Malaria

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INFECTIONS OF THE BLOOD AND RETICULOENDOTHELIAL SYSTEM

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Malaria Terrie Taylor, Tsiri Agbenyega

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The clinical presentation of uncomplicated malaria is a nonspecific, undifferentiated febrile illness. It is not possible to confirm or exclude the diagnosis of malaria based on clinical presentation alone Malaria infection in non-immune individuals is a medical emergency Malaria infection is not synonymous with malaria illness, particularly in malaria-endemic areas where older children and adults have acquired immunity to malaria disease and are commonly found with asymptomatic parasitemias The diagnosis of malaria should be parasitologically confirmed by the microscopic visualization of parasites on a peripheral blood smear or detecting parasite antigen with a rapid diagnostic test (RDT) Repeating smears every 12 hours for 36–48 hours if initial smears are negative is warranted in non-immune individuals who are at risk. It not necessary to time smears with elevations in temperature to make a parasitologic diagnosis Patients who are unable to take anti-malarial medication by mouth require parenteral therapy – a loading dose is essential When possible, decisions regarding the use of anti-malarial medications should be based on parasitologic evidence (blood film or malaria RDT)

INTRODUCTION Malaria is an ancient and enduring scourge of mankind with a rich and fascinating history [1]. About 3 billion people – nearly half of the world’s population – are at risk of malaria infection and illness. Every year, this leads to about 250 million malaria cases and nearly 1 million malaria deaths. Malaria has shaped the human genome, complicated major military campaigns, eluded pharmacologic attacks, adversely affected international economic indicators and frustrated generations of clinicians, scientists and policy makers. Malaria is an acute and chronic disease caused by obligate intracellular protozoa of the genus Plasmodium. Historically, four species of malaria parasites were considered capable of infecting humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae; however, recently, a fifth – Plasmodium knowlesi – has been recognized as a significant human pathogen [2]. The majority (56%) of malaria infections are in sub-Saharan Africa, followed by Southeast Asia (27%), the Eastern Mediterranean (12%) and South America (3%) [3]. The parasites are transmitted to humans by female Anopheles mosquitos. The clinical presentation is highly variable but

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is generally characterized by an undifferentiated febrile illness with headache, chills and rigors, anemia and splenomegaly. Plasmodium falciparum is the species most commonly associated with severe and complicated disease. Plasmodium vivax is the dominant species found outside of Africa; its distribution (the Middle East, Asia, the Western Pacific and Central and South America) complements that of P. ovale (primarily West Africa). Plasmodium malariae has a worldwide distribution, generally in isolated pockets, and, to date, P. knowlesi is restricted to South and Southeast Asia, primarily in areas harboring macaque monkeys (Fig. 96.1). In sub-Saharan Africa, nearly all of the malaria-associated morbidity and mortality is caused by P. falciparum. Individuals of all ages remain susceptible to infection, but immunity to severe disease develops over time, the result of repeated exposure to bites from infected anopheline mosquitoes. Anti-disease immunity is related to transmission intensity, but its specific characteristics and determinants are not well understood. Non-immune individuals – typically young children in sub-Saharan Africa, but tourists and soldiers in other malaria-endemic areas are included in this category – are at risk of developing severe and complicated malaria. Semi-immune people can be infected (i.e. parasitemic) but asymptomatic; when semi-immune people do develop a malaria illness, it is generally marked by fever and malaise and rarely becomes life-threatening. There is a broad geographic overlap between the distributions of HIV and malaria, especially falciparum malaria. Co-infection is associated with a transient increase in HIV RNA [4]. HIV-infected individuals, particularly those with CD4 counts <200 cells/µl, are more susceptible to malaria infection and have higher parasitemias [5]. Data on whether HIV serostatus has any impact on malaria disease severity are conflicting. Contemporary efforts to address the multiple challenges of malaria control, prevention and, perhaps, elimination (reduction to zero of malaria infection in a defined geographic area) or eradication (permanent extinction of malaria transmission throughout the world) include using combination chemotherapy exclusively (to slow the development and spread of drug resistant parasites), attempting to develop a malaria vaccine and scaling-up interventions which are known to be effective (e.g. long-lasting insecticide-treated bed nets, indoor residual spraying of insecticide).

EPIDEMIOLOGY TRANSMISSION The epidemiology of malaria is fundamentally determined by the dynamics and intensity of parasite transmission. Vector abundance and longevity are major contributors to transmission rates and these are strongly influenced by temperature, rainfall and humidity. The most direct measure of transmission intensity is the entomologic inoculation rate (EIR) – the number of infectious female anopheline bites per person per year. In general, EIRs of <10/year are considered “low transmission”, 10–49/year “intermediate transmission” and

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Stable, PfAPI > 0.1 per thousand pa

Unstable, PfAPI < 0.1 per thousand pa

Stable, PfAPI > 0.1 per thousand pa

Unstable, PfAPI < 0.1 per thousand pa

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FIGURE 96.1 P. falciparum malaria risk defined by annual parasite incidence (top) and temperature and aridity (bottom). Areas were defined as stable (dark blue areas, where PfAPI ≥0.1 per thousand pa), unstable (light blue, where PfAPI <0.1 per thousand pa), or no risk (no color). The few areas for which no PfAPI data could be obtained, mainly found in India, are not colored. The borders of the 87 countries defined as P. falciparum endemic are shown. The aridity mask excluded risk in a step-wise fashion, reflected mainly in the larger areas of unstable (light blue) areas compared to the top panel, particularly in the Sahel and southwest Asia (southern Iran and Pakistan). Reproduced from Guerra CA, Gikandi PW, Tatem AJ, et al. The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med 2008;5(2):e38.

> 50/year “high transmission”. For clinicians working in settings where data on EIRs are not readily available, surrogate measures include the spleen rate and parasite prevalence rates in children (Box 96.1). Transmission dynamics are regarded as stable when transmission is constant throughout the year, or predictably seasonal. Unstable transmission (characteristic of epidemics) occurs when there are changes in the environment (e.g. sudden, heavy rains) or in the population (e.g. migration). Malaria transmission is also influenced by climate. The optimal conditions occur when the temperature is between 20°C and 30°C and the mean relative humidity is at least 60%. Sporogony does not occur at temperatures below 16°C or higher than 33°C. Water temperatures regulate the duration of the aquatic cycle of the mosquito vector. A high relative humidity increases mosquito longevity and therefore increases the probability that an infected mosquito will survive long enough to become infective. The proximity of human habitation to breeding sites directly influences vector-human contact and, therefore, transmission. The stability of breeding sites is influenced by water supply, soil and vegetation.

Irrigation schemes, dams and other man-made changes affecting land use can radically alter stable patterns of malaria transmission.

ACQUIRED IMMUNITY The incidence and prevalence of malaria illness is determined largely by acquired immunity. The burden of disease and death is borne by non-immune individuals. In areas of stable transmission (e.g. most of sub-Saharan Africa), young children are the non-immune individuals at risk of life-threatening malaria. Older children and adults are “semi-immune”; their malaria infections may be asymptomatic or they may develop uncomplicated malaria illnesses. Attributing a cause-and-effect relationship between parasites and the often nonspecific symptoms of an uncomplicated malaria illness in semi-immune patients is difficult and bedevils the diagnosis of a “malaria illness” in this group (see “Interpreting the results of malaria diagnostic tests” below). Where transmission is unstable, there is little acquired immunity and individuals from all age groups can develop severe disease. Whether

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BOX 96.1  Useful Malaria Vocabulary Pre-patent period: the time from inoculation of sporozoites from mosquitoes until asexual erythrocytic stage parasites are detected by microscopy in the bloodstream. This measure can be influenced by the parasite detection technique (PCR > rapid diagnostic tests > microscopy). l Incubation period: the time from inoculation of sporozoites from mosquitoes until an individual develops clinical signs or symptoms of malaria – this is always longer than the prepatent period, but the time difference is determined by immune status. Non-immune individuals develop symptoms with low parasitemias, so the incubation period is shorter than in semi-immune individuals, who may be able to tolerate significant parasitemias without becoming symptomatic. l Recurrence: repeat intra-erythrocytic infection causing malaria-associated symptoms. l Relapse: a recurrent infection caused by a new brood of blood-stage parasites emerging from hypnozoites in the liver (P. vivax, P. ovale). l Recrudescence: a recurrent infection caused by the growth of an undetectable blood stage infection (generally the result of drug resistance, unusual pharmacokinetics or an incomplete dose). It can also occur in immunocompromised individuals, most famously with P. malariae. l Re-infection: a recurrent infection caused by new exposure to infective mosquitoes, best differentiated from recrudescence by molecular methods. l Endemicities: this traditional measure has been based on different indicators over the years, and is most useful as a general l

acquired immunity can wax and wane with transmission intensity remains to be seen [6], but this will become increasingly important as malaria control efforts increase and expand.

INNATE IMMUNITY On a population level, several genetic polymorphisms and mutations conferring risk or protection have been identified; most involve mutations in the alpha or beta chain of hemoglobin (hemoglobinopathies), such as sickle cell anemia and trait, the thalassemias, hemoglobin C, red blood cell enzyme deficiencies, such as glucose 6 phosphate deficiency (G6PD), or mutations affecting the red cell exoskeleton, such as ovalocytosis. Individuals with sickle cell trait (HbAS) are less likely to develop severe malaria once infected than are individuals who are homozygous (HbAA). Practically speaking, information on genetic polymorphisms is rarely available quickly enough to be useful during an acute illness; it may be potentially useful when considering risks associated with travel to malariaendemic areas and it provides some insight into mechanisms of disease pathogenesis, susceptibility and protection.

NATURAL HISTORY, PATHOGENESIS, AND PATHOLOGY Malaria is usually transmitted during the bite of an infected female Anopheles mosquito or, more rarely, through the direct inoculation of infected red blood cells (i.e. congenital malaria, transfusion malaria and malaria from contaminated needles).

LIFECYCLE Infection begins when sporozoites in mosquito saliva enter the bloodstream and, within 30 minutes, have invaded hepatocytes (Fig 96.2).

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description of the relationship between parasite transmission and malaria disease in a given setting (Table 96-6). Stable malaria is present when natural transmission occurs over many years and there is a predictable incidence of illness and prevalence of infection. Transmission is generally high and epidemics are unlikely. Unstable malaria occurs in settings where transmission rates vary from year to year and population immunity is low. Epidemics are more likely in this setting. Autochthonous (indigenous) malaria is contracted locally. Secondary cases are those derived from imported cases and are referred to as introduced malaria. Induced malaria is acquired by blood transfusion, shared needles, intentional inoculation, or laboratory accident. Cryptic malaria cases are those that occur in isolation and are not associated with secondary cases. Imported malaria infections are associated with individuals returning from malaria-endemic areas. Increased international air travel has escalated the incidence of imported malaria (and other infectious diseases) to non-endemic areas. Tourists often travel during the incubation period and do not become ill until after they return home. Entomologic inoculation rate: sporozoite positive mosquito bites per unit time. Annual parasite incidence (API): number of new parasite confirmed cases per 1000 population. Spleen rate: proportion of individuals in a stated age range with enlarged spleens.

The duration of the asexual replication phase inside the hepatocytes varies from 11–12 days in P. falciparum, P. vivax and P. ovale, to 35 days in P. malariae (Table 96-1). The nucleus undergoes repeated division, resulting in the formation of thousands of uninucleate merozoites, each measuring 0.7–1.8 μm in diameter. The nucleus of the liver cell is displaced, but there is no inflammatory reaction in the surrounding liver tissue, and the host is asymptomatic. In P. falciparum and P. malariae infections, the liver tissue schizonts/ meronts rupture at about the same time and none persists in the liver. In contrast, P. vivax and P. ovale have two types of exoerythrocytic forms: a primary type develops and ruptures within 6–9 days; the secondary type – the hypnozoite – may remain dormant in the liver for weeks, months, or up to 5 years before developing, and causing relapses of erythrocytic infection unless the patient is treated with primaquine – a drug that targets this lifecycle stage. The pre-patent period for P. knowlesi in humans has not yet been determined. Most infected hepatocytes rupture when the schizont forms mature and the merozoites that are released into the circulation quickly attach to, and invade, red blood cells. Plasmodium falciparum and P. knowlesi are capable of invading erythro­ cytes of any age, but P. vivax and P. ovale selectively invade reticulocytes. Serial cycles of asexual replication take place in erythrocytes and, again, the duration varies with the species, ranging from 24 hours in P. knowlesi to 48 hours in P. falciparum, P. vivax and P. ovale, and 72 hours in P. malariae (Table 96-1). The youngest stages in the blood are small, rounded trophozoites, known as ring forms. As they grow, they become more irregular and ameboid. During development, the parasites consume hemoglobin leaving an iron-containing compound known as hematin or hemozoin as the product of digestion; it is visible in the cytoplasm of the parasite as dark granules. The schizont/meront stage begins when the

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Malaria Transfer of infected RBC by transfusion or shared needles from another person (without hepatic cycle)

Release merozoites after minimum of 5.5 days

Develop schizonts

Hepatic schizogony (some P. vivax or ovale, not falciparum or malariae, can remain dormant hypnozoites for several months up to 5 years) Only sporozoites enter liver cells

Sporozoites injected into human skin from infected female Anopheles mosquito salivary glands

Mature into schizonts Penetrate RBC to form ring trophozoites

Erythrocytic cycle

RBC release merozoites to cause: • Anemia • Splenomegaly • Fever • Nausea • Vomiting • Rigors • Headache • Coma

Macrogametocytes and microgametocytes are taken with blood meal by female Anopheles mosquito, develop gametes which fuse to form diploid zygote and ookinete

Ookinete

FIGURE 96.2 Malaria lifecycle.

parasite undergoes nuclear division and culminates in segmentation to form merozoites. In response to a variety of stimuli, some parasites undergo gametocytogenesis. When male and female gametes are ingested by a female anopheline taking a blood meal from a human host, the sexual replication phase of the malaria parasite ensues, starting in the mosquito mid-gut and ending in the salivary glands. The erythrocytic lifecycle continues until it is abrogated by effective chemotherapy or reined in by the host’s acquired immunity. The life cycle of P. falciparum differs from the other four human malaria parasites in one important respect: during the latter half of the intra-erythrocytic cycle, mature falciparum-infected red blood cells (schizonts) effectively disappear from the peripheral blood.

These late-stage parasites are very active metabolically, consuming up to 75 times more glucose than earlier ring stages and generating lactate as an end product. At this stage, the red cell surface is studded with “knobs” (proteins of parasite origin) and these mediate the cytoadherence of parasitized red cells to receptors on the luminal surface of endothelial cells. This leads to sequestration of the parasitized red cells in various organs (brain, gut, subcutaneous fat, cardiac muscle), particularly in capillaries and post-capillary venules, in such large numbers that blood flow is impaired [7] (Fig. 96.3). The “natural history” of malaria infection and illness is difficult to capture. In its early stages, a malaria illness is indistinguishable from other common causes of fever. In endemic areas, and for returning travelers, if malaria infections are identified as such and treated

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TABLE 96-1  Parasite Characteristics Characteristic

P. falciparum

P. vivax

P. malariae

P. ovale

P. knowlesi

Geographic distribution

Widespread

Widespread, but rare in West Africa

West Africa, Philippines, Indonesia, Papua New Guinea

Infrequent, localized areas

South Asia

Clinical disease

Can be severe

Generally mild, occasionally severe

Generally mild*

Generally mild

Generally mild, but can be severe

Pre-patent period (days)

11–12

11–12

33

11–12

Unknown

Incubation period (days)

13–14

13–14

35

13–14

Unknown

Exoerythrocyctic (liver) cycle (days)

5.5–7

6–8

9

12

16

Intra-erythrocytic cycle (hrs)

43–52

48

72

48

24

Sequestrationcytoadherence

Yes

No

No

No

No

Earliest appearance of gametocytes (days)

10

3

Unknown

Unknown

Unknown

Hypnozoite stage (i.e. potential for relapse from liver stage)

No

Yes

No

Yes

No

Age of red blood cell infected by the parasite

All ages

Reticulocytes

Reticulocytes

Older red cells

All ages

Peripheral parasitemia

High; multiply infected cells common

Low

Low

Low

May be high

Rarely seen in peripheral blood, 16–20 merozoites

20–24 merozoites – generally more than 12

4–16 merozoites – usually <12

6–12 merozoites – usually <12

8–16 merozoites – usually <12

Morphology (light microscope)   Rings   Trophozoites   Schizonts   Gametocytes

*Severe malaria in a patient thought to have P. malariae should raise the suspicion of P. knowlesi.

promptly with effective drugs, clinical progression is rare. If the initial symptoms are not attributed to malaria, “tertiary care” may not be sought until complications (commonly coma and convulsions) develop. Volunteers who are “challenged” with the bites of infected mosquitoes for research studies are provided with effective therapy at the first sign of infection and their natural history is truncated at that point. The mean incubation period (Box 96.1) is 8.9 days (range 7–14); the most commonly reported symptoms are fatigue, myalgias, arthralgias, headache, chills and nausea. The mean pre-patent period (Box 96.1) is slightly longer (10.5 days, range 9–14) and the appearance of peripheral parasitemia is associated with a mild, transient pancytopenia in most patients.

fevers are rarely as periodic as the erythrocytic cycles themselves, probably because parasite population dynamics within a host are not synchronous.

PATHOGENESIS

Hypoglycemia

Pathophysiologic changes in malaria are caused by a number of different parasite-derived stimuli involving many different organ systems. Blood-stage parasites are the main source of these various stimuli; exoerythrocytic stages, gametocytes and sporozoites do not induce pathophysiologic changes. Malaria pathogenesis and pathology are linked inextricably to stages in the lifecycle (Fig. 96.2).

Fever Schizont rupture is the likely source of the fevers associated with malaria, although the specific pyrogens have yet to be identified. The

Anemia Malarial anemia results largely from the hemolysis of infected red blood cells at the time of schizont rupture, accelerated immunemediated destruction of uninfected red blood cells, bone marrow suppression and dyserythropoiesis, despite appropriate concentrations of erythropoietin. Severe intravascular hemolysis, also known as blackwater fever and manifesting as hemoglobinuria, can precipitate acute renal failure. Because of its deleterious effects on the central nervous system (CNS), and because of the necessity for treatment with exogenous glucose, this is the most important of the biochemical aberrations described to date [8]. Hypoglycemia (usually defined as blood glucose concentrations <40 mg/dL or 2.2 mmol/L) can develop, prior to any antimalarial treatment, in up to 20% of children with severe P. falciparum malaria. Plasma insulin levels are low and gluconeogenic precursors and adrenal hormones are present in high concentrations in the blood, so parasite consumption of glucose and/or inadequate hepatic gluconeogenesis are the most likely etiologies for pretreatment of hypoglycemia. It is not possible to detect hypoglycemia on clinical

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FIGURE 96.3 Four human tissue autopsy samples demonstrating sequestration and other pathologies in cerebral malaria. (A) The brain: several of the classic features can be seen including a ring hemorrhage surrounding a blood vessel which contains a fibrin plug; distended congested blood vessels throughout the section; and sequestered parasites (hematoxylin and eosin [H&E], 200×). (B) The colon has many parasites sequestered in tissues, similar to the entire glandular gastrointestinal tract, which are most prominent in the small capillaries of the lamina propria. In this section, the presence of later stage trophozoites and schizonts can be readily appreciated (H&E, 400×). (C) The adipose tissue of the skin can variably contain sequestered parasites within the rich vessel network (H&E, 1000×). Many other organs, including the heart (D), show variable amounts of sequestered parasites (H&E, 400×). (Courtesy of Dr Danny A Milner).

grounds in these patients, so in situations where the blood glucose cannot be measured in comatose parasitemic patients, immediate treatment with 50% dextrose is recommended. Unconscious patients who present with pretreatment hypoglycemia have a worse prognosis than those who do not, and the risk of a poor outcome is inversely associated with blood glucose concentrations, even those above the traditional cutoff of 2.2 mmol/L (40 mg/dL) [8]. Anti-malarial treatment can precipitate hypoglycemia. Rapid infusions of quinine (>10 mg/kg/hr) can stimulate pancreatic insulin secretion; pregnant women appear to be especially susceptible to this complication of treatment.

Metabolic acidosis Acidosis is now recognized as an important marker of severity in falciparum malaria infections. “Acidotic breathing” alone was associated with a 19% mortality rate in Kenyan children. In this population, the mortality rate in children with impaired consciousness uncomplicated by acidotic breathing was 12%; in children with acidotic breathing and impaired consciousness, the mortality rate was 32% [8] (Fig. 96.4). Elevated plasma and cerebrospinal fluid (CSF) lactate levels are also associated with a poor outcome but few studies have

examined both pH and lactate, so although they are likely to be highly correlated, the precise relationship is not known. Acidosis and hypoglycemia are strongly associated, suggesting parasite and/or host metabolism may be contributing to both. Full-blown circulatory shock is rarely a feature of severe and complicated malaria, so grossly impaired perfusion is unlikely to be a cause of the metabolic acidosis of malaria. This acidosis generally improves rapidly once intravenous (IV) treatment with an effective anti-malarial drug and maintenance fluids is started. The transient nature of the acidosis is consistent with the possibility that seizures are a contributing factor. Convulsions are common in malaria, and seizures alone can cause an acute lactic acidosis. Acidosis persists longer in those patients who die and is also associated with a slower respiratory rate; this suggests that the usual centrally-mediated respiratory response to metabolic acidosis may be compromised in these patients.

Acute respiratory distress (ARDS) Non-cardiogenic pulmonary edema is a common feature of complicated malaria in adults, but only rarely develops in children. The specific cause of this syndrome in malaria patients has yet to be identified [9].

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Acidosis Cerebral malaria

28%

24%

15% 35%

16%

18%

Uncomplicated malaria

Severe malarial anemia 4%

FIGURE 96.4 Venn diagram of complicated malaria syndromes. The percentage values represent the mortality rates in Kenyan children with the various syndromes. (Adapted from Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med 1995;332: 1399–404).

Renal abnormalities Nonspecific mildly elevated urea nitrogen and creatinine levels, proteinuria and abnormal urinary sediment are common in malaria. Acute renal failure is a common complication of severe malaria, particularly in adults. As in cerebral malaria, the insult often resolves and most patients do not require long-term dialysis [10].

Neurologic changes and coma The clinical syndrome of cerebral malaria is associated with the sequestration of erythrocytes harboring late-stage P. falciparum parasites (trophozoites and schizonts) in the cerebral microcirculation. Putative mechanisms include obstruction leading to hypoperfusion with anoxic damage, endothelial cell activation and blood–brain barrier compromise, and platelet activation with microthrombus formation (Fig. 96.3). Alternatively, a cytokine cascade leading to a systemic inflammatory response-type scenario, initiated by the interaction of parasitized red cells and host immune cells has been postulated; this mechanism would be independent of sequestration and could be invoked for the other four species of malaria parasite involved in human disease [11].

CLINICAL FEATURES PRODROMAL SYMPTOMS Some patients have vague prodromal symptoms, such as malaise, myalgia, low back pain, headache, anorexia and mild fever, before parasitemia can be detected by the usual microscopic techniques. These manifestations may persist for 2–3 days before an acute paroxysm begins. The incubation period, or time from exposure to onset of symptoms, can be prolonged by partial immunity and/or by chemoprophylaxis.

PERIODICITY In primary attacks, several days are required before the periodicity predicted by the lengths of various parasite lifecycles is established. Often, in patients with “asynchronous” infections, this periodicity is

never clinically apparent. After 5–7 days, P. vivax, P. malariae and P. ovale infections can become synchronous and cause periodic febrile paroxysms. In P. vivax and P. falciparum malaria, schizonts mature and rupture with tertian periodicity, i.e. every 48 hours; P. vivax malaria has been referred to as benign tertian malaria and P. falciparum malaria as malignant tertian malaria. Plasmodium malariae schizonts rupture at 72-hour intervals, causing a quartan periodicity. The typical paroxysm has an abrupt onset with a feeling of coldness and a chill. The patient’s teeth may chatter prompting the need for warmth or cover. Within 30–60 minutes, the patient feels hot and has profuse sweating, usually accompanied by a headache, malaise and myalgia. Temperatures of 40–41°C (104–106°F) are usual in primary falciparum infections, but peak fevers in infections with the other three species of plasmodia are usually lower, i.e. 39–40°C (102–104°F). The hot stage lasts from 2–6 hours. The sweating stage, in which the patient’s temperature falls rapidly, lasts 2–3 hours. The entire paroxysm averages 9–10 hours. In between paroxysms, the patient may feel well.

UNCOMPLICATED MALARIA Uncomplicated malaria illness is by far the most common clinical manifestation of a malaria infection and fever, or history of fever, is the most common symptom. There are no pathognomonic signs by which “uncomplicated malaria” can be distinguished from common viral causes of fever (Box 96.2). The presence of malaria parasitemia increases the odds of a causal connection, especially in non-immune individuals, where peripheral parasitemia is nearly always associated with symptoms. Many semi-immune individuals (generally long-term residents of malaria-endemic areas) can harbor parasites without becoming symptomatic and, in these individuals, peripheral blood parasitemia may well be “incidental” to the symptoms [12]. In practical terms, symptomatic, parasitemic individuals who are alert enough to take oral medications are considered to have “uncomplicated malaria”. Important aspects of the clinical history include travel itinerary, malaria precautions (chemoprophylaxis, use of bed nets and repellents) and recent prior treatment with anti-malarial drugs. The physical exam is useful for identifying other potential etiologies. In endemic areas, the presence of hepato- or splenomegaly tilt the differential diagnosis toward malaria, as does thrombocytopenia. For nonimmune travelers, the presence of fever, splenomegaly, hyperbilirubinemia and thrombocytopenia make malaria more likely [13]. Common presenting signs are generalized constitutional symptoms including fever, chills, dizziness, backache, myalgia, malaise and fatigue (frequently summarized as “total body pain” by endemic-area adults). Gastrointestinal symptoms (i.e. anorexia, nausea, vomiting, abdominal pain and diarrhea) can be prominent, causing confusion with gastroenteritis. Patients may have nonproductive cough and dyspnea, consistent with acute respiratory infections. Young children and semi-immune adults may present with only fever and headache.

LABORATORY FINDINGS Anemia, leukopenia and thrombocytopenia are usual. The reticulocyte count is normal or depressed, despite the hemolysis, and becomes elevated usually 5–7 days after the parasitemia has cleared. Urinalysis reveals albuminuria and urobilinogen; increased conjugated bilirubin is present in many patients. Some patients are jaundiced and concomitant abnormalities in liver function tests may cause diagnostic confusion with viral hepatitis. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST), are usually elevated. Both the direct and the indirect bilirubin can be elevated. Prothrombin times can be prolonged. Hyponatremia is not uncommon; in some patients, the clinical picture is consistent with inappropriate secretion of antidiuretic hormone (ADH), but this is not a universal finding. Increases in serum creatinine and blood urea nitrogen may be transient, or they may presage acute renal failure. Hypoglycemia frequently complicates falciparum malaria and can occur both before treatment and as a result of quinine therapy. The five human malaria parasites have similar clinical presentations for uncomplicated disease and are best distinguished from each other

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BOX 96.2  Differential Diagnosis of Uncomplicated Malaria* Symptoms

Physical exam

Lab tests

Geography

Malaria

Fever Nonspecific myalgias, arthalgia, malaise Nausea, vomiting

Hepatomegaly Splenomegaly

Malaria smear positive Thrombocytopenia Hyperbilirubinemia

Primarily tropical areas

Viral syndromes (flu, pneumonia, early gastroenteritis)

Fever Nonspecific myalgias, arthalgia, malaise Nausea, vomiting

Lymphadenopathy

Low white cell count, lymphocyte predominant

Worldwide, frequently seen in local epidemics

Bacterial pneumonia

Fever Productive cough

Tachypnea Increased respiratory effort (inter- and subcostal recession, use of accessory muscles) Crepitations (rales) Decreased oxygen saturation (<90%)

Leukocytosis

Worldwide

Meningitis (bacterial or viral)

Fever Altered mental status

Neck stiffness

Concomitant parasitemia uncommon in bacterial meningitis WBCs in CSF (> 5–10/μl, or >10 times higher than the predicted CSF WBC count†)

Dengue

Retro-orbital pain Pain/tenderness of the extraocular eye muscles, particularly on extreme lateral gaze

Skin rash develops in at least 50% by day 2–3

Leukopenia Thrombocytopenia

Less common in sub-Saharan Africa

Leptospirosis

Fever, headache, dry cough, shaking, chills, nausea, vomiting, diarrhea, muscle pain, abdominal pain

Muscle tenderness (myositis), conjunctivitis, hepatosplenomegaly

Elevated creatine kinase, abnormal urine sediment, proteinuria, normal to elevated WBC counts

Worldwide distribution, association with fresh-water exposure

Typhus

High fever, dry cough, low back pain, headache, nausea, vomiting, abdominal pain, diarrhea, nausea, chills, delirium, photophobia, myalgia

Rash begins on the chest and spreads to the rest of the body (except the palms of the hands and soles of the feet). The early rash is a light rose color and fades when pressed. Later, the rash becomes dull and red and does not fade. People with severe typhus may also develop small areas of bleeding into the skin (petechiae)

Anemia Thrombocytopenia Two-to-five-fold elevation of liver enzymes

Worldwide distribution, murine typhus (Rickettsia typhi) seen in areas of poor hygiene and cold tempertures. Epidemic typhus (Rickettsia prowzekii) associated with exposure to rat fleas or rat feces

Viral hemorrhagic fevers

Fever, bleeding diathesis, malaise, fatigue, myalgias, headache, vomiting, diarrhea, hypotension, shock

Flushing of the face and chest, frank bleeding, ecchymoses, renal failure, edema

Cytopenias seen early in illness with elevated WBC seen in late disease, coagulation abnormalities

Worldwide distribution and caused by several families of RNA viruses

*Individual patients may have more than one diagnosis. † Predicted CSF WBC count/μl = CSF RBC count × (peripheral blood WBC count ÷ peripheral blood RBC count). CSF, cerebrospinal fluid; RBC, red blood cell; WBC, white blood cell.

by geography (Fig. 96.1), by parasite density (parasitemias >2% are more commonly seen in P. falciparum and P. knowlesi) and by parasite morphology – best appreciated on thin blood films (Table 96.1). Low-grade infections of P. malariae can persist for years and individuals with P. vivax and P. ovale may have pre-patent periods of a year or more.

Non-immune individuals with P. falciparum infections may deteriorate very rapidly; prompt and effective treatment in this high-risk group is important and should be provided on an emergent basis. When feasible, patients should be monitored closely to detect early signs of clinical deterioration. A high index of suspicion is warranted for travelers and others who have been in malaria-endemic areas.

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TABLE 96-2  Features of Complicated Malaria Physical findings

Laboratory investigations

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l l l l l

l

l l

Impaired consciousness/ unrousable coma (Blantyre Coma Score <2) (children > adults) Prostration (unable to walk or sit up) Failure to feed Convulsions (more than 2 in 24 hours) (children > adults) Acidotic breathing (children > adults) Shock (systolic blood pressure <70 mmHg in adults, <50 mmHg in children) Clinical jaundice + evidence of another organ dysfunction (adults > children) Abnormal spontaneous bleeding Pulmonary edema (radiologic evidence) (adults > children)

l

l

l l

l l

Hypoglycemia (<2.2 mmol/L or 40 mg/ dl) (children > adults) Metabolic acidosis (plasma bicarbonate <15 mmol/L) (children > adults) Severe anemia (hemoglobin <5 g/dl, PCV < 15%) (children > adults) Hemoglobinuria Hyperparasitemia (>2%, or 100,000/μl in low transmission setting, >5%, or 250,000/μl in high transmission settings) Hyperlactatemia (>5 mmol/L) Renal impairment (creatinine> 265 μmol/L) (adults > children)

FIGURE 96.5 Child in coma with eyes wide open.

PCV, packed cell volume.

FIGURE 96.6 Pallor.

Serial examination of the peripheral blood (every 12 hours) may aid in the identification of low density parasitemias; thrombocytopenia is another helpful clue in oligo-parasitemic or initially aparasitemic patients.

relatively rapid; most children who survive an episode of cerebral malaria have regained full consciousness within 48 hours. The rapid evolution and reversibility of the dramatic neurologic features of cere­ bral malaria are among the most intriguing aspects of the disease.

COMPLICATED MALARIA

The clinical history is generally notable for a sudden deterioration in the patient’s clinical status – the transition from uncomplicated to complicated malaria can be as brief as a single seizure.

Long considered to be unique to falciparum malaria, several of the features of complicated malaria (Table 96-2) have now been described in patients with P. vivax and P. knowlesi infections. In addition to the complications described in Table 96-2, splenic rupture is a rare complication of P. vivax infections, and nephrotic syndrome is occasionally seen in patients after a P. malariae illness. In a parasitemic patient, the presence of any of the clinical or laboratory features of complicated malaria represents a medical emergency; these patients should be provided with the best available medical care. The clinical presentation of complicated malaria is different in adults than it is in children (Table 96-2). Cerebral malaria alone is more characteristic of pediatric severe malaria, whereas multi-organ system involvement is seen frequently in adults with complicated malaria illnesses. Cerebral malaria is a highly variable clinical syndrome consisting of P. falciparum parasitemia of any density and coma (Blantyre Coma Score <2 in children/Glasgow Coma Score <9 in adults, unrelated to hypoglycemia, meningitis or a postictal state). Children with cerebral malaria frequently demonstrate symptoms suggesting widespread involvement of the CNS, including generalized tonic-clonic convulsions, focal seizures, posturing (opisthotonos, decerebrate rigidity, decorticate rigidity), conjugate gaze deviations and respiratory rhythm abnormalities (including Cheyne-Stokes respirations). Convulsions (focal and generalized) are very common, particularly in children. Intracranial pressure is often elevated in children with cerebral malaria and deaths consistent with various herniation syndromes have been described. An unusual feature of pediatric malarial comas is that the eyes are frequently wide open (Fig. 96.5) – this can be confusing for parents and caregivers. Among patients who survive, the recovery is

With point-of-care bedside tests for malaria parasitemia, blood glucose, hemoglobin or hematocrit and lactate combined with a careful physical examination, nearly all patients with complicated malaria can be identified quickly and without sophisticated laboratory support. Important elements of the physical examination include inspection for prostration (the inability to sit unaided or, in infants who cannot yet sit, to look for the mother’s breast and feed) and deep breathing, assessing the Blantyre [14] or Glasgow Coma Score (Box 96.3), inspecting nail beds and conjunctivae for pallor (Fig. 96.6), cardiac and pulmonary auscultation for signs of high output cardiac failure (i.e. a systolic murmur, a gallop rhythm, widened pulse pressure, enlarging liver), measuring blood pressure and checking capillary refill (Box 96.4) (to identify patients in shock), and palpating the abdomen to identify hepato- and splenomegaly and urinary retention. Acute renal failure will become evident over time on the basis of urinary output and can be confirmed by measures of serum creatinine. In order to identify hyperparasitemia, the capacity to stain blood films and count parasites is required. Among patients meeting the standard clinical case definition of cere­ bral malaria [15], a careful ocular funduscopic exam is very useful for distinguishing patients with “true” cerebral malaria from patients with incidental parasitemias and a non-malarial cause of coma (see “Complicated Malaria” below).

METABOLIC ACIDOSIS Capillary blood pH <7.3, plasma bicarbonate <15 mmol/L or plasma lactate concentrations >5 mmol/L are all associated with severe disease and with poor outcomes. Acidosis, manifested clinically as

M alar ia

BOX 96.3  Coma Scales for Adults and Children Glasgow Coma Scale (GCS; adults) Motor Response (to painful stimuli: pressure on nail bed, sternum, supraorbital ridge)

Verbal Response (to painful stimuli or speech)

Eyes

Blantyre Coma Score (BCS; children)

Obeys commands Localizes Flexion/withdraws Abormal flexion (decorticate) Extension (decerebrate) No response

6 5 4 3 2 1

Oriented, converses normally Confused, disoriented Utters inappropriate words Incomprehensible sounds Makes no sounds

5 4 3 2 1

Opens eyes spontaneously Opens eyes in response to voice Opens eyes in response to pain Does not open eyes

4 3 2 1

BOX 96.4  Assessing Capillary Refill 1. Observe the color of the nail bed. 2. Press on the nail bed of any digit until it blanches completely. 3. Release pressure. 4. Count (“one-one thousand, two-one thousand) until the nail bed completely regains its normal color. 5. Normal capillary refill is <2 seconds; prolonged capillary refill times suggest that the patient is in shock. Self-calibration by the examining clinician is helpful.

abnormally deep breathing is a poor prognostic feature in parasitemic children with or without neurologic compromise.

SEVERE ANEMIA Life-threatening anemia can develop rapidly; children who have adjusted to a low hemoglobin or hematocrit can rapidly decompensate when challenged by a febrile illness such as malaria. Decisions regarding blood transfusion are difficult, particularly in malariaendemic areas where HIV infection is common. Decisions to transfuse are generally made on the basis of hemodynamic grounds (signs of high-output heart failure include hypotension, poor capillary refill, systolic murmurs and hepatosplenomegaly), level of consciousness and evidence of acidosis. Estimates of parasite density are helpful in predicting the need for blood transfusion (see below, “Treatment”). Anemic children who are clinically stable may be treated conservatively, but close observation is recommended.

RESPIRATORY FAILURE Respiratory failure associated with ARDS can develop rapidly; clinically it is indistinguishable from the ARDS that develops as a result of septicemia, toxic inhalants or other causes. Patients become hypoxemic and may require mechanically-assisted ventilation. Aggressive management of malaria-associated ARDS should be used wherever available.

Localizes Withdraws

2 1

Extension (decerebrate) No response

0 0

Normal cry, appropriate speech

2

Abnormal cry Makes no sounds

1 0

Follows moving objects Unable to follow moving objects

1 0

blood pressure, cold and clammy extremities, hypoglycemia and acidosis. In most cases, this represents septic shock and pathogens are cultured from the blood. The judicious administration of antibiotics, fluids and inotropes is recommended for this small group of patients. The sudden onset of hypotension in a patient with vivax malaria should prompt consideration of splenic rupture or subcapsular bleeding.

ACUTE RENAL FAILURE Mild proteinura, azotemia and oliguria occur frequently in otherwise uncomplicated P. falciparum infections. Acute renal failure is another complication that is far more common among adults than among children; it is also more common in patients with hemoglobinuria (“blackwater fever”). Acute renal failure can also result from acute tubular necrosis, a sequelae of reduced renal perfusion. Anuria is a poor prognostic sign and hemoperfusion, renal or peritoneal dialysis are often necessary. Few data exist to describe the proportion of patients on dialysis who recover renal function but, as in cerebral malaria, renal abnormalities are reversible and patients appropriately supported through the critical period often enjoy a full recovery.

POST-MALARIA NEUROLOGIC SYNDROME This is a rare transient neurologic syndrome, reported most commonly in non-immune travelers after a successfully treated episode of severe falciparum malaria. The onset is generally within 1–2 weeks of recovery, but can be as long as 2 months after. The clinical features range from confusion and tremors, to aphasia, seizures, ataxia, psychosis and impaired consciousness. There may be a lymphocytic pleocytosis in the CSF; imaging studies may or may not show nonspecific white matter changes. The symptoms are generally self-limiting; steroids have been used with good results in some patients [16].

MALARIA IN PREGNANCY The effects of malaria infection in pregnancy are visited on the expectant mother via peripheral parasitemia and on the fetus/newborn via parasite sequestration in the intervillous spaces of the placenta.

ALGID MALARIA

In general, pregnant woman are more susceptible to malaria infection than their non-pregnant counterparts; this is most noticeable in areas of low transmission, where few adults have acquired anti-disease immunity. Susceptibility to infection decreases with each succeeding pregnancy.

The majority of patients with severe malaria remain well perfused, but a small proportion develop algid malaria – defined as low

The placenta provides a new site for sequestration, a phenomenon unique to infections with P. falciparum, and, as with peripheral

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parasitemia, semi-immune women are less likely to have placental sequestration than non-immune women, and the placentae of multigravidae are less likely to contain evidence of parasite sequestration than those of primigravidae. The receptor on the syncytiotrophoblast lining the intervillous spaces of the placenta is chondroitin sulfate A, and binding is mediated by a specific variant surface antigen, var2csa [17]. Clinical manifestations in the mother are determined by the extent of acquired immunity. In sub-Saharan Africa, where most studies have been carried out, mild febrile illnesses and anemia are the most common features. In relatively non-immune pregnant women, severe and complicated malaria, often characterized by hypoglycemia and pulmonary edema, can occur. Pregnancy-induced immune suppression generally results in more severe disease, especially in the group at highest risk, primigravid, non-immune women. Parasitemia rates are at their highest during the second trimester, and the period of increased risk can extend into the post-partum period for 1–2 months [18]. Adverse maternal and perinatal outcomes of malaria in pregnancy include anemia, miscarriage, fetal growth restriction (small for gestational age), low birth weight (<2500 g at birth), pre-term births and congenital infection. Again, the likelihood of these outcomes is related to maternal gravidity and degree of acquired anti-malarial immunity.

TRANSFUSION MALARIA Any of the five species of human malaria can be transmitted directly from an infected blood donor, accidental infection by a contaminated needle, or from infected intravenous drug users sharing needles. The incubation period following infection is as short as a few days for P. falciparum, but can be up to 40 days or longer for P. malariae [19].

PATIENT EVALUATION, DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS UNCOMPLICATED MALARIA At the individual patient level, accurate diagnosis and treatment of uncomplicated malaria enhances the chances of a prompt cure and minimizes the likelihood of disease progression. At the population level, the appropriate management of uncomplicated malaria, particularly large numbers of patients with uncomplicated malaria, as is common in endemic areas, will diminish the reservoir of infected individuals while minimizing the development and spread of drugresistant parasites. To minimize the unnecessary or inappropriate use of anti-malarial drugs, parasitologic confirmation of clinically suspected cases is now recommended by the World Health Organization (WHO) [20]. Malaria parasites can be identified in a sample of peripheral blood via light microscopy or using rapid diagnostic tests (RDTs), which are based on the detection of parasite enzymes or antigens. When it is performed well, light microscopy is sensitive and specific and allows for the recognition of various malaria parasite species. There is a large initial cost for acquiring equipment and training technicians, and ongoing quality assurance and quality control are expensive, but the day-to-day operational costs are low, especially when high throughput is required. The “gold standard” approach uses Giemsa stain and oilimmersion microscopy. RDTs are antigen-based dipstick, cassette or card tests in which a colored line indicates that plasmodial antigens have been detected. They are relatively simple to perform and interpret and they do not require electricity, but not all tests can distinguish between species, and some cannot distinguish new infections from recently and effectively-treated infections (Box 96.5). The choice of a specific RDT

BOX 96.5  Microscopy versus Malaria Rapid Diagnostic Tests (RDTs) Thin film microscopy

Thick film microscopy

RDTs

Speciation

Yes

Possible

Yes

Quantification

Yes

Optimal

RDTs give qualitative “yes” or “no” results but intensity of the parasite line correlates to antigen present

Can use to follow response to treatment

Yes

Yes

No; HRP2- based tests specific for P. falciparum can remain positive for days after successful treatment.

Electricity required

Yes

Yes

No

Training and skill required

Extensive training; acquired skill

Limited training; can be used in remote settings

Sensitivity

Vary by skill of microscopist

Vary among tests

Cost

May be less expensive in busy settings

$0.50–$1 per test

Storage

Temperature ranges; humidity a problem unless individually foil-wrapped White cell count, platelet count, Borrelia, Trypanosoma, Babesia spp.

Detects other pathogens in blood

No

Malaria parasites detected

All species Species differentiation on the basis of different morphologies

All species

P. falciparum only and P. falciparum/P. vivax combinations

Mixed infections

Yes

Yes

Usually no

False-positives

Artifact

Artifact

Antigenemia can persist after parasitemia has cleared

False-negatives

Low parasite density

HRP2, histidine-rich protein 2.

Prozone effect Low parasite density

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depends on its intended use. For example, does it need to distinguish between a recent malaria infection and a current infection? Should it be able to distinguish between falciparum and non-falciparum species? Will treatment decisions be based on the results, or is it being employed for epidemiologic purposes? The choice of which malaria RDT to use in a given situation is complex and depends on availability, cost, quality of the test and performance characteristics. The WHO sponsors independent RDT product testing in collaboration with the Foundation for Innovative New Diagnostics (FIND), the Special Program for Research and Training in Tropical Diseases (TDR) and the WHO Global Malaria Program (GMP). Testing is performed at the US Centers for Disease Control and Prevention (CDC). Summary results of the most recent round are available online [21]. These comparisons help to inform procurement decisions for national malaria control programs and to guide United Nations (UN) procurement policies. In resource-constrained endemic areas, parasitologic diagnosis is not always available – even when it is available, quality and accuracy are a continuing challenge. When parasitologic diagnoses are not available, algorithms devised on the basis of the prevalence of parasitemia in various age groups [22] help to balance the risk of under-treating those at risk of progressing to severe disease against the risks of unnecessary drug use in the semi-immune population, excessive costs and drug pressure, which could accelerate the development of drug resistant parasites. Serial parasitologic assessments after the start of treatment are helpful for documenting response to treatment; if these are paired with an assessment of anemia (either hemoglobin concentration or hemato­ crit), it may be possible to anticipate the need for blood transfusion (see below for guidelines).

BLOOD FILMS The gold standard of malaria diagnosis remains the blood film. For detecting parasites, a thick blood film is superior as it concentrates the red cells by a factor of 20–40. Identifying species on thick films may be difficult because the red cells have lysed and the morphologic features of the parasites have been altered. Species identifications are made more easily using thin blood films. Thick and thin films can be prepared on the same slide, although they are processed differently (thin films must be fixed in methanol before they are stained). Quantitating parasitemias, even semiquantitatively (0, + - ++++) is useful for predicting whether the illness is likely to be caused by malaria, for anticipating the need for blood transfusion and for following response to anti-malarial treatment. Parasites can be counted as a percentage of red cells on a thin film, or against white blood cells on a thick film, and if the total red cell or white cell counts are known, the parasite densities can be calculated. Blood can be stained with Giemsa, Leishman, Field or Wright’s stains. The most important initial distinction is to determine whether malaria parasites are present: for this, a thick film is most efficient. Species identification is best done on thin films (Table 96-1). The golden brown malaria pigment (hemozoin) in monocytes or leukocytes suggests a current or recent malaria infection, even in the absence of a patent parasitemia.

INTERPRETING THE RESULTS OF MALARIA DIAGNOSTIC TESTS In practice, clinicians in malaria-endemic areas with little diagnostic capacity prescribe anti-malarial drugs to symptomatic individuals whenever parasites are detected; however, the clinical challenge is to decide if additional treatment (e.g. antibiotics) is needed. In semiimmune individuals, asymptomatic or “incidental” parasitemia is common, and the presence of peripheral parasitemia can be misleading. In these individuals, it would be prudent to consider other etiologies for the symptoms, particularly in patients with lower density parasitemias (Box 96.2). Anti-malarial treatment is warranted if parasites are detected, but additional treatment may also be required.

A second dilemma is the febrile individual with a negative malaria test. Withholding anti-malarial drugs in situations where malaria infection is a real possibility is difficult for clinicians. The dangers of missing a malaria diagnosis and thus delaying treatment are well known. This apprehension, accompanied by a degree of skepticism regarding the reliability of the parasitologic diagnosis (especially via microscopy), is used to justify a “better safe than sorry” approach to the use of anti-malarial drugs. In malaria-endemic areas, patients themselves, along with parents and other caregivers, have come to expect malaria chemotherapy for many febrile illnesses. Clinical evidence for other non-malaria diagnoses should be sought (Box 96.2) to support the decision to withhold anti-malarials in patients who are not infected with plasmodia. The absence of parasites in the peripheral blood should prompt the clinician to consider other etiologies of the patient’s symptoms. In non-immune patients at risk for malaria infection, several parasitologic assessments carried out at 12-hour intervals during a 36–48 hour period are recommended before concluding that the individual is free of infection. Intra-erythrocytic falciparum parasites are typically in circulation for the first 24–36 hours of the 48-hour lifecycle, and the intra-erythrocytic parasites for the other four infecting species are always present in the peripheral blood, so it is not necessary to “time” blood collections to any particular symptoms (e.g. fever, rigor, diaphoresis). The WHO recommends withholding anti-malarial treatment in the face of negative (often repeatedly negative) tests; in practice, as noted above, this can be difficult, given the well-known dangers of untreated malaria and the challenges of obtaining a reliable parasitologic diagnosis.

COMPLICATED MALARIA Parasitemic individuals with any of the clinical or laboratory features described in Table 96-2 are likely to have complicated malaria, but the possibility of a “false-positive” assessment should be considered, particularly (but not exclusively) in the semi-immune population. The mortality rate of untreated severe malaria is probably over 75%; with good management, the mortality rate of cerebral malaria is roughly 15–20%. Concomitant meningitis should be excluded via lumbar puncture; if a lumbar puncture is contraindicated on clinical grounds, the patient should be provided with the appropriate antibiotic coverage (penicillin + gentamicin, or ceftriaxone). Co-infections with blood-borne bacteria are common and should be sought when the capacity exists [23, 24]. Septic shock should be considered in the differential diagnosis and empiric antibiotic therapy administered if there are signs of acidosis or impaired perfusion. An autopsy-based study of pediatric cerebral malaria demonstrated that the standard clinical case definition of cerebral malaria was incorrect in approximately 25% of cases – non-malarial causes of death were identified and those patients had no evidence of parasite sequestration in the cerebral microcirculation. In contrast, 75% of cases in this series did have cerebral sequestration of parasitized erythrocytes and no other causes of death were identified at autopsy [25]. The best clinical indicator of “true” cerebral malaria was the presence of at least one of the three features of a recently described malaria retinopathy: vessel color changes, macular or extra-macular whitening, and whitecentered hemorrhages [26] (Fig 96.7). With autopsy findings as the gold standard, the specificity of retinal findings is 93%, the sensitivity is 97% and the positive and negative predictive values are 97% and 93% respectively. Malarial retinopathy is best appreciated in eyes that have been fully dilated with mydriatics (a combination of tropicamide and phenyl­ ephrine eye drops will dilate the eyes within 15–20 minutes) and examined with a hand-held direct ophthalmoscope (which provides magnification) and an indirect ophthalmoscope (which provides a three-dimensional perspective, as well as a wider field of view). These examinations are routine for trained ophthalmologists, but nonophthalmologist clinicians can learn to recognize these features, too. Ninety percent of retinopathy-positive patients can be identified on

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HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE

FIGURE 96.7 Malaria retinopathy. Examples of clinical ocular fundus findings in African children with P. falciparum malaria. 1, Retinal hemorrhages, some with white centers. 2. Grade 2 macular whitening, less than 1/3 of the disc area of whitening. 3. Grade 2 macular whitening, between 1/3 and 1 disc area of whitening. 4. Grade 3 macular whitening, greater than 1 disc area of whitening. 5. Grade 1 extramacular whitening, note 2 foci of whitening. 6. Grade 2 extramacular whitening; scattered white spots in the upper half of the photograph represent the density of whitening for the 2+ grade. 7. Grade 3 extramacular whitening; this definite mosaic represents the minimum whitening for the 3+ grade. 8. Grade 3 extramacular whitening; confluence of whitening. 9. Abnormal vessels; orange delineation of vessels. 10. Abnormal vessels; segmental whitening. 11. Abnormal vessels, extensive delineation of capillaries with some irregular delineation of terminal portion of larger vessels. (From Lewallen S, Harding SP, Ajewole J, et al. A review of the spectrum of clinical ocular fundus findings in P. falciparum malaria in African children with a proposed classification and grading system. Trans Roy Soc Trop Med Hyg 1999;93:619–22.).

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the basis of observations of the optic disc, the macula and the area in between [27]. Severe pneumonia was a common cause of death in parasitemic children who satisfied the clinical case definition of cerebral malaria in the autopsy study described above. Pneumonia may be suspected on the basis of the history and physical examination, and should definitely be considered when oxygen saturations are <90%. Given the frequency of this particular co-morbidity, empiric antibiotic therapy based on the clinical assessment is reasonable [28]. If pediatric patients have a history of aspirin intake, or if there is hepatomegaly in the face of recurrent hypoglycemia, Reyes Syndrome should be included in the differential diagnosis.

TREATMENT CLEARING THE PARASITE For patients who are able to swallow, oral medications (Table 96-3) are recommended [20]. Prior treatment is common, and should be taken into consideration when deciding how to treat individual patients; quinine use following mefloquine may be arrhythmogenic, for instance. Although chloroquine is no longer recommended by the WHO as the primary treatment of P. falciparum infections, it remains the most commonly used drug in a few parts of the world including Haiti, the Dominican Republic, most regions of the Middle East, and Central America, west of the Panama Canal. Even in settings where chloroquine-resistance is widespread, the drug, an effective analgesic and antipyretic, has considerable popularity. Chloroquine is recommended for the blood-stage infections of P. malariae, P. ovale and most P. vivax infections. Chloroquine-resistant vivax malaria has been reported from Indonesia and Papua New Guinea, and those infections should be treated with artemisinin combination therapies, atovaquone-proguanil, mefloquine or quinine followed by doxycyline or tetracycline. Primaquine is required for radical cures of the liver stage parasites in P. vivax and P. ovale. In most situations, a daily dose (0.25–0.5 mg/ kg) of primaquine for two weeks is sufficient. Patients should be screened for G6PD-deficiency prior to administration of primaquine. In settings where laboratory testing is not available, a test dose of primaquine followed by careful observation and repeated measures of hemoglobin or hematocrit may be necessary. In general, though, monotherapy for falciparum malaria has been supplanted by drug combinations (co-formulated or co-packaged) of artemisinin-based compounds (rapidly parasiticidal, but with short half-lives) and partner drugs (more slowly acting, but with longer half-lives). The artemisinins typically clear 90% of the parasites within 24–36 hours and the partner drug clears the rest. Most regimens (Table 96-3) require twice daily administration of the drug combination over three days. The WHO currently recommends five different combinations; specific choices depend on prevailing parasite drug sensitivities, procurement opportunities and cost [20]. For patients who are unable to swallow, parenteral drug treatment is required; both options are contemporary formulations of traditional, plant-based remedies. Quinine (and its stereoisomer, quinidine) come from the bark of the cinchona tree and the artemisinins are derived from Artemesia annua, known colloquially as “sweet wormwood”. The cinchona alkaloids have been the mainstay of treatment for complicated malaria since they were introduced to Europe from Peru in the 17th century. Quinine is used more commonly, but quinidine is as effective, albeit more likely to engender cardiac dysrhythmias. Although the IV route is preferred, intramuscular administration is effective – the drug, as formulated (at 300 mg base/ml) is fairly acidic, though and should be diluted 4–6-fold prior to intramuscular injection. Large-volume injections should be divided between two large muscle masses (preferably the anterior thighs).

Irrespective of the alkaloid selected, a loading dose is required in order to achieve a therapeutic drug concentration quickly. More care is required to administer quinine and quinidine than the artemisinins. Quinine and quinidine, when infused too rapidly, stimulate the pancreatic secretion of insulin and hypoglycemia may ensue. Intravenous quinine was enshrined as the treatment for severe malaria well before pharmacokinetic studies were possible; current regimens have evolved on the basis of experience and some computer model­ ing. Regimens for intramuscular quinine and the intravascular/ intramuscular formulations of the artemisinin derivatives are based on sound pharmacokinetics (Table 96-4). Randomized clinical trials comparing IV quinine with IV artesunate have established the superiority of IV artesunate in adults and children [29, 30]. Patients with complicated malaria should receive parenteral antimalarials for at least 24 hours; after that, a full course of an effective oral drug can be administered, beginning as soon as the patient can swallow (Table 96-4).

PREGNANT PATIENTS For pregnant women living in malaria-endemic areas, the WHO recommends Intermittent Preventive Treatment during pregnancy (IPTp) [20] with two doses of sulfadoxine-pyrimethamine (SP) administered at monthly intervals after the onset of fetal movements. IPTp should be extended into the third trimester for HIV-infected pregnant women who are not taking cotrimoxazole prophylaxis. Chemotherapy for pregnant women who develop malaria illnesses during pregnancy is similar to that recommended for non-pregnant patients with the following caveats: l l l l

l

l

few pharmacokinetic studies have been carried out in pregnant women; chloroquine is well tolerated; the recommended doses of quinine and quinidine are safe; mefloquine may be associated with an increased risk of stillbirth [31], but can be used when no other treatment options are available; tetracycline, doxycycline, primaquine and halofantrine are contraindicated in pregnancy, and neither primaquine or the tetracyclines should be used while breastfeeding; primaquine is contraindicated during pregnancy, given the uncertain G6PD status of the fetus.

There are very few data on the safety of the artemisinin drugs during pregnancy; in general, they are not recommended during the first trimester and amodiaquine use during pregnancy is eschewed because of the risk of agranulocytosis.

TREATING THE PATIENT Supportive care Dedicated nursing care is important in the management of these patients. Vital signs, urine output and an appropriate coma score should be monitored as frequently as possible. The most common causes of a drop in coma score following the initiation of therapy are convulsions, hypoglycemia and anemia. Blood glucose, lactate, parasitemia and hemoglobin/hematocrit can be monitored every 4–6 hours on fingerprick samples of blood. Patients not on ventilatory support should be nursed in the lateral decubitus position to minimize the chance of aspiration. IV fluids containing 5% dextrose are important initially, but nasogastric tube feeding can be started within 18–24 hours of admission if the patient is unable to eat.

Fever There is no consensus on how best to treat malarial fevers. Aggressive fever management may decrease the risk of convulsions and subsequent neurologic damage but parasite sequestration is less effective at higher temperatures. Acetaminophen/paracetamol and ibuprofen are all effective antipyretics in malaria patients.

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TABLE 96-3  Oral Anti-Malarial Drugs Parasite

Treatment regimens

Clinical caveats

P. falciparum

WHO-recommended artemisinin-based combination therapy (ACT): l Artemether + lumefantrine (AL) Given at 0, 8, 24, 36, 48 and 60 hours: 5–15 kg: 1 tablet 16–25 kg: 2 tablets 26–35 kg: 3 tablets >35 kg: 4 tablets (adult dose) l Artesunate + amodiaquine (AS + AQ) 4 mg/kg/day AS and 10 mg/kg/day AQ daily for 3 days l Artesunate + mefloquine (AS + MQ) 4 mg/kg/day AS daily for 3 days. MQ can be taken as 15 mg/kg on day 1 and 10 mg/kg on day 2, or as 8.3 mg/kg/daily for 3 days l Artesunate + sulfadoxine-pyrimethamine (AS + SP) 4 mg/kg AS daily for 3 days; 25 mg/1.25 mg/kg SP on Day 1 l Dihydroartemisinin + piperaquine (DHA + PPQ) 4 mg/kg AS plus 18 mg/kg PPQ daily for 3 days

Generally very well-tolerated

Other options: l Chloroquine (if known to be chloroquine sensitive) Adults: 600 mg base (=1000 mg salt) p.o., followed by 300 mg base (=500 mg salt) p.o. at 6, 24 and 24 hours Children: 10 mg base/kg p.o., followed by 5 mg base/kg p.o. at 6, 24 and 48 hours l Oral quinine sulfate plus doxycycline, tetracycline or clindamycin

Chloroquine can cause significant pruritus in dark-skinned individuals Overdoses (>2 g) can be fatal; adrenaline and diazepam are antidotes Bitter taste Bitter taste Frequent dosing needed because of a short half-life Cinchonism: tinnitus, nausea, headaches, dizziness and disturbed vision Overdosing leads to cardiotoxicity, more so with quinidine

l

Quinine sulfate: 542 mg base (= 650 mg salt) p.o. three times a day for 3 days (7 days for infections acquired in Southeast Asia) l Doxycycline: 100 mg p.o. twice a day for 7 days l Tetracycline: 250 mg p.o. four times a day for 7 days l Clindamycin: 20 mg base/kg/day, p.o., divided three times a day for 7 days

Rapid IV or IM administration can precipitate hypoglycemia Doxycycline and tetracycline are not recommended during pregnancy or in children under the age of 8 years. Clindamycin is recommended for these two groups Doxycycline should be taken with food to minimize the risk of esophageal erosions Both drugs may cause photosensitivity and disrupt normal flora enough to precipitate vaginal yeast infections

l

Atovaquone targets an element of the parasite electron transport chain and is thus well-tolerated by the host Proguanil interferes with folate metabolism and has been associated with aphthous oral ulcers Side effects include vomiting, dizziness, and exacerbation of cardiac conduction abnormalities Not recommended for individuals with a history of psychiatric disorders May disrupt sleep or cause vivid dreams

Atovaquone-proguanil Adult tablet: 250 mg atovaquone, 100 mg proguanil Pediatric tablet: 62.5 mg atovaquone, 25 mg proguanil 5–8 kg: two 25-mg pediatric tablets daily for 3 days 9–10 kg: three 25-mg pediatric tablets daily for 3 days 11–20 kg: one adult 100-mg tablet daily for 3 days 21–30 kg: two adult 100-mg tablets daily for 3 days 31–40 kg: three adult 100-mg tablets daily for 3 days >40 kg: four adult 100-mg tablets daily for 3 days l Mefloquine Adults: 684 mg base (= 750 mg salt) p.o., followed by 456 mg base (= 500 mg salt) p.o., 6–12 hours later Children: 13.7 mg base/kg (= 15 mg salt/kg) p.o., followed by 9.1 mg base/kg (= 10 mg salt/kg) p.o., 6–12 hours later Treatment failure within 14 days Second-line treatment: l a different ACT, known to be effective in the region l AS + tetracycline, doxycycline or clindamycin, for 7 days l quinine + tetracycline, doxycycline or clindamycin, for 7 days See above for details re dosage regimens Treatment failure after 14 days Repeat the original ACT unless it contained MQ; in that case, use a different ACT

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TABLE 96-3  Oral Anti-Malarial Drugs—cont’d Parasite

Treatment regimens

P. vivax, P. ovale

Chloroquine See above for details re dosage regimen Radical cure (liver stages) l 14-day course of primaquine Adult: 15 mg daily for 14 days. In Oceania and Southeast Asia, the dose of primaquine should be 30 mg daily for 14 days Children: 0.25 mg base/kg body weight, taken with food once daily for 14 days. In Oceania and Southeast Asia, the dose of primaquine should be 0.5 mg/kg body weight. In mild/moderate G6PD deficiency: Adult: 45–60 mg weekly for 8 weeks Children: 0.75 mg base/kg body weight should be given once a week for 8 weeks. In severe G6PD deficiency, primaquine is contraindicated and should not be used

Clinical caveats

Primaquine is contraindicated in individuals with G6PD deficiency and during pregnancy Malaria infection as a result of blood transfusion or organ transplantation does not require radical cure Primaquine is a gametocytocidal drug

Chloroquine resistant P. vivax (Papua New Guinea, Indonesia)

Artemisinin-based combination therapy: l DHA + PPQ l AL l AS + AQ followed by primaquine Quinine + doxycycline or tetracycline, followed by primaquine Atovaquone-proguanil followed by primaquine Mefloquine followed by primaquine See above for details re dosage regimens

AS + SP is not effective in many locales

P. malariae, P. knowlesi

Chloroquine See above for details re dosage regimen

Effective against gametocytes

G6PD, glucose 6 phosphate deficiency; IM, intramuscular; IV, intravenous; WHO, World Health Organization.

TABLE 96-4  Parenteral Anti-Malarial Drugs Parasite

Treatment regimens

P. falciparum

For all regimens: l Continue parenteral treatment for at least 24 hours l When the patient is able to swallow, administer a treatment dose of a locally-effective drug (ACT, oral quinine + doxycycline or clindamycin, atovaquone-proguanil, mefloquine)

Clinical caveats

Artesunate 2.4 mg/kg IV at 0, 12 and 24 hours, then daily until oral medication can be given

Well-tolerated Effective against a broad range of lifecycle stages (early ring stages up to schizonts and gametocytes)

Quinine dihydrochloride: IV Loading dose: 12.5 mg base/kg (= 20 mg salt/kg), IV, over 4 hours Maintenance dose: 20–30 mg/kg salt/day (divided into 2–3 daily doses, every 8–12 hours) Quinine should be used with caution in patients on mefloquine prophylaxis Quinine dihydrochloride: IM Loading dose: 6.25 mg base/kg (= 10 mg/kg salt), IM (dilute quinine to 60 mg/ml), repeat after 4 hours Maintenance doses: 6.25 mg base/kg (=10 mg/kg salt), IM, every 8–12 hours Quinidine gluconate Loading dose: 24 mg salt/kg loading dose, IV, over 4 hours Maintenance dose: 12 mg salt/kg, IV over 4 hours, every 8 hours, for at least 24 hours or until oral medication can be given

Cardiotoxic Can induce hypoglycemia Most effective against late rings and early trophozoites

Artemether Loading dose: 3.2 mg/kg body weight IM Maintenance dose: 1.6 mg/kg IM per day until oral medication can be given

Well-tolerated Effective against a broad range of lifecycle stages (early ring stages up to schizonts and gametocytes)

IM, intramuscular; IV, intravenous.

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Convulsions

Pulmonary edema/ARDS

Fits are a very common complication of malaria illnesses. Febrile convulsions are distinguished by a fairly rapid recovery of consciousness but, in patients with cerebral malaria, the coma is often initiated with a convulsion. Multiple fits are common, as are clinically “silent” fits, evident only electroencephalographically. In practice, decisions regarding the use of anti-epileptic drugs are made on the basis of a thoughtful and detailed clinical exam focusing on the eyes (looking for evidence of nystagmus, hippus [also known as pupillary athetosis – spasmodic, rhythmic (<0.04 Hz), but irregular dilating and contracting pupillary movements involving the sphincter and dilator muscles] and absence of the light reflex), the respiratory rate and rhythm (shallow, irregular respirations may be a “seizure equivalent”), the mouth and fingers (infrequent fine twitching movements of the tongue, a single finger, or the corner of the mouth can also be seizure equivalents). Occasionally, seizures emerge when hypoglycemia is corrected. Often a trial of a rapidly acting anticonvulsant (i.e. paraldehyde or diazepam) can help to identify subtle convulsions.

This complication is more common in adults, and can develop several days after admission and the initiation of anti-malarial treatment. Prompt intubation and assisted ventilation are the only recognized treatments; clinical trials of this specific malaria complication have not been carried out, so treatment recommendations are based on extrapolations from other conditions [35].

Standard anticonvulsant protocols are difficult to develop because of the heterogeneity of the patient population, but commonly used drugs include the benzodiazpines (IV, per rectum [PR] or sublingual), paraldehyde (IM), phenobarbital (IV) and phenytoin (IV). There is little experience with levetiracetam in malaria to date, but it may prove to be useful. A study of prophylactic phenobarbital, administered on admission to children with cerebral malaria, was deleterious [32]; as a result, clinicians are advised to treat clinically-evident seizures and to watch for subtle evidence for subclinical events.

Many trials of adjuvant therapies targeting putative pathogenic processes have been conducted. Only a few, even when subjected to meta-analysis, have been adequately powered, and none has demonstrated a positive impact on outcome (Table 96-5).

Anemia The evidence base for treating severe malarial anemia is scanty. “Transfusion triggers” are difficult to develop because the rate at which an anemia develops is as important as the absolute value of the hemoglobin concentration but, in general, transfusions begin to be considered when the hemoglobin drops below 5 gm/dL [packed cell volume (PCV) = 15%]. Clinical clues include signs of hemodynamic instability (passive congestion of the liver, systolic flow murmurs, extra heart sounds, rales, tachycardia) and cerebral hypoperfusion. The clinical decision regarding transfusion should take into account the peripheral parasitemia, as well as the hemoglobin concentration (or hematocrit): the higher the parasitemia, the lower the hemoglobin or hematocrit are likely to drop. The usual practice is to transfuse whole blood (20 ml/kg) or packed cells (10 ml/kg), irrespective of the degree of the anemia or the intensity of the parasitemia. About 5% of pediatric patients require a second transfusion.

Hypoglycemia Patients with severe malaria can develop hypoglycemia if quinine is infused too rapidly; when it develops as part of the disease process, it worsens the prognosis for the patient. If hypoglycemia is identified, the patient should be given 50% dextrose (1 ml/kg) IV, and the glucose should be re-checked soon thereafter and then regularly until they regain consciousness.

Acidosis Acidosis in severe malaria is manifested as deep, Kussmaul-like respirations [33] and can occur with, or without, associated hyperlactatemia. It is frequently a sign of hypovolemia [34]. A large trial in children with a variety of febrile illnesses (57% had malaria) and “compensated shock” compared bolus therapy (normal saline and albumin) with conservative management with no boluses and found that outcomes were significantly better in those who received no additional fluid bolus [35]. When justified, blood transfusions are helpful in this situation; when blood is not indicated, cautious fluid repletion, beginning with normal saline (10 ml/kg) may be helpful. Acidosis may also be a sign of sepsis so collecting a blood culture and starting empiric antibiotic therapy may be justified.

Renal failure This complication is also more common in adults with severe malaria than in children. Untreated, the mortality rate is over 70%. Patients should receive adequate renal replacement therapy – hemofiltration is superior to peritoneal dialysis in terms of mortality and costeffectiveness [36]. The role of hemodialysis has not been assessed in a randomized trial, but is likely to be superior to peritoneal dialysis in patients who are hemodynamically stable [37].

Treating the process

CONCLUSION Malaria remains a major cause of morbidity and mortality in endemic areas, and is the largest single cause of fever in travelers returning from malaria-endemic regions. Prompt recognition and treatment of malaria disease is helpful in terms of preventing disease progression, and prompt recognition and treatment of non-malarial disease (even in parasitemic individuals) is equally important. Patients with severe and complicated malaria can be managed well in resource-poor settings with careful attention to IV fluid support, blood transfusions, convulsions, blood glucose and the airway.

PLASMODIUM OVALE Plasmodium ovale was first described in the blood of a soldier returning from East Africa in 1922 [38]. Although P. ovale has been reported from all continents, it is only in tropical Africa and New Guinea that it is relatively common. In West Africa, a blood film P. ovale parasite positive rate between 0.7% and 10% has been found [39]. Plasmodium ovale is a common cause of morbidity in the endemic communities with the highest incidence of febrile episodes among children aged 0–7 years old, but clinical attacks can be seen in all age groups. Plasmodium ovale can be seen in up to 15% of returning travelers. As febrile episodes are often treated empirically in endemic areas and the confirmation of low-density P. ovale infections by microscopy is demanding, the true incidence of P. ovale malaria is likely underestimated. Plasmodium ovale in African immigrants can present months after arrival in a new region. Characterization of P. ovale from Southeast Asia based on the small subunit rRNA gene and parts of the cysteine protease, ookinete surface protein and cytochrome b genes, indicate that P. ovale can be divided into at least two types – classic and variant – which do not differ morphologically [40]. Variant P. ovale is associated with a higher parasite density in humans. A recent study of 55 P. ovale isolates from around the world showed that variant and classic P. ovale co-exist and do not recombine [41]. Plasmodium ovale causes a relatively mild form of malaria that is very rarely severe (ARDS) or fatal (death caused by splenic rupture reported). The most frequent symptoms are fever with temperatures higher than 38.5°C (seen in half the cases), body aches, chills, nausea, abdominal pain, diarrhea and nonproductive cough. Mild heptomegaly and splenomegaly, thrombocytopenia lower than 100,000/mm3, elevation in hepatic enzymes (AST/ALT) and mild

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TABLE 96-5  Trials of Adjuvant Therapy in Complicated Malaria Therapeutic Intervention

Pathogenic Target

Impact

Recommendation

Reference

Dexamethasone

Cerebral edema

No effect/deleterious effect

Not recommended currently

[87, 88]

Intravenous immune globulin

Reverse sequestration

Sequential trial, halted because superiority was unlikely

Not recommended

[89]

Phenobarbital

Seizure prophylaxis

Adverse effect when administered to all patients with cerebral malaria

Not recommended for use on all patients, but should be considered in those with a documented history of seizures

[32]

Mannitol

Cerebral edema

No effect on outcome

Not recommended currently

[90, 91]

Erythropoietin

Neuroprotection, anti-cytokine

In progress

Await outcome of study

[92]

Desferrioxamine

Inhibit parasite growth, protect against free radicalmediated damage

No impact on outcome

Not recommended

[93, 94]

Dichloroacetate

Lactic acidosis

Positive impact on lactic acidosis, unknown effect on mortality

Not used routinely

[95]

Anti-tumor necrosis Cytokine cascade factor antibody

Positive impact on fever, but no effect on outcome

Not recommended

[96]

L-arginine

Improve endothelial cell function, generate nitric oxide

In progress

Await outcome of study

[97]

N-acetylcysteine

Antioxidant

No effect noted on multiple outcome indicators

Not recommended

[98]

Activated charcoal

Immune modulation

Prevents CM in mice, does not interfere with artesunate kinetics in healthy volunteers

Await outcome of study

[99]

Crystalloids vs. colloids

Intravascular volume depletion Intravenous fluid boluses were and acidosis found to be deleterious

Fluid boluses in moderately dehydrated [35] patients are not recommended

Pentoxifylline

Inhibition of TNF

Trend toward improved survival in earlier studies, not substantiated subsequently

Not recommended

[100–104]

Levamisole

Inhibit sequestration

Trial underway

Await outcome of study

[29, 30]

Exchange blood transfusion

Enhance parasite clearance

Improved parasite clearance times, no impact on outcome

Worth a try only in settings where intravascular volume can be monitored

[105, 106]

Source for trials currently underway: http://www.controlled-trials.com (accessed 13 Mar 2011). CM, cerebral malaria; TNF, tumor necrosis factor.

TABLE 96-6  Endemicity Criterion

Hypoendemic

Mesoendemic

Hyperendemic

Holoendemic

Reference

Spleen rate: 2–9 years

0–10%

11–50%

>50%

>75%

[83]

Parasite prevalence: 2–9 years

0–10%

11–50%

>50%

>75%

Stability

Unstable

Types of epidemic

True

Exaggerated seasonal

Entomological Inoculation Rate (EIR)

<0.25

0.25–10

Stable

[84] [85]

11–140

>140

[86]

The degree of endemic malaria is determined by examination of a statistically significant sample of a population and is assessed and classified as in the Table.

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hyperbilirubinemia are seen in about 50% of patients. The hemoglobin count tends to be normal. The undifferentiated febrile clinical presentation cannot be distinguished from other malarias. Plasmodium ovale is considered a relapsing malaria [42]. However, the relapse frequency and relapse interval of P. ovale is poorly described. Recently, the existence of a true hypnozoite in P. ovale malaria has been questioned [43]. The existence of P. ovale hypnozoites has never been proven by biologic experiments. On one hand, indirect evidence of the existence of hypnozoites, i.e. reports on the occurrence of true relapses undoubtedly caused by this parasite is rare; true P. ovale relapses have been reported only occasionally. On the other hand, P. ovale cases reported without any preventive medication where relapses did not occur outnumber reported relapses caused by this parasite. If true hypnozoites exist then the relapse frequency must be very low.

DIAGNOSIS There tends to be lower initial parasitemias (<500 parasites per μl) with P. ovale malaria, making the diagnosis by routine microscopy insensitive. Plasmodium ovale and P. vivax can be difficult to distinguish morphologically by oil immersion microscopy. Mixed infections, especially in endemic areas, are common. In endemic regions where P. falciparum and/or P. vivax predominate, P. ovale is frequently overlooked. For more accurate diagnosis and estimates of the burden of P. ovale infections, more sensitive diagnostic methods are needed [44]. Plasmodium ovale malaria is currently problematic to diagnose in travelers, with early attempts complicated by the lack of specific clinical features, the rarity of biologic changes and the poor sensitivity of diagnostic tools to detect low parasitaemia. Thus, the diagnosis is commonly delayed or missed. Molecular diagnosis and differentiation of the two subspecies can be accomplished with PCR protocols in reference laboratories [45], but the genetic polymorphisms of the two subspecies require appropriate protocols [46]. Rapid diagnostic tests (RDTs) have not been developed to detect P. ovale, and the performance of currently-available RDTs varies greatly in their capability to detect P. ovale parasites. Sensitivity varies between 0% and 80%, with parasite density a key factor [47–50]. A negative RDT test result cannot exclude the diagnosis of P. ovale malaria.

TREATMENT Chloroquine at 25 mg/kg divided over three days is the treatment of choice if a mono-infection with P. ovale is confirmed. Artemisinin combination treatments (ACTs) are effective and could be used in settings of diagnostic uncertainty. Currently, a radical cure dose of 30 mg primaqine base (0.5 mg/kg) by mouth daily for 14 days is recommended to eliminate hypnozoites; however, note the controversy in this regard above. Use of lower dose primaquine has been associated with therapeutic failures and recurrent P. ovale malaria [51].

PLASMODIUM MALARIAE Plasmodium malariae was first described by Golgi in 1886 when he noted the relationship between the 72-hour lifecycle of the parasite in the blood of patients and the corresponding appearance of fever and chills (the paroxysm) [52]. Fever caused by P. malariae was historically known as “quartan malaria” because of the appearance of fever every fourth day (assuming the first day of fever is day 1). Plasmodium malariae has been reported from all continents but is only relatively common in tropical Africa and the Southwest Pacific. The prevalence of P. malariae varies from less than 1% to as high as 30–40% in focal areas of West Africa and Indonesia based on

standard light microscopy detection of parasites on thick films. In the endemic communities, P. malariae is a common cause of morbidity with the highest incidence of febrile episodes among children less then 10 years old. As febrile episodes are often treated empirically and the confirmation of low-density P. malariae infections by mi­croscopy is difficult, the true incidence of P. malariae malaria is underestimated. Plasmodium malariae is unique in that without treatment, blood stage parasites persist for extremely long periods of time – likely the lifetime of the host. The persistent, low-density parasitemia in otherwise healthy individuals may produce distinctive clinical features, or individuals may be so asymptomatic that they qualify as blood donors. This is why P. malariae causes about 25% [53] of transfusion related cases of malaria although it accounts for only 1–2% of imported cases of malaria [54]. Likewise, asymptomatic persons can re-introduce P. malariae into previously malaria-free areas [55]. Years later, when carriers are immunosuppressed with drugs [56] or stressed by surgery [57], the parasites can recrudesce and they become symptomatic with typical symptoms of malaria. The most important and unique feature of prolonged P. malariae parasitemia is an irreversible, immune-mediated, nephrotic symdrome first noted in West Africa in the 1960s [58, 59]. Nephrotic syndrome caused by P. malariae can also present outside of malaria endemic areas years after the last exposure [60].

CLINICAL PRESENTATION Plasmodium malariae is a relatively mild form of malaria, although the initial paroxysms can be similar to those seen with P. falciparum and P. vivax. The undifferentiated febrile presentation is indistinguishable from other malarias. Deaths associated with P. malariae are not from acute infection but rather caused by end-stage renal disease [61]. The nephrotic syndrome associated with chronic P. malariae is caused by an immune complex, basement membrane nephropathy and presents no differently from nephrotic syndrome associated with other causes. Usually, there is a several-month history of progressively worsening lower extremity edema, frothy urine, hyper­tension and multiple abnormal laboratory findings including proteinuria, hypoalbuminemia, hyperlipidemia, high serum creatinine and anemia. Renal biopsy is usually required to confirm the diagnosis and properly guide management [61]. Plasmodium malariae as the true cause of the nephrotic syndrome may be very difficult to diagnose because the patients may have exceedingly low parasitemias and negative rapid diagnostic test (RDT) results. Parasitologic confirmation in this syndrome requires exhaustive, expert, microscopic review of smears and carefully directed molecular methods [60].

DIAGNOSIS The preferred diagnostic method to confirm P. malariae remains traditional Giemsa-stained thick and thin peripheral blood smears. In the growing parasite, pigment increases rapidly with many jetblack granules. The trophozoite assumes variable shapes but often stretches across the width of the red blood cell to appear as a “band form” (see Fig. 96.3), which is often considered diagnostic, although this band form can be seen with other species, especially P. knowlesi and P. inui. Red blood cells infected with trophozoites of P. malariae parasites are not enlarged and do not contain prominent stippling, which distinguishes them from P. vivax and P. ovale [62]. When considering the microscopic diagnosis of P. malariae, three considerations should be kept in mind: l

there tends to be lower initial and maximal parasitemias with P. malariae than with other species because the number of merozoites per red blood cell replication cycle is lower (6–14), the

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three-day versus two-day developmental cycle produces slower growth, and P. malariae’s preference for older red blood cells limits the number of cells that can be infected [62]; l in endemic regions where P. falciparum and/or P. vivax predominate, mixed infections are the rule and P. malariae is frequently overlooked unless more sensitive diagnostic methods, such as molecular diagnostic tests, are used [63]; l even careful microscopic examination may not be sufficient to morphologically distinguish P. knowlesi – an emerging cause of severe and potentially fatal malaria in Southeast Asia – from P. malariae on the peripheral smear [64]. Molecular methods may be needed to confirm the diagnosis of P. malariae where the two parasite distributions overlap. RDTs for malaria are not developed to specifically diagnose P. malariae, and the detection of parasites relies on various pan-Plasmodium capture reagents not specifically optimized for P. malariae. The performance of currently available RDTs varies greatly (0–100%) in their capability to detect P. malariae parasites. Clinical studies are usually designed to evaluate the sensitivity and specificity of RDTs for P. falciparum and P. vivax, and small numbers of P. malariae are encountered and reported. Whether the poor sensitivity is because of the very low parasitemias (and presumably low antigen levels) in patients or because of the lack of cross-reaction with the capture reagents is not known. A negative RDT test result cannot exclude the diagnosis of P. malariae malaria. Molecular testing is not commercially available or standardized, and results may vary based on regional differences in target gene sequences; caution should be used when relying solely on molecular results to make clinical decisions. As also seen in P. ovale, the targets of P. malariae molecular probes may exhibit geographic variation suggesting subspecies of P. malariae [65] and an additional reason why PCR reactions could yield a false-negative result.

TREATMENT The treatment of choice for the typical, uncomplicated febrile illness associated with P. malariae mono-infection is chloroquine at 25 mg/kg total dose divided over three days. Artemisinin combination treatments (ACTs), as well as other anti-malarial drugs, are effective and could be used in settings of diagnostic uncertainty. Clinicians should be aware of the possibility of occasional recurrent parasitemias with clinical symptoms following treatment with a standard course of chloroquine [66]. These cases likely represent delayed parasite clearance rather than true resistance. There is a 16–59 day range in the length of the pre-patent period in experimental mosquito transmitted P. malariae [62] and it is thought that some parasites could emerge from the liver days or weeks after treatment is initiated when drug levels are inadequate to prevent parasitemia [67]. On such occasions, either re-treatment with a full treatment course of chloroquine or another standard anti-malarial treatment regimen would be satisfactory. Treating the underlying P. malariae in fully established nephrotic syndrome does not improve renal function, as segmental sclerosis and hyalinization of the nephron are irreversible. These patients often become hemodialysis dependent. To prevent end-stage renal disease, P. malariae must be considered, diagnosed and effectively treated as soon as renal symptoms develop [61].

PLASMODIUM KNOWLESI Plasmodium knowlesi is primarily a parasite infecting macaque monkeys. Sporadic human infections, generally linked to macaque exposures, were the rule [68], (aside from a brief flirtation with P. knowlesi as malaria therapy for syphilis in the 1930s [69]), until a 2004 outbreak of “hyperparasitemic P. malariae” in the Kapit division of Malaysian Borneo was confirmed as P. knowlesi using molecular methods [70]. Plasmodium knowlesi is now established as a

common cause of malaria on the Malaysian Peninsula in particular, and in Southeast Asia in general, especially in populations living in close proximity to the simian reservoir [81]. The most common clinical syndrome is a febrile illness, indistinguishable from uncomplicated falciparum malaria, but a small proportion of patients (<10%) progress to severe and complicated disease, in which respiratory distress (ARDS) and renal failure feature more prominently than in severe falciparum malaria [68, 71–74]. In contrast to falciparum malaria, coma is a relatively rare complication of infection with P. knowlesi. Surprisingly, the salient findings in the one case of fatal P. knowlesi malaria that was autopsied are similar to fatal falciparum malaria: there was selective accumulation of parasitized red cells in the brain, heart and kidneys, the brain was slate gray in color and there were petechial hemorrhages scattered through the cerebrum and cerebellum [75]. Plasmodium knowlesi is a quotidian parasite, undergoing asexual replication every 24 hours, which may explain the relatively high incidence of severe anemia [73]. Thrombocytopenia, often profound, is nearly a constant feature in P. knowlesi infections, but no clinically evident coagulopathies have been reported [71–74]. The disease in children is fairly similar to that in adults, but there is one striking contrast in pediatric infections with P. knowlesi compared with P. falciparum: pediatric P. knowlesi infection is restricted to school-age children, whereas falciparum malaria affects all ages [72]. Microscopically, P. knowlesi resembles P. falciparum young ring stages and P. malariae in the mature trophozoite blood stages, therefore a high index of suspicion and judicious use of molecular methods are required to establish the diagnosis definitively [76]. Median parasitemias are typically approximately 1400 parasites per microliter (interquartile range 6–250,000) [71]. To date, there is no evidence that P. knowlesi is a relapsing malaria and, thus far, treatment with a wide variety of anti-malarial drugs (quinine, artesunate, various artemisinin combination therapies [ACTs], mefloquine, with and without primaquine) have been successful [71–74]. Plasmodium knowlesi malaria has been called the “fifth human malaria”, but there is, as yet, no definitive evidence for cyclical transmission by mosquitoes from human to human. Without this evidence, it remains a simian malaria with occasional zoonotic human infections [77]. Analysis of archival blood films suggests that P. knowlesi has infected humans for many years in Malaysian Borneo [78] and recent epidemiologic studies suggest that macaque monkeys are the reservoir host [79]. The recent upsurge in clinical episodes may be related to changes in human exposure to monkeys, deforestation and a decline in P. vivax infections [80].

DIAGNOSIS Plasmodium knowlesi infections are limited to areas where humans (local residents or travelers) are near the reservoir hosts: long-tailed (Macaca fasciularis) and pig-tailed macaques (Macaca nemestrina). Microscopic identification of a malaria infection is the first step, but because of the morphologic similarities between P. falciparum, P. malariae and P. knowlesi, the definitive diagnosis of P. knowlesi rests on molecular detection using a nested PCR technique [14]. Combinations of rapid diagnostic tests (RDTs) can be used to increase diagnostic certainty, but there is no RDT specifically for P. knowlesi at this time.

TREATMENT This parasite has been subjected to less drug pressure than any other malaria parasite infecting humans and has been fully susceptible to a broad range of anti-malarial drugs administered according to standard oral and parenteral regimens (chloroquine, quinine, artemether-lumefantrine, artesunate [71–74]). Primaquine has been used as presumptive anti-relapse treatment, but there is no evidence of a hypnozoite stage, so it may not be necessary [74].

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