Current Diagnosis & Treatment in Infectious Diseases

Section VII - Parasitic Infections

80. Malaria and Babesia

Gary W. Procop abesiaMD

David H. Persing MD, PhD

PLASMODIUM SPP.

  • Exposure history, such as travel, recent transfusion, or living in close proximity to an international airport.
  • Nonfalciparum malaria: chills and fever spikes, followed by defervescence and fatigue; symptoms may be cyclic every 48–72 h.
  • Falciparum malaria: fever spikes and chills, often noncyclic and associated with rapidly progressive systemic symptoms.
  • Detection and identification of a Plasmodiumspecies in a thick and thin blood smear, respectively.
  • Molecular detection of P falciparum's histidine-rich protein by enzyme-linked immunosorbent assay (ELISA) or PlasmodiumDNA by polymerase chain reaction (PCR) followed speciation by probe hybridization or DNA sequencing.

General Considerations

  • Epidemiology.Malaria, a disease of antiquity, was recognized by Hippocrates and described possibly as early as 1700 BC in ancient Chinese texts. Malaria is a global disease that occurs most commonly in the tropics; however, transmission may also occur in temperate zones. In the 19th and early 20th centuries, Plasmodium species were widely distributed in the United States. This distribution included the southern United States, the Mississippi River Valley, and extensions as far north as Minnesota and Michigan.

Today, primarily in tropical areas, Plasmodium parasites continue to cause > 100 million cases of malaria per year. This results in an estimated 1–2 million deaths annually, many of whom are children. In fact, greater than 90% of severe, life-threatening malaria occurs in children. The distribution of the mosquito vector and the prevalence of disease in indigenous populations are the major factors that determine the distribution of the Plasmodium parasite.

Mosquito-infested areas, such as swamps, have long been associated with high attack rates of malaria. Environments that support long-standing, stagnant water promote mosquito breeding. Currently, endemic areas include parts of the Caribbean, northern South America, Central America, parts of Africa, India, parts of Australia, Southeast Asia, and many of the Asian Pacific Islands.

Malaria also occurs sporadically in nonendemic areas. In many instances, this represents imported, latent disease. Malarial relapses may present months after travelers have returned from endemic areas. These patients have usually been incompletely treated or have taken insufficient chemoprophylaxis.

Relapsing malaria is caused by reactivation of the latent hypnozoite phase of P vivax or P ovale. Patients who develop malaria may be treated with a wide variety of agents. The most commonly used antimalarial drugs, chloroquine and mefloquine, are effective against the symptomatic, erythrocytic phase of P vivax and P ovale and may result in apparent cures. These drugs, however, are ineffective against the hepatic hypnozoites. Patients treated in such a manner are incompletely treated and are at risk for malarial relapse.

Some patients may report never having had a previous episode of malaria. Specific questioning, however, often reveals a brief lapse in chemoprophylaxis. A lapse in chemoprophylaxis may result in a window period of subprophylactic drug levels. During this window period, sporozoites injected by an infected mosquito during a blood meal may reach and infect the liver. Any parasites (merozoites) that emerge from the liver while the patient is taking chemoprophylaxis are rapidly killed and the patient remains asymptomatic. Hypnozoites, however, may become active months after return from an endemic area, long after the cessation of chemoprophylaxis. The proper identification of P vivax and P ovale is important because only these species form hepatic hypnozoites and may result in malarial relapse.

In nonendemic areas, the cases of so-called “airport malaria” may occur. It is thought that mosquito vectors from endemic areas may be transported with airline cargo. An individual in a nonendemic area who lives in close proximity to an airport may become infected if bitten by these mosquitos. The propagation of the parasite is usually not sustained in the environment. This is either because of a lack of a suitable mosquito host or because of the low number of parasites in the community. When the prevalence of malaria is low, the probability of a mosquito ingesting gametocytes is very low. Additionally, if infected mosquitos are rare, they may take a nonhuman blood meal and thereby disrupt the parasitic cycle.

Mosquito transmission is the most common route of infection, but other modes of transmission exist. Transmission may result from intravenous drug abuse (shared needles) or blood transfusion. In these instances, only the erythrocytic cycle is established, because hepatocytes can be infected only by the sporozoite form of the parasite.

  • Microbiology.Numerous Plasmodium species exist; however, only four species are known to infect humans. These species are P falciparum, P vivax, P ovale, and P malariae. Worldwide, P vivax causes the vast majority of disease (~ 80%), followed by P falciparum (~ 15%).

Depending on the infecting plasmodial organism, malaria differs in severity, complications, prognosis, and treatment. Therefore, with the exception of differentiating P vivax from P ovale, it is important to promptly and properly speciate the organism. Malaria is typically separated into two disease types: falciparum and nonfalciparum. This distinction emphasizes the severity of P falciparum malaria, which is a medical emergency in the nonimmune individual. Among the nonfalciparum species, it is important to distinguish P vivax and P ovale from P malariae. The former two species have a dormant hepatic stage, which requires separate treatment to avoid malarial relapse.

The identification of Plasmodium organisms and the differentiation of the various species remain primarily based on parasite morphology in Giemsa-stained blood preparations. Organism detection is the initial task in the laboratory diagnosis of malaria. This is accomplished by the examination of a thick blood preparation. The examination of a thick preparation is an important part of the examination of blood for parasites and should not be bypassed, unless plasmodia have already been detected in a routine peripheral blood smear. The thick preparation increases the diagnostic yield compared with the examination of the thin blood smears. In the thick preparation, a larger volume of blood may be screened more rapidly. This becomes critical in detecting low-grade parasitemia, such as that associated with long-term P malariae infections or early in the course of malaria.

Thick preparations are made by placing 1–2 drops of the patient's blood together on a glass slide. The blood is not smeared and allowed to air dry. This slide is then stained by the Giemsa method, without methanol fixation. The unfixed erythrocytes (RBCs) lyse in the hypotonic stain solution. The stained preparation is first examined under 10× magnification, then under 100× oil immersion.

Filariasis is endemic to many of the same regions that harbor the malaria parasites and may cause cyclic fevers. The microfilariae are easily detected in thick blood preparations at 10× magnification. The purpose of the 100× oil immersion examination is to detect Plasmodium species.

In Giemsa-stained preparations, the Plasmodium parasites have red chromatin and light-blue cytoplasm (Figure 80-1). The ring forms of any Plasmodium species and the gametocytes of P falciparum are the structures most easily identified in thick preparations. Practice is required to differentiate Plasmodium amoeboid and schizont forms from platelets and debris. Thin blood smears must be examined if the thick preparations demonstrate the presence of a Plasmodium species.

The methanol-fixed, Giemsa-stained thin blood smear is used for Plasmodium speciation. Useful criteria for the differentiation of Plasmodium species are listed in Table 80-1. However, only rarely are all of these morphologic features present in a blood smear. Differentiation must be made on all information available. The morphologic criteria useful in differentiating the Plasmodium species are briefly discussed.

The crescent-shaped gametocyte is pathognomonic of P falciparum (Figure 80-2), but, unfortunately, this structure is not always present. Features in the peripheral smear, that in combination may be used to identify P falciparum, include the presence of small, delicate-appearing ring trophozoites, infected erythrocytes that remain normocytic, and the presence of predominantly ring trophozoites, with a conspicuous absence or relative rarity of more advanced forms. A high parasitemia and erythrocytes infected with multiple organisms are more commonly seen in patients with falciparum malaria. Appliqué forms and two chromatin centers per ring trophozoite are also suggestive of P falciparum, but may be present in other Plasmodium species.

 

Figure 80-1. Thick preparation demonstrating two ring forms of P vivax. (Giemsa stain; 1000× magnification.)

Table 80-1. Useful differentiating characteristics of Plasmodium species.a

Morphologic Feature

P falciparum

P malariae

P vivax/P ovale

RBCs

·  Infected RBCsize

·  Normocellular

·  Normocellular

·  Increased

·  RBC stippling

·  Coarse dots, commalike, occasionally present (Maurer's dots)

·  None present

·  Fine stippling (Schuffner's dots— P vivax); (Jame's stippling— P ovale)

Rings

·  Parasite load

·  Often high

·  Often low

·  Intermediate

·  > 1 organism/cell

·  Common

·  Low

·  Occasional

·  Appliqué forms

·  Present

·  Usually absent

·  Usually absent

Advanced forms

·  Advanced forms

·  Usually absent, except in severe disease

·  Present

·  Present

·  Ameboid forms

·  N/A

·  Basket, band, and in–distinct amoeboid forms

·  Indistinct forms

·  Number of merozoites/cell

·  N/A

·  6–12 (average 8)

·  P vivax: 12–24 (average 16)

·  P ovale: 8–12 (average 8)

·  Amount of RBC occupied by schizont

·  N/A

·  Entire cell

·  P vivax: entire cell

·  P ovale: fills 2/3 of cell

·  Distinctive “banana–shaped” gametocyte

·  Present

·  Absent

·  Absent

Other Features

·  Cycle of fever

·  Usually without established cycle

·  72 h

·  48 h

·  Hypnozoitesb

·  Absent

·  Absent

·  Present

aKnowledge of species endemic to the area wherein the patient contracted malaria is also useful in limiting the diagnostic possibilities.

b In nonendemic areas, this is often demonstrated by reactivation several months after leaving an endemic area.

 

Figure 80-2. Pathognomonic, crescent-shaped gametocyte of P falciparum. (Giemsa stain; 1000× magnification.)

Unlike P falciparum, P vivax and P ovale produce thicker and larger ring trophozoites, the infected RBCs become macrocytic, and advanced forms, such as amoeboid trophozoites, schizonts, or both are usually present in the peripheral smear (Figures 80-3 and 80-4). In an appropriately pH-balanced Giemsa stain (pH 6.8–7.0), RBCs infected by P vivax or P ovale may demonstrate fine eosinophilic stippling. This fine stippling should not be confused with larger, coarse, comma-shaped dots (Maurer's dots) that may be present in P falciparum-infected erythrocytes. Appliqué forms are typically not present in P vivax- or P ovale- infected erythrocytes, and ring trophozoites usually have only a single chromatin dot. Occasionally, more than one trophozoite may be present per erythrocyte. Although P vivax and P ovale can be differentiated from one another, this is difficult and requires parasitology expertise. Differentiation of P vivax and P ovale is usually not indicated or performed, because the disease produced by these organisms is similar and the treatment is identical.

 

Figure 80-3. Plasmodium vivax late trophozoite/early schizont stage. Schuffner's dots are prominent. (Giemsa stain; 1000× magnification.)

 

Figure 80-4. P malariae developing schizont; at least five merozoites are present. (Giemsa stain; 1000× magnification.)

P malariae-infected RBCs invariably contain some advanced plasmodial forms and, like P vivax and P ovale, the ring forms produced are thick. Stippling, however, is not observed. Specialized advanced forms, such as the band form and the basket form, are highly suggestive of P malariae. Like P falciparum, the ring trophozoites may occasionally contain two chromatin dots and the infected RBCs remain normocytic.

It should be noted that there may be coinfections with more than one Plasmodium species. Coinfections, especially in individuals who live in areas endemic for more than one Plasmodium species, are relatively common. These mixed infections are important to detect because of differences in disease prognosis and therapy.

  • Pathogenesis.The definitive host and vector for the Plasmodium parasite is the female Anopheles mosquito. Asexual reproduction and gametogenesis occur in the human intermediate host. The parasitic life cycle is similar for all Plasmodium species. However, important differences do exist.

Infecting sporozoites originate from the salivary gland of the female Anopheles mosquito. These are transmitted into the human during a blood meal. The sporozoites then migrate via the bloodstream to the liver where hepatocytes become infected. In the liver, tissue schizonts are formed. These contain numerous, asexually derived merozoites. From a single sporozoite, this phase of asexual reproduction results in a 10,000 to 30,000-fold organism amplification. This portion of the asexual reproduction cycle is common to all Plasmodium species.

Unique to the life cycle of P vivax and P ovale is the production of dormant hepatic hypnozoites. The hepatic hypnozoites may represent a form of parasite adaptation to climate. In temperate zones, this would enable the malarial parasite to “over-winter” in the human host. This strategy would prove advantageous when climatic conditions limit the activity of the mosquito vector. The hypnozoites, after a dormancy period between 6 and 12 months, become active and produce tissue schizonts.

Upon maturation, the tissue schizonts rupture, and the merozoites are released into the bloodstream. The merozoites then infect RBCs wherein occurs the second phase of asexual reproduction. Intra-erythrocytic asexual replication is also common to all Plasmodium species. P falciparum and P malariae may invade erythrocytes of any age, whereas P vivax and P ovale selectively parasitize only young RBCs. Younger RBCs still maintain their full complement of cytoplasmic membrane and expand with the growth of the organism. Older RBCs, infected with either P falciparum or P malariae, fail to expand with the growth of the parasite and remain normocytic with respect to uninfected RBCs. These features are useful in the laboratory differentiation of Plasmodium species.

After RBC infection, there is another cycle of asexual replication. Initially, a ring form develops (Figure 80-5), followed by differentiation into an amoeboid trophozoite form (Figure 80-3). This is followed by the development of an intra-erythrocytic schizont, which contains many merozoites (Figure 80-4). This phase results in a 6 to 32-fold asexual amplification of the organism for each infected RBC. The number of merozoites produced in the intra-erythrocytic schizont varies between species. Schizonts present in the blood smear are useful for speciation.


The developing parasites metabolize glucose and use RBC hemoglobin. The parasitic use of hemoglobin produces the characteristic hemozoin pigment as a waste product.

 

Figure 80-5. Ring form of P vivax. The infected cell is slightly macrocytic. (Giemsa stain; 1000× magnification.)

The erythrocyte-based, asexual reproduction cycle culminates with RBC rupture. The merozoites are released into the bloodstream where erythrocytes are again infected. This cycle of erythrocyte infection, merozoite replication, and RBC rupture is repetitive and may become highly synchronized. This synchronization is most classically seen in benign tertian malaria caused by P vivax. The rupture of the RBCs and release of the merozoites correlate with the clinical symptoms of malaria. The RBC-based reproduction cycle of P vivax and P ovale occurs every 48 h, whereas the erythrocytic cycle of P falciparum occurs between 36 and 48 h. The erythrocytic cycle of P malariae occurs approximately every 72 h.

The RBC-infecting merozoite may alternatively undergo differentiation into either a micro or macrogametocyte. These gametocytes may be ingested by the female Anopheles mosquito during a blood meal. Fusion of the gametocytes takes place within the gut of the mosquito. The diploid zygote matures and invades the gut wall. Meiotic division ensues, which results in haploid sporozoites. The sporozoites migrate to the mosquito's salivary gland to complete the parasitic cycle.

FALCIPARUM MALARIA

Clinical Findings

  • Signs and Symptoms.Fevers are often continual, with irregular spikes and associated chills and paroxysms. Patients with severe falciparum malaria may disclose central nervous system changes (prostration, convulsions, and impaired consciousness) and develop respiratory distress, abnormal bleeding, and circulatory collapse. Fatigue and malaise are nonspecific symptoms of malaria. These are in part caused by hypoglycemia and anemia. Hypoglycemia results from both decreased oral intake during illness and plasmodial use of blood glucose by the Embden-Meyerhof pathway. Anemia results from parasite-associated hemolysis and in some instances disseminated intravascular coagulation. Plasmodium infections cause elevated tumor necrosis factor alpha (TNF-α) levels, particularly in individuals with severe disease. This may also contribute to hypoglycemia and anemia.

In situations of hyperparasitemia, intra and extravascular hemolysis may be severe. Excessive hemolysis and hepatic involvement cause hyperbilirubinemia and jaundice. Free hemoglobin, bilirubin, and malarial pigment are excreted and turn the urine brown to black. This manifestation, although not limited to P falciparum malaria, is termed “blackwater fever.”.

Falciparum malaria, particularly in the nonimmune, constitutes a medical emergency. Although patients with hyperparasitemia have high mortality rates, even those with parasitemias < 5% may suffer severe morbidity and death. Fatalities result from the immediate effects and sequelae of microvascular obstruction and extensive hemolysis. The microvascular obstruction is caused by specific cytoadherence between P falciparum-parasitized RBCs and endothelial cells. Obstruction of the cerebral vasculature is the most serious manifestation and may cause mental status changes that range from mild confusion to coma. Similar microvascular compromise in various organ systems may result in renal failure, noncardiogenic pulmonary edema, or gastroenteritis.

  • Laboratory Findings.Three thick blood smears (see above), spaced ~ 12 h apart, should detect any of the Plasmodium species. High levels of parasitemia in patients infected by P falciparum may be obvious in peripheral blood smears examined secondary to an abnormal hematopoietic profile. In such instances, a microbiologist or pathologist with expertise in infectious disease pathology should examine the peripheral smear and determine which of the Plasmodium species is present. It should be remembered that the routine Wright stain, which is used in many institutions for the peripheral blood smear exam, is not pH balanced and may not disclose the eosinophilic stippling in P vivax or P ovale-infected RBCs. Harbingers of a poor prognosis present in the thin smear include hyperparasitemia, the presence of mature plasmodial forms (indicative of a larger sequestered biomass of parasites), and a high proportion (> 5%) of polymorphonuclear leukocytes which contain phagocytosed malarial pigment (indicative of recent schizogony). Other laboratory findings are nonspecific and reflect the specific organ involvement.

Blood smears may disclose RBC fragmentation, reflecting the hemolytic process. Similarly, the urine may be dark in color, and hemoglobin and bilirubin may be detected. Other abnormal indices may be present in the urinalysis, depending on the severity of renal involvement. Hyperbilirubinemia may be present depending on hepatic involvement and the duration and severity of disease. Abnormal coagulation studies, including decreased fibrinogen levels, elevated D-dimers, and thrombocytopenia, may be present in patients with disseminated intravascular coagulation. Blood gas analysis may reveal hypoxemia, depending on the severity of pulmonary edema and the presence of hyaline membrane disease.

  • Imaging.Computed tomography or magnetic resonance imaging may be performed if mental status changes are present. These may reveal evidence of ischemic injury or edema and nonspecific changes.
  • Complications.The microvascular congestion, secondary to adhesion between parasitized RBCs and endothelial cells, results in protean clinical manifestations. Complications generally occur in the tissues most sensitive to hypoxia and ischemia. Alterations in cerebral blood flow cause mental status changes, including disorientation, headache, coma, and death. Hepatic and gastrointestinal involvement may result in jaundice and enterocolitis, respectively. Involvement of the alveolar capillaries causes noncardiogenic pulmonary edema, which may be exacerbated by fluid retention secondary to renal failure. Oxygen exchange may be further compromised with the development of adult respiratory distress syndrome. Acute renal failure is multifactorial and results from the renal overload of free hemoglobin and malarial pigment, as well as the microvascular compromise and associated hypoxia. Microvascular damage may result in activation of the coagulation and thrombolytic cascades. Disseminated intravascular coagulation exacerbates the hemolytic anemia and further compromises an already insufficient microvascular circulation.

Hypoglycemia, common in Plasmodium infections, worsens tissue injury. The causes of hypoglycemia are nutritional, immune mediated, parasitic, and iatrogenic. Inadequate oral intake and parasite use of glucose contribute to hypoglycemia. Immune-mediated mechanisms, such as elevations of TNF-α, may also contribute to hypoglycemia. Therapy-induced elevations in blood insulin, secondary to quinine and quinidine, cause hypoglycemia.

In pregnancy, P falciparum becomes sequestered in the maternal sinuses of the placenta (Figure 80-6). This and the aforementioned complications increase the probability of adverse outcomes for the fetus. Obstetric complications include spontaneous abortion, premature labor and delivery, and maternal death. Transplacental infection of the neonate or “congenital malaria” is rare, but may occur. Primaparas (women pregnant with their first child) are at increased risk for adult respiratory distress syndrome. Pulmonary edema and adult respiratory distress syndrome in pregnancy may be due to the physiologic hypervolemia of pregnancy and an increase in the peripheral vascular resistance after delivery. Pregnancy-associated and quinine-associated hypoglycemia may exacerbate that caused by the parasitosis.

 

Figure 80-6. Sequestration of P falciparum-infected RBCs in the maternal sinuses of the placenta. This photomicrograph was taken after quinidine therapy. The corresponding peripheral blood smear was almost devoid of parasites. (Hematoxylin and eosin stain; 600× magnification.)

NONFALCIPARUM MALARIA (P VIVAX, P OVALE, P MALARIAE)

Clinical Findings

  • Signs and Symptoms.Patients with nonfalciparum malaria invariably develop fever and chills that may become cyclic. Initially, patients experience chills, which are followed by fever (Box 80-1). Patients with malaria often manifest many nonspecific symptoms such as weakness, malaise, headache, and myalgias. As the disease progresses, signs of anemia, such as pale conjunctiva, may be seen. Splenomegaly and mild hepatomegaly may also be present. After hours of fever, defervescence occurs with marked diaphoresis. Patients are weakened and exhausted from the severity of the disease. In established infections caused by P vivax and P ovale, a periodicity may occur approximately every 48 h. P vivax and P ovale infections are clinically indistinguishable. Although similar, disease caused by P ovale is usually less severe, relapses less frequently, and more often spontaneously resolves. Both of these Plasmodium species produce latent disease and may produce relapses months after the initial infection.

Malaria from P malariae has a longer incubation period and possibly more severe paroxysms than are seen with P vivax and P ovale. The clinical periodicity of P malariae may become regular and occur in 72-h intervals. This is termed benign quartian malaria. Some infections with P malariae may be subclinical and persist for years, but P malariae does not produce latent disease.

  • Laboratory Findings.Three thick blood smears, spaced ~ 12 h apart, should detect any of the Plasmodium species. In instances of subclinical P malariae infection, parasitemia is extremely low and may be difficult to identify even in thick preparations.

Blood smears and urinalysis reveal evidence of hemolysis, but usually to a lesser degree than with infections caused by P falciparum. Elevated albumin levels are present in the urine of patients with P malariae-associated nephrotic syndrome.

  • Imaging.Hepatosplenomegaly and splenic complications, such as rupture, may be visualized by computed tomography scans or magnetic resonance imaging.
  • Complicatons.Complications with P vivax are rare, although coma and sudden death have been reported. Individuals with splenomegaly are at higher risk for splenic rupture. Infections with P malariae may be indolent and mild, but immune complex-associated glomerulonephritis and nephrotic syndrome may occur.

BOX 80-1 Plasmodium-Associated Syndromes

P vivax/ P ovale

Cyclic episodes that consist of chills followed by fever, which is followed by defervescence and diaphoresis; cyclic every 48 h

P malariae

Cyclic episodes that consist of chills, followed by fever, which is followed by defervescence and diaphoresis; cyclic every 72 h; possible immune–complex—mediated glomerulonephritis

P falciparum

Continuous fevers with irregular spikes, possible hyperparasitemia with microvascular damage and compromise. This is a medical emergency in the nonimmune. Microvascular compromise may lead to central nervous system damage, renal and pulmonary failure, and death.

Differential Diagnosis

Nonfalciparum malaria. Many of the signs and symptoms of nonfalciparum malaria are nonspecific. There are many causes of anemia and hepatosplenomegaly. Malaria is endemic in many underdeveloped areas; indigenous people in these countries may suffer from protein-calorie malnutrition and are exposed to a wide variety of infectious agents. Impoverished children with dietary deficiencies may be anemic, and those with protein deficiencies may have protuberant abdomens. Numerous infectious diseases may present with hepatomegaly, splenomegaly, or both. Liver enlargement, spleen enlargement, or both may be seen in patients with amebic liver abscesses, Chaga's disease, visceral leishmaniasis, schistosomiasis, echinococcosis, clonorchiasis, and typhoid fever. Noninfectious causes of hepatosplenomegaly, anemia, or both include thalassemias and other hemoglobinopathies, myelofibrosis, and hematopoietic malignancies.

The symptoms of nonfalciparum malaria may also be nonspecific and may be present in a wide variety of diseases. This is especially true early in the course of malaria, before any synchronization of the erythrocytic cycle. Many tropical diseases, such as visceral leishmaniasis, filariasis, and dengue fever, may present with nonspecific symptoms similar to those present in malaria. If cyclic symptoms occur, filariasis should be considered. Pneumonia, urinary tract infections, and other less exotic causes of fever and chills must also be considered. Fever, chills, and night sweats are constitutional symptoms that may be seen with hematopoietic malignancies. P malariae has been associated with nephrotic syndrome, but other etiologies, such as post-infectious immune-complex glomerulonephritis and systemic lupus erythematosis, must be also be considered. The differential diagnosis of nonfalciparum malaria is extensive and may only be successfully narrowed by history, careful physical examination, and laboratory studies.

Falciparum Malaria. The differential diagnosis of falciparum malaria is also extensive. The focus of the differential diagnosis is usually based on the most severely affected organ system. If only generalized fever and chills are present, the differential is broad. These symptoms may be seen in a wide variety of infections (see above) or may represent the constitutional symptoms that may accompany some lymphoproliferative disorders. The mental status changes present in cerebral malaria may also be seen in patients with brain abscesses, meningitis, tumor, or cerebral or subdural hemorrhage. Gastrointestinal symptoms, such as abdominal pain and diarrhea, may be present in patients with bacterial or viral gastroenteritis, chronic colitis, or ischemic colitis. Similarly, involvement of the liver may suggest viral hepatitis, typhoid fever, or other hepatic disorders. The pulmonary edema and adult respiratory distress syndrome that may occur in falciparum malaria are clinically indistinguishable from those caused by many other etiologies. The astute cytologist, however, may detect the presence of a Plasmodium species in RBCs present in respiratory tract samplings (sputa or bronchoalveolar lavage) and may thereby identify the etiology of the respiratory pathology. The hemolytic anemia present in malaria may be clinically indistinguishable from other causes of hemolytic anemia but is usually readily distinguished by an examination of a peripheral blood smear.

When ring forms are present, the possibility of babesiosis must also be considered. Recent travel to Plasmodium- or Babesia-endemic areas is important supportive information. Babesia species may be excluded by the presence of advanced amoeboid or schizont forms and by the presence of malarial pigment. Babesia species do not produce amoeboid forms or schizonts, and they do not metabolize hemoglobin to form pigment. These criteria usually readily differentiate Babesia species from P vivax, P ovale, and P malariae. The differentiation of Babesia species and P falciparum is more difficult, because RBCs infected with either Babesia species or P falciparum usually contain only small, delicate ring forms. Furthermore, infections with both these organisms may show more than one ring form per RBC and high degrees of parasitemia.

A useful approach to the differentiation of Babesia and P falciparum is to search for pathognomonic forms, to perform an exhaustive search for advanced plasmodial forms and malarial pigment, and to obtain a detailed clinical and travel history. The pathognomonic forms of Babesia spp. and P falciparum are the tetrad of merozoites (Maltese cross) and the crescent-shaped gametocyte, respectively. Unfortunately, these forms are not always present in the blood smear. An exhaustive search may demonstrate a rare amoeboid or schizont form in P falciparum infections, especially in patients with severe disease, but this is not guaranteed. The presence of malarial pigment also differentiates Plasmodium species from Babesia species. In morphologically indeterminate instances, historical information may be the most helpful information available. Alternatively, molecular methods may be used to differentiate these organisms. These, however, are not routinely available in many areas.

Diagnosis

The first clue to clinicians of the possibility of malaria is often from a history of travel to a malaria-endemic area. Patients should be asked about their travel history, and the clinician should probe for any information about travel to malaria-endemic areas in either the recent or distant past. If patients have traveled to malaria-endemic areas, they should be asked if they received chemoprophylaxis and if they ever contracted malaria. Specific questioning concerning any travel to endemic areas in the past may reveal the possibility of infections with nonfalciparum Plasmodium species, which may cause disease months to years after the initial infection and return from endemic areas.

Mosquito-based transmission in naturally endemic areas is the most frequent mode of transmission, but less common modes of transmission may also occur. Plasmodial organisms in the erythrocytic phase may also be parenterally transmitted, through intravenous drug abuse (shared needles) or blood transfusion. This mode of transmission is infrequent in the United States and other nonendemic locales and is directly related to the frequency of infected donors. Historical information regarding having contracted malaria and recent travel to malaria-endemic areas is useful for screening potential blood donors. As mentioned earlier in this chapter, another group of individuals who may contract malaria are those who live in close proximity to an international airport.

The signs and symptoms of malaria depend somewhat on the infecting Plasmodium species. Early in the course of disease, nonsynchronized fever and chills may be present with other nonspecific symptoms such as fatigue, malaise, myalgia, and headache. The classic, nonfalciparum malarial cycle consists of shaking chills, followed by high, spiking fever, and finally defervescence with exhaustion. This cycle is most commonly seen with infections by P vivax but is also common with infections caused by P ovale and P malariae. The cyclic nature of the symptoms reflects the synchronization of the erythrocytic malarial cycle and is a clinical clue to malaria. When highly synchronized, this cycle occurs approximately every 48 h for infections caused by P vivax and P ovale and every 72 h for infections caused by P malariae.

The erythrocytic cycle of P falciparum becomes synchronized less frequently than malaria caused by other Plasmodium species. Patients with P falciparuminfections more commonly demonstrate daily chills and fever spikes. The signs and symptoms of falciparum malaria are highly variable. The ischemic changes produced by the microvascular congestion may manifest in any organ system (see above). Therefore the clinical presentation usually depends on the organ system most severely affected. For this reason, malaria must remain in the differential diagnosis for a wide variety of disorders, especially if patients have recently visited malaria-endemic locales. Most patients demonstrate some degree of anemia and hypoglycemia. Headache, seizures, mental status changes, and coma may be seen in patients with cerebral malaria. Blackwater fever from the excretion of blood, hemoglobin, and malarial pigment is common in patients with renal involvement. The involvement of the gastrointestinal tract may produce nausea, vomiting, diarrhea, and abdominal pain. Hepatic involvement may result in jaundice, with elevations in serum levels of bilirubin and liver enzymes. Not surprisingly, primary gastrointestinal and hepatic manifestations of P falciparum malaria are commonly mistaken for self-limited bacterial or viral enteritis and viral hepatitis, respectively.

Although clinical history and physical examination findings may suggest malaria, the definitive diagnosis is made in the laboratory. Although ELISA and PCR-based assays for the detection of the malarial parasite are available, the examination of thick blood smears remains the most cost-effective method in the United States. Thick blood smears should be performed on the peripheral blood of patients suspected to have malaria. If the first blood smear is negative, two more should be performed at 12-h intervals. When a Plasmodium species is detected in a thick blood smear, thin blood smears should be made for plasmodial speciation.

If available, highly sensitive and specific molecular methods may be used for the detection of Plasmodium species. Molecular assays used for Plasmodium identification include the detection of P falciparum's histidine-rich protein 2 by ELISA and the detection of Plasmodium nucleic acid by PCR. Dipstick technology has been applied to the detection of histidine-rich protein 2. This allows for a sensitive and specific molecular detection system to be available in the field. The detection of Plasmodium nucleic acids by the PCR may soon become the gold standard. PCR-based detection systems offer excellent sensitivity and specificity. This system is extremely useful for patients with low-grade parasitemia. The use of preamplification immunomagnetic separation of Plasmodium species and specific colorimetric detection of PCR products may enhance sensitivity and make this technology more user friendly. The PCR-based assay may use either species-specific DNA primers or broad-range Plasmodium-specific primers. When broad-range primers are used, speciation is accomplished by either DNA sequencing or Southern-blotting/microtiter plate hybridization with species-specific nucleic acid probes. In nonendemic areas, the molecular detection of plasmodia may be impractical, because costly reagents and kits may expire with only minimal use.

Treatment

In the treatment of malaria, specific antiplasmodial therapy and supportive care are essential to reduce morbidity and mortality. The basic principles of antiplasmodial therapy are defined below. Therapeutics and dosages for the most commonly used antimalarial agents are listed in Box 80-2. It should be noted that antimalarial drugs exist in both salt and base formulations, and potentially dangerous dosing errors may occur unless care is taken. Updated information regarding the treatment and prophylaxis of malaria are available through the Centers for Disease Control and Prevention and the World Health Organization.

P vivax, P ovale, P malariae, and chloroquine-sensitive P falciparum. Chloroquine phosphate is given to eradicate the RBC phase. Oral therapy is usually sufficient for infections with P vivax, P ovale, and P malariae and for P falciparum infections that are not severe. Intravenous administration of antiplasmodial agents should be used for patients with severe falciparum malaria. Side effects of chloroquine may include gastrointestinal disturbances, pruritis, dizziness, and headache. Chloroquine resistance is widespread among P falciparum and rarely has been reported for P vivax. Alternative regimens include mefloquine and quinine. Patients infected with either P vivax or P ovale must also be given primaquine phosphate to eradicate hepatic hypnozoites. The failure to use primaquine may result in malarial relapse at a later date. Primaquine phosphate may cause hemolytic anemia in patients with glucose-6-phosphatase deficiency; additional side effects include gastrointestinal and central nervous system disturbances. In infections caused by these organisms during pregnancy, chloroquine is the drug of choice, and quinine is an alternative. Although not yet approved by the Food and Drug Administration, mefloquine is also probably safe during pregnancy; mefloquine should not be used for severe falciparum malaria, since intravenous therapy is required and there is no parenteral formulation for mefloquine. Although quinine may be used in pregnancy, it may cause uterine contractions and contributes to hypoglycemia. Primaquine and halofantrine are contraindicated in pregnancy.

Chloroquine-resistant P falciparum. Oral regimens for patients that do not have severe disease or have severe disease and access to only minimal healthcare facilities consist of quinine given with pyrimethamine-sulfadoxine or followed by either tetracycline or clindamycin. Other oral therapies include mefloquine and quinidine gluconate. Injections of artesunate or artemether or suppositories of artemisinin or artesunate may be useful in instances of limited healthcare. If oral therapy is not possible or if severe disease is present, parenteral therapy with quinine hydrochloride or quinidine gluconate may be given. Pregnant women with chloroquine-resistant malaria who do not have severe disease may be treated with intravenous quinine, sulfonamide/ pyrimethamine (in areas such as India and some regions of Africa, where P falciparum is likely to be sensitive) and mefloquine. Mefloquine should not be used for severe falciparum malaria, since intravenous therapy is required, and there is no parenteral formulation for mefloquine. Exchange transfusion may be lifesaving for patients with hyperparasitemia and should be considered if this option exists. The indications for exchange transfusion are a parasitemia of > 10% combined with severe disease, therapeutic failure, or poor prognostic factors or a parasitemia of > 30%, even in the absence of clinical complications.

Prognosis

The prognosis of nonfalciparum malaria is generally good. These organisms are usually responsive to therapy. Relapses of P vivax or P ovale malaria can be avoided with appropriate therapy. P malariae responds well to therapy; however, rare renal involvement may contribute to morbidity and mortality.

The prognosis in falciparum malaria, especially for the nonimmune, is guarded. Malaria caused by P falciparum constitutes a medical emergency until proven otherwise. Multisystem organ damage may occur with extreme morbidity and high mortality. Death may occur rapidly from microvascular compromise and subsequent hypoxemia. Involvement of the central nervous system, lungs, and kidneys is especially devastating. Prompt administration of appropriate antimalarial agents, possible exchange transfusion and supportive care significantly reduce morbidity and mortality.

Prevention & Control

Vector Control. An understanding of the habit and behavior of the female Anopheles mosquito is useful in disease prevention. Marshlike areas and even microenvironments with standing water serve as breeding areas for the Anopheles mosquitos. Avoidance of mosquito-infested areas and elimination of standing water decrease the likelihood of being bitten. If these areas cannot be avoided, insect repellent should be used. Anopheles mosquitoes are evening and nighttime feeders; therefore a combination of mosquito netting and insect repellent at bedtime is encouraged. Mosquito netting impregnated with insecticides is optimal for nighttime barrier protection. The large-scale use of insecticides for vector control usually provides only a short-term solution; insecticide-resistant mosquito strains develop rapidly.

BOX 80-2 Treatment of Malaria

 

Children

Adults

P falciparum malaria from areas with chloroquine resistance1,2

First Choice

·  Mefloquine, 25 mg/kg, not to exceed the adult dosage, PO, taken with ≥8 oz of water (single dose)

·  Mefloquine, five 250-mg tablets (1250 mg) PO, with ≥8 oz of water (single dose)

Second Choice

Quinine sulfate, 25 mg/kg/d PO with one of the following:

·  Doxycycline,3 2 mg/kg/d for 7 d, given with the quinine
OR

·  Followed by pyrimethamine–sulfadoxine (0.25 tablet: age <1 yr; 0.5 tablet, age 1–3 yr; 1.0 tablet, age 4–8 yr; 2 tablets, age 9–14 yr
OR

·  Followed by clindamycin, 20–40 mg/kg/d
in 3 divided doses

·  Quinine sulfate, 650 mg PO every 8 h for 3–7 d, with one of the following:

·  Doxycycline, 100 mg twice daily for 7 d
OR

·  Followed by 3 pyrimethamine–sulfadoxine tablets.
OR

·  Followed by clindamycin, 900 mg three times a day for 5 d

Parenteral Therapy

·  Quinine dihydrochloride, 20 mg of salt/kg IV loading dose in 5% dextrose given over 4 h, followed by 10 mg of salt/kg given over 2–4 h, every 8 h (maximum dose, 1800 mg/d)
OR

·  Quinidine gluconate, 10 mg salt/kg loading dose in normal saline, with slow infusion lasting 1–2 h, (maximum dose, 600 mg), followed by continuous infusion at 0.02 mg/kg/min

·  Quinine dihydrochloride, 20 mg of salt/kg IV loading dose in 5% dextrose given over 4 h, followed by 10 mg of salt/kg given over 2–4 h, every 8 h (maximum dose, 1800 mg/d)
OR

·  Quinidine gluconate, 10 mg salt/kg loading dose in normal saline, with slow infusion lasting 1–2 h, (maximum dose, 600 mg), followed by continuous infusion at 0.02 mg/kg/min

Malaria caused by P vivax, P ovale, P malariae, and chloroquine–sensitive P falciparum

First Choice

·  Chloroquine, 10 mg base/kg PO loading dose (not to exceed 600 mg base), followed by 5 mg base/kg (not to exceed 300 mg base) given 6 h after the first dose and again on days 2 and 3

·  Chloroquine, 600 mg base (1000 mg chloroquine phosphate) PO loading dose, followed by 300 mg base given 6 h after the first dose and again on days 2 and 3

Latent disease caused by P vivax/P ovale

First Choice

·  Primaquine phosphate, 0.3 mg base (0.5 mg salt) /kg/d × 14 d

·  Primaquine phosphate, 15.3 mg base (26.5 mg salt) qd PO × 14 d
OR

·  45 mg base (79 mg salt) per wk × 8 wk

1Severe falciparum malaria should be treated with parenteral therapy; mefloquine should not be used for the treatment of severe falciparum malaria, since there is no parenteral formulation. Options include quinine (as above), quinidine, artesunate and artemether.
2Exchange transfusion may be life saving in nonimmune patients with severe falciparum malaria and is indicated if parasitemia is > 30% or if parasitemia is > 10% and poor prognostic factors are present (i.e. elderly, schizonts in peripheral blood), there are severe systemic manifestations (i.e. cerebral malaria, pulmonary or renal failure) or therapeutic failure.
3Do not use doxycycline in pregnant women or in children < 8 years of age.

Chemoprophylaxis. Chloroquine is still a useful chemoprophylactic agent in areas without a high prevalence of chloroquine-resistant strains (Box 80-3). The emergence of chloroquine resistance in P falciparum and more recently in P vivax has limited the usefulness of this drug as a chemoprophylactic agent. In areas where chloroquine resistance is found, mefloquine, doxycycline, or chloroquine plus proguanil may be used for prophylaxis.

Months before departure, travelers to endemic areas should consult physicians experienced in tropical disease prevention. Chemoprophylaxis must begin weeks before departure to ensure an absence of drug hypersensitivity and adequate serum levels. Records should be kept during travel of any failure to maintain the dosing schedule. Chemoprophylaxis should continue for 4 weeks after leaving endemic areas. If episodes of noncompliance have occurred and the patient has not become ill, they are still at risk for malaria if they visited P vivax- or P ovale-endemic areas.

Information regarding various aspects of malaria, including treatment and prophylaxis, is regularly updated by the World Health Organization and Centers for Disease Control and Prevention. Respective World Wide Web sites are http://www.who.ch/ and http://www.cdc.gov/cdc.htm. Information on various aspects of malaria and other diseases is available from the Centers for Disease Control and Prevention via fax, toll free, at 1-888-232-3228.

BOX 80-3 Control of Malaria

Vector Control

·  Avoid mosquito-infested areas.

·  Wear protective clothing during evening and nighttime hours.

·  Use mosquito repellant (containing 30–35% DEET for adults or 6–10% DEETfor children).

·  Spray bedclothes and mosquito netting with the insect repellent permethrin.

·  Unless absolutely necessary, pregnant women should not travel to P falciparum–endemic areas.

Prophylactic Measures

·  Chloroquine remains the drug of choice in areas without known chloroquine resistance.

·  Mefloquine is used in areas with known chloroquine–resistant strains.

·  Doxycycline should be used when mefloquine cannot be taken, except by pregnant women, children < 8 y old, or those who are hypersensitive to doxycycline

·  Chloroquine & proguanil should be used only for patients who cannot take mefloquine or doxycycline

Emergency Self Treatment of Possible Malaria

·  Individuals using chloroquine prophylaxis in areas where chloroquine-resistant strains may reside must have one or more treatment doses of Fansidar (25 mg pyrimethamine + 500 mg sulfadoxine/tablet) (adult dosage: 3 tablets PO as a single dose; pediatric dosage: 5–10 kg, ½ tablet; 11–20 kg, 1 tablet; 21–30 kg, 1 ½ tablets; 31–45 kg, 2 tablets; > 45 kg, adult dose)

Vaccine Development. A highly effective malaria vaccine is yet to be developed. This will likely remain a difficult task, particularly because of the antigenic variability characteristic of Plasmodium species. Vaccine targets currently being studied include the sporozoite, the merozoite, and the gametocyte. The respective goals of these vaccine targets are to prevent infection, to decrease the severity and complications of disease, and to arrest development in the mosquito and prevent the production of infective sporozoites.

BABESIA SPP.

Essentials of Diagnosis

  • Nonspecific clinical manifestations.
  • Exposure: tick exposure, blood transfusion, or both.
  • Morphologic, serologic, or molecular evidence of infection.

General Considerations

The members of the genera Babesia and Theileria are protozoan parasites. These organisms are of medical, veterinary, and economic importance. Babesia species cause disease in humans and animals. The genus Theileria is the etiologic agent of cattle fever in Eurasia and Africa; it has also been implicated in human disease.

Common to both genera is an intra-erythrocytic phase. These organisms develop pear-shaped intra-erythrocytic ring forms and are therefore referred to as piroplasms. An exo-erythrocytic schizont stage has been demonstrated only for Theileria species.

Babesia species were first discovered in cattle in 1888, and they were subsequently found to be the etiologic agent of Texas cattle fever. Human babesiosis was first definitively demonstrated in a splenectomized Yugoslavian cattle farmer in 1957. Babesia divergens, a cattle parasite, was the species implicated in this infection. This particular organism causes severe and fatal infections in Europe, in splenectomized individuals. This is in contrast to babesiosis in the United States.

Babesia species are highly endemic in the northeastern portion of North America, but infections have been reported from the southern, midwestern, and western United States. Unlike babesiosis in Europe, infections usually occur in normosplenic individuals and are usually caused by the smaller parasite B microti. This parasite is predomininately maintained in a white-footed mouse (Peromyscus leucopus) reservoir, but other small rodents may also be infected. B microti is transmitted from mouse to mouse and from mouse to human by the hard-bodied tick (Ixodes scapularis, previously known as I dammini). Trans-stadial (stage-to-stage) transmission occurs within the tick, but transovarial passage has not been demonstrated. The larval and nymph stages of I scapularis typically feed on small rodents and thereby acquire the Babesia parasite. The predominant host for the adult Ixodes tick is the white-tailed deer. Deer are not infected by B microti, but the expanding deer population may contribute to the distribution of both the tick and parasite. This tick vector and the mouse reservoir also harbor the etiologic agent of Lyme disease, Borrelia burgdorferi (Chapter 65), and the agent of human granulocytic ehrlichiosis (Chapter 68).

A new species of piroplasm, WA-1, has more recently been associated with human infection in the western United States. This organism is antigenically and genotypically distinct from B microti. Genotypic data suggest that this species may be more closely related to B gibsoni, a dog parasite, or the Theileria species. Presumably, a tick vector is also necessary for natural transmission, but this has yet to be established.

Clinical Findings

  • Signs and Symptoms.In North America, the majority of Babesia infections are asymptomatic, but severe and life-threatening infections are documented (Box 80-4). The symptoms in most mild infections are nonspecific and include myalgia, malaise, low-grade fever with chills, fatigue, nausea with or without vomiting, and headache. Severe manifestations probably reflect host susceptibility rather than parasite virulence. The manifestations of severe infection include exacerbations of the symptoms noted above, as well as hemolytic anemia. These patients may be jaundiced and develop dark urine secondary to intravascular hemolytic anemia. Severe manifestations occur more frequently in splenectomized, elderly, or immunocompromised individuals.

Coinfection with B burgdorferi should be considered in patients with babesiosis. Borrelia species, which cause relapsing fever and Lyme disease, are also transmitted by the Ixodes tick. There is also extensive geographic overlap in the distribution of Borrelia species and B microti. Krause et al studied patients infected with either B microti or B burgdorferi and compared them with patients coinfected by these organisms. They found that patients coinfected with B microti and B burgdorferi have longer and more severe disease than patients infected with B burgdorferi alone. In animal models, Babesia species are known to cause immunosuppression. Similarly, coinfected subjects have evidence of elevated spirochetemia. The exacerbation of symptoms found by Krause et al could conceivably result from transient immunosuppression by Babesia species and a subsequent increased spirochetemia.

The cattle-associated parasites B divergens and B bovis cause human babesiosis in Europe. In this region, splenectomized individuals are at increased risk for infection by these organisms. These patients develop a severe hemolytic disease and have a high fatality rate.

  • Laboratory Findings.Wright- or Giemsa-stained, thick blood preparations may be used to detect the presence of parasites. Thin blood smears are then used for morphologic studies. Most commonly, nonspecific ring forms are present (Figure 80-7), which must be differentiated from a Plasmodium species (see Plasmodium section above). Rarely, the parasites may appear as the characteristic “Maltese cross.” This consists of a tetrad of merozoites and is pathognomonic for Babesia species.
  • Imaging.Magnetic resonance imaging or computed tomography scan of the abdomen may identify nonspecific changes in the spleen.
  • Differential Diagnosis.The nonspecific symptomatology seen in patients with babesiosis may also be seen in a wide variety of infectious diseases. Important etiologic agents in the differential diagnosis of tick-borne disease include Rickettsia rickettsii and other spotted fever group rickettsiae, B burgdorferi and other Borrelia species, Ehrlichia chaffeensis and Ehrlichia canis, and the coltivirus responsible for Colorado tick fever. Infections by these organisms often lack characteristic physical examination findings, and the definitive diagnosis may rely solely on laboratory findings. If the tick is retained, identification may be useful in limiting the differential diagnosis.
  • Complications.Most infections are asymptomatic, and complications are rare. Complications are more likely in immunocompromised hosts, the very young, and the elderly. Complications include an exacerbation of an already weakened state, severe hemolytic anemia and the sequelae thereof, or, rarely, adult respiratory distress syndrome. As previously mentioned, coinfecting pathogens transmitted by the same tick bite must be considered. Coinfections may produce more severe clinical manifestations and may contribute to higher mortality rates.

BOX 80-4 Babesia–Associated Syndrome

More Common

·  Asymptomatic

Less Common

·  Mild infection: myalgia, low–grade fever with chills, fatigue, nausea, headache

·  Severe infection (more common in splenectomized, elderly, or immuno–compromised patients): hemolytic anemia (with jaundice and dark urine), exacerbation of the above symptoms

Diagnosis

Many Babesia infections are subclinical and are discovered incidentally. Babesiosis should be suspected in patients with mild, nonspecific symptoms who have recently visited endemic wooded areas and report a tick bite. Babesiosis should be considered in patients who have recently received an RBC transfusion. Babesia species, like Plasmodium species, may also be transmitted by this blood product. The symptoms of babesiosis are nonspecific. Therefore the definitive diagnosis of babesiosis is made in the laboratory.

 

Figure 80-7. Small ring forms of the WA-1 strain of babesia. (Giemsa stain; 1000× magnification.)

As for the detection of Plasmodium species, thick and thin blood smears are used for the detection and speciation of Babesia species. The thick smear allows for the more rapid screening of greater quantities of blood. This is important because low-grade parasitemia may be present in Babesia infections. Species determination is often suggested by the species endemic to the geographic area of exposure. Organism morphology, particularly size, is important for speciation. These should be examined in thin blood smear preparations.

In some instances, the differentiation of Babesia species from P falciparum may be difficult. When only small ring forms are present in a blood smear, a Babesia species must be differentiated from a Plasmodium species, particularly P falciparum. The absence of hemozoin pigment and appliqué forms supports the identification of a Babesia species. Unfortunately, hemozoin pigment may also be absent in erythrocytes containing young plasmodial (ie, ring) trophozoites. Babesia species may also be excluded if the characteristic crescent-shaped gametocytes of P falciparum are identified. Similarly, malaria is excluded if the tetrad of merozoites, pathognomonic of Babesia species, is identified. Probably most important is historical information, such as a history of travel to an endemic area and exposure to the appropriate tick or mosquito vector.

In most instances, the combination of history, clinical presentation, and morphologic features is sufficient to establish the appropriate diagnosis. In difficult cases, molecular methods may be used to differentiate these organisms. The histidine-rich protein 2 of P falciparum may be detected in whole blood by ELISA, and species-specific nucleic acid may be detected for either organism by PCR.

Treatment

Mild Babesia infections in immunocompetent individuals usually resolve without antimicrobial therapy. In cases of severe disease or in immunocompromised patients, the combination of clindamycin and quinine is the treatment of choice (Box 80-5). The clindamycin may be given orally, intravenously, or intramuscularly. Intravenous quinidine may also be used.

Prognosis

The vast majority of patients infected by B microti have subclinical infections that usually resolve without incident. The prognosis for immunocompromised individuals and the elderly is guarded, because these patients may have a more severe course. Patients who are coinfected with B burgdorferi carry a worse prognosis than do patients infected by either organism alone. Prognostic information is not available for infections caused by the WA-1 agent because so few cases have been reported. Splenectomized patients who may be infected by B divergens in Europe have a grave prognosis.

BOX 80-5 Treatment of Babesiosis

 

Children

Adults

First Choice

·  Clindamycin (20 mg/kg/d) for 7–10 d, PLUS quinine (25 mg/kg/d PO) taken for 7–10 d

·  Clindamycin (300–600 mg every 6 h) PLUS quinine (650 mg PO every 6–8 h) taken for 7–10 d

BOX 80-6 Control of Babesiosis

Prophylactic Measure

·  Avoid tick–infected areas

·  Use appropriate clothing and tick repellants if avoidance is impractical

·  Perform a body and scalp search for ticks on leaving infested areas

Prevention & Control

The avoidance of outdoor activities in tick-infested, Babesia-endemic areas is the most effective means of prevention (Box 80-6). If avoidance of these areas is impractical, tick repellents should be used, and appropriate clothing should be worn. After leaving tick-infested areas, one should perform a thorough body and scalp search for ticks.

REFERENCES

Breman JG, Campbell CC: Combatting severe malaria in African children. Bull WHO 1988;66:611.

Gelfand JA: Babesia. In Mandell GL, Bennett JE, and Dolin R, Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.

Krause PJ et al: Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness. JAMA 1996;275:1657.

Krogstad DJ: Plasmodium species (malaria). In Mandell GL, Bennett JE, and Dolin R, Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.

Parra ME, Evans CB, Taylor DW: Identification of Plasmodium falciparum histidine-rich protein 2 in the plasma of humans with malaria. J Clin Microbiol 1991;29:1629.

Persing DH et al: Detection of Babesia microti by polymerase chain reaction. J Clin Microbiol. 1992;30:2097.

Pruthi RK et al: Human babesiosis. Mayo Clin Proc 1995;70:853.

Quick RE et al: Babesiosis in Washington State—a new species of Babesia. Ann Intern Med 1993;119:284.

Ryan ET, Kain KC: Health Advice and Immunizations for Travelers. NEJM 2000;342:1716.

Seesod N et al: An integrated system using immunomagnetic separation, polymerase chain reaction, and colorimetric detection for diagnosis of Plasmodium falciparum. Am J Trop Med Hyg 1997;56:322.

World Health Organization: Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94(Suppl 1):1.