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Babesiosis
Frederick W. Nielson, MD, Captain USAF
J. David Honeycutt, MD, FAAFP, FAWM
image BASICS
DESCRIPTION
  • Rare tick-borne hemolytic disease caused by intraerythrocytic protozoan parasites of the genus Babesia
  • Infrequently reported outside the United States
    • Sporadic cases have been reported from
      • France, Italy, the United Kingdom, Ireland, the former Soviet Union, Mexico (1)
      • China has reported a reemergence of cases.
    • In the United States, infections have been reported in many states, but most endemic areas are:
      • Islands off the coast of Massachusetts (including Nantucket and Martha's Vineyard)
      • New York (including Long Island, Shelter Island, and Fire Island)
      • Connecticut
      • In these areas, asymptomatic infection is common (1).
  • Incubation period varies from 5 to 33 days:
    • Most patients do not recall specific tick exposure.
    • After transfusion of infected blood, the incubation period can be up to 9 weeks (1).
  • System(s) affected: cardiovascular, gastrointestinal, hemic/lymphatic/immunologic, musculoskeletal, nervous, pulmonary, renal/urologic
Pediatric Considerations
Transplacental and perinatal transmission have been rarely reported (1,2).
Geriatric Considerations
  • Morbidity and mortality are higher in patients >60 years.
  • Cases occurring in patients >70 years are more common in those with medical comorbidities.
EPIDEMIOLOGY
Babesiosis affects patients of all ages. Most patients present in their 40s or 50s (1).
Incidence
  • In 2012, there were 911 cases reported to the CDC.
  • Prevalence is difficult to estimate due to lack of surveillance and asymptomatic infections.
  • Transfusion-associated babesiosis and transplacental/perinatal transmission have been reported (1).
  • A 1-year seroconversion study of patients in New York, at high risk for tick-borne diseases, showed antibodies to Babesia microti in 7 of 671 individuals (1%) (1).
ETIOLOGY AND PATHOPHYSIOLOGY
  • B. microti (in the United States) and Babesia divergens and Babesia bovis (in Europe) cause most human infections (1). B. divergens and a new strain Babesia ducani appear to be more virulent. Other species have been identified in case reports. All share morphologic, antigenic, and genetic characteristics (1).
  • Ixodid (hard-bodied) ticks, particularly Ixodes dammini (Ixodes scapularis: deer tick) and Ixodes ricinus, are the primary vectors. The white-footed mouse is the primary reservoir.
  • Infection is passed to humans through the saliva of a nymphal-stage tick during a blood meal. Sporozoites introduced at the time of the bite enter red blood cells form merozoites through binary fission (classic morphology on blood smear). Humans are a dead-end host for B. microti.
RISK FACTORS
  • Residing in endemic areas
  • Asplenia
  • Immunocompromised state
GENERAL PREVENTION
  • Avoid endemic regions during the peak transmission months of May to September (1).
  • Appropriate insect repellent is advised during outdoor activities, especially in wooded or grassy areas:
    • 10-35% N,N-diethyl-meta-toluamide (DEET) provides adequate protection (1).
  • Early removal of ticks via daily skin checks; the tick must remain attached for at least 24 hours before the transmission of B. microti occurs (1).
  • Examine pets for ticks.
COMMONLY ASSOCIATED CONDITIONS
  • Coinfection with Borrelia burgdorferi and B. microti, particularly in endemic areas (1)
  • Coinfection with Ehrlichia (1).
image DIAGNOSIS
PHYSICAL EXAM
  • High fever (up to 40°C [104°F])
  • Hemodynamic instability (shock in extremely ill)
  • Hepatomegaly and splenomegaly (mild if noted)
  • Rash (uncommon)
  • CNS involvement includes headache, photophobia, neck and back stiffness, altered sensorium, and emotional lability.
  • Jaundice and dark urine may develop later in course of illness.
DIFFERENTIAL DIAGNOSIS
  • Bacterial sepsis
  • Hepatitis
  • Lyme disease
  • Ehrlichiosis
  • Leishmaniasis
  • Malaria
  • HIV
  • EBV
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Requires a high index of clinical suspicion. Nonspecific laboratory clues include evidence of mild to severe hemolytic anemia, normal to slightly depressed leukocyte count (1), elevated LDH or transaminase level, elevated BUN and Cr, proteinuria with hemoglobinuria (1,2).
  • Definitive diagnosis is made by blood smear
    • A Wright- or Giemsa-stained peripheral blood smear demonstrates intraerythrocytic parasites (2)[B].
    • Dividing “cross-like” tetrads of merozoites (Maltese cross) are pathognomonic (2).
    • Serial blood smears may be required as low parasite load early in the illness may make identification difficult (2).
    • Can be confused with Plasmodium falciparum on peripheral smear
  • If blood smears are negative but suspicion remains, IgM serologies through indirect immunofluorescent antibody testing (IFAT) for B. microti antigen are available:
    • The cutoff titer for a positive result varies by laboratory protocol. Titers of >1:64 or a 4-fold increase from baseline are consistent with B. microti infection (3). Titers may exceed >1:1,024 in acute infection (2)[B]. Titers often persists for 8 to 12 months and can last for years.
    • In New England, seroprevalence varies between 0.5% and 16% (3).
  • Detection of B. microti by polymerase chain reaction (PCR) is more sensitive and equally specific in acute cases. PCR can also be used to monitor disease progression (2)[B]. Newer real-time PCR tests have a sensitivity and specificity approaching 100%.
  • When lab tests are inconclusive and infection is strongly suspected, inoculation of laboratory animals with patient blood reveals B. microti organisms in the blood of the animal within 2 to 4 weeks (2).
Follow-Up Tests & Special Considerations
Monitoring intraerythrocytic parasitemia helps guide treatment (4)[C].
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Diagnostic Procedures/Other
Based on blood smear, history, and epidemiologic information (2)
image TREATMENT
GENERAL MEASURES
  • In areas endemic for Lyme disease and ehrlichiosis, consider adding doxycycline (Vibramycin) 100 mg BID PO until serologic testing is completed (1)[C].
  • Resistance to standard medications has emerged in severely immunocompromised patients (2).
  • Consider treating asymptomatic patients if parasitemia persists for >3 months; otherwise, do not treat in absence of symptoms (1),(4)[C].
MEDICATION
First Line
  • Mild to moderate infection with B. microti: 7 to 10 days of atovaquone 750 mg PO BID plus azithromycin 500 to 1,000 mg/day PO on day 1, followed by 250 mg/day afterward. Pediatrics: atovaquone 20 mg/kg (max 750 mg) BID and azithromycin 10 mg/kg (max 500 mg) on day 1, then 5 mg/kg (max 250 mg) (4)[B]. For severe B. microti infection: oral quinine 650 mg TID or QID plus oral clindamycin 600 mg TID for 7 to 10 days. Pediatrics: clindamycin 7 to 10 mg/kg (max 600 mg) TID or QID and quinine 8 mg/kg (max 650 mg) TID. IV formulations can be used (4)[C].
  • Persistent or relapsing babesiosis: Treat for 6 weeks, including 2 weeks after Babesia is no longer detected on blood smear (5)[B].
Second Line
  • Combination of quinine sulfate 650 mg PO TID and clindamycin 600 mg PO TID or 1.2 g parenterally BID for 7 to 10 days is the most commonly used treatment. Pediatric: quinine 8 mg/kg (max 650 mg) every 6 to 8 hours for 7 to 10 days and clindamycin 7 to 10 mg/kg (max 600 mg) PO q6-8h for 7 to 10 days. Some experts prefer this regimen for severe infections (4)[C].
  • Other drugs including tetracycline, primaquine, sulfadiazine (Microsulfon), and sulfadoxine/pyrimethamine (Fansidar) have been evaluated. Results vary. Pentamidine (Pentam) is moderately effective in diminishing symptoms and decreasing parasitemia (1)[C].
ISSUES FOR REFERRAL
Severe disease: Consider consultation with hematology and infectious disease for exchange transfusion in extremely ill patients (blood parasitemia >10%, massive hemolysis, and asplenia) (2)[C].
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • If left untreated, silent babesiosis may persist for months or years (2).
  • 139 hospitalized cases in New York State between 1982 and 1993:
    • 9 patients (7%) died.
    • 25% of the patients were admitted to the ICU.
    • 25% hospitalized for >14 days.
  • Alkaline phosphatase levels >125 U/L, WBC counts >5 × 109/L, history of cardiac abnormality, history of splenectomy, presence of heart murmur, and parasitemia of 4% or higher are associated with disease severity (6)[B].
Patient Monitoring
The need for clinical and lab monitoring depends on disease severity. Severe infections: Follow hematocrit and parasitemia levels until clinical improvement and parasitemia is <5%. Mild to moderate: Expect clinical improvement within 48 hours and complete resolution within 3 months (4)[C].
REFERENCES
1. Mylonakis E. When to suspect and how to monitor babesiosis. Am Fam Physician. 2001;63(10): 1969-1974.
2. Vannier E, Krause PJ. Human babesiosis. N Engl J Med. 2012;366(25):2397-2407.
3. Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015;29(2): 357-370.
4. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134.
5. Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis. 2008;46(3):370-376.
6. White DJ, Talarico J, Chang HG, et al. Human babesiosis in New York State: review of 139 hospitalized cases and analysis of prognostic factors. Arch Intern Med. 1998;158(19):2149-2154.
Additional Reading
  • Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68(9):1951-1961.
  • Florescu D, Sordillo PP, Glyptis A, et al. Splenic infarction in human babesiosis: two cases and discussion. Clin Infect Dis. 2008;46(1):e8-e11.
  • Herwaldt BL, Linden JV, Bosserman E, et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med. 2011;155(8):509-519.
  • Hilton E, DeVoti J, Benach JL, et al. Seroprevalence and seroconversion for tick-borne diseases in a high-risk population in the northeast United States. Am J Med. 1999;106(4):404-409.
  • Joseph JT, Purtill K, Wong SJ, et al. Vertical transmission of Babesia microti, United States. Emerg Infect Dis. 2012;18(8):1318-1321.
  • Kuwayama DP, Briones RJ. Spontaneous splenic rupture caused by Babesia microti infection. Clin Infect Dis. 2008;46(9):e92-e95.
  • Martinot M, Zadeh MM, Hansmann Y, et al. Babesiosis in immunocompetent patients, Europe. Emerg Infect Dis. 2011;17(1):114-116.
  • Mosqueda J, Olvera-Ramirez A, Aguilar-Tipacamu G, et al. Current advances in detection and treatment of babesiosis. Curr Med Chem. 2012;19(10): 1504-1518.
  • Teal AE, Habura A, Ennis J, et al. A new real-time PCR assay for improved detection of the parasite Babesia microti. J Clin Microbiol. 2012;50(3): 903-908.
Codes
ICD10
B60.0 Babesiosis
Clinical Pearls
  • If left untreated, silent babesial infection may persist for months or even years.
  • Most patients do not recall tick exposure, and incubation can last up to a month.
  • Ticks must remain in place for 24 hours to transmit infection—encourage daily “tick checks” if people are exposed in high-risk areas.
  • First-line treatment for mild or moderate disease is atovaquone plus azithromycin.
  • Patients with mild to moderate disease should show clinical improvement within 48 hours after starting therapy. Symptoms should fully resolve within 3 months.
  • Coinfection with B. burgdorferi and Ehrlichia species is common in endemic areas. In areas endemic for Lyme disease and ehrlichiosis, consider adding doxycycline until serologic testing is completed.