchy distribution in tropical and subtropical regions worldwide. In comparison to the other three human Plasmodium species, it exhibits slow development in both the human and mosquito hosts. Infection with P. malariae is the mildest but also the most chronic, and may persist in the human host for many years. It appears that this chronicity is not caused by hypnozoites, but rather, recrudescence of the initial attack from small numbers of blood stage forms that have persisted in internal organs.10 As such, patients can present with P. malariae-related illness long after they have left endemic areas where they first acquired the infection. Even though P. malariae infection is generally mild, it can cause a chronic nephrotic syndrome which has a poor prognosis.6,10
(A) Characteristic “band” trophozoite of P. malariae on thin blood smear (note intact shape and size of the RBC); (B)P. malariae schizont. (With permission from the Centers for Disease Control and Prevention.)
There is now evidence that P. knowlesi, a Plasmodium species that usually infects monkeys, has crossed over to cause malaria in humans in southeast Asia, notably in Malaysia31. P. knowlesi is now considered a fifth human malaria species. It is not clear at this point if P. knowlesi preferentially infects a subset of red cells, but it multiplies rapidly and can cause very high levels of parasitemia. Morphologically, it can be confused with P. malariae on microscopic examination.
P. knowlesi malaria, because of its rapid life cycle, can cause high level parasitemia, severe seizures and rapidly lead to death32. Since P. knowlesi can be mistaken for P. malariae on microscopy, it should be considered in any severely ill patient with malaria acquired in southeast Asia, particularly in patients who are thought to have P. malariae infection on microscopy but have high-level parasitemia, as high-level parasitemia with P. malariae infection is unusual. PCR testing at a reference lab is currently the only way to identify P. knowlesi infection. Cloroquine plus sulfadoxine-pyrimethamine should be used to treat P. knowlesi infections31,32; quinine is an alternative in severely ill patients.
It is not uncommon for patients to present with concurrent infections from two or more Plasmodium species. Mixed infections are common in endemic malarious areas. The most common types of mixed infections are P. falciparum/P. vivax in subtropical regions, and P. falciparum/P. malariae in tropical Africa,10 however, P. falciparum/P. ovale is particularly common in West Africa.
Additional complications, generally caused by P. falciparum, are listed below; other species will be mentioned, if they are more likely to cause a particular complication.
Seizures are quite common in children with mild or severe malaria, and children are more likely than adults to have seizures with malarial infection.12,18 Fifty to eighty percent of children with cerebral malaria have seizures.10,12 In a recent study, close to 40% of all children admitted with malaria in a malaria endemic area experienced seizures.13 However, in children with malaria, seizures may also occur as a result of profound hypoglycemia, dehydration, or fever, and may be generalized, focal, single, or multiple in nature.12
Children are more likely than adults to develop hypoglycemia. It is especially common in children younger than 3 years, those with seizures, high levels of parasitemia, or in deep coma.12 The manifestations of hypoglycemia are similar to those of cerebral malaria, and it is critically important to treat the former as soon as possible in order to establish or rule out cerebral malaria. In some cases, treatment of hypoglycemia reverses neurological symptoms that may have been ascribed to cerebral malaria. Note that quinine can induce or worsen hypoglycemia, so blood glucose levels should be closely monitored during its use.
Acute renal failure is more common in older children and adults, and is characterized by elevated serum creatinine and blood urea, and oliguria or anuria caused by acute tubular necrosis.12,33,34 The incidence of acute renal failure in falciparum malaria is between 1% and 4%; it may reach up to 60% in patients with severe malaria.32 It is usually reversible with appropriate treatment. Blackwater fever is a rarer form of acute renal failure associated with P. falciparum malaria, and results from severe intravascular hemolysis and hemoglobinuria.33 Patients present with flank pain, vomiting, severe anemia and oliguria with passage of dark, cola-colored urine, hence the name “blackwater.” G6PD deficiency should be excluded in patients with hemoglobinuria, since antimalarial and other oxidant drugs (notably primaquine) can trigger hemolysis in such individuals, even without malarial infection.12
Hyperreactive Malarial Splenomegaly
Also known as tropical splenomegaly syndrome, hyperreactive malarial splenomegaly (HMS) is defined as gross splenomegaly (>10 cm below the costal margin) in a long-term resident of a malarious area, presence of antimalarial antibodies, elevated serum IgM, and clinical and immunological response to antimalarial treatment.35,36 HMS occurs in areas of intense malaria transmission, and is more common in young and middle-aged adults.36,37 Although the exact mechanism is unclear, there is thought to be an exaggerated polyclonal B lymphocyte stimulation in response to chronic and repeated exposure to any of the 4 human malaria parasites.10,36,37 As a result, high levels of antimalarial antibodies are produced, and there is accompanying immune complex deposition in the liver and spleen. Patients present with a grossly enlarged spleen, often with hepatomegaly, abdominal pain, anemia, cachexia, and hypersplenism (normochromic, normocytic anemia, thrombocytopenia, leucopenia, and reticulocytosis).36–38 There may be no evidence for acute malarial infection on blood smear. In some cases, patients develop massive hemolysis and/or overwhelming infection, which increases mortality. The backbone of treatment is long-term administration of chloroquine, proguanil, or sulfadoxine-pyrimethamine,35,36 with most patients achieving significant reduction in spleen size. In general, chloroquine has been the drug of choice; repeated treatment with sulfadoxine-pyrimethamine is generally avoided because of the increased risk of Stevens-Johnson syndrome with prolonged therapy. The treatment course is several months to up to a year, or until splenomegaly has adequately improved.
Congenital Malaria Infection
As with other infectious diseases such as rubella, cytomegalovirus, and varicella, malaria can be transmitted transplacentally to the developing fetus from the mother. In endemic areas, up to 1 in 4 babies born to infected mothers are parasitemic, but many of these children are asymptomatic and clear parasitemia without treatment.39P. falciparum and P. vivax are most often implicated in pregnancy-related and congenital malaria. Malaria may cause or exacerbate maternal anemia, which may lead to placental insufficiency. As a result, infants with congenital malaria can also present with low birth weight because of intrauterine growth retardation.12 Symptomatic infants usually present at 2–8 weeks of life, and may have fever, poor oral intake, lethargy, anemia, and hepatosplenomegaly.12,39 Cerebral malaria, and the organ dysfunction of severe malaria is rare in infants.12,16