AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Babesiosis is an intraerythrocytic parasitic infection caused by protozoa of the genus Babesia and transmitted through the bite of the Ixodes tick, the same vector responsible for transmission of Lyme disease. While most cases are tick-borne, transfusion and transplacental transmission have been reported. In the United States, babesiosis is usually an asymptomatic infection in healthy individuals. Several groups of patients become symptomatic, and, within these subpopulations, significant morbidity and mortality occur. The disease most severely affects patients who are elderly, immunocompromised, or asplenic. Among those symptomatically infected, the mortality rate is 10% in the United States and 50% in Europe.

Pathophysiology

Babesiosis is a zoonotic disease maintained by the interaction of tick vectors, transport hosts, and animal reservoirs. The primary vectors of the parasite are ticks of the genus Ixodes. In the United States, the black-legged tick, Ixodes scapularis (also known as Ixodes dammini) is the primary vector for the parasite; in Europe, Ixodes ricinus appears to be the primary tick vector. In each location, the Ixodes tick vector for Babesia is the same vector that locally transmits Borrelia burgdorferi, the agent implicated in Lyme disease. The primary US animal reservoir is the white-footed mouse, Peromyscus leucopus. Additionally, white-tailed deer serve as transport hosts for the adult tick vector, I scapularis. In Europe, the primary animal reservoir is cattle. 


The Ixodid ticks ingest Babesia during feeding from the host, multiply the protozoa in their gut wall, and concentrate it in their salivary glands. The tick inoculates a new host when feeding again. The parasite then infects red blood cells (RBCs) and differentiated and undifferentiated trophozoites are produced. The former produce 2-4 merozoites that disrupt the RBC and go on to invade other RBCs. This leads to hemolytic anemia, thrombocytopenia, and atypical lymphocyte formation. Alterations in RBC membranes cause decreased conformability and increased red cell adherence, which can lead to development of acute respiratory distress syndrome (ARDS) among those severely affected.

Frequency

United States

The first US case of babesiosis was reported on Nantucket Island in 1966. An increasing trend over the past 30 years may be the result of restocking of the deer population, curtailment of hunting, and an increase in outdoor recreational activities. Between 1968 and 1993, more than 450 cases of Babesia infections were confirmed in the United States. However, the actual prevalence of this disease is unknown because most infected patients are asymptomatic.

International

The first case of human babesiosis was reported in 1957 from the former Yugoslavia in an asplenic farmer. Approximately 40 cases have been reported since then, mostly in Ireland, the United Kingdom, and France. Sporadic case reports of babesiosis in Japan, Korea, China, Mexico, South Africa, and Egypt have also been documented.

Mortality/Morbidity

The US mortality rate is significant.

• Twenty-five percent of adults and 50% of children infected with babesiosis are asymptomatic and/or improve spontaneously without treatment.
• Less than 10% of patients with babesiosis have died in the United States, mostly composed of elderly or asplenic patients.

• Approximately 20% of patients with babesiosis are co-infected with Lyme disease. These patients experience more severe symptoms for a longer duration than those with either disease alone.

In Europe, babesiosis is a life-threatening disease.

• Fifty-three percent of infected patients become comatose and die.
• Eighty-three percent of infected patients are asplenic.

Sex

The male-to-female ratio is about 1:1.

Age

Babesiosis affects all age groups with similar frequency; however, patients older than 50 years are at increased risk for severe infection and death.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients report a history of travel to an endemic area between the months of May and September. This is the period during which the Ixodes tick is in its infectious nymph stage; however, most do not recall the tick bite. The incubation period is between 1 and 4 weeks. The signs and symptoms mimic malaria and range in severity from asymptomatic to septic shock.

• Symptoms
  
  
  • Generalized weakness
  • Fatigue
  • Depression
  • Fever
  • Anorexia and weight loss
  • CNS - Headache, photophobia, neck stiffness, altered sensorium
  • Pulmonary - Cough, shortness of breath
  • GI - Nausea, vomiting, abdominal pain
  • Musculoskeletal - Arthralgia and myalgia
  • Renal - Dark urine

Physical

• Fever
• Rigors
• Diaphoresis
• Altered mental status
• Renal insufficiency/failure
• Pulmonary edema
• Hepatosplenomegaly
• Jaundice
• Shock

Causes

More than 100 species of Babesia exist, but only a small number of species are known to be responsible for the majority of symptomatic disease. The causative agent of babesiosis varies according to geographic region.

• In the United States, human infection with Babesia species is primarily due to Babesia microti, found mostly in northeastern and midwestern states. A few cases have been reported in Missouri, California, and Washington and are found to be caused by Babesia-like agents named after their geographic location, MO1 (Missouri), CA-1 (California), and WA-1 (Washington).
• In Europe, the causative agent of babesiosis is typically Babesia divergens, though B microti and B microti-like agents have been identified.
• Several reported cases of infection via blood transfusions from donors who lived in or traveled to an endemic area have been documented. All of these cases have occurred in the United States with the exception of one patient in Canada (acquired from a donor who became infected while in the United States) and one in Japan. The rate of acquiring B microti from a unit of packed red cells has been estimated to be 1 in 600-1800 in endemic areas.
• Case reports of transplacental/perinatal transmission have been documented.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In individuals who are asymptomatic, laboratory studies may be unremarkable.
• Wright- or Giemsa-stained peripheral blood smear
  
  
  • This test reveals intraerythrocytic parasites (ring forms with a central pallor) and, rarely, pathognomonic tetrads of budding trophozoites, the so-called Maltese cross.
  • The smear result may be negative in individuals with asymptomatic infection.
  • Level of parasitemia does not correspond to severity of disease, although patients who are mildly ill may have less than 1% parasitemia and patients who are severely ill may have greater than 85% parasitemia. High parasite levels are especially seen in asplenic patients.
• Complete blood count (CBC) with differential may demonstrate mild-to-severe hemolytic anemia, thrombocytopenia, atypical lymphocytes, and leukopenia.
• Liver function test results often reveal mildly elevated hepatic transaminase levels, erythrocyte sedimentation rate (ESR), lactic dehydrogenase (LDH) level, alkaline phosphatase level, and serum bilirubin level.
• Urinalysis may reveal hemoglobinuria, proteinuria, and a dark color may be present.
• Direct Coombs test result may or may not be positive.
• Pulse oximetry results will be low in hypoxic patients with severe disease.

Imaging Studies

• Chest radiography may be indicated for patients with respiratory complications including suspected pneumonia or ARDS.

Other Tests

• Further testing specific for babesiosis takes place outside of the ED.
• Inoculation of a golden hamster or mouse with B microti-infected patient blood or a gerbil with B divergens-infected blood and subsequent antibody analysis of the animal's blood is used to confirm diagnosis when peripheral blood smear and laboratory results are equivocal. However, this test requires checking the animal periodically over 6-8 weeks, making the test time- and labor-intensive and impractical for rapid diagnosis.
• Polymerase chain reaction
• • Polymerase chain reaction (PCR) is more sensitive and equally specific when compared with peripheral smear evaluation and hamster inoculation.
  • PCR may be useful in monitoring the infection, although it cannot differentiate between acute/active forms and chronic forms of the disease.
• Immunofluorescence antibody testing
• • Immunofluorescence antibody test (IFA) is considered the criterion standard for serologic detection of B microti infection.
  • This test is used to confirm the diagnosis when the peripheral blood smear result is negative.
  • A titer of greater than 1:64 is considered positive.
  • A greater than 4-fold rise in titer or a single titer greater than 1:256 is suggestive of acute infection, with a gradual decline seen over weeks to months
  • Correlation between severity of symptoms and titer levels is poor.
• Enzyme-linked immunosorbent assay immunoglobulin M Lyme titer
• • Enzyme-linked immunosorbent assay (ELISA) immunoglobulin M (IgM) Lyme test is used because of the high percentage (25%) of patients co-infected with Lyme disease.
  • Co-infection increases the severity of disease; therefore, diagnosing and treating both infections is important.
• Immunoblot antibody test
• • This test has similar sensitivity and specificity for diagnosing babesiosis as that of IFA.
  • Potential advantages over IFA include the lack of need for concentrated serum samples and ease of use, as immunoblot assays can be performed by generalist technicians versus trained microscopists.

Procedures

• Because of the possibility of hemophagocytic syndrome, bone marrow biopsy is indicated in patients whose laboratory studies reveal pancytopenia and whose physical examination reveals hepatosplenomegaly, fever, coagulopathy, or lymphadenopathy.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

• Suspicion of babesiosis in a patient with a history of exposure in an endemic area, tick bite, fever, chills, and fatigue is crucial.
• Peripheral blood smear or immunologic testing (see Workup) is necessary to make the diagnosis.
• If the patient is otherwise healthy and asymptomatic, no treatment is required.
• CBC with differential is important to determine the severity of infection.
• Immediately start elderly, immunocompromised, or asplenic patients on a combination treatment regimen of intravenous clindamycin and oral quinine or intravenous atovaquone and intravenous azithromycin to avoid acute renal failure.
• Intubation and mechanical ventilation may be required for patients who develop respiratory distress or failure.

Consultations

• Consult an infectious disease specialist on all babesiosis-infected patients who require hospital admission.
• Consult a hematologist for whole-blood exchange transfusion in severe cases.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antibiotic and antimalarial therapy should begin immediately after diagnosis in symptomatic patients to reduce the level of parasitemia. The standard treatment has been clindamycin and quinine, but this regimen occasionally fails and patients report frequent side effects including tinnitus, decreased hearing, and diarrhea. A drug regimen consisting of atovaquone and azithromycin has been shown to be effective when clindamycin and quinine fail, and patients experience much fewer side effects, typically diarrhea and rash. Parasitemia may persist despite treatment with either of the described drug regimens. In areas endemic for Lyme disease, physicians should consider treating for Lyme disease empirically.

Asymptomatic patients with positive smears and/or PCR results should have these studies repeated and a course of treatment started if parasitemia persists more than 3 months. Additionally, patients initially treated may require re-treatment if repeat smears or PCR are positive more than 3 months after initial therapy.

Partial or whole-blood exchange transfusion is indicated for patients with severe babesiosis, as demonstrated by high parasitemia (>10%); significant hemolysis; and/or renal, hepatic, or pulmonary dysfunction.

Drug Category: Antibiotics

Therapy should cover all likely pathogens in the context of this clinical setting.

Drug Name	Azithromycin (Zithromax)
Description	Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Treats mild-to-moderate microbial infections. Administer in combination with atovaquone.
Adult Dose	Day 1: 500 mg PO Days 2-7: 250 mg PO Immunocompromised patients: Higher doses of 600-1000 mg/d may be used
Pediatric Dose	Day 1: 10 mg/kg/d PO; maximum of 500 mg/dose Days 2-5: 5 mg/kg/d PO; maximum of 250 mg/dose
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzyme levels and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized patients, geriatric patients, or debilitated patients

Drug Category: Antiprotozoals

These agents may contribute to the eradication of the parasite.

Drug Category: Anti-malarials

These agents are effective in eradicating the parasite.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Monitor level of oxygenation and watch for development of respiratory complications after initiation of treatment in patients who present with respiratory complaints. Respiratory distress may be due to endotoxin sensitivity; endotoxin release often results from medication-induced intraerythrocytic death of the parasites.
• In severe cases, exchange transfusion may be the only means of reducing the level of parasitemia.
• Mechanical ventilation may be necessary in patients with severe disease.
• Monitor CBC for development of hemophagocytic syndrome.
• If the patient does not respond to or cannot tolerate treatment with clindamycin and quinine, commence alternative treatment with atovaquone and azithromycin.

Deterrence/Prevention

• Exposure to endemic areas
  
  
  • Persons at risk of severe infection should avoid endemic areas between the months of May and September.
  • Skin should be covered with appropriate clothing, including tucking long pants inside socks.
  • Early removal of ticks from humans and pets should prevent transmission of disease; a tick must remain attached for at least 24 hours for transmission of the parasite.
  • Tick repellent, such as products with 10-35% diethyltoluamide (DEET), should be applied on skin and clothes.
  • People from endemic areas who report a fever within the last 2 months or a history of tick bite are not allowed to donate blood.

Complications

• Respiratory
  
  
  • Patients who have undergone splenectomy are unable to clear infected RBCs, thereby leading to higher levels of parasitemia, eventually leading to hypoxemia and subsequent risk of cardiopulmonary arrest.
  • In severe cases, damage to RBC membranes, decreased deformability, and cytoadherence to capillaries and venules lead to pulmonary edema and respiratory failure.
  • These respiratory problems begin after treatment has been initiated when intraerythrocytic death of parasites has been postulated to cause sensitivity to endotoxin.
  • ARDS may be due to mechanisms such as endotoxemia, complement activation, immune complex deposition, cytoadherence, microemboli, and disseminated intravascular coagulation.
• Cardiac
  
  
  • Myocardial infarction
  • Congestive heart failure
• Renal
  
  
  • Renal insufficiency
  • Renal failure
• Postsplenectomy patients may develop hemophagocytic syndrome, acute renal failure, and generalized seizure.
• Coma can occur, possibly due to severe sepsis, ARDS, or multisystem organ failure.
• Co-infection with Lyme disease is a possible complication.

Prognosis

• In the United States, the prognosis is excellent; most patients recover spontaneously. Patients who have had their spleen removed are at the greatest risk for severe complications and death.
  


• In Europe, most symptomatic patients are asplenic, which contributes to a poor prognosis. More than 50% of patients become comatose and die.
  


• Babesiosis may continue for more than 2 months after treatment; asymptomatic infections can persist silently for months to years. Patients with positive smears or PCR more than 3 months after initial treatment should be re-treated, regardless of the presence or absence of seizures.

Patient Education

• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider diagnosis in children
• Failure to initiate immediate therapy in individuals considered at high risk (ie, asplenic, elderly, immunocompromised)
• Administration of quinine therapy to a patient who is pregnant

Special Concerns

• Pregnancy
• • Do not give quinine to pregnant patients.
  
  
  • If the infection is subclinical, drug therapy is not indicated.
  
  
  • Combination therapy with clindamycin and quinine or atovaquone and azithromycin is more effective than either atovaquone or azithromycin alone.
  
  


• Geriatric patients: Initiate therapy with clindamycin and quinine immediately.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 27, 2007