126 - 231 Malaria

231 Malaria

sulfadiazine, and macrolides. The CDC recommends that miltefosine now be included, as for treatment of other free-living amebae. Clini­ cians should contact the CDC Emergency Operations Center at (770)-488-7100 for assistance in diagnosis and treatment.

■ ■FURTHER READING Amebiasis Shirley DAT et al: A review of the global burden, new diagnostics, and current therapeutics for amebiasis. Open Forum Infect Dis 5:ofy161, 2018. Uddin MJ et al: Host protective mechanisms to intestinal amebiasis. Trends Parasitol 37:165, 2021. Yanagawa Y et al: Clinical features and gut microbiome of asymptom­ atic Entamoeba histolytica infection. Clin Infect Dis 73:e3163, 2021. Yanagawa Y et al: Diversity of plasticity of virulent characteristics of Entamoeba histolytica. Trop Med and Infect Dis 8:255, 2023. Free-Living Amebae Cope JR et al: The epidemiology and clinical features of Balamuthia mandrillaris disease in the United States, 1974–2016. Clin Infect Dis 68:1815, 2019. Gharpure R et al: Epidemiology and clinical characteristics of pri­ mary amebic meningoencephalitis caused by Naegleria fowleri: A global review. Clin Infect Dis 73:e19, 2021. Haston JC et al: The epidemiology and clinical features of non-keratitis Acanthamoeba infections in the United States, 1956–2020. Open Forum Infect Dis 10:ofac682, 2023. PART 5 Infectious Diseases Elizabeth A. Ashley, Nicholas J. White

Malaria Humanity has but three great enemies: Fever, famine, and war; of these by far the greatest, by far the most terrible, is fever. —William Osler, 1896 Malaria is a protozoan disease transmitted by the bite of infected female Anopheles mosquitoes and is the most important of the para­ sitic diseases of humans. In 2022, there were an estimated 249 million cases in 85 malaria-endemic countries and 608,000 deaths (i.e., ~1660 deaths each day). Two countries had an estimated 43% of these deaths: TABLE 231-1  Characteristics of Plasmodium Species Infecting Humans CHARACTERISTIC P. FALCIPARUM P. VIVAX P. OVALEa P. MALARIAE P. KNOWLESI Duration of intrahepatic phase (days) 5.5

5.5 Number of merozoites released per infected hepatocyte 30,000 10,000 15,000 15,000 20,000 Approximate duration of erythrocytic cycle (h)

Red cell preference Younger cells (but can invade cells of all ages) Reticulocytes and cells up to 2 weeks old Morphology Usually only ring forms; banana-shaped gametocytes Irregularly shaped large rings and trophozoites; enlarged erythrocytes; Schüffner’s dots Pigment color Black Yellow-brown Dark brown Brown-black Dark brown Ability to cause relapses No Yes Yes No No aGenomic studies have revealed P. ovale to be two sympatric species: P. ovale curtisi and P. ovale wallikeri, which are morphologically very similar but may have different incubation periods and latencies. bAlso known as James’s dots.

Nigeria (31%) and Democratic Republic of the Congo (12%). Malaria was eliminated from the United States, Canada, Europe, and Russia

50 years ago, but its prevalence rose in many parts of the tropics between 1970 and 2000. In response to this rise, there was substantial investment aimed at increasing access to accurate diagnosis, effective treatments, and insecticide-treated bed nets. Between 2000 and 2015, malaria mortality rates decreased dramatically as a result of highly effective control programs in several countries; since then, however, progress has reversed and estimated global case numbers, mainly in sub-Saharan Africa, have risen steadily. Meanwhile an increasing num­ ber of countries that had low malaria transmission are now targeting malaria elimination. This ambitious goal is threatened by increasing resistance to antimalarial drugs and insecticides. Malaria remains today, as it has been for centuries, a heavy burden on tropical communities, a threat to nonendemic countries, and a danger to travelers. ETIOLOGY AND PATHOGENESIS Six species of the genus Plasmodium cause nearly all malarial infections in humans. These are P. falciparum, P. vivax, two morphologically iden­ tical sympatric species of P. ovale (curtisi and wallikeri), P. malariae, and—in Southeast Asia—the monkey malaria parasite P. knowlesi (Table 231-1). Occasionally humans are also infected with the monkey parasites P. simium (South America) and P. cynomolgi (Southeast Asia). While almost all deaths are caused by falciparum malaria, P. knowlesi and occasionally P. vivax can also cause severe illness. Human infec­ tion begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary glands during a blood meal (Fig. 231-1). These microscopic motile forms of the malaria parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction. By this amplification process (known as intrahepatic or preerythrocytic schizogony), a single sporozoite may produce from 10,000 to >30,000 daughter merozoites. These few swollen infected liver cells containing the hepatic schizonts eventually burst, discharging motile merozoites into the bloodstream. The merozoites then invade red blood cells (RBCs) to become trophozoites and, in nonimmune subjects, multiply 6- to 20-fold every 48 h (P. knowlesi, 24 h; P. malariae, 72 h). When the parasites reach densities of ~50/μL of blood (~100 million parasites in total in the blood of an adult), the symptomatic stage of the infec­ tion begins. In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain inert for a period ranging from 2 weeks to ≥1 year. These dormant forms, or hypnozoites, are the cause of the relapses that characterize infection with these species. Attachment of merozoites to erythrocytes is mediated via a com­ plex interaction with several different binding ligands and specific erythrocyte surface receptors. P. falciparum merozoites bind via FINDING FOR INDICATED SPECIES Reticulocytes Older cells Younger cells Infected erythrocytes, enlarged and oval with tufted ends; Schüffner’sb dots Band or rectangular forms of trophozoites common Resembles P. falciparum (early trophozoites) or P. malariae (later trophozoites, including band forms)

Sporozoites Liver Ookinete Merozoites Zygote RBC Gamete In mosquito gut Schizont Gametocytes FIGURE 231-1  The malaria transmission cycle from mosquito to human and targets of immunity. In Plasmodium vivax and P. ovale infections some liver stage parasites remain dormant (“hypnozoites”) and awake weeks or months later to cause relapses. RBC, red blood cell. erythrocyte- binding antigen 175 to glycophorin A and via EBA-140 to glycophorin C. The other glycophorins (B and D) also contribute. The merozoite reticulocyte-binding protein homologue 5 (PfRh5) plays a critical role binding to red cell basigin (CD147, EMMPRIN). P. vivax binds to receptors on developing erythrocytes. The Duffy blood-group antigen Fya or Fyb plays an important role in invasion of P. vivax and P. knowlesi. Most West Africans and people with origins in that region have the Duffy-negative FyFy phenotype and are generally resistant to P. vivax malaria. During the first few hours of intraerythrocytic development, the small “ring forms” of the different malaria species appear similar under light microscopy. As the trophozoites enlarge, species-specific characteristics become evident, malaria pigment (hemozoin) becomes visible, and the parasite assumes an irregular or ameboid shape. By the Predominant species circulating P. faIciparum P. knowlesi P. vivax P. falciparum + P. vivax FIGURE 231-2  Malaria-endemic countries showing predominant Plasmodium species. Plasmodium vivax is common in the Horn of Africa and in Mauritania but relatively unusual elsewhere in the continent.

end of the intraerythrocytic life cycle, the parasite has consumed two-thirds of the RBC’s hemoglobin and has grown to occupy most of the cell. It is now called a schizont. Multiple nuclear divisions have taken place (schizogony or merog­ ony). The infected RBC then ruptures to release 6–30 daughter merozoites, each potentially capable of invading a new RBC and repeating the cycle. The disease in human beings is caused by the direct effects of the asexual parasite— RBC invasion and destruction—and by the host’s reaction. Some of the bloodstage parasites develop into morpho­ logically distinct, longer-lived sexual forms (gametocytes) that can transmit malaria. In falciparum malaria, a delay of several asexual cycles precedes this switch to gametocytogenesis. Female gametocytes typically outnumber males by 4:1. Immature (stage I to IV) game­ tocytes are sequestered preferentially in the bone marrow and are also found in the spleen, brain, and intestine.

Pre-erythrocytic Antibodies to sporozoites block invasion of hepatocytes CD4+ and CD8+ T cells kill intrahepatic parasites Antibodies to merozoites block invasion of RBCs Antibodies to malaria “toxins” Asexual erythrocytic Transmission Antibodies to parasite antigens on infected RBCs block cytoadherence to endothelium and augment splenic clearance Cell-mediated immunity and antibody-dependent cytotoxicity kill intraerythocytic parasites Antibodies block fertilization, development, and invasion After being ingested in the blood meal of a biting female anopheline mos­ quito, the male gametocyte exflagellates and divides rapidly into eight motile male gametes. These fuse with female gametocytes, undergoing two rounds of sexual division (meiosis) to form a zygote in the insect’s midgut. This zygote matures into an ookinete, which penetrates and encysts in the mosquito’s gut wall. The resulting oocyst expands by asexual division until it bursts to liberate myriad motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into another human at the next feed, thus completing the parasite’s life cycle. CHAPTER 231 Malaria EPIDEMIOLOGY Malaria occurs throughout most of the tropical regions of the world (Fig. 231-2). P. falciparum predominates in Africa, New Guinea, and Hispaniola (i.e., the Dominican Republic and Haiti); P. vivax is more

common in Central and South America and most of Asia. The preva­ lence of these two species is approximately equal in Oceania. P. malariae is found in most endemic areas, especially throughout sub-Saharan Africa, but is much less common. P. ovale is relatively unusual outside of Africa. In endemic areas, submicroscopic asymptomatic infections (detectable by polymerase chain reaction [PCR]) with all human malaria parasites are much more common than microscopy-detected infections. P. knowlesi causes human infections commonly on the island of Borneo and, to a lesser extent, elsewhere in Southeast Asia, where the main hosts, long-tailed and pig-tailed macaques, are found.

The epidemiology of malaria is complex and may vary considerably even within relatively small geographic areas. Endemicity traditionally has been defined in terms of rates of microscopy-detected parasitemia or palpable spleens in children 2–9 years of age and has been classi­ fied as hypoendemic (<10%), mesoendemic (11–50%), hyperendemic (51–75%), and holoendemic (>75%). In holo- and hyperendemic areas (e.g., certain regions of tropical Africa or coastal New Guinea) where there is intense P. falciparum transmission, people may sustain one or more infectious mosquito bites per week and are infected repeatedly throughout their lives. In such settings, malaria morbidity and mortal­ ity are substantial during early childhood. Immunity against disease is hard won in these areas following repeated symptomatic infections in childhood, but, if the child survives, infections become increasingly asymptomatic. These asymptomatic older children and adults are a major source of malaria transmission. As control measures progress and urbanization expands, environmental conditions become less conducive to malaria transmission, and all age groups may lose protec­ tive immunity and become susceptible to illness. Constant, frequent, year-round infection is termed stable transmission. In areas where transmission is low, erratic, or focal, full protective immunity is not acquired, and symptomatic disease may occur at all ages. This situation usually exists in hypoendemic areas and is termed unstable transmis­ sion. Even in stable transmission areas, there is often an increased incidence of symptomatic malaria during the rainy season coincid­ ing with increased mosquito breeding and transmission. Malaria can behave like an epidemic disease in some areas, particularly those with unstable malaria, such as northern India (the Punjab region), the Horn of Africa, Rwanda, Burundi, southern Africa, and Madagascar. Epi­ demics may occur when changes in environmental, economic, or social conditions (e.g., heavy rains following drought or migration—usually of refugees or workers—from a nonmalarious region to an area of high transmission) are compounded by relaxation or breakdown in malaria control and prevention services caused by underinvestment, war, or civil disorder. Epidemics often result in high mortality rates among all age groups. The principal determinants of the epidemiology of malaria are the number (density), the human-biting habits, and the longevity of the anopheline mosquito vectors. More than 100 of the >400 anoph­ eline species can transmit malaria, but the ~40 species that do so com­ monly vary considerably in their efficiency as malaria vectors. More specifically, the transmission of malaria is directly proportional to the density of the vector, the square of the number of human bites per day per mosquito, and the tenth power of the probability of the mosquito’s surviving for 1 day. Mosquito longevity is particularly important as a determinant of malaria transmissibility because the parasite’s develop­ ment within the mosquito—from gametocyte ingestion to subsequent inoculation (sporogony)—lasts 8–30 days, depending on ambient temperature. In order to transmit malaria, the vector mosquito must therefore survive for >7 days. Sporogony is not completed at cooler temperatures—i.e., <16°C (<60.8°F) for P. vivax and <21°C (<69.8°F) for P. falciparum; thus, transmission does not occur below these tem­ peratures or at high altitudes. Global warming is resulting in malaria transmission at higher altitudes than previously. The most effective mosquito vectors of malaria are those, such as the Anopheles gambiae species complex in Africa, that are long-lived, occur in high densities in tropical climates, breed readily, and bite humans in preference to other animals. The entomologic inoculation rate (i.e., the number of sporo­ zoite-positive mosquito bites per person per year) is the most common measure of malaria transmission and varies from <1 in some parts of Latin America and Southeast Asia to >300 in parts of tropical Africa. PART 5 Infectious Diseases

PATHOPHYSIOLOGY ■ ■ERYTHROCYTE CHANGES After invading an erythrocyte, the growing malarial parasite pro­ gressively consumes and degrades intracellular proteins, principally hemoglobin. The potentially toxic heme is detoxified by lipid-mediated crystallization to biologically inert hemozoin (malaria pigment). The parasite also alters the RBC membrane by changing its transport prop­ erties, exposing cryptic surface antigens, and inserting new parasitederived proteins. The RBC becomes more irregular in shape, more antigenic, and less deformable. In P. falciparum infections, membrane protuberances appear on the erythrocyte’s surface 12–15 h after cell invasion. These “knobs” extrude a high-molecular-weight, antigenically variant, strain-specific erythro­ cyte membrane adhesive protein (PfEMP1) that mediates attachment to receptors on venular and capillary endothelium (cytoadherence). Several vascular receptors have been identified; intercellular adhesion molecule 1 and endothelial protein C receptor are important in the brain, VAR2CSA (which binds chondroitin sulfate A) predominates in the placenta, and CD36 binds parasitized RBCs in most other organs. Erythrocytes containing more mature parasites stick inside and even­ tually block capillaries and venules. Infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythro­ cytes (agglutination). The processes of cytoadherence, rosetting, and agglutination are central to the pathogenesis of falciparum malaria. They result in the sequestration of infected RBCs in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered P. falciparum parasites continue to develop out of reach of the principal host defense mechanism: splenic processing and filtration. As a consequence, only the younger ring forms of the asexual P. falciparum parasites circulate in the peripheral blood, and the level of peripheral parasitemia variably underestimates the true number of parasites within the body. In severe malaria, unin­ fected erythrocytes also become less deformable, which compromises their passage through the partially obstructed capillaries and venules and shortens their survival. In the other human malarias, significant sequestration does not occur, and all stages of the parasite’s development are evident on peripheral-blood smears. P. vivax and P. ovale show a marked predilec­ tion for young RBCs and P. malariae for old cells; these species produce a level of parasitemia that seldom exceeds 2%. In contrast, P. falciparum can invade erythrocytes of all ages and may be associated with very high parasite densities. Dangerously high parasite densities may also occur in P. knowlesi infections, with rapid increases as a result of the shorter (24-h) asexual life cycle. ■ ■HOST RESPONSE Initially, the host responds to malaria infection by activating nonspe­ cific defense mechanisms. Splenic immunologic and filtrative clearance functions are augmented, and the removal of both parasitized and uninfected erythrocytes is accelerated. The spleen also removes dam­ aged ring-form parasites (a process known as “pitting”) from within the red cell and returns the once-infected cells back to the circula­ tion, where their survival is shortened. The parasitized cells escaping splenic removal are destroyed when the schizont ruptures. The mate­ rial released induces monocyte/macrophage activation and the release of proinflammatory cytokines, which cause fever and other pathologic effects. Temperatures of ≥40°C (≥104°F) damage mature parasites; in untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regu­ lar fever spikes and rigors that originally characterized the different malarias. These regular fever patterns (quotidian, daily; tertian, every 2 days; quartan, every 3 days) are seldom seen today as patients receive prompt and effective antimalarial treatment. The geographic distributions of the thalassemias, sickle cell dis­ ease, hemoglobins C and E, hereditary ovalocytosis, and glucose6-phosphate dehydrogenase (G6PD) deficiency closely resemble that of falciparum malaria before the introduction of control measures. This similarity suggests that these genetic disorders confer protection

against death from falciparum malaria. HbA/S heterozygotes (sickle cell trait) have a sixfold reduction in the risk of dying from severe fal­ ciparum malaria and are correspondingly protected from the bacterial infections that complicate malaria. Hemoglobin S–containing RBCs impair parasite growth at low oxygen tensions, and P. falciparum–infected RBCs containing hemoglobin S or C exhibit reduced cytoadherence because of reduced surface presentation of the adhesin PfEMP1. Para­ site multiplication in HbA/E heterozygotes is reduced at high parasite densities. In Melanesia, children with α-thalassemia have more fre­ quent malaria (both vivax and falciparum) in the early years of life, which appears to protect them against severe disease. In Melanesian ovalocytosis and in Africans with the Dantu blood group, rigid eryth­ rocytes resist merozoite invasion. G6PD deficiency provides some pro­ tection against severe P. falciparum infections but has a much stronger protective effect against P. vivax infections. Nonspecific host defense mechanisms stop the infection’s expan­ sion, and the subsequent strain-specific immune response then con­ trols the infection. Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection (premunition). Asymptomatic parasitemia is very common among adults and older children living in regions with stable and intense malaria transmission (i.e., holo- or hyperendemic areas) and also in parts of low-transmission areas. Parasitemia in asymptomatic infections fluctuates in density but often averages ~5000/mL—which is just below the level of microscopy detection but sufficient to generate transmissible densities of gametocytes. Immunity is mainly specific for both the species and the strain of infecting malarial parasite. Both humoral immunity and cellular immunity are necessary for protection, but the mechanisms of each are incompletely understood (Fig. 231-1). Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA, although much of this antibody is unrelated to protec­ tion. Antibodies to a variety of parasite antigens presumably act in concert to limit in vivo replication of the parasite. In P. falciparum infections, the variant surface adhesin PfEMP1 is the most important of these antigens. Passive transfer of maternal antibody contributes to the partial protection of infants from severe malaria in the first months of life. This complex immunity to disease declines when a person lives outside an endemic area for several months or longer. Several factors retard the development of cellular immunity to malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T-cell recognition; malaria antigen–specific immune unresponsiveness; and the enormous strain diversity of malarial parasites, along with the ability of the parasites to express variant immunodominant antigens on the erythrocyte surface that change during the course of infection. Parasites may persist in the blood for months or years (or, in the case of P. malariae, for decades) if treatment is not given. The complexity of the immune response in malaria, the sophistication of the parasites’ evasion mechanisms, and the lack of a good in vitro correlate with clinical immunity have all slowed progress toward effective vaccines. CLINICAL FEATURES Malaria is a common cause of fever in tropical countries. Clinical diag­ nosis is notoriously unreliable. The first symptoms of malaria are non­ specific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, cough, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, the neck stiffness and photophobia of meningitis do not occur. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rig­ ors occur at regular intervals, are unusual and at presentation suggest infection (often relapse) with P. vivax or P. ovale. The temperature of nonimmune individuals and children often rises above 40°C (104°F), with tachycardia and sometimes delirium. Childhood febrile convul­ sions may occur with any of the malarias, but generalized seizures

are associated specifically with falciparum malaria and may herald the development of encephalopathy (cerebral malaria). Many clinical abnormalities have been described in acute malaria, but most patients with uncomplicated infections have few abnormal physical findings other than fever, malaise, mild anemia, and (in some cases) a palpable spleen. Anemia is common among young children living in areas with stable transmission (e.g., much of West Africa) and increases in preva­ lence where resistance has compromised the efficacy of antimalarial drugs. Frequent vivax malaria relapse is an important cause of anemia in young children in some areas (e.g., on the island of New Guinea). In nonimmune individuals with acute malaria, the spleen takes several days to become palpable, but splenic enlargement is found in a high proportion of otherwise healthy individuals in malaria-endemic areas and reflects repeated infections. Slight enlargement of the liver is also common, particularly among young children. Jaundice may develop in patients with otherwise uncomplicated malaria and usually resolves over 1–3 weeks. Malaria is not associated with a rash. Petechial hem­ orrhages in the skin or mucous membranes—features of viral hemor­ rhagic fevers and leptospirosis—develop only very rarely in severe falciparum malaria, although thrombocytopenia is usual.

■ ■SEVERE FALCIPARUM MALARIA Appropriately and promptly treated, uncomplicated falciparum malaria (i.e., where the patient can sit or stand unaided and can swallow medicines and food) carries a mortality rate of <0.1%. However, once vital-organ dysfunction occurs or the total proportion of erythrocytes infected increases to >2% (a level corresponding to >1012 parasites in an adult), mortality risk rises steeply, depending on the immunity of the host. The major manifestations of severe falciparum malaria are shown in Table 231-2, and features indicating a poor prognosis are listed in Table 231-3. CHAPTER 231 Cerebral Malaria  Coma is a characteristic and ominous feature of falciparum malaria and, even with treatment, has been associated with death rates of ~20% among adults and 15% among children. Any obtundation, delirium, or abnormal behavior in falciparum malaria should be taken very seriously. The onset of coma may be gradual or sudden following a convulsion. Malaria Cerebral malaria manifests as a diffuse symmetric encephalopathy; focal neurologic signs are unusual. Although some passive resistance to head flexion may be detected, signs of meningeal irritation are absent. The eyes may be divergent, and bruxism and a pout reflex are common, but other primitive reflexes are usually absent. The corneal reflexes are preserved, except in deep coma. Muscle tone may be either increased or decreased. The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor; the abdominal and cremasteric reflexes are absent. Flexor or extensor posturing may be seen. On routine fun­ doscopy, ~15% of patients have retinal hemorrhages; with pupillary dilation and indirect ophthalmoscopy, this figure increases to 30–40%. Papilledema (8% among children, rare among adults) and cotton wool spots (<5%) also occur. More specific funduscopic abnormalities

(Fig. 231-3) include discrete spots of retinal opacification (30–60%) and decolorization of a retinal vessel or segment of vessel (occasional cases). Convulsions, which are usually generalized and often repeated, occur in ~10% of adults and up to 50% of children with cerebral malaria. More covert seizure activity is common, particularly among children, and may manifest as repetitive tonic–clonic eye movements or even hypersalivation. Whereas adults rarely (<3% of cases) suffer obvious neurologic sequelae, ~10% of children surviving cerebral malaria— especially those with hypoglycemia, severe anemia, repeated seizures, and deep coma—have residual neurologic deficits when they regain consciousness; hemiplegia, cerebral palsy, cortical blindness, deafness, and impaired cognition may all occur. The majority of these deficits improve markedly or resolve completely within 6 months. However, the prevalence of some other deficits increases over time; ~10% of children surviving cerebral malaria have a persistent language deficit. There may also be deficits in learning, planning and executive functions, atten­ tion, memory, and nonverbal functioning. The incidence of epilepsy is increased and life expectancy is decreased among these children.

TABLE 231-2  Manifestations of Severe Falciparum Malaria SIGNS MANIFESTATIONS Major Unarousable coma/ cerebral malaria Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion; a Glasgow Coma Score <11, or in young children a Blantyre Coma Score of <3 Acidemia/acidosis Arterial pH of <7.25, base deficit >8 meq/L, or plasma bicarbonate level of <15 mmol/L; venous lactate level of ≥5 mmol/L; manifests as labored deep breathing, often termed “respiratory distress” Severe normochromic, normocytic anemia Hematocrit of <15% or hemoglobin level of <50 g/L (<5 g/dL) with parasite density of >10,000/μLa Renal failure Serum or plasma creatinine level of >265 μmol/L (>3 mg/dL) or blood urea level of >20 μmol/Lb Pulmonary edema/ adult respiratory distress syndrome Noncardiogenic pulmonary edema, often aggravated by overhydration; radiologically confirmed or oxygen saturation <92% on room air with a respiratory rate >30/ min, often with chest wall indrawing and crepitations on auscultation Hypoglycemia Plasma glucose level of <2.2 mmol/L (<40 mg/dL) Hypotension/shock Systolic blood pressure of <70 mmHg in children 1–5 years or <80 mmHg in adults; with evidence of impaired perfusion or capillary refill >2 s Bleeding/ disseminated intravascular coagulation Significant bleeding and hemorrhage from the gums, nose, and gastrointestinal tract and/or evidence of disseminated intravascular coagulation Convulsions More than two generalized seizures in 24 h; signs of continued seizure activity, sometimes subtle (e.g., tonicclonic eye movements without limb or face movement) PART 5 Infectious Diseases Other Hemoglobinuriac Macroscopic black, brown, or red urine; not associated with effects of oxidant drugs and red blood cell enzyme defects (such as G6PD deficiency) Extreme weakness Prostration; inability to sit unaidedd Hyperparasitemia Parasitemia level of >5% in nonimmune patients (>10% in any patient) Jaundice Serum bilirubin level of >50 mmol/L (>3 mg/dL) if combined with a parasite density of >100,000/μL or other evidence of vital-organ dysfunction aThis is nonspecific and may include patients with chronic anemia; a parasitemia threshold of 100,000/μL is more specific for acute malarial anemia. bThese are criteria for adults. Lower values reflect severe malaria in children. cHemoglobinuria may also occur in uncomplicated malaria and in patients with G6PD deficiency, particularly if they take oxidant drugs such as primaquine. dIn children who are normally able to sit. Abbreviation: G6PD, glucose-6-phosphate dehydrogenase. Hypoglycemia  Hypoglycemia, an important and common com­ plication of severe malaria, is associated with a poor prognosis and is particularly problematic in children and pregnant women. Hypoglyce­ mia in malaria results from both a failure of hepatic gluconeogenesis and an increase in the consumption of glucose by the host and, to a much lesser extent, the malaria parasites. Hypoglycemia may be compounded by quinine, a powerful stimulant of pancreatic insulin secretion, which is still sometimes used in endemic areas for the treat­ ment of both severe and uncomplicated falciparum malaria. In severe disease, the clinical diagnosis of hypoglycemia is difficult: the usual physical signs (sweating, gooseflesh, tachycardia) are absent, and the neurologic impairment caused by hypoglycemia cannot be distin­ guished from that caused by malaria. Acidosis  Acidosis, resulting from accumulation of organic acids, is an important cause of death from severe malaria, which in adults is often compounded by renal impairment. Hypovolemia is not a major contributor to acidosis. Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues where sequestered parasites inter­ fere with microcirculatory flow, lactate production by the parasites,

TABLE 231-3  Features Indicating a Poor Prognosis in Severe Falciparum Malaria Clinical Marked agitation Hyperventilation (respiratory distress) Low core temperature (<36.5°C; <97.7°F) Bleeding Deep coma Repeated convulsions Anuria Shock Laboratory Biochemistry   Hypoglycemia (<2.2 mmol/L)   Hyperlactatemia (≥5 mmol/L)   Acidemia (arterial pH <7.25, base deficit >8 meq/L, or serum HCO3 <15 mmol/L)   Elevated serum creatinine (>265 μmol/L)   Elevated total bilirubin (>50 μmol/L)   Elevated liver enzymes (AST/ALT 3 times upper limit of normal)   Elevated muscle enzymes (CPK ↑, myoglobin ↑)   Elevated urate (>600 μmol/L) Hematology   Leukocytosis (>12,000/μL)   Severe anemia (PCV <10%)   Coagulopathy   Low platelet count (<50,000/μL)   Prolonged prothrombin time (>3 s)   Prolonged partial thromboplastin time   Decreased fibrinogen (<200 mg/dL) Parasitology   Hyperparasitemia   Increased mortality at >100,000/μL   High mortality at >500,000/μL   >20% of parasites identified as pigment-containing trophozoites and schizonts   >5% of neutrophils contain visible malaria pigment Note: Increased risk of concomitant bacteremia in adults if >20% parasitemia. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; PCV, packed cell volume. and a failure of hepatic and renal lactate clearance. Hyperlactate­ mia commonly coexists with hypoglycemia. Acids of gut origin are important contributors to acidosis. In children, ketoacidosis may also contribute. Hydroxyphenyllactic acid, α-hydroxybutyric acid, and β-hydroxybutyric acid concentrations are elevated. Acidotic breathing, sometimes called “respiratory distress,” is a sign of poor prognosis. It is followed often by circulatory failure refractory to volume expansion or inotropic drug treatment and ultimately by respiratory arrest. Plasma concentrations of bicarbonate or lactate are the best biochemical prog­ nosticators in severe malaria. Noncardiogenic Pulmonary Edema  Adults with severe falci­ parum malaria may develop noncardiogenic pulmonary edema (adult respiratory distress syndrome) even after several days of antimalarial therapy. The mortality rate is >80%. The pathogenesis is unclear. Pul­ monary edema can be readily precipitated by overly vigorous adminis­ tration of IV fluid. Noncardiogenic pulmonary edema can also develop in otherwise uncomplicated vivax malaria, where recovery is usual. Renal Impairment  Acute kidney injury is common in severe falciparum malaria. Oliguric renal failure requiring temporary renal replacement therapy is an important manifestation in adults but is unusual among children. The pathogenesis of renal failure is unclear but may be related to erythrocyte sequestration and agglutination interfering with renal microcirculatory flow and metabolism. Clini­ cally and pathologically, this syndrome manifests as acute tubular

FIGURE 231-3  The eye in cerebral malaria: perimacular whitening and palecentered retinal hemorrhages. (Courtesy of N. Beare, T. Taylor, S. Harding, S. Lewallen, and M. Molyneux; with permission.) necrosis. Acute renal failure may occur simultaneously with other vitalorgan dysfunction (in which case the mortality risk is high) or may progress as other disease manifestations resolve. In survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17 days (Chap. 321). Early dialysis or hemo­ filtration considerably improves the chances of survival, particularly in acute hypercatabolic renal failure. Hematologic Abnormalities  Anemia results from accelerated RBC removal by the spleen, obligatory RBC destruction at parasite schi­ zogony, and ineffective erythropoiesis. In severe malaria, the deform­ ability of both infected and uninfected RBCs is reduced. The degree of reduced deformability correlates with prognosis and with the develop­ ment of anemia. Splenic clearance of all RBCs is increased. In nonim­ mune individuals and in areas with unstable transmission, anemia can develop rapidly and transfusion is often required. A hemoglobin of ≤3 g/dL on presentation is associated with increased mortality. Acute hemolytic anemia with massive hemoglobinuria (“blackwater fever”) may occur. Hemoglobinuria may contribute to renal injury. Some patients with blackwater fever have G6PD deficiency, but in the majority of cases, it is unclear why massive hemolysis has occurred. In nonimmune patients, sudden hemolysis may follow many days after artesunate treatment of hyperparasitemia, usually as a result of rela­ tively synchronous loss of once-parasitized “pitted” RBCs. As a conse­ quence of repeated malarial infections, children in high-transmission areas are usually anemic and often develop severe anemia. This results from both shortened survival of uninfected RBCs and marked dys­ erythropoiesis. Anemia is a common consequence of antimalarial drug resistance, which results in repeated or continued infection. Slight coagulation abnormalities are common in falciparum malaria, and mild thrombocytopenia is usual (a normal platelet count should question the diagnosis of malaria). Fewer than 5% of patients with severe malaria have significant bleeding with evidence of disseminated intravascular coagulation. Hematemesis from stress ulceration or acute gastric erosions may occur rarely. Liver Dysfunction  Mild hemolytic jaundice is common in malaria. Severe jaundice is associated with P. falciparum infections; is more common among adults than among children; and results from hemolysis, hepatocyte injury, and cholestasis. Liver failure does not occur. When accompanied by other vital-organ dysfunction (often

TABLE 231-4  Relative Incidence of Severe Complications of Falciparum Malaria NONPREGNANT ADULTS PREGNANT WOMEN CHILDREN COMPLICATION Anemia + ++ +++ Convulsions + + +++ Hypoglycemia + +++ +++ Jaundice +++ +++ + Renal failure +++ +++ + Pulmonary edema ++ +++ + Note: –, rare; +, infrequent; ++, frequent; +++, very frequent. renal impairment), liver dysfunction carries a poor prognosis. Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism. Occasional patients with falciparum malaria may develop deep jaundice (with hemolytic, hepatic, and cholestatic com­ ponents) without evidence of other vital-organ dysfunction, in which case the prognosis is good. Other Complications  HIV/AIDS and malnutrition predispose to more severe malaria in nonimmune individuals. Malaria anemia is worsened by concurrent infections with intestinal helminths, hook­ worm in particular. Approximately 6% of children diagnosed with severe malaria have concomitant bacteremia. In adults, the proportion is lower (<1%), except in those with very high parasite counts (>20% parasitemia). In areas of moderate and high malaria transmission, differentiating severe malaria from sepsis with incidental parasitemia in childhood is very difficult, and severe malaria is overdiagnosed. In endemic areas, Salmonella spp. bacteremia has been associated specifically with P. falciparum infections. Chest infections and cath­ eter-associated urinary tract infections are common among patients who are unconscious for >3 days. Aspiration pneumonia may follow generalized convulsions. The frequencies of complications of severe falciparum malaria are summarized in Table 231-4. CHAPTER 231 Malaria ■ ■MALARIA IN PREGNANCY Malaria in early pregnancy causes fetal loss. In areas of high malaria transmission, falciparum malaria in primi- and secundigravid women is associated with low birth weight (average reduction, ~170 g) and con­ sequently increased infant mortality rates. In general, infected mothers in areas of stable transmission remain asymptomatic despite intense accumulation of parasitized erythrocytes in the placental microcircu­ lation. Maternal HIV infection predisposes pregnant women to more frequent and higher-density malaria infections, predisposes their new­ borns to congenital malarial infection, and exacerbates the reduction in birth weight associated with malaria. In areas with unstable transmission of malaria, pregnant women are prone to severe infections and are particularly likely to develop high P. falciparum parasitemias complicated by anemia, hypoglycemia, and acute pulmonary edema. Fetal distress, premature labor, and stillbirth or low birth weight are common results. Fetal death is common in severe malaria. Congenital malaria occurs in <5% of newborns of infected mothers; its frequency and the level of parasitemia are related directly to the timing of maternal infection and the parasite density in maternal blood and in the placenta. P. vivax malaria in pregnancy is also associated with a reduction in birth weight (average, 110 g), but in contrast to fal­ ciparum malaria, this effect is more pronounced in multigravid than in primigravid women. About 300,000 women die in childbirth yearly, with most deaths occurring in low-income countries; maternal death from hemorrhage at childbirth is correlated with malaria-induced anemia. ■ ■MALARIA IN CHILDREN Most of the estimated >600,000 deaths from falciparum malaria each year are in young African children. Convulsions, coma, hypoglycemia, metabolic acidosis, and severe anemia are relatively common among children with severe malaria, whereas deep jaundice, oliguric acute kid­ ney injury, and acute pulmonary edema are unusual. Severely anemic children may present with labored deep breathing, which previously

has been attributed incorrectly to “anemic congestive cardiac failure” but is usually caused by metabolic acidosis. In general, children toler­ ate antimalarial drugs well and respond rapidly to treatment. Younger children, and in particular malnourished children, require higher body weight–adjusted antimalarial drug doses than older children or adults.

■ ■TRANSFUSION MALARIA Malaria can be transmitted by blood transfusion, needlestick injury, or organ transplantation. The incubation period is often short because there is no preerythrocytic stage of development, and thus there are no relapses of P. vivax and P. ovale infections. The clinical features and management of these cases are the same as for naturally acquired infec­ tions, although primaquine is not needed for radical cure of vivax or ovale malaria as there are no liver stages. CHRONIC COMPLICATIONS OF MALARIA ■ ■HYPERREACTIVE MALARIAL SPLENOMEGALY Chronic or repeated malarial infections produce hypergammaglobu­ linemia; normochromic, normocytic anemia; and, in certain situations, splenomegaly. Some residents of malaria-endemic areas in tropical countries exhibit an abnormal immunologic response to repeated infections that is characterized by massive splenomegaly, hepato­ megaly, marked elevations in serum IgM and malarial antibody titers, hepatic sinusoidal lymphocytosis, and (in Africa) peripheral B-cell lymphocytosis. This syndrome has been associated with the produc­ tion of cytotoxic IgM antibodies to CD8+ T lymphocytes, antibodies to CD5+ T lymphocytes, and an increase in the ratio of CD4+ to CD8+ T cells. These events may lead to uninhibited B-cell production of IgM and the formation of cryoglobulins (IgM aggregates and immune com­ plexes). This immunologic process stimulates lymphoid hyperplasia and clearance activity and eventually produces splenomegaly. Patients with hyperreactive malarial splenomegaly present with an abdominal mass or a dragging sensation in the abdomen and occasional sharp abdominal pains suggesting perisplenitis. There is usually anemia and some degree of pancytopenia (hypersplenism). In some cases, malaria parasites cannot be found in peripheral-blood smears by microscopy. Respiratory and skin infections are common and many patients die of overwhelming sepsis. Persons with hyperreactive malarial splenomegaly living in endemic areas should receive antimalarial chemoprophylaxis; the results are usually good. In nonendemic areas, anti­ malarial treatment is advised. Some cases have been mistaken for hematologic malignancy. However, in other cases refractory to therapy, clonal lymphop­ roliferation may develop, and this can evolve into a malignant lymphoproliferative disorder. PART 5 Infectious Diseases ■ ■QUARTAN MALARIAL NEPHROPATHY Chronic or repeated infections with P. malariae (and possibly with other malarial species) may cause soluble immune complex injury to the renal glomeruli, resulting in the nephrotic syndrome. Other unidentified factors must contribute to this process since only a very small proportion of infected patients develop renal disease. The his­ tologic appearance is that of focal or segmental glomerulonephritis with splitting of the capillary basement membrane. Subendothelial dense depos­ its are seen on electron microscopy, and immu­ nofluorescence reveals deposits of complement and immunoglobulins and P. malariae antigens are often visible. A coarse-granular pattern of basement membrane immunofluorescent deposits (predominantly IgG3) with selective proteinuria carries a better prognosis than a fine-granular, predominantly IgG2 pattern with nonselective pro­ teinuria. Quartan nephropathy is mainly a disease A B C D E F FIGURE 231-4  Thin blood films of Plasmodium falciparum. A. Young trophozoite. B. Old trophozoite. C. Trophozoites in erythrocytes and pigment in polymorphonuclear cells. D. Mature schizont. E. Female gametocyte. F. Male gametocyte. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)

of children and is rarely reported nowadays. It usually responds poorly to treatment with either antimalarial agents or glucocorticoids and cytotoxic drugs. ■ ■BURKITT’S LYMPHOMA AND EPSTEIN-BARR VIRUS INFECTION It is possible that malaria-related immune dysregulation provokes infection with lymphoma viruses. Childhood Burkitt’s lymphoma is strongly associated with Epstein-Barr virus (EBV) and with high transmission of P. falciparum. Chronic P. falciparum malaria drives large numbers of EBV-infected cells through the lymph node germinal centers and deregulates activation-induced cytidine deaminase, result­ ing in DNA damage, c-myc translocations, and sometimes lymphoma. DIAGNOSIS OF MALARIA When a patient in or from a malarious area presents with fever, thick and thin blood smears should be prepared and examined immediately to confirm the diagnosis and identify the species of infecting parasite (Figs. 231-4 through 231-10). In general, if the blood smear is negative when examined by an experienced microscopist, the patient does not have malaria. If reliable microscopy is not available, a rapid test should be performed. Malaria is not a clinical diagnosis. ■ ■DEMONSTRATION OF THE PARASITE The definitive diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained peripheral-blood smears. Of the Romanowsky stains, Giemsa at pH 7.2 is preferred; Field’s, Wright’s, or Leishman’s stain can also be used. Staining of parasites with the fluo­ rescent dye acridine orange allows more rapid diagnosis of malaria (but not speciation of the infection) in patients with low-level parasitemia. Both thin (Figs. 231-4, 231-5, 231-10) and thick (Figs. 231-6, 231-7, 231-8, and 231-9) blood smears should be examined. The thin blood smear should be air-dried, fixed in anhydrous methanol, then stained; the RBCs in the tail of the film should then be examined under oil immersion (×1000 magnification). The density of parasitemia is expressed as the number of parasitized erythrocytes per 1000 RBCs. The thick blood film should be of uneven thickness. The smear should be dried thoroughly and stained without fixing. As many layers of

A B C D E FIGURE 231-5  Thin blood films of Plasmodium vivax. A. Young trophozoite. B. Old trophozoite. C. Mature schizont. D. Female gametocyte. E. Male gametocyte. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) erythrocytes overlie one another and are lysed during the staining pro­ cedure, the thick film has the advantage of concentrating the parasites (by 40- to 100-fold compared with a thin blood film) and thus increas­ ing diagnostic sensitivity. Both parasites and white blood cells (WBCs) are counted, and the number of parasites per unit volume is calculated from the total leukocyte count. Alternatively, a WBC count of 8000/μL is assumed. This figure is converted to the number of parasitized eryth­ rocytes per microliter. A minimum of 200 WBCs should be counted under oil immersion. Interpretation of blood smears, particularly thick films, requires some experience because artifacts are common. Before a thick smear is judged to be negative, 100–200 fields should be examined. In high-transmission areas, the presence of up to 10,000 parasites/μL of blood may be tolerated without symptoms or signs in partially immune individuals. Thus, in these areas, the detection of low-density malaria parasitemia is sensitive but has low specificity in identifying malaria as the cause of illness. Because the prevalence of asymptomatic parasitemia is often high, low-density parasitemia is a common incidental finding in other conditions causing fever. ■ ■RAPID DIAGNOSTIC TESTS Rapid, simple, sensitive, and specific antibody-based diagnostic stick or card tests that detect P. falciparum–specific histidine-rich protein 2 (PfHRP2), lactate dehydrogenase, or occasionally aldolase antigens in finger-prick blood samples have become the main method of A B FIGURE 231-6  Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)

CHAPTER 231 malaria diagnosis in endemic areas (Table 231-5). Some of these rapid diagnostic tests (RDTs) carry a second antibody (either pan-malaria or P. vivax–specific) and so distinguish falciparum malaria from the less dangerous malarias. PfHRP2-based RDTs may remain positive for several weeks after acute infection. This prolonged positivity is a disadvantage in high-transmission areas where infections are frequent but helps in the diagnosis of severe malaria in patients who have taken antimalarial drugs and cleared peripheral parasitemia but who still have a strongly positive PfHRP2 test. A major disadvantage of RDTs is that they do not quantify parasitemia. Widespread use of PfHRP2 RDTs has put strong selection pressure on P. falciparum populations in some areas, leading to an increased prevalence of mutant parasites with deletion of PfHRP2/3 genes that are not detected by the current generation of PfHRP2-based tests. This is a particular problem in the horn of Africa but increasingly reported elsewhere. Malaria The relationship between parasite density and prognosis is complex and variable; in general, patients with >105 parasites/μL are at increased risk of dying, but nonimmune patients may die with much lower counts, and partially immune persons may tolerate parasite densities many times higher with only minor symptoms. In severe malaria, a poor prognosis is indicated by a predominance of more mature P. falciparum parasites (i.e., >20% of parasites with visible pigment) in the peripheral-blood film or by the presence of phagocytosed malarial pigment in >5% of neutrophils (an indicator of recent schizogony). In P. falciparum infections, gametocytemia peaks 1 week after the peak of asexual parasite densities. Because the mature gametocytes of P. falci­ parum (unlike those of other plasmodia) are not affected by most anti­ malarial drugs, their persistence does not mean there is drug resistance or a need to re-treat if a full course of appropriate treatment has been given. Phagocytosed malarial pigment seen inside peripheral-blood monocytes may provide a clue to recent infection if malaria parasites are not detectable. After parasite clearance, this intraphagocytic malar­ ial pigment is often evident for several days in peripheral-blood films, and for longer in bone marrow aspirates or smears of fluid expressed after intradermal puncture. Molecular diagnosis by PCR amplification of parasite nucleic acid is more sensitive than microscopy or rapid diagnostic tests for detecting malaria parasites and defining malarial species. PCR is used in refer­ ence centers but should not be used for primary diagnosis in endemic

A B C FIGURE 231-7  Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) areas as it is too sensitive. In epidemiologic surveys, ultrasensitive PCR detection (1000 times more sensitive than microscopy) has proved very useful in identifying asymptomatic infections as control and eradica­ tion programs drive parasite prevalences down to very low levels and in identifying residual “hot spots” of transmission. Serologic diagnosis with either indirect fluorescent antibody or enzyme-linked immuno­ sorbent assays is useful for screening of prospective blood donors and may prove useful as a measure of transmission intensity in future epide­ miologic studies. Serology has no place in the diagnosis of acute illness. ■ ■LABORATORY FINDINGS IN ACUTE MALARIA Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia, with reac­ tive lymphocytosis and eosinophilia in the weeks after acute infection. The platelet count is usually reduced to ~105/μL (a normal platelet count may point to another diagnosis). The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acutephase proteins are elevated. Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia. Antithrombin III levels are reduced even in mild infection. In uncomplicated malaria, plasma concentra­ tions of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal. Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicar­ bonate, phosphate, and albumin, together with elevations in lactate, BUN, creatinine (adjusted for age and body mass), urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin. Hypergam­ maglobulinemia is usual in immune and semi-immune subjects living in malaria-endemic areas. Urinalysis generally gives normal results. In adults and children with cerebral malaria, the mean cerebrospinal fluid (CSF) opening pressure at lumbar puncture is ~160 mm H2O; usually the CSF content is normal or there is a slight elevation of total protein level (<1.0 g/L [<100 mg/dL]) and cell count (<20/μL). PART 5 Infectious Diseases TREATMENT Malaria Patients with severe malaria and those unable to take oral drugs should receive parenteral antimalarial therapy immediately (Table 231-6). Antimalarial drug susceptibility testing can be A B C FIGURE 231-8  Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)

performed but yields results too slowly to influence the choice of treatment. Molecular markers of resistance to various antimalarial drugs have been identified such as dhfr mutations (antifols), Pfcrt mutations (chloroquine), Pfkelch13 mutations (artemisinin), Pfpm1 or Pfpm2 gene amplification (piperaquine) and Pfmdr1gene ampli­ fication (mefloquine), which are used in population surveillance studies. The World Health Organization (WHO) recommends

artemisinin-based combination therapy (ACT) as first-line treat­ ment for uncomplicated P. falciparum malaria in malaria-endemic areas. An ACT comprises an artemisinin derivative (e.g., artesunate, artemether, or dihydroartemisinin), combined with a single partner drug from another antimalarial drug class in a fixed-dose cofor­ mulation. ACTs are also the recommended first-line treatment for P. knowlesi infections, and either chloroquine or an ACT is recom­ mended for the other malarias. The choice of ACT depends on the likely sensitivity of the infecting parasites to the partner drug. ACTs may be unavailable in temperate countries, where treatment recom­ mendations are limited to the registered available drugs. Despite increasing evidence of chloroquine resistance in P. vivax (from parts of Indonesia, Oceania, eastern and southern Asia, and Central and South America), chloroquine remains an effective treatment for P. vivax malaria in many areas and for P. ovale and P. malariae infections everywhere. Artemisinin resistance in P. falciparum emerged in Southeast Asia in the late 2000s, where it was followed by piperaquine and mefloquine resistance in some areas. Significant artemisinin resis­ tance is now prevalent throughout the Greater Mekong Subregion and has now emerged and spread in East Africa. As new antima­ larials are still years away, it has been suggested that current ACTs should now combine two slowly eliminated partner drugs to pro­ vide mutual protection against resistance (triple ACTs). Falsified or substandard antimalarial drugs are sold in many Asian and African countries and may be the cause of treatment failures. Characteris­ tics of antimalarial drugs are shown in Table 231-7. SEVERE MALARIA In large randomized controlled clinical trials, parenteral artesunate, a water-soluble artemisinin derivative, reduced severe falciparum malaria mortality rates by 35% in Asian adults and children and by 22.5% in African children compared with quinine treatment. Artesunate therefore is now the drug of choice for all patients with

A B C FIGURE 231-9  Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) A B C D FIGURE 231-10  Thin blood films of Plasmodium knowlesi. A. Young ring stages B. Older ring stages C. Mature trophozoites D. Schizonts (B and C may look very similar to the “band forms” of P. malariae). (From Kesinee Chotivanich, Cell and Tissue Culture Resources Unit laboratory and MORU, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.) TABLE 231-5  Standard Methods for the Diagnosis of Malariaa METHOD PROCEDURE ADVANTAGES DISADVANTAGES Thick blood filmb Blood should be uneven in thickness but thin enough that the hands of a watch can be read through part of the spot. Stain dried, unfixed blood spot with Giemsa, Field’s, or another Romanowsky stain. Count number of asexual parasites per 200 WBCs (or per 500 WBCs at low densities). Count and report gametocytes separately.c Thin blood filmd Stain fixed smear with Giemsa, Field’s, or another Romanowsky stain. Count number of RBCs containing asexual parasites per 1000 RBCs. In severe malaria, assess stage of parasite development and count neutrophils containing malaria pigment.e Count and report gametocytes separately.c PfHRP2 dipstick or card test A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibody capture of parasitic antigens reads out as a colored band. Plasmodium LDH dipstick or card test A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibody capture of parasitic antigens reads out as two colored bands. One band is genus specific (all malarias) or P. vivax specific, and the other band is specific for P. falciparum. Microtube concentration methods with acridine orange staining Blood is collected in a specialized tube containing acridine orange, anticoagulant, and a float. After centrifugation, which concentrates the parasitized cells around the float, fluorescence microscopy is performed. aMalaria cannot be diagnosed clinically with accuracy, but treatment should be started on clinical grounds if laboratory confirmation is likely to be delayed. In areas of the world where malaria is endemic and transmission rates are high, low-level asymptomatic parasitemia is common in otherwise healthy people. Thus, malaria may not be the cause of a fever in a parasitemic patient, although in this context, the presence of >10,000 parasites/μL (~0.2% parasitemia) does indicate that malaria is likely to be the cause. Antibody and polymerase chain reaction (PCR) tests have no role in the diagnosis of malaria except that PCR is increasingly used for genotyping and speciation in mixed infections and for detection of low-level parasitemia in asymptomatic residents of endemic areas. bAsexual parasites/200 WBCs × 40 = parasite count/μL (assumes a WBC count of 8000/μL). See Figs. 231-6 through 231-10. cP. falciparum gametocytemia may persist for days or weeks after clearance of asexual parasites. Gametocytemia without asexual parasitemia does not indicate active infection. dParasitized RBCs (/1000) × hematocrit × 125.6 = parasite count/μL. See Figs. 231-4, 231-5 and 231-10. eThe presence of >100,000 parasites/μL (~2% parasitemia) is associated with an increased risk of severe malaria, but some patients have severe malaria with lower counts. At any level of parasitemia, the finding that >50% of parasites are tiny rings (cytoplasm thickness less than half of nucleus width) carries a relatively good prognosis. In a severely ill patient, the presence of visible pigment in >20% of parasites or of phagocytosed pigment in >5% of polymorphonuclear leukocytes (indicating massive recent schizogony) carries a worse prognosis. fPersistence of PfHRP2 is a disadvantage in high-transmission settings, where many asymptomatic people have positive tests, but can be used to diagnostic advantage in low-transmission settings when a sick patient has previously received unknown treatment (which, in endemic areas, often consists of antimalarial drugs). In this situation, a positive PfHRP2 test indicates that the illness is falciparum malaria, even if the blood smear is negative. Abbreviations: LDH, lactate dehydrogenase; PfHRP2, P. falciparum histidine-rich protein 2; RBCs, red blood cells; WBCs, white blood cells.

CHAPTER 231 Sensitive (0.001% parasitemia); species specific; inexpensive Requires experience (artifacts may be misinterpreted as low-level parasitemia); underestimates true count Malaria Rapid; species specific; inexpensive; in severe malaria, provides prognostic informatione Insensitive (<0.05% parasitemia); uneven distribution of P. vivax, as enlarged infected red cells concentrate at leading edge Robust and relatively inexpensive; rapid; sensitivity similar to or slightly lower than that of thick films (~0.001% parasitemia) Detects only Plasmodium falciparum; remains positive for weeks after high-density infectionsf; does not quantitate P. falciparum parasitemia; evasion of detection by certain strains due to polymorphisms/deletions in HRP2/3 genes Rapid; sensitivity similar to or slightly lower than that of thick films for P. falciparum (~0.001% parasitemia) May miss low-level parasitemia with P. vivax, P. ovale, and P. malariae and may not speciate these organisms; does not quantitate P. falciparum parasitemia; lower sensitivity for detection of P. knowlesi, which may be misidentified as P. falciparum Sensitivity similar or superior to that of thick films (~0.001% parasitemia); ideal for processing large numbers of samples rapidly Does not speciate or quantitate; requires fluorescence microscopy

TABLE 231-6  Regimens for the Treatment of Malariaa TYPE OF DISEASE OR TREATMENT REGIMEN(S) Uncomplicated Malaria Known chloroquine-sensitive strains of Plasmodium vivax, P. malariae, P. ovale, P. falciparumb Chloroquine (10 mg of base/kg stat followed by 5 mg/kg at 12, 24, and 36 h or by 10 mg/kg at 24 h and 5 mg/kg at 48 h) or Amodiaquine (10–12 mg of base/kg qd for 3 days) Radical treatment for P. vivax or P. ovale infection (prevention of relapse) In addition to chloroquine or amodiaquine or ACT, primaquine (0.5 mg of base/kg qd in Southeast Asia and Oceania [total dose 7 mg/kg] and 0.25 mg/kg elsewhere [total dose 3.5 mg/kg]) should be given for 14 days to prevent relapse.c In mild G6PD deficiency, 0.75 mg of base/kg should be given once weekly for 8 weeks. Primaquine should not be given in severe G6PD deficiency. Single dose tafenoquine (adult dose 300 mg) is being introduced for radical cure in some areas alongside quantitative G6PD testing. Can be given only If G6PD levels are normal. P. falciparum malaria Artesunated,e (4 mg/kg qd for 3 days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single dose or Artesunated (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)d,e or Artemether-lumefantrined (1.5/9 mg/kg bid for 3 days with food) or Artesunated (4 mg/kg qd for 3 days) plus mefloquine (24–25 mg of base/kg—either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3)f or DHA-piperaquined (target dose: 4/24 mg/kg qd for 3 days in children weighing <25 kg and 4/18 mg/kg qd for 3 days in persons weighing ≥25 kg) or Artesunate-pyronaridined (4/12 mg/kg qd for 3 days) Second-line treatment/treatment of imported malaria (if other ACT not available) Artesunatee (2 mg/kg qd for 7 days) or quinine (10 mg of salt/kg tid for 7 days) plus 1 of the following 3: Tetracyclinef (4 mg/kg qid for 7 days) Doxycyclinef (3 mg/kg qd for 7 days) Clindamycin (10 mg/kg bid for 7 days) or Atovaquone-proguanil (20/8 mg/kg qd for 3 days with food) PART 5 Infectious Diseases Severe Falciparum Malariag,h,i   Artesunatee (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary; for children weighing <20 kg, give 3 mg/kg per dose) or, if unavailable, Artemethere (3.2 mg/kg stat IM followed by 1.6 mg/kg qd) or, if unavailable, Quinine dihydrochloride (20 mg of salt/kgj infused over 4 h, followed by 10 mg of salt/kg infused over 2–8 h q8hk) aIn endemic areas where malaria transmission is low, except in pregnant women and infants, a single dose of primaquine (0.25 mg of base/kg) should be added as a gametocytocide to all falciparum malaria treatments to prevent transmission. This is safe, even in G6PD deficiency. bVery few areas now have chloroquine-sensitive P. falciparum malaria. cRecent large studies indicate that these total doses can be condensed into 7-day primaquine regimens. dIn areas where the partner drug to artesunate is known to be effective. Fixed-dose co-formulated combinations are available. The World Health Organization recommends artemisinin combination regimens as first-line therapy for falciparum malaria in all tropical countries and advocates use of fixed-dose combinations. eArtemisinin derivatives are not readily available in some temperate countries. f Tetracycline and doxycycline should not be given to pregnant women or to children <8 years of age. gOral treatment should be substituted as soon as the patient recovers sufficiently to take fluids by mouth. hArtesunate is the drug of choice when available. The data from large studies in Southeast Asia showed a 35% lower mortality rate than with quinine, and very large studies in Africa showed a 22.5% reduction in mortality rate compared with quinine. The doses of artesunate in children weighing <20 kg should be 3 mg/kg. iPatients with severe malaria acquired in an area where artemisinin resistance has been confirmed should be given parenteral artesunate and quinine together at standard treatment doses. jA loading dose should not be given if therapeutic doses of quinine have definitely been administered in the previous 24 h. kInfusions can be given in 0.9% saline and 5–10% dextrose in water. Infusion rates for quinine should be carefully controlled. Abbreviations: ACT, artemisinin combination therapy; DHA, dihydroartemisinin; G6PD, glucose-6-phosphate dehydrogenase. severe malaria everywhere. Artesunate is given by IV injection but is also absorbed rapidly following IM injection. Artemether and the closely related drug artemotil (arteether) are oil-based formulations given by IM injection; they are erratically absorbed and do not confer the same survival benefit as artesunate. A rectal formulation of artesunate has been developed as a community-based prerefer­ ral treatment for patients in the rural tropics who cannot take oral medications. Prereferral administration of rectal artesunate has been shown to decrease mortality rates among severely ill children without access to immediate parenteral treatment. IV artesunate is approved by the U.S. Food and Drug Administration for the treatment of severe malaria and can be obtained from major drug distributors in the United States. Although parenteral quinine is steadily being replaced by parenteral artesunate in endemic areas, it may still have a small role in the treatment of presumed artemis­ inin-resistant severe falciparum malaria, where a precautionary

approach is adopted and both artesunate and quinine are given together in full doses. Severe falciparum malaria constitutes a medical emergency requiring intensive nursing care and careful management. Frequent evaluation of the patient’s condition is essential. Adjunctive treat­ ments such as high-dose glucocorticoids, urea, heparin, dextran, desferrioxamine, antibody to tumor necrosis factor α, high-dose phenobarbital (20 mg/kg), mannitol, or large-volume fluid or albu­ min boluses have proved either ineffective or harmful in clinical trials and should not be used. In acute renal failure or severe meta­ bolic acidosis, hemofiltration or hemodialysis should be started as early as possible. In severe malaria, parenteral antimalarial treatment should be started immediately, and in endemic areas, because of the diffi­ culty in distinguishing sepsis from severe malaria, broad-spectrum antibiotics should also be started in children. Artesunate, given

TABLE 231-7  Properties of Antimalarial Drugs DRUG(S)a PHARMACOKINETIC PROPERTIES ANTIMALARIAL ACTIVITY MINOR TOXICITY MAJOR TOXICITY Quinine Good oral and IM absorption (quinine); Cl and Vd reduced, but plasma protein binding (principally to α1 acid glycoprotein) increased (90%) in malaria; quinine t1/2: 16 h in malaria, 11 h in healthy persons Acts mainly on trophozoite blood stage; kills gametocytes of P. vivax, P. ovale, and P. malariae (but not P. falciparum); no action on liver stages Chloroquine Good oral absorption, very rapid IM and SC absorption; complex pharmacokinetics; enormous Cl and Vd (unaffected by malaria); blood concentration profile determined by distribution processes in malaria; t1/2: 1–2 months. Active desethyl metabolite about 25% of parent drug concentrations As for quinine, but acts slightly earlier in asexual cycle Piperaquine Adequate oral absorption, may be enhanced by fats; similar pharmacokinetics to chloroquine; t1/2: 21–28 days As for chloroquine; resistance has emerged in Southeast Asia Amodiaquine Good oral absorption; largely converted to active metabolite desethylamodiaquine; t1/2: 4–5 days As for chloroquine, but more active against chloroquine-resistant P. falciparum Primaquine Complete oral absorption; active metabolite produced mainly via CYP2D6; t1/2: 5–7 h Radical cure; eradicates hepatic forms of P. vivax and P. ovale; kills P. falciparum gametocytes; kills developing liver stages of all species Mefloquine Adequate oral absorption; no parenteral preparation; t1/2: 14–20 days (shorter in malaria) As for quinine; resistance has emerged in Southeast Asia Lumefantrine Highly variable absorption related to fat intake; t1/2: 3–4 days As for quinine None identified None identified Artemisinin and derivatives (artemether, artesunate) Good oral absorption; good absorption of IM artesunate but slow and variable absorption of IM artemether; artesunate and artemether biotransformed to active metabolite dihydroartemisinin; all drugs eliminated very rapidly; t1/2: <1 h Broader stage specificity and more rapid than other drugs; no action on liver stages; kills all but fully mature gametocytes of P. falciparum Pyrimethamine Good oral absorption, variable IM absorption; t1/2: 4 days For blood stages, acts mainly on mature forms; causal prophylactic Proguanilb (chloroguanide) Good oral absorption; biotransformed to active metabolite cycloguanil; t1/2: 16 h; biotransformation reduced by oral contraceptive use and in pregnancy Causal prophylactic; not used alone for treatment Atovaquoneb Highly variable absorption related to fat intake; t1/2: 30–70 h Acts mainly on trophozoite blood stage None identified None identified Tetracycline, doxycyclinec Excellent absorption; t1/2: 8 h for tetracycline, 18 h for doxycycline Weak antimalarial activity; should not be used alone for treatment Pyronaridine Rapid variable absorption, large Vd; t1/2: 12–14 days Acts mainly on trophozoite blood stage; kills gametocytes of P. vivax, P. ovale, and P. malariae (but not P. falciparum); no action on liver stages Arterolane t1/2: 3 h Broad stage specificity; no action on liver stages; kills all but fully mature gametocytes of P. falciparum aSeveral antimalarial drugs are formulated as different salts (e.g., phosphate, sulfate, hydrochloride) and are therefore prescribed as base equivalents. For example, chloroquine phosphate 250 salt contains 155 mg base equivalent. It is very important to check when prescribing that the correct dose is being given. bAtovaquone and proguanil are prescribed as a fixed-dose combination. This and proguanil alone should not be given if the estimated glomerular filtration rate is <30 mL/min. cTetracycline and doxycycline should not be given to pregnant women or to children <8 years of age. Abbreviations: Cl, systemic clearance; ECG, electrocardiogram; G6PD, glucose-6-phosphate dehydrogenase; Vd, total apparent volume of distribution.

Common: cinchonism (tinnitus, high-tone hearing loss, nausea, vomiting, dysphoria, postural hypotension); ECG QT interval prolongation (usually by <10%). Rare: diarrhea, visual disturbance, rashes. Note: very bitter taste Common: hypoglycemia. Rare: hypotension, blindness, deafness, cardiac arrhythmias, thrombocytopenia, hemolysis, hemolytic-uremic syndrome, vasculitis, cholestatic hepatitis, neuromuscular paralysis. Common: nausea, dysphoria, pruritus in dark-skinned patients, postural hypotension, ECG QT prolongation. Rare: accommodation difficulties, keratopathy, hypoglycemia, rash. Note: bitter taste but usually well tolerated Acute: hypotensive shock (parenteral), cardiac arrhythmias, neuropsychiatric reactions. Chronic: retinopathy (cumulative dose, >100 g), skeletal and cardiac myopathy Occasional epigastric pain, diarrhea, ECG QT prolongation None identified Nausea (tastes better than chloroquine), dysphoria, headache, bradycardia, ECG QT prolongation Agranulocytosis; hepatitis, mainly with prophylactic use; should not be used with efavirenz Nausea, vomiting, diarrhea, abdominal pain, hemolysis, methemoglobinemia Serious hemolytic anemia in severe G6PD deficiency; hemoglobinuria CHAPTER 231 Nausea, giddiness, dysphoria, fuzzy thinking, sleeplessness, nightmares, sense of dissociation Neuropsychiatric reactions, convulsions, encephalopathy Malaria Reduction in reticulocyte count (but not anemia); neutropenia at high doses; in some cases, delayed anemia after treatment of severe malaria with hyperparasitemia Anaphylaxis, urticaria, fever Well tolerated Megaloblastic anemia, pancytopenia, pulmonary infiltration Well tolerated; mouth ulcers and rare alopecia Megaloblastic anemia in renal failure Gastrointestinal intolerance, deposition in growing bones and teeth (tetracycline), photosensitivity, moniliasis, benign intracranial hypertension Renal failure in patients with impaired renal function (tetracycline) Gastrointestinal intolerance, anemia, transient elevation of aminotransferases, hypoglycemia, headache None identified Gastrointestinal intolerance, transient elevation of aminotransferases None identified

by either IV or IM injection, is simple to administer, very safe, and rapidly effective. It does not require dose adjustments in liver dysfunction or renal failure. It should be used in pregnant women with severe malaria. If artesunate is unavailable and arte­ mether or quinine is used, an initial loading dose must be given so that therapeutic concentrations are reached as soon as possible. Quinine causes dangerous hypotension if injected rapidly and so must be administered carefully by rate-controlled infusion only. If this approach is not possible, quinine may be given by deep IM injections into the anterior thigh. The optimal therapeutic range for quinine in severe malaria is not known with certainty, but total plasma concentrations of 8–15 mg/L for quinine are effective and do not cause serious toxicity. If the patient remains seriously ill or in acute renal failure for >2 days, maintenance doses of quinine should be reduced by 30–50% to prevent toxic accumulation of the drug. The initial dose should never be reduced. Convulsions should be treated promptly with IV (or rectal) benzodiazepines. The role of prophylactic anticonvulsants in children is uncertain. If respira­ tory support is not available, a full loading dose of phenobarbital (20 mg/kg) to prevent convulsions should not be given as it may cause respiratory arrest. Levetiracetam is the preferred anticonvul­ sant to control seizures.

When the patient is unconscious, the blood glucose level should be measured every 6 h for at least 24 h. All patients should receive a continuous infusion of dextrose, and blood concentra­ tions ideally should be maintained above 4 mmol/L. Hypoglyce­ mia (<2.2 mmol/L or 40 mg/dL) usually occurs within the first 24 h and should be treated immediately with bolus glucose. The parasite count and hematocrit should be measured every 6–12 h. Anemia develops rapidly. There is uncertainty as to the optimal thresholds for transfusion as there is some evidence that moderate anemia may be beneficial in a patient with severe malaria and vital organ dysfunction. It is recommended that if the hematocrit falls to <20%, whole blood (preferably fresh) or packed cells should be transfused slowly, with careful attention to circulatory status. In areas with higher malaria transmission, where blood for transfu­ sion is in short supply, a threshold of 15% is widely used. Renal function should be checked at least daily. Children presenting with very severe anemia (hemoglobin <4 g/dL) and acidotic breathing require immediate blood transfusion. Management of fluid balance is difficult in severe malaria, particularly in adults, because of the thin dividing line between overhydration (leading to pulmonary edema) and underhydration (contributing to renal impairment). Fluid balance management is different from that in sepsis: fluid boluses are potentially dangerous in severe malaria. Nasogastric feeding should be delayed in nonintubated patients (for 60 h in adults and 36 h in children) to reduce the risk of aspiration pneu­ monia. As soon as the patient can take fluids, oral therapy should be substituted for parenteral treatment and a full 3-day course of ACT given. Mefloquine should be avoided as follow-on treatment for severe malaria because of the increased risk of post-malaria neurologic syndrome. PART 5 Infectious Diseases In areas of high transmission of both P. falciparum and P. vivax (the island of New Guinea), severe and potentially life-threatening anemia is common among children, and both species contribute. Elsewhere, severe vivax malaria may occur but is uncommon. Many patients have had comorbidities contributing to vital-organ dysfunction. Noncardiogenic pulmonary edema may occur. P. knowlesi can cause severe disease associated with high parasite densities. Acute kidney injury, respiratory distress, and shock have all been described, but cerebral malaria does not occur. Treatment for severe vivax and knowlesi malaria should follow the recommen­ dations given for falciparum malaria. UNCOMPLICATED MALARIA P. falciparum and P. knowlesi infections should be treated with an artemisinin-based combination because of their propensity for high parasite densities and severe disease. Infections with sensitive strains of P. vivax, P. malariae, and P. ovale should be treated either with an

ACT or oral chloroquine (total dose, 25 mg of base/kg). The ACT regi­ mens now recommended are safe and effective in adults, children, and pregnant women (all trimesters). The WHO recommends that artemether-lumefantrine should be given preferentially in the first trimester of pregnancy, if available, since there is the most experi­ ence with this drug. The rapidly eliminated artemisinin component is an artemisinin derivative (artesunate, artemether, or dihydroar­ temisinin) given for 3 days, and the partner drug is usually a more slowly eliminated antimalarial to which P. falciparum in the area is sensitive. Six ACT regimens are currently recommended by the WHO: artemether-lumefantrine, artesunate-mefloquine, dihydro­ artemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, artesunate-amodiaquine, and artesunate-pyronaridine. In areas of low malaria transmission or to contain resistance spread, a single dose of primaquine (0.25 mg/kg) should be added to ACT as a P. falciparum gametocytocide to reduce the transmissibility of the infection. This low dose of primaquine is safe even in G6PD deficiency. Pregnant women should not be given primaquine. Atovaquone-proguanil is highly effective everywhere, although it is seldom used in endemic areas because of its high cost and the propensity for rapid emergence of resistance. Clinical recovery is slower after atovaquone-proguanil treatment than after ACT. Of great concern is the spread of artemisinin-resistant P. falciparum in Southeast Asia and East Africa. Infections with these resistant parasites are cleared slowly from the blood, with parasite clearance half-lives >5 h and clearance times typically exceeding 3 days. Cure rates with ACT have fallen to unacceptably low levels in some areas. Triple antimalarial combinations are under evaluation with promising results to date. The 3-day ACT regimens are all well tolerated, although meflo­ quine is associated with increased rates of vomiting and dizziness. As second-line treatment for recrudescence following first-line therapy, a different ACT regimen may be given. Patients should be monitored for vomiting for 1 h after the administration of any oral antimalarial drug. If there is vomit­ ing, the dose should be repeated. Symptom-based treatment, with acetaminophen (paracetamol) administration, lowers fever and thereby reduces the patient’s propensity to vomit these drugs. Minor central nervous system (CNS) reactions (nausea, dizziness, sleep disturbances) are common. The incidence of serious adverse neuropsychiatric reactions to mefloquine treatment is ~1 in 1000 in Asia but may be as high as 1 in 200 among African and white ethnic groups. Amodiaquine may also cause adverse CNS effects. All the antimalarial quinolines (chloroquine, piperaquine amodiaquine, mefloquine, and quinine) exacerbate the orthostatic hypotension associated with malaria, and all are tolerated better by children than by adults. Chloroquine, amodiaquine, and piperaquine all prolong ventricular repolarization (QT prolongation) but, at currently rec­ ommended doses, are not proarrhythmic. Pregnant women, young children, patients unable to tolerate oral therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evalu­ ated carefully and hospitalization considered. If there is any doubt as to the identity of the infecting malarial species, treatment for falciparum malaria should be given. A negative blood smear read by an experienced microscopist makes malaria very unlikely but does not rule it out completely; thick blood films should be checked again 1 and 2 days later to exclude the diagnosis. Nonimmune patients receiving treatment for malaria should have daily parasite counts performed to confirm reduction until the thick films are negative for asexual parasite stages. If the asexual parasitemia has not cleared by 7 days (and adherence is assured), second-line treat­ ment should be administered. To eradicate persistent liver stages and prevent relapse (radi­ cal treatment), primaquine (0.5 mg of base/kg in East Asia and Oceania and 0.25 mg/kg elsewhere) should be given once daily for 14 days to patients with P. vivax or P. ovale infection after laboratory tests for G6PD deficiency have proved negative. The same total dose may be given over 7 days. If the patient has a mild variant of G6PD deficiency, primaquine can be given in a

dose of 0.75 mg of base/kg (maximum, 45 mg) once weekly for 8 weeks. Pregnant women with vivax or ovale malaria should not be given primaquine but should receive suppressive prophylaxis with chloroquine (5 mg of base/kg per week) until 1 month after delivery, after which radical treatment can be given. The slowly eliminated 8-aminoquinoline tafenoquine has been registered in some countries (currently recommended adult dose 300 mg, which may be too low; dose-optimization studies are ongo­ ing). This allows radical cure to be given in a single dose. The consequent risk of protracted hemolysis in G6PD deficiency, including in female heterozygotes who may test as normal with current G6PD screens (which detect <30–40% of normal enzyme activity), requires that all patients should have a quantitative test of G6PD activity before receiving tafenoquine. Only those with

70% of normal activity should receive the drug. MANAGEMENT OF COMPLICATIONS OF MALARIA Acute Renal Failure  If plasma levels of BUN or age- and weightadjusted creatinine rise despite adequate rehydration, fluid admin­ istration should be restricted to prevent volume overload. As in other forms of hypercatabolic acute kidney injury, renal replace­ ment therapy is best performed early (Chap. 321). Hemofiltration and hemodialysis are more effective than peritoneal dialysis and are associated with lower mortality risk. Some patients with renal impairment pass small volumes of urine sufficient to allow con­ trol of fluid balance; these cases can be managed conservatively if other indications for dialysis do not arise. Renal function usually improves within days, but full recovery may take weeks. Acute Pulmonary Edema (Acute Respiratory Distress Syndrome)  This syndrome is caused by increased pulmonary capillary permeability. Patients should be positioned with the head of the bed at a 45° elevation and should be given oxygen and IV diuretics. Positive-pressure ventila­ tion should be started early if the immediate measures fail (Chap. 316). Rarely, patients may require extracorporeal membrane oxygenation. Hypoglycemia  An initial slow injection of 20% dextrose (2 mL/kg over 10 min) should be followed by an infusion of 10% dextrose (0.10 g/kg per hour). The blood glucose level should be checked regularly thereafter as recurrent hypoglycemia is common, par­ ticularly among patients receiving quinine. In severely ill patients, hypoglycemia commonly occurs together with metabolic (lactic) acidosis and carries a poor prognosis. Sepsis  In malaria-endemic areas where a high proportion of children are parasitemic, it is usually impossible to distinguish severe malaria from bacterial sepsis with confidence. These chil­ dren should be treated with both antimalarials and broad-spectrum antibiotics with activity against nontyphoidal Salmonella species from the outset. Ideally all patients with severe malaria should have blood cultures taken, and empirical antibiotics should also be given to adults with >20% parasitemia. Antibiotics should be considered for severely ill patients of any age who are not responding to anti­ malarial treatment or who deteriorate unexpectedly. Other Complications  Patients who develop spontaneous bleeding should be given fresh blood and IV vitamin K. Convulsions should be treated with IV or rectal benzodiazepines and, if necessary, respi­ ratory support. Aspiration pneumonia should be suspected in any unconscious patient with convulsions, particularly with persistent hyperventilation; IV antimicrobial agents and oxygen should be administered, and pulmonary hygiene should be undertaken. GLOBAL CONSIDERATIONS The goal of global eradication of malaria remains a challenge. After substantial progress from 2000 to 2015, the global burden of malaria has been steadily increasing. Malaria eradication will require strong leadership, increased national commitment, and substantial interna­ tional support. The two main tools used to control malaria are insec­ ticide-treated bed nets (ITNs), previously shown to reduce all-cause

mortality in African children by 20%, and the ACTs. Pyrethroid resis­ tance and artemisinin resistance in Africa pose major threats to global malaria control. Newer ITNs combine pyrethroids with chlorfenapyr (a pyrrole insecticide) or pyriproxyfen (an insect growth regulator). New drugs to treat malaria are in development but still years away. Two very similar pre-erythrocytic vaccines (RTS,S/AS01 and RTS/ matrix M) have been recommended by WHO for deployment. These vaccines provide relatively short-duration protection and are given to young children. Other challenges to malaria eradication include the widespread distribution of Anopheles breeding sites, the enormous number of infected persons, behavioral changes (to avoid ITN contact) in anopheline mosquito vectors, and inadequacies in human and mate­ rial resources, infrastructure, and control programs. Eliminating vivax malaria is further hindered by the lack of a simple, safe, radical curative regimen. The animal reservoir of P. knowlesi presents another challenge to eradication of this species.

MALARIA PREVENTION Malaria may be contained by judicious use of insecticides to kill the mosquito vector, rapid diagnosis, patient management, and—where effective and feasible—administration of intermittent preventive treat­ ments, seasonal malaria chemoprevention, or chemoprophylaxis to high-risk groups such as pregnant women and young children. Indoor residual spraying with insecticides is practiced as part of an integrated vector control program in endemic countries, and a combination neo­ nicotinoid-pyrethroid has been developed in an attempt to delay the emergence of insecticide resistance. Focal elimination of P. falciparum can be accelerated safely by mass treatment with slowly eliminated antimalarials such as dihydroartemisinin-piperaquine. In addition to the two malaria vaccines now available, an irradiated live sporozoite vaccine is in late-stage development, and research on many other vac­ cine candidates is ongoing. CHAPTER 231 ■ ■PERSONAL PROTECTION AGAINST MALARIA Simple measures to reduce the frequency of bites by infected mosqui­ toes in malarious areas are very important. These measures include the avoidance of exposure to mosquitoes at their peak feeding times (usu­ ally dusk to dawn) and the use of insect repellents containing 10–35% DEET (or, if DEET is unacceptable, 7% picaridin), suitable clothing, and ITNs or other insecticide-impregnated materials. Widespread use of bed nets treated with residual pyrethroids reduces the incidence of malaria in areas where vectors bite indoors at night. Malaria ■ ■CHEMOPROPHYLAXIS (Table 231-8; https://wwwnc.cdc.gov/travel/yellowbook/2020/travelrelated-infectious-diseases/malaria) Recommendations for malaria pro­ phylaxis depend on knowledge of local patterns of drug sensitivity in Plasmodium species and the likelihood of acquiring malarial infection. Drugs effective against resistant P. falciparum should be used (atovaquoneproguanil, doxycycline, or mefloquine). Chemoprophylaxis is never entirely reliable, and malaria should always be considered in the differ­ ential diagnosis of fever in patients who have traveled to endemic areas, even if they are taking prophylactic antimalarial drugs. Chemoprevention in Pregnancy  Pregnant women planning to visit malarious areas should be warned about the potential risks and advised to avoid all nonessential travel. All pregnant women who live in endemic areas should be encouraged to attend regular antenatal clin­ ics. Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria; this drug is generally considered safe in the second and third trimesters of pregnancy; the data on firsttrimester exposure, although limited, are reassuring. Chloroquine and proguanil are regarded as safe, but there are now very few regions where these drugs can be recommended for protection. The safety of other prophylactic antimalarial agents in pregnancy has not been established. In endemic areas, intermittent preventive treatment in pregnancy (IPTp) involves giving treatment doses of sulfadoxine-pyrimethamine (SP) at each antenatal visit (maximum, once monthly) in the second and third trimesters of pregnancy. Women with HIV infection who are taking trimethoprim-sulfamethoxazole as prophylaxis should not

TABLE 231-8  Drugs Used in the Prophylaxis of Malariaa DRUG USAGE ADULT DOSE PEDIATRIC DOSE COMMENTS Atovaquoneproguanil (Malarone) Prophylaxis in areas with chloroquine- or mefloquine-resistant Plasmodium falciparum 1 adult tablet POb 5–8 kg: ½ pediatric tabletc daily ≥8–10 kg: ¾ pediatric tablet daily ≥10–20 kg: 1 pediatric tablet daily ≥20–30 kg: 2 pediatric tablets daily ≥30–40 kg: 3 pediatric tablets daily ≥40 kg: 1 adult tablet daily Chloroquine phosphate (Aralen and generic) Prophylaxis only in the very few areas with chloroquine-sensitive P. falciparumc or areas with P. vivax only 300 mg of base (500 mg of salt) PO once weekly Doxycycline (many brand names and generic) Prophylaxis in areas with chloroquine- or mefloquine-resistant P. falciparumd 100 mg PO qd (except in pregnant women; see Comments) Hydroxychloroquine sulfate (Plaquenil) An alternative to chloroquine for primary prophylaxis only in the very few areas with chloroquine-sensitive P. falciparumd or areas with P. vivax only 310 mg of base (400 mg of salt) PO once weekly PART 5 Infectious Diseases Mefloquine (Lariam and generic) Prophylaxis in areas with chloroquine-resistant P. falciparumd 228 mg of base (250 mg of salt) PO once weekly Primaquine For prevention of malaria in areas with mainly P. vivax 30 mg of base (52.6 mg of salt) PO qd Primaquine Terminal prophylaxis to decrease risk of relapses of P. vivax and P. ovale 30 mg of base (52.6 mg of salt) PO qd for 14 days after departure from the malarious area aSeveral antimalarial drugs are formulated as different salts (e.g., phosphate, sulfate, hydrochloride) and are therefore prescribed as base equivalents. For example, chloroquine phosphate 250 salt contains 155 mg base equivalent. It is very important to check when prescribing that the correct dose is being given. bAn adult tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride. cA pediatric tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. dVery few areas now have chloroquine-sensitive falciparum malaria. eOne tablet contains 228 mg of base (250 mg of salt). Abbreviation: G6PD, glucose-6-phosphate dehydrogenase. Source: Centers for Disease Control and Prevention, https://www.cdc.gov/malaria/travelers/index.html. be given concomitant SP. Dihydroartemisinin-piperaquine is being evaluated as an alternative. Children born to nonimmune mothers in malaria-endemic areas (usually expatriates moving to these areas) should receive prophylaxis from birth. Chemoprevention for Children in Endemic Areas  Seasonal malaria chemoprevention (SMC) involves giving monthly treatment doses of amodiaquine and SP to children (between 3 months and 5 years of age) in endemic areas of Africa. Originally designed for the intense 3- to 4-month rainy season malaria transmission period across the Sahel region of Africa, it is now introduced in other parts of Africa

Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. Atovaquone-proguanil is contraindicated in persons with severe renal impairment (creatinine clearance rate, <30 mL/min). In the absence of data, it is not recommended for children weighing <5 kg, pregnant women, or women breast-feeding infants weighing <5 kg. Atovaquone-proguanil should be taken with food or a milky drink. 5 mg of base/kg (8.3 mg of salt/ kg) PO once weekly, up to maximum adult dose of 300 mg of base Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Chloroquine may exacerbate psoriasis. ≥8 years of age: 2 mg/kg PO qd, up to adult dose Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 4 weeks after leaving such areas. Doxycycline is contraindicated in children aged <8 years and in pregnant women. 5 mg of base/kg (6.5 mg of salt/ kg) PO once weekly, up to maximum adult dose of 310 mg of base Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Hydroxychloroquine may exacerbate psoriasis. ≤9 kg: 4.6 mg of base/kg (5 mg of salt/kg) PO once weekly

9–19 kg: ¼ tablete once weekly 19–30 kg: ½ tablet once weekly 30–45 kg: ¾ tablet once weekly 45 kg: 1 tablet once weekly Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas. Mefloquine is contraindicated in persons allergic to this drug or related compounds (e.g., quinine and quinidine) and in persons with active or recent depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Use with caution in persons with psychiatric disturbances or a history of depression. Mefloquine is not recommended for persons with cardiac conduction abnormalities. 0.5 mg of base/kg (0.8 mg of salt/kg) PO qd, up to adult dose; should be taken with food Begin 1–2 days before travel to malarious areas. Take daily at the same time each day while in the malarious areas and for 7 days after leaving such areas. Primaquine is contraindicated in persons with G6PD deficiency. It is also contraindicated during pregnancy. 0.5 mg of base/kg (0.8 mg of salt/kg), up to adult dose, PO qd for 14 days after departure from the malarious area This therapy is indicated for persons who have had prolonged exposure to P. vivax and/or P. ovale. It is contraindicated in persons with G6PD deficiency as well as during pregnancy. where malaria is less seasonal and more drug resistant, although its effectiveness there is not known. Hundreds of millions of doses are now dispensed annually. Perennial malaria chemoprevention (PMC) is a loosely described intervention involving giving treatment doses, usually of SP, to young children when they attend health services for immunizations or whenever convenient for control programs. It has replaced intermittent preventive treatment for infants. Children should not receive both SMC and PMC. Chemoprevention in Travelers  Travelers to a malaria-endemic region should start taking antimalarial drugs 2 days to 2 weeks before