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Author: Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Editors: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Om Prakash Sharma, MD, FRCP, FCCP, DTM&H, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Author and Editor Disclosure

Synonyms and related keywords: babesiosis, Babesia, Babesia infection, Babesia microti, B microti, Babesia divergens, B divergens, Ixodes, Ixodes scapularis, I scapularis, Ixodes dammini, I dammini, Babesia bigemina, B bigemina, Babesia bovis, B bovis, Babesia major, B major, Babesia equi, B equi, Babesia canis, B canis, Babesia felis, B felis, Babesia microti, B microti, tick-borne infection, tick disease, tickborne illness, tick-borne illness, tick infection, malaria, Lyme disease, protozoan infection, Ixodidae, Texas cattle fever

Background

Babesiosis is a tick-borne malarialike illness caused by species of the intraerythrocytic protozoan Babesia. Humans are opportunistic hosts for Babesia when bitten by nymph or adult ticks.

Babesiosis is named for Victor Babes, who first identified the RBC protozoan in 1888. Babes noticed intraerythrocytic protozoa in cattle with febrile hemoglobinuria. In 1893, Smith and Kilbourne discovered that the protozoa was transmitted by ticks and was the cause of Texas cattle fever. In 1957, the first human case of babesiosis, in a Yugoslavian cattle farmer, was described. The first case in the United States case was reported in Nantucket, Massachusetts, in 1969.

Currently, Babesia infection is transmitted by various tick vectors in Europe, Asia, and the northwestern and northeastern United States.

Babesiosis is a zoonotic infection in which ticks transmit Babesia organisms from a vertebrate reservoir to humans; the infection is incidental in humans. The primary Babesia species that infect cattle include Babesia divergens, Babesia bigemina, Babesia bovis, and Babesia major. In horses, the main species of Babesia is Babesia equi. Babesia canis is the primary species in dogs, and Babesia felis is the main species in cats. Babesia microti is the species found in mice.

Pathophysiology

The clinical signs and symptoms of babesiosis are related to the parasitism of RBCs by Babesia. Fever, hemolytic anemia, and hemoglobinuria may result from Babesia infection. As with malaria, RBC fragments may cause capillary blockage and/or microvascular stasis, explaining liver, splenic, renal, and CNS involvement. As with malaria, cells of the reticuloendothelial system (RES) in the spleen remove damaged RBC fragments from the circulation. RBC destruction results in hemolytic anemia.

Babesiosis elicits a B-lymphocyte response and a T-lymphocyte response. As with malaria, the primary immune response is a T-cell–mediated cellular immunity, and a secondary reactive polyclonal hypergammaglobulinemia occurs because of excessive B-lymphocyte reactivity.

Frequency

United States

Babesiosis is common in endemic areas of the northeastern and northwestern United States, particularly Long Island, New York, and Nantucket and Martha's Vineyard, Massachusetts. Infections have also been reported in the upper Midwest. In endemic areas, the organism may also be transmitted by blood transfusion.1, 2, 3, 4, 5, 6

International

Babesiosis occurs in areas of Europe and Asia, where the tick vector and vertebrate host reside.

Mortality/Morbidity

  • Babesiosis in otherwise healthy hosts produces an acute infectious disease that resembles malaria. Mortality due to babesiosis is uncommon in patients with normal splenic function.
  • Patients who are asplenic have a more fulminant and prolonged clinical course and may have overwhelming infection and a fatal outcome.

Race

  • Babesiosis has no predilection for race.

Sex

  • Babesiosis has no predilection for sex.

Age

  • Persons of any age can be affected with babesiosis.



History

The history of babesiosis includes fever and chills. Patients with babesiosis have symptoms similar to those of malaria. Symptoms are related to the degree of RBC parasitemia.

Physical

Most patients with babesiosis have few, if any, physical findings. A minority of patients have jaundice and splenomegaly.

Causes

  • Babesia organisms may be transmitted in utero.
  • Persons who come into contact with nymphs or adult Ixodidae ticks are at risk for acquiring babesiosis.
  • Large populations of field mice and white-tailed deer are likely to support a large Ixodidae tick population, which perpetuates areas endemic for babesiosis.
  • Babesiosis is caused by Babesia species, and the main species in the United States is B microti. B divergens is the main species in Europe.
  • Other Babesia species, namely B divergens and B bovis, occasionally cause disease in humans. B divergens and B bovis primarily infect cattle. Another strain, WA-1, has been implicated in human babesiosis on the west coast of the United States.
  • Babesiosis is a zoonosis that requires Babesia to be present in vertebrate vectors, such as white-tailed deer, white-footed mouse, and Ixodes ticks.
    • The main tick vectors of babesiosis include Ixodes scapularis and Ixodes dammini. Ixodes ticks are small and differ from the large Dermacentor ticks that transmit Rocky Mountain spotted fever (RMSF) and ehrlichiosis.
    • The white-footed mouse is the primary enzootic reservoir. After feeding on infected white-footed mice, the tick larvae become infected with B microti. The tick larvae are maintained as the tick develops from the larval phase to the nymphal phase. Nymphs infected with B microti may transmit the Babesia organisms to other mice or rodents or to a human host.
    • Adult Ixodes tick populations are maintained in white-tailed deer. Larvae, nymphs, and adult ticks all may infect humans, but the nymph is the primary vector of B microti infection in humans.
    • The I scapularis life cycle requires 2 years for completion, beginning from egg deposition in the spring. Larvae take 1 year, until the next spring, to develop to the nymph stage. Nymphs feed for 3-4 days on white-footed mice or rodents and mature into adults the following fall. Adults mate and feed on white-tailed deer during the spring; the adults then deposit their eggs and die. The white-footed mouse is necessary to perpetuate the Babesia organisms, and the deer is needed to perpetuate the Ixodes tick population.
    • Humans acquire babesiosis when in close proximity to large populations of white-footed mice infected with Babesia and white-tailed deer infested with I scapularis or I dammini ticks.
  • Babesiosis may also be transmitted via blood transfusion.



Ehrlichiosis
Lyme Disease
Malaria
Rocky Mountain Spotted Fever
Typhoid Fever

Other Problems to be Considered

Babesiosis usually manifests as an undifferentiated acute febrile illness that resembles malaria. Patients who previously had non–Plasmodium falciparum malaria may be experiencing a relapse of their previous malarial infection. A relapse of their malaria may be diagnosed based on prior exposure or infection as many as 40 years previously with a non-falciparum malaria. Diagnosis is based on demonstrated plasmodia in properly prepared Giemsa-stained or Wright-stained thick or thin blood smears. Patients with recrudescent malaria may have low levels of parasitemia and usually have increased malaria immunoglobulin G (IgG) titers.

Patients who present with a malarialike illness always should be questioned regarding potential for previous exposure to malaria.

Patients should also be questioned about a previous history of Lyme disease. Although the signs and symptoms of Lyme disease differ from those of babesiosis, the Ixodidae tick vector associated with Lyme disease may also transmit Babesia organisms. Co-infections of Lyme disease and babesiosis are uncommon but can occur.

Ehrlichiosis (ie, "spotless" RMSF) also presents as an acute febrile infection that resembles RMSF. Because of the separate tick vectors, patients with ehrlichiosis are unlikely to be co-infected with Lyme disease or babesiosis. While seropositivity to Lyme disease and ehrlichiosis is common in endemic areas, clinical co-infection remains rare. Increased Ehrlichia titers with an IgG antibody titer equal to or greater than 1:64 or a 4-fold or greater change in antibody titers on immunofluorescent antibody (IFA) testing is diagnostic of ehrlichiosis.

Patients with ehrlichiosis often have leukopenia, anemia, and thrombocytopenia. The erythrocyte sedimentation rate (ESR) is minimally elevated in ehrlichiosis. Levels of serum transaminases may be mildly increased in ehrlichiosis, as with babesiosis, typhoid fever, and RMSF.

Typhoid fever, RMSF, and Lyme disease may be differentiated from babesiosis, ehrlichiosis, and malaria based on the presence or absence of hemolytic anemia. Hemolytic anemia is not a typical feature of typhoid fever, RMSF, or Lyme disease.

Except for Lyme disease and typhoid fever, thrombocytopenia is a feature of all of these infectious diseases. Leukopenia is a common finding in typhoid fever, RMSF, babesiosis, and ehrlichiosis but is not a characteristic finding in Lyme disease.

Splenomegaly may be present in patients with typhoid fever, malaria, babesiosis, ehrlichiosis, and RMSF but is not a feature of Lyme disease.

Arthropod-borne viral infections may be confused with babesiosis. However, arboviral illnesses are characterized by the extreme rapidity of onset and clinical severity, which is not the case in babesiosis unless the spleen is absent.

Relative bradycardia is a cardinal finding in many infectious diseases. Many arboviral infections (eg, yellow fever, dengue fever, African hemorrhagic fever [Ebola]) are characterized by relative bradycardia. Relative bradycardia is a common finding in patients with malaria, RMSF, and babesiosis but is not a feature of Lyme disease.

In rare cases, typhoidal Epstein-Barr virus (EBV) infections, mononucleosis, or typhoidal tularemia is confused with babesiosis. EBV-specific antibody testing and tube agglutination testing for tularemia can help exclude these diagnostic possibilities if they are considered in the differential diagnoses.

Typhoid fever is suggested by a severe headache and apathetic faces with few, if any, localizing signs. Splenomegaly may be present later in the course of the illness. A normal or slightly decreased peripheral WBC count is the characteristic hematologic finding in typhoid fever. The presence of eosinophilia or thrombocytopenia suggests an alternate diagnosis. Typhoid fever may be diagnosed based on staining or culturing the organism in RES tissues or body fluid, ie, blood, urine, or feces.

Typhoid fever may resemble babesiosis and its clinical presentation. As with babesiosis, physical signs are usually absent in patients with typhoid fever. Patients with typhoid fever often present with constipation rather than diarrhea, which may be helpful because neither constipation nor diarrhea is a feature of babesiosis.

Headache is a prominent feature of malaria and typhoid fever but is less prominent with babesiosis and ehrlichiosis and is mild if present in Lyme disease.

Human monocytic ehrlichiosis (HME), human granulocytic anaplasmosis (HGA), and human granulocytic ehrlichiosis (HGE) may be diagnosed serologically in patients with a nonspecific febrile illness in endemic areas. These may also be diagnosed based on Wright stain on peripheral blood smears or buffy-coat preparations that demonstrate regularly stained cytoplasmic inclusions in monocytes or, less commonly, lymphocytes, which are mulberry-shaped and are called morulae. Morulae are seen more frequently in HME than in HGE.

Babesiosis rarely affects the lungs. However, patients with babesiosis may develop noncardiogenic pulmonary edema, which may resemble pneumonia on chest radiography.



Lab Studies

Patients from areas endemic for babesiosis who present with a malarialike illness should undergo a workup for babesiosis with the following direct and indirect tests.

  • Lactate dehydrogenase (LDH) and a properly stained peripheral blood smear offer the most important results in patients with suspected babesiosis who have a malarialike illness. Quantitatively stained buffy-coat smears concentrate WBCs and increase the likelihood of demonstrating Babesia in the peripheral blood. As with malaria, multiple peripheral-stained thin smears or stained buffy-coat preparations may be necessary to detect low levels of Babesia parasitemia.
    • Wright or Giemsa stain on thin blood smears reveals the ring forms of babesiosis. The ability to identify babesiosis depends on the expertise and experience of the microbiologist or physician and the degree of parasitemia.
    • Most patients with intact splenic function who are mildly to moderately ill with babesiosis have 10% or less of parasitemia in their peripheral blood.
    • Patients with asplenia usually have greater degrees of parasitemia.
    • Patients with Babesia infection, in addition to having intraerythrocytic ring forms, may also demonstrate merozoites arranged in a tetrad configuration that resembles a Maltese cross.
    • Tetrad forms are pathognomonic of babesiosis. Babesiosis may be differentiated from malaria based on the absence of pigment hemozoin, which is not present in babesiosis.
  • Complete blood cell count and erythrocyte sedimentation rate
    • A CBC count should be obtained to look for the presence of hemolytic anemia, Howell-Jolly bodies indicative of splenic dysfunction, leukopenia, lymphopenia, thrombocytopenia, and an elevated ESR.
    • Hemolytic anemia, lymphopenia, and thrombocytopenia are the typical findings in babesiosis.
    • Atypical lymphocytes may be present, as they are in malaria, and the number of atypical lymphocytes is not related to the degree of parasitemia or the severity of illness.
    • As with malaria, the diagnosis of babesiosis should be questioned if the serum LDH level is not elevated. Increased LDH levels reflect the degree of parasitemia/severity of Babesia.
  • Serum protein electrophoresis (SPEP): This test should be obtained, and results usually show a polyclonal gammopathy indicative of B-lymphocyte hyperreactivity SPEP (polyclonal gammopathy) in response to T-lymphocyte suppression by Babesia.
  • Liver function tests
    • LFTs should be obtained to look for elevated transaminase levels, an elevated alkaline phosphatase level, hyperbilirubinemia, and a decreased haptoglobin level. These abnormalities are variably present in patients with babesiosis.
    • Obviously, the total bilirubin and haptoglobin values reflect the intensity of the infection. Increased serum transaminase levels are usually mildly and transiently elevated. A decreased haptoglobin level suggests a significant degree of intravascular hemolysis.
  • Urinalysis
    • Urinalysis should be obtained to check for hemoglobinuria.
    • The degree of hemoglobinuria is related to the intensity of the Babesia infection.
  • Serology
    • Immunoglobulin M (IgM) or IgG IFA B microti titers may be obtained in patients with suspected babesiosis who have negative findings on peripheral smears, eg, low levels of parasitemia.
    • A single IgM IFA titer of 1:64 or greater is diagnostic of babesiosis. Increased IgG IFA Babesia titers indicate past exposure rather than current infection.
    • Serum creatinine measurements should be obtained to assess potential renal insufficiency. Care must be taken to consider other causes of an increased serum creatinine level before ascribing these changes to Babesia infection.
  • Polymerase chain reaction: This test may be used to help diagnose recrudescent Babesia infection in patients who have previously had babesiosis or in those whose treatment is of questionable effectiveness.



Medical Care

Patients with severe babesiosis need to be hospitalized. In addition to receiving anti-Babesia treatment, they may require supportive care.

Consultations

  • Anyone with a zoonotic infectious disease or malarialike illness should have the benefit of a consultation with an infectious disease specialist.
  • Consultation with a nephrologist is advisable in patients with renal insufficiency due to babesiosis or renal insufficiency superimposed on preexisting renal disease.
  • Consultation with a hematologist should be obtained in patients with severe hemolysis.



The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug NameClindamycin (Cleocin) plus quinine (Formula Q)
DescriptionAnti-Babesia agents. Quinine inhibits growth of parasite by increasing the pH within intracellular organelles and possibly by intercalating into DNA of the parasites. Quinine alone is ineffective, and clindamycin must be used in conjunction.
Clindamycin is a lincosamide for treatment of serious skin and soft-tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult DoseClindamycin: 600 mg PO q8h for 7 d
Quinine: 650 mg PO q8h for 7 d
Pediatric DoseClindamycin: 20 mg/kg/d PO divided tid for 7 d
Quinine: 25 mg/kg/d PO divided tid for 7 d
ContraindicationsDocumented hypersensitivity; optic neuritis; tinnitus; black water fever; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
InteractionsAluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K–dependent clotting factors; digoxin serum concentrations may increase when digoxin administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing a decrease in the metabolism of succinylcholine
Clindamycin increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
PregnancyX - Contraindicated; benefit does not outweigh risk
PrecautionsCaution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and, thus, can cause cardiac arrhythmias; adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug NameAtovaquone (Mepron) plus azithromycin (Zithromax)
DescriptionPreferred regimens for severe babesiosis. Exchange transfusion may be considered in severe cases of babesiosis not responding to any Babesia therapy.
Atovaquone may inhibit metabolic enzymes, which, in turn, inhibits growth of microorganisms. Atovaquone should not be used alone. Resistance may develop; always use in conjunction with another anti-Babesia agent, preferably azithromycin.
Adult DoseAtovaquone: 750 mg PO suspension q12h
Azithromycin: 500 mg/d PO day 1, then 250 mg/d days 2-5
Pediatric DoseAtovaquone
11-20 kg: 250 mg PO q12h
21-30 kg: 500 mg PO q12h
31-40 kg: 750 mg PO q12h
>40 kg: 1 g PO q12h
Azithromycin: 10 mg/kg PO on day 1, then 5 mg/kg on days 2-5
ContraindicationsDocumented hypersensitivity
InteractionsAtovaquone may increase zidovudine serum levels; coadministration with rifamycin and TMP-SMZ may decrease atovaquone levels; 40% decrease in plasma concentration of atovaquone when coadministered with tetracycline; metoclopramide decreases serum concentration of atovaquone
Azithromycin 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; not to be administered with pimozide
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsCaution in elderly persons and persons with hepatic and renal impairment; may increase hepatic enzymes and cholestatic jaundice; site reactions can occur with IV azithromycin route; bacterial or fungal overgrowth may result with prolonged antibiotic use; caution with prolonged QT interval, pneumonia, or patients who are hospitalized, elderly, or debilitated

Drug NameAzithromycin (Zithromax)
DescriptionInhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose500 mg/d IV, at least 2 d
Pediatric Dose10 mg/kg
PO day 1; 5 mg/kg days 2-5
ContraindicationsDocumented hypersensitivity; hepatic impairment; administration with pimozide
InteractionsMay cause QT prolongation with itraconazole, sparfloxacin, and other medications (probably very rare); 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
PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
PrecautionsSite reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function or prolonged QT intervals; caution in patients who are hospitalized, elderly, or debilitated



Further Inpatient Care

  • Patients being treated for babesiosis should be monitored clinically, and serial blood smears should be obtained to document the degree of parasitemia and the effectiveness of therapy.
  • Serial CBC counts may be obtained to access the reticulocyte response and decrease in the hemolytic process.
  • Exchange transfusion may be life saving in severe cases.

Further Outpatient Care

  • Patients with mild-to-moderate babesiosis who are discharged from the hospital should undergo the same laboratory tests as hospitalized patients.

In/Out Patient Meds

  • The medications are administered orally in all but the most extreme cases and are the same in inpatient and outpatient settings.
  • Persons with severe cases of babesiosis are obviously treated in inpatient settings, with the same anti-Babesia medications administered intravenously.

Deterrence/Prevention

  • If possible, people should avoid entering highly tick-infested areas where babesiosis is endemic. If avoidance of these areas is not possible, care should be taken cover exposed body areas. Although the Ixodes ticks are small, patients should check themselves for ticks after coming out of a highly infested tick area. Ticks should be removed carefully and as soon after exposure as possible.
  • Diethyltoluamide (DEET) may be used on clothing or exposed areas of the body to prevent tick bites.

Complications

  • The complications of babesiosis are related to the degree of intravascular hemolysis. The main complications include jaundice, hemoglobinuria, and potential renal failure.

Prognosis

  • Most cases of babesiosis are subclinical or are mildly symptomatic. The prognosis is excellent in patients with intact splenic function. Most fatalities occur in patients with asplenia.

Patient Education

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



Medical/Legal Pitfalls

  • Lyme disease is occasionally a co-infection in patients with babesiosis because both are transmitted by I scapularis and I dammini ticks.
  • Co-infection with RMSF or ehrlichiosis is rare because these zoonoses are transmitted by the large Dermacentor ticks rather than by the small Ixodes ticks.
  • While babesiosis should be considered in patients with a malarialike illness in endemic areas, babesiosis is a difficult infectious disease to diagnose. Although the index of suspicion should be high in areas endemic for Babesia infection, patients with babesiosis have few, if any, localizing signs to suggest the disease. Confirmation of the diagnosis depends on the degree of parasitemia and the expertise and experience of the laboratory personnel. All of the findings in babesiosis are nonspecific, and only the demonstration of Babesia in the peripheral smear can rapidly confirm the diagnosis.

Special Concerns

  • Patients with asplenia should take particular care to avoid tick-infested areas.
  • Patients with congenital or acquired asplenia should be expected to have severe or fulminant babesiosis.



Media file 1:  Peripheral smear showing babesiosis.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo



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Babesiosis excerpt

Article Last Updated: Jul 28, 2008