Babesiosis

Babesiosis

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Edouard Vannier, Peter J Krause

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Babesiosis is an emerging infectious disease caused by intra-erythrocytic protozoan parasites. Frequent symptoms include fever, fatigue, chills, sweats and headache Babesiosis typically is transmitted by Ixodes ticks, occasionally through blood transfusion and, rarely, transplacentally Healthy people over 50 years of age and immunocompromised individuals, including those who are asplenic, have a malignancy or HIV infection, are at increased risk of severe disease and death Definitive diagnosis is made by visualizing parasites on peripheral blood smears or amplifying Babesia DNA by PCR. Detection of anti-Babesia antibody in serum indicates active or past infection Standard therapy is a single 7–10-day course of atovaquone and azithromycin or clindamycin and quinine. Partial or complete exchange transfusion is recommended for severe cases. Highly immunocompromised individuals with persistent infection should be treated for at least 6 weeks, including 2 weeks after the parasite is no longer detected on blood smear

INTRODUCTION Babesiosis is a tick-borne infectious disease caused by intra-erythrocytic protozoan parasites of the genus Babesia. Wild and domestic animals are reservoir hosts for more than 100 Babesia species. Humans are infected by a few of these species. The parasite is named in honor of the Romanian pathologist Viktor Babes who investigated the cause of febrile hemoglobinuria in cattle and visualized the microorganism in their red blood cells. Described since biblical times as an important disease of livestock, babesiosis was first recognized as a human disease in 1956. Thousands of cases have subsequently been reported, primarily in the USA where babesiosis is classified as an emerging infectious disease.

EPIDEMIOLOGY GEOGRAPHIC DISTRIBUTION USA The first confirmed human case was identified in 1969 on Nantucket Island and was caused by Babesia microti, a parasite of small rodents. Babesia microti is the most common cause of human babesiosis and

is now endemic in the northeast (from Maine to Delaware) and in the upper mid-west (Minnesota and Wisconsin). The number of cases and the geographical range of babesiosis have steadily increased over the last two decades. In 2009, more than 700 cases were reported to public health departments in endemic states, although this number is certainly an underestimate. Babesiosis became a nationally notifiable disease in January 2011. Factors thought to account for the emergence of babesiosis include an increase in deer that are a critical host in the lifecycle of the vector tick (Ixodes scapularis), spread of B. microtiinfected ticks to new areas and a heightened awareness of the disease by physicians and the general public [1]. Several cases caused by Babesia duncani have been reported on the west coast. A few cases caused by Babesia divergens-like organisms have been reported from Kentucky, Missouri, and Washington State [1].

Europe About 30 cases have been attributed to B. divergens, a parasite of cattle [2]. Most have been reported from the UK, Ireland and France, particularly from regions with extensive cattle farming. Isolated cases have been reported from Croatia (index case), Finland, Georgia (exUSSR), Spain, Portugal and Sweden. A single autochthonous case of B. microti infection has been documented in Germany. Four cases infected with Babesia venatorum (EU1), a species closely related to B. odocoilei that infect white-tailed deer in the USA, have been reported from Italy, Austria and Germany [2].

Asia, Africa and South America Two cases in Taiwan and one in Japan were infected with B. microtilike organisms [1]. A case in South Korea has been attributed to Babesia K01, a species closely related to those found in sheep. In the few cases reported from Africa, China, and India, the Babesia spp. were not fully characterized. Asymptomatic infection has been reported from Mexico and Colombia.

MODE OF TRANSMISSION Babesia microti is typically transmitted during the blood meal of infected Ixodes scapularis nymphal ticks. Transmission occurs from May through to September, with most cases presenting from June to August. Most infected individuals do not recall a tick bite. The tick species that transmit B. duncani and B. divergens-like organisms remain unknown. In Europe, Ixodes ricinus is the main vector for transmission of B. divergens and B. venatorum. Babesia microti is the most commonly reported microorganism transmitted through blood transfusion in the USA [3–5]. More than 150 cases have been reported, primarily following packed red blood cell transfusion, but many cases are thought to go unreported or unrecognized [3]. Transfusion-transmitted B. duncani infection has been documented on three occasions [5]. Transfusion-transmitted babesiosis can occur anywhere and at any time of the year, but most cases are reported in endemic areas during autumn and winter. The incubation period varies from 1 to 9 weeks but in one case was 6 months. Of the 11 deaths attributed to transfusion-transmitted babesiosis and

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reported to the US Food and Drugs Administration (FDA) between 1998 and 2008, ten occurred between 2005 and 2008 [4, 5]. Recent increases in the number of transfusion-transmitted babesiosis cases and associated mortality are a major concern of the transfusion medicine community. Babesiosis has rarely been transmitted transplacentally. Three such cases have been reported, all caused by B. microti.

CLINICAL MANIFESTATIONS BABESIA MICROTI INFECTION Symptoms of B. microti infection vary in number and intensity. Three patterns of infection have been described: i) asymptomatic infection; ii) mild-to-moderate viral-like illness; and, iii) severe illness that may be fulminant and culminate in prolonged illness or death. As many as a quarter of adults and half of children do not have symptoms [6]. Asymptomatic infection may persist for weeks to months following resolution of symptoms, even after standard antibiotic therapy has been administered [7]. The infection is also asymptomatic during the incubation period that typically lasts from 1 to 4 weeks following tick bite. Babesiosis is a viral-like illness that consists of a gradual onset of malaise and fatigue followed by fever as high as 40.6°C (105°F) and one or more of the following: chills, sweats, headache, myalgia, anorexia, non-productive cough, arthralgia and nausea [1, 6]. Less commonly noted are emotional lability and depression, hyperesthesia, sore throat, abdominal pain, conjunctival injection, photophobia and weight loss. Fever is the most common finding on physical examination. Rash is seldom noted, although ecchymoses and petechiae have been described. Mild splenomegaly, hepatomegaly, or both, occasionally occur. Slight pharyngeal erythema, jaundice, hematuria, and retinopathy with splinter hemorrhages and retinal infarcts have been reported. Severe infection requires hospital admission and often occurs in people over 50 years of age and in people immunocompromised by asplenia, malignancy, HIV infection or immunosuppressive drugs [1, 8]. The most common complications consist of pulmonary edema [acute respiratory distress syndrome (ARDS)], disseminated intravascular coagulopathy (DIC), congestive heart failure and renal failure [9]. Splenic infarcts and splenic rupture have been noted. Highly immunocompromised hosts may experience a persistent or relapsing illness [8]. Outcome is fatal in 6–9% of all hospitalized cases and up to 28% of cases in immunocompromised hosts.

OTHER BABESIA INFECTIONS Patients infected with B. divergens present with a fulminant illness and nearly all reported cases have occurred in splenectomized individuals [2]. Symptoms include high fever, shaking chills, intense sweats, headache, myalgia and lumbar and abdominal pain. Hemoglobinuria and jaundice are almost always present. Several decades ago most cases were fatal but, with the advent of exchange transfusion combined with effective antibiotic therapy, death is rare. Cases of B. duncani infection have been few and have ranged in severity from asymptomatic to fatal. Similarly, B. venatorum infection has ranged from mild to severe.

FIGURE 100.1 Ring forms of Babesia microti on a Giemsa-stained human blood film (magnification x1000).

TABLE 100-1  Diagnosis of Babesiosis Epidemiology l l l

Residence in, or travel to, an area endemic for babesiosis Ixodes tick bite within 1 to 4 weeks Blood transfusion within 1 to 9 weeks

Symptoms l

Fever, fatigue, chills, sweats, headache, myalgia, anorexia, non-productive cough, arthralgia and nausea l Less common: emotional lability and depression, hyperesthesia, sore throat, abdominal pain, conjunctival injection, photophobia and weight loss

Signs on physical examination l l

Fever Splenomegaly, hepatomegaly, pallor

Common laboratory diagnostic procedures l l l

Visualization of Babesia parasites on peripheral blood smears Amplification of Babesia DNA in blood using PCR Presence of serum Babesia IgM antibody or a fourfold rise in Babesia IgG antibody

When parasites are too few to be detected on blood smears, as often occurs in the early phase of infection and after resolution of symptoms, infection is best detected by PCR [1]. Amplification and sequence analysis of the entire18S rRNA gene allows for molecular classification of Babesia species.

The diagnosis of babesiosis should be considered in any person who resides in, or has traveled to, an endemic area and who presents with symptoms of babesiosis during the summer or early autumn.

Supportive laboratory findings include moderate-to-severe hemolytic anemia, thrombocytopenia, an elevated reticulocyte count and an elevated erythrocyte sedimentation rate. The leukocyte count is normal-to-slightly decreased, with a “left shift.” In severe cases, elevated serum bilirubin and liver enzyme concentrations, elevated serum blood urea nitrogen and creatinine concentrations, and hematuria and proteinuria are noted.

The definitive diagnosis of babesiosis is made by microscopic analysis of Giemsa-stained thick or thin blood smears, although parasites can be visualized using Wright’s stain (Fig. 100.1, Table 100-1) [1]. Babesia typically appear as ring forms that may be mistakenly identified as Plasmodium falciparum. Trophozoites divide by binary fission, yielding two to four merozoites that remain in close proximity. The four merozoites are distributed as a “Maltese cross”, but this pattern is seldom noted.

Immunofluorescence assay (IFA) serology is useful in confirming the diagnosis. IgM antibody titers ≥1 : 64 and IgG antibody titers of ≥1 : 1024 signify active, or recent, infection. IgG titers typically decrease to ≤1 : 64 within 12 months. Thin blood smears, PCR and serology tests are available at most large commercial laboratories in endemic areas. Certain university medical center laboratories and the Centers for Disease Control and Prevention (CDC) serve as reference laboratories.

DIAGNOSIS

Babesiosis

TREATMENT BABESIA MICROTI INFECTION Patients are occasionally diagnosed with Babesia infection after they have become asymptomatic following acute illness. No controlled trials are available to guide optimal therapy for such patients, but a regimen of atovaquone and azithromycin for 7–10 days has been suggested for people who experience asymptomatic parasitemia for 3 months or longer in order to minimize the risks of clinical relapse and transfusion-transmitted babesiosis. Mild-to-moderate viral-like illness is best treated with the combination of atovaquone and azithromycin for 7–10 days (Table 100-2). Severe infection should be treated with the combination of clindamycin and quinine, although quinine is often associated with transient hearing impairment or gastrointestinal upset. In the first antibiotic treatment trial for human babesiosis [10], the combination of atovaquone and azithromycin was compared with clindamycin and quinine – the first successful therapeutic regimen used for the treatment of babesiosis. These combinations were equally effective in clearing symptoms and parasitemia. Adverse effects were reported in 15% of patients who received atovaquone and azithromycin compared with 72% of those who received clindamycin and quinine. Drug reactions were so severe that the regimen was discontinued or the dosage decreased in about a

TABLE 100-2  Treatment of Babesiosis Treatment

Dose

Frequency

Atovaquone and azithromycin Atovaquone

Adult: 750 mg Child: 20 mg/kg (maximum 750 mg/dose)

Every 12 hours Every 12 hours

Azithromycin

Adult: 500–1000 mg 250 mg Child: 10 mg/kg (maximum 500 mg/dose) 5 mg/kg (maximum 250 mg/dose)

On day 1 On subsequent days On day 1 On subsequent days

Clindamycin and quinine Clindamycin

Quinine

Adult: 600 mg Child: 7–10 mg/kg (maximum 600 mg/dose) Intravenous administration Adult: 300–600 mg Child: 7–10 mg/kg (maximum 600 mg/dose)

Every 8 hours Every 6–8 hours

Adult: 650 mg Child: 8 mg/kg (maximum 650 mg/dose)

Every 6–8 hours Every 8 hours

Every 6 hours Every 6–8 hours

All antibiotics are administered by mouth, unless otherwise specified. All doses are administered for 7–10 days except for persistent or relapsing infection (see text). For immunocompromised patients, successful treatment regimens have included higher doses of azithromycin (600–1000 mg per day) in combination with atovaquone. Exchange transfusion Partial, or complete, exchange transfusion should be considered for the treatment of severe cases, including those who experience parasitemia >10%, severe anemia, pulmonary edema, or renal or hepatic compromise.

third of those taking clindamycin and quinine, but in only 2% of those taking atovaquone and azithromycin. Partial, or complete, exchange blood transfusion is recommended in case of intense parasitemia (>10%), severe anemia, pulmonary edema, or renal or hepatic compromise [1]. For highly immunocompromised people who suffer persistent infection, antimicrobial therapy should be administered for at least 6 weeks, including 2 weeks during which the parasite is no longer detected on blood smear [8].

OTHER BABESIA INFECTIONS Babesia divergens infections are treated with exchange transfusion in combination with clindamycin and quinine [2]. The combination of pentamidine and trimethoprim-sulfamethoxazole was successfully used to treat a mild case of B. divergens infection. Infections with B. duncani and B. venatorum are treated with clindamycin and quinine, along with exchange transfusion and hemodialysis, when necessary.

PREVENTION Areas where ticks, deer and mice are known to thrive should be avoided during the primary transmission season, especially by people who are immunocompromised. Clothing that covers the lower part of the body and that is sprayed or impregnated with diethyltoluamide, dimethyl phthalate or permethrin (Permanone) is recommended. A search for ticks on people and pets should be carried out and the ticks removed with the use of tweezers when possible. Application of acaricide to deer decreases the risk of tick-borne disease in people by reducing tick numbers. In the USA, the indefinite deferral of prospective blood donors who report past Babesia infection is the only measure currently employed to protect the blood supply. The results of an interim analysis of the first laboratory-based strategy for screening blood donors who are infected with Babesia suggests that the combined use of Babesia microti IFA and qPCR is effective in reducing the incidence of transfusion-transmitted babesiosis. Treatment of blood products with pathogen reduction methods is being developed [4–5]. No vaccine for human babesiosis is available.

ACKNOWLEDGEMENTS This work was supported by a generous gift from The Gordon and Llura Gund Foundation and grants from the National Institutes of Health (R01 AG019781 [EV] and R21 AI088079 [PJK]).

REFERENCES 1. Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008;22:469–88. 2. Hunfeld KP, Hildebrandt A, Gray JS. Babesiosis: Recent insights into an ancient disease. Int J Parasitol 2008;38:1219–37. 3. Herwaldt BL, Linden JV, Bosserman E, et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med 2011;155: 509–19. 4. Gubernot DM, Nakhasi HL, Mied P, et al. Transfusion-transmitted babesiosis in the United States: Summary of a workshop. Transfusion 2009;49:2759–71. 5. Leiby DA. Transfusion-transmitted Babesia spp.: bull’s-eye on Babesia microti. Clin Microbiol Rev 2011;24:14–28. 6. Krause PJ, McKay K, Gadbaw J, et al. Increasing health burden of human babesiosis in endemic sites. Am J Trop Med Hyg 2003;68:431–6. 7. Krause PJ, Spielman A, Telford SR, III, et al. Persistent parasitemia after acute babesiosis. N Engl J Med 1998;339:160–5. 8. Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008;46:370–6. 9. Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis 2001;32:1117–25. 10. Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000;343:1454–8.

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