CHAPTER 124: BABESIOSIS

Babesiosis is an emerging tick-borne infectious disease caused by protozoan parasites of the genus Babesia that invade and eventually lyse red blood cells (RBCs). Most cases are due to Babesia microti and occur in the United States, particularly in the Northeast and upper Midwest. The infection typically is mild in young and otherwise healthy individuals but can be severe and sometimes fatal in persons >50 years of age and in immunocompromised patients. Sporadic cases have been reported in Europe and the rest of the world.

Geographic distribution

More than 100 Babesia species are found in wild and domestic animals; a few of these species cause infection in humans (Fig. 124-1). B. microti, a parasite of small rodents, is the most common etiologic agent of human babesiosis and is endemic in the northeastern and upper midwestern United States. Seven states in these two regions (Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin) account for >95% of the reported cases. Other etiologic agents include Babesia duncani and B. duncani–type organisms on the West Coast and Babesia divergens–like organisms in Kentucky, Missouri, and Washington State.

The primary causative agent of human babesiosis in Europe is B. divergens, but Babesia venatorum and B. microti also have been reported. In Asia, cases due to B. microti–like organisms have been documented in Japan, Taiwan, and the People’s Republic of China. A case caused by B. venatorum also has been reported from the People’s Republic of China. A case of B. microti infection was described in Australia. Sporadic cases due to uncharacterized species have been reported in Colombia, Egypt, India, Mozambique, and South Africa.

Incidence

More than 1100 cases were reported in the United States in 2011, the year the disease became nationally notifiable. This figure represents a fivefold increase in incidence over the past decade. The incidence of babesiosis is markedly underestimated because symptoms are nonspecific and because young healthy individuals typically experience a mild or asymptomatic infection and may not seek medical attention. Fewer than 50 cases of B. divergens, B. divergens–like, and B. venatorum infections have been reported. Babesiosis caused by B. duncani and B. duncani–type organisms has also been sporadic, with fewer than 10 reported cases.

Modes of transmission

In the United States, B. microti is transmitted to humans primarily by the nymphal stage of the deer tick (Ixodes scapularis), the same tick that transmits the causative agents of Lyme disease (Chap. 82) and human granulocytotropic anaplasmosis (Chap. 83). Transmission generally occurs from May through October, with three-fourths of cases presenting in July and August. The vectors for transmission of B. duncani and B. divergens–like organisms are thought to be Ixodes pacificus and Ixodes dentatus, respectively. In Europe, Ixodes ricinus is the vector for B. divergens and B. venatorum. In Japan, B. microti–like organisms have been found in Ixodes ovatus ticks.

Babesiosis occasionally is acquired through transfusion of blood or blood products. B. microti is the most common transfusion-transmitted pathogen reported to the U.S. Food and Drug Administration, and more than 170 such cases have been identified. Three transfusion-transmitted cases caused by B. duncani have been documented. Transfusion-transmitted cases occur year-round, although most cases occur from June through November. More than 80% of cases occur in endemic areas. Transfusion-transmitted babesiosis occurs in nonendemic areas when unrecognized Babesia-contaminated blood products are imported from endemic areas: asymptomatically infected residents of endemic areas donate blood in nonendemic areas, or residents of nonendemic areas travel to endemic areas, become infected, and donate blood after they return home. Approximately three-quarters of the transfusion-transmitted babesiosis cases reported between 1979 and 2009 occurred in the last decade of this period, and about one-fifth of patients died.

Seven cases of probable or confirmed congenital B. microti infection have been described. Other cases of neonatal babesiosis have been acquired by transfusion or tick bite.

Asymptomatic B. microti infection

At least 20% of adults and 40% of children do not experience symptoms following B. microti infection. Asymptomatic infection, whether treated or not, may persist for >1 year after acute babesial illness. There is no evidence of long-term complications following asymptomatic infection; however, people who are asymptomatically infected may transmit the infection when they donate blood.

Mild to moderate B. microti illness

Symptoms typically develop following an incubation period of 1–4 weeks after tick bite and 1–9 weeks (but as long as 6 months) after transfusion of blood products. Patients experience a gradual onset of malaise, fatigue, and weakness. Fever can reach 40.9°C (105.6°F) and is accompanied by one or more of the following: chills, sweats, headache, myalgia, arthralgia, nausea, anorexia, and dry cough. Less common symptoms include sore throat, photophobia, abdominal pain, vomiting, weight loss, shortness of breath, and depression. On physical examination, fever is the salient feature. Ecchymoses and petechiae have been reported. An erythema migrans rash signifies concurrent Lyme disease (Chap. 82). Splenomegaly and hepatomegaly occasionally are noted. Lymphadenopathy is absent. Jaundice, slight pharyngeal erythema, and retinopathy with splinter hemorrhages and retinal infarcts rarely occur. Symptoms typically last 1–2 weeks, but fatigue may persist for several months.

Severe B. microti illness

Severe babesiosis requires hospital admission and typically occurs in patients with one or more of the following: age of >50 years, neonatal prematurity, male gender, asplenia, HIV/AIDS, malignancy, hemoglobinopathy, and immunosuppressive therapy. More than one-third of hospitalized patients develop complications, including acute respiratory distress syndrome, disseminated intravascular coagulation, congestive heart failure, renal failure, splenic infarcts, and splenic rupture. Patients who develop complications tend to have severe anemia (hemoglobin, ≤10 g/L). Laboratory prognostic factors for severe outcome—defined by hospitalization for >14 days, an intensive care unit stay of >2 days, or death—include an elevated alkaline phosphatase level (>125 U/L) and parasitemia of >4%. The fatality rate is 5–9% among hospitalized patients but is ~20% among immunocompromised patients and patients with transfusion-transmitted babesiosis.

Other Babesia infections

Cases of B. duncani infection range in severity from asymptomatic to fatal. Clinical manifestations are similar to those reported for B. microti infection. All three patients infected with B. divergens–like organisms in the United States required hospitalization; one died. Most cases of B. divergens infection in Europe have occurred in people lacking a spleen. The incubation period is 1–3 weeks. Symptoms appear suddenly and consist of fever (>41°C or 105.8°F), shaking chills, drenching sweats, headache, myalgia, and lumbar and abdominal pain. Hemoglobinuria and jaundice are commonly noted, and mild hepatomegaly may occur. If the infection is not treated, patients often develop pulmonary edema and renal failure. All four patients infected with B. venatorum in Europe had been splenectomized; their illness ranged from mild to severe, and none died. A child in China who developed B. venatorum illness had an intact spleen and survived the infection.

Anemia is a key feature of the pathogenesis of babesiosis. Hemolytic anemia caused by rupture of infected RBCs generates cell debris that may accumulate in the kidney and cause renal failure. Anemia also results from the clearance of intact RBCs as they pass through the splenic red pulp and encounter resident macrophages. Babesia antigens expressed at the RBC membrane promote opsonization and facilitate uptake by splenic macrophages. In addition, RBCs are poorly deformable as a result of oxidation generated by the parasite and the host immune response and are filtered out as they attempt to squeeze across the venous vasculature. Bone marrow suppression due to cytokine production may also contribute to anemia.

An appropriate immune response is necessary for the control and clearance of Babesia. However, several lines of evidence suggest that an excessive response contributes to pathogenesis. Studies using laboratory mice have clearly established that CD4+ T cells are critical for resistance to and resolution of B. microti infection. CD4+ T cells are a major source of interferon γ (IFN-γ), and lack of this cytokine causes resistant mice to become highly susceptible to B. microti. IFN-γ is central to host resistance in B. duncani infection, but natural killer cells are its main source. B. duncani infection is more severe than B. microti infection in rodents and is characterized by pulmonary inflammation. Tumor necrosis factor α is expressed around alveolar septa, whereas IFN-γ is detected around pulmonary vessels. Blockade of either cytokine promotes the survival of mice infected with B. duncani.

A diagnosis of babesiosis should be considered for any patient who lives or travels in a Babesia-endemic area and presents with a febrile illness in the late spring, summer, or early autumn or within 6 months after a blood transfusion. Co-infection with Babesia should be considered in cases of Lyme disease or human granulocytotropic anaplasmosis when symptoms are more severe or prolonged than usual.

Screening laboratory tests can help support the diagnosis of babesiosis. A complete blood count often shows anemia and thrombocytopenia. Low hematocrit, hemoglobin, and haptoglobin levels and elevated reticulocyte counts and lactate dehydrogenase levels are consistent with hemolytic anemia. Liver enzyme tests often reveal elevated levels of alkaline phosphatase, aspartate and alanine aminotransferases, and bilirubin. Urinalysis may show hemoglobinuria, excess urobilinogen, and proteinuria. Elevated levels of blood urea nitrogen and serum creatinine indicate renal compromise.

A specific diagnosis usually is established by microscopic examination of Giemsa-stained thin blood smears (Fig. 124-2). Babesia trophozoites appear round, pear-shaped, or ameboid. The ring form is most common and lacks the central brownish deposit (hemozoin) typical of Plasmodium falciparum trophozoites (see Fig. 125-1C). Other distinguishing features are the absence of schizonts and gametocytes and the occasional presence of tetrads (“Maltese cross”). Tetrads are characteristic of B. microti, B. duncani, and B. divergens–like organisms in human erythrocytes. Because the number of parasitized RBCs may be low, particularly at the onset of symptoms, identification of the parasite may require multiple blood smears over several days. Parasitemia levels can range from 1% to 20% in immunocompetent hosts and can be as high as 85% in immunocompromised patients. If parasites cannot be identified by microscopy and the disease is still suspected, amplification of the babesial 18S rRNA gene by polymerase chain reaction (PCR) is recommended. Quantitative PCR has greatly lowered the threshold for detection of B. microti DNA.

Serology can suggest or confirm the diagnosis of babesiosis. An indirect immunofluorescent antibody test for B. microti is most commonly used. IgM titers of ≥1:64 and IgG titers of ≥1:1024 suggest active or recent infection. Titers typically decline over 6–12 months. Antibodies to B. microti do not cross-react with B. duncani or B. divergens antigen. In B. divergens infection, serology is of limited use because symptoms often appear before antibodies can be detected. Sera from patients infected with B. divergens–like organisms or B. venatorum are reactive against B. divergens antigen.

No vaccine is available for human use. There is no role for antibiotic prophylaxis. Individuals who reside in endemic areas, especially those at risk for severe babesiosis, should wear clothing that covers the lower part of the body, apply tick repellents (such as DEET) to clothing, and limit outdoor activities where ticks may abound from May through October. The skin should be thoroughly examined after outdoor activities, and ticks should be removed with tweezers. Individuals with a history of symptomatic babesiosis or with positive Babesia serology are indefinitely deferred from donating blood.