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Babesiosis

Chapter 232 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Parasitic

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Babesiosis is an emerging infectious disease caused by protozoan parasites of the genus Babesia that invade and lyse red blood cells (RBCs).
  2. Most cases in the United States are caused by Babesia microti and are reported from the Northeast and upper Midwest during summer months (June-August).
  3. Transmission occurs primarily via the bite of an infected Ixodes scapularis tick (deer tick) or via blood transfusion (transfusion-transmitted babesiosis).
  4. Asplenia and immunosuppression are major risk factors for severe disease; asplenia is a major risk factor for severe disease because the spleen is the immunodominant organ in babesiosis.
  5. Diagnosis is confirmed by microscopic examination of Giemsa-stained thin blood smears showing intraerythrocytic ring forms or pathognomonic tetrads (Maltese cross).
  6. First-line treatment for mild to moderate B. microti infection is atovaquone plus azithromycin for 7–10 days.
  7. First-line treatment for severe babesiosis is oral atovaquone plus IV azithromycin; clindamycin plus quinine is an alternative but has higher toxicity.
  8. Red cell exchange (RCE) is recommended when parasitemia is high (>10%) or clinical status deteriorates with complications like renal failure or respiratory distress.
  9. Mortality is low in immunocompetent patients (~0.6% in CDC data 2011-2015) but higher in immunocompromised patients (~20%).
  10. Tafenoquine is an emerging treatment option for relapsing cases but is contraindicated in G6PD deficiency.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Geographic distribution of human babesiosis and associated tick (defined by ≥5 cases)
2 🖼 Figure Giemsa-stained thin blood films showing Babesia microti parasites

1. DEFINITION & OVERVIEW

  • Babesiosis is an emerging infectious disease caused by protozoan parasites of the genus Babesia that invade and eventually lyse red blood cells (RBCs).
  • Most cases occur in the United States during the summer months and are caused by Babesia microti, a species typically found in small rodents and transmitted by the deer tick, Ixodes scapularis.
  • Symptoms are those of a flu-like illness.
  • For most patients, a single standard course of atovaquone plus azithromycin is sufficient to achieve cure.
  • Highly immunocompromised patients and asplenic individuals are at risk of persistent infection and should be treated for a longer duration.
  • Adjunct red cell exchange can be useful for severe cases.
  • In the absence of vaccine and chemoprophylaxis, persons at risk of severe babesiosis should minimize their exposure to ticks and, if possible, avoid endemic areas.

2. EPIDEMIOLOGY

  • Cases are reported weekly by state health departments to the Centers for Disease Control and Prevention (CDC) via the National Notifiable Diseases Surveillance System.
  • In 2023, more than 3200 cases were reported from 33 of the 40 states in which babesiosis is notifiable.
  • In 2011, when babesiosis became a nationally notifiable disease, 1126 cases were reported to the CDC.
  • The increase in incidence over time is best explained by a greater density of ticks in highly endemic areas and by the northward expansion of these ticks.
  • Although B. microti and Borrelia burgdorferi (the agent of Lyme disease) are transmitted by the same tick species, the geographic expansion of babesiosis has lagged behind that of Lyme disease.
  • Other factors contributing to the rise in the incidence of babesiosis include greater exposure to ticks due to forest fragmentation in suburban areas and increased leisure activities in grassy or wooded areas.

Geographic Distribution

  • United States: Most cases (>95%) are caused by B. microti and are reported from the Northeast (Massachusetts, Rhode Island, Connecticut, Vermont, New Hampshire, Maine, New York, New Jersey) and the upper Midwest (Minnesota, Wisconsin).
  • Other Babesia species seldom cause disease.
  • Symptomatic infection with Babesia duncani and B. duncani–type organisms has been reported from Washington State, Oregon, and California.
  • Symptomatic infection with Babesia divergens–like organisms has been documented in the central states of Arkansas, Missouri, Michigan, and Kentucky and also in Washington State and Pennsylvania.
  • Europe: More than 40 cases have been attributed to B. divergens since the index case was reported from Croatia in 1957. The infection is rarely diagnosed in immunocompetent individuals; most patients lack a spleen or have functional hyposplenism. Most cases occur in France and Ireland, particularly in regions with cattle farms.
  • Asia: B. microti was recognized as a human pathogen in Taiwan in the late 1990s. In the past decade, babesiosis has gained the status of emerging infectious disease in mainland China. In the northeastern province of Heilongjiang, B. venatorum and B. crassa–like organisms have caused mild disease in immunocompetent individuals.
  • Remainder of the World: Three cases of babesiosis caused by B. microti have been reported from Canada. Babesiosis is a reportable disease in Manitoba and Quebec. In Yucatan, Mexico, four cases of febrile illness have been attributed to B. microti.
  • In 2011, when babesiosis became a nationally notifiable disease, 1126 cases were reported to the CDC.
  • In 2023, more than 3200 cases were reported from 33 of the 40 states in which babesiosis is notifiable.
  • The incidence of transfusion-transmitted babesiosis (TTB) sharply increased during the first two decades of the millennium.
  • In May 2020, the American Red Cross (ARC) began to test all blood donations collected in the 15 jurisdictions that account for 99% of tick-borne babesiosis cases and 95% of TTB cases.
  • During the following 13 months, no suspected TTB cases were reported to the ARC.
  • From 2010 to 2017, B. microti–positive donations were linked to 81 TTB cases (~10 cases per year).

Risk Factors

  • Most patients (~80%) who present with symptoms of babesiosis are ≥50 years.
  • Those who are admitted to a hospital are a decade older (median age, 68 years) than those who are not (median age, 59 years).
  • Aside from tick exposure and advanced age, major risk factors for severe babesiosis include asplenia and immunosuppression.
  • Asplenia can be congenital, functional (e.g., due to celiac disease or hemoglobinopathies such as sickle cell disease and thalassemia), or acquired (due to splenectomy).
  • Immunosuppression often is iatrogenic and associated with conditions such as autoimmune disorders, chronic inflammatory disorders, malignancies, or transplantation.
  • Risk factors for TTB include conditions that require transfusion of blood components, particularly RBCs.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • A few Babesia species have been implicated as etiologic agents of human babesiosis.
  • These species use wild or domesticated mammals as reservoir hosts and are maintained in their enzootic cycle by ticks.
  • Humans are incidental, dead-end hosts.
  • Most cases are reported from across the Northern Hemisphere; the predominant etiologic agent varies by continent.

Modes of Transmission

  • Tick Bite: B. microti is acquired primarily during the blood meal of an I. scapularis tick. Less than one-half (~45%) of patients recall a tick bite within the 8 weeks prior to symptom onset. Both nymphs and adult ticks can transmit B. microti; tick larvae are not infected because B. microti is not transmitted transovarially.
  • Blood Transfusion: More than 300 cases of transfusion-transmitted babesiosis (TTB) caused by B. microti have been reported. Most cases involve packed RBCs; a few have been attributed to frozen-deglycerolized RBCs and whole blood–derived platelets contaminated with RBCs but none to apheresis platelets. At the time of transfusion, the age of the refrigerated RBC units has ranged from 4 to 42 days, indicating that B. microti remains viable throughout the RBC unit’s shelf life.
  • Vertical Transmission: Passage of B. microti across the placenta has been documented but is rare. Symptoms typically develop during the third to the sixth week of life and often consist of fever accompanied by pallor and lethargy. Parasitemia at presentation has ranged from 2% to 5%.
  • Solid Organ Transplantation: This unusual mode of transmission has been highlighted in a single case report. Two patients received a diagnosis of babesiosis 8 weeks after transplantation of a kidney allograft obtained from a single donor who had received multiple transfusions shortly before his death.
  • Other Babesia Species: B. duncani and B. divergens–like organisms are thought to be transmitted by Dermacentor albipictus and Ixodes dentatus ticks, respectively. B. venatorum is found in roe deer, and B. crassa in sheep. Rabbits are suspected reservoirs for B. divergens–like parasites.

Pathogenesis

  • Anemia: RBC debris generated by hemolysis may accumulate in the kidney vasculature and cause renal failure. Free hemoglobin is rapidly complexed by haptoglobin. Once haptoglobin is depleted, the heme group is oxidized, released from hemoglobin, and complexed by hemopexin. Excessive hemolysis results in excess free hemoglobin, which scavenges and consumes nitric oxide, leading to thrombus formation and vascular inflammation.
  • RBC Lysis in Small Capillaries: RBC lysis in small capillaries of the spleen may trigger localized necrosis, leading to splenic infarction. Exposed to oxidative stress, RBCs become poorly deformable and are filtered out by splenic macrophages as they attempt to pass through the red pulp.
  • Erythrophagocytosis: Erythrophagocytosis, along with the mounting of an immune response, contributes to splenomegaly and splenic infarction.
  • Inflammation: Fever, chills, and sweats likely result from the systemic inflammatory response triggered by RBC lysis. Excessive inflammation promotes end-organ pathology, leading to renal and pulmonary compromise.
  • The Spleen: The spleen is the immunodominant organ in babesiosis. This feature, along with the clearance of parasitized RBCs, explains why asplenia is a major risk factor for severe disease.
  • Protective Immunity: Protective immunity involves CD4+ T cells, particularly T1 cells, as revealed by high-grade parasitemia in mice depleted of CD4+ T cells or treated with an interferon γ–neutralizing antibody. The importance of CD4+ T cells is corroborated by the severity of babesiosis in patients with AIDS and in allograft recipients.
  • Antibodies: In immunocompetent mice, Tfh cell expansion is accompanied with germinal center formation and antibody secretion. Although nearly every immunocompetent patient tests positive for B. microti antibody at diagnosis, a role for antibodies is uncertain.
  • Persistent, Relapsing Babesiosis: Persistent, relapsing babesiosis often occurs in patients treated with rituximab for a cancer or an autoimmune disorder; this observation suggests that B cells, and presumably antibodies, are critical for parasite clearance in some individuals.

4. CLINICAL FEATURES

  • Symptoms typically appear 1–4 weeks after the bite of an infected tick but 3–7 weeks (median, 37 days; range, 11–176 days) after transfusion of contaminated blood components.
  • Patients experience a gradual onset of fatigue with or without malaise that is followed within days by fever and one or more of the following: chills, night sweats, headache, myalgia, and anorexia.
  • Fever is persistent or intermittent and has reached 40.9°C (105.6°F).
  • Less common symptoms include arthralgia, nausea, dry cough, neck stiffness, emotional lability, and sore throat.
  • Diarrhea, vomiting, abdominal pain, and joint swelling are rare.
  • Dark urine and jaundice raise the suspicion of severe hemolytic anemia and may be accompanied by shortness of breath.

Physical Examination Findings

  • Fever is the salient feature.
  • The skin may be pale or yellowish.
  • A focal red rash, if present, denotes the site of the tick bite.
  • An erythema migrans rash signifies concurrent Lyme disease or southern tick-associated rash illness (STARI).
  • Ecchymoses and petechiae are rare.
  • Examination of the eyes may be remarkable for scleral icterus, which is consistent with severe hemolysis.
  • Retinopathy with splinter hemorrhages and retinal infarcts are rare.
  • Tenderness of the abdominal upper left quadrant suggests splenomegaly, which may be accompanied by hepatomegaly.
  • Left-sided abdominal pain raises suspicion of splenic infarction or splenic rupture.
  • Unexplained hypotension accompanied by tachycardia reinforces suspicion of splenic rupture.
  • Splenic infarction and subcapsular hematoma can occur in the absence of splenic rupture.
  • Splenic infarcts appear as wedge-shaped hypodense lesions on CT.
  • A hyperdense fluid surrounding the spleen is consistent with hemoperitoneum caused by splenic rupture.

Severity & Complications

  • Severe babesiosis requires hospital admission. The median length of hospital stay is 4 days (interquartile range, 3–7).
  • Severe babesiosis can be accompanied by one or several complications.
  • The leading complication is acute renal failure (20%).
  • The second most common complication is acute respiratory failure (7%).
  • Less common complications include supraventricular arrhythmia, heart failure, disseminated intravascular coagulation, and shock.
  • At least one transfusion of red blood cells is given to one of five patients hospitalized for babesiosis.
  • Patients diagnosed >7 days after symptom onset are predisposed to severe complicated babesiosis, which has been defined as an illness requiring admission to an intensive care unit (ICU); an illness complicated by acute respiratory distress syndrome, heart failure or shock; or an illness requiring dialysis, intubation or RBC exchange.
  • Among clinical features, diarrhea and nausea or vomiting are strong predictors of severe babesiosis as just defined.
  • Asplenia and autoimmune disorders predispose to severe disease, but underlying cardiac conditions do not.
  • Despite therapy, babesiosis can be fatal. Prior to the turn of the millennium, when clindamycin plus quinine was the regimen of choice for treatment of babesiosis, fatality rates ranging from 5% to 9% were reported.
  • Since atovaquone plus azithromycin has become the first-line therapy, a fatal outcome is rare.
  • Of the 7612 cases of babesiosis reported to the CDC in 2011–2015, 46 (0.6%) ended in death.
  • Death is more frequent among those ≥65 years of age.
  • A review of claims for 10,305 Medicare recipients who were diagnosed with babesiosis between 2006 and 2013 revealed that 1% had died within 30 days.
  • Among those admitted to a hospital, the fatality rate was 3%.
  • Fatality is high in immunocompromised patients (~20%) and those with splenic rupture or splenic infarction (6%).

Other Babesia Infections

  • B. duncani: The eight documented cases of B. duncani infection reported in the United States were moderate to severe; one patient died. Symptoms were similar to those evoked by B. microti.
  • B. divergens: All seven patients infected with B. divergens–like organisms had been splenectomized and experienced a severe illness that required hospitalization; three died.
  • B. venatorum: All 5 patients infected with B. venatorum in Europe had been splenectomized; their illness ranged from mild to severe, and none died. The 32 cases of B. venatorum infection reported from northeastern China occurred in spleen-intact residents. Symptoms were similar to those evoked by B. microti, although chills were rare.
  • B. crassa: Seven patients were hospitalized for intermittent fever as high as 40°C. Only 4 patients were treated with clindamycin (without quinine); all 32 patients recovered. Cases of B. crassa–like infection reported from northeastern China also occurred in spleen-intact residents. Fever, anemia, and myalgia were less common than among patients infected with B. microti, but headache was as common and nausea or vomiting more common. No patient was admitted to a hospital. Only 3 of the 31 patients were given clindamycin (without quinine); none died.
  • B. motasi: Cases of B. motasi–like infection in South Korea were severe; 1 patient died but the other recovered following clindamycin monotherapy.

5. DIFFERENTIAL DIAGNOSIS

  • Malaria: For travelers who have returned from P. falciparum–endemic areas and reside in a Babesia-endemic area, a negative result in the BinaxNOW malaria test readily rules out falciparum malaria when microscopy cannot.
  • Lyme Disease: Because one-half of patients diagnosed with babesiosis are infected with B. burgdorferi, a diagnosis of babesiosis should prompt a diagnostic evaluation for Lyme disease.
  • Other Tick-Borne Pathogens: Other tick-borne pathogens, although rarely implicated in cases of coinfection with B. microti, may be considered; these include Anaplasma phagocytophilum and Borrelia miyamotoi.
  • HELLP Syndrome: Given that babesiosis is an imitator of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, a diagnosis of babesiosis should be considered for pregnant women who are at risk of tick exposure and have laboratory abnormalities that define this syndrome.

6. INVESTIGATIONS & DIAGNOSIS

  • A diagnosis of babesiosis should be considered for patients who experience symptoms compatible with babesiosis and may have been exposed to ticks in an endemic area, particularly from late spring to early fall, or were transfused with blood components, particularly packed RBCs, in the past 6 months.
  • Given that I. scapularis ticks can be coinfected with B. microti and B. burgdorferi, babesiosis should be considered in any Lyme disease patient for whom symptoms worsen or do not abate within days or weeks of initiation of appropriate antibiotic therapy.

Routine Laboratory Testing

  • Complete Blood Count: Often remarkable for anemia. An elevated reticulocyte count signifies stress-induced erythropoiesis.
  • Hemolysis Markers: Low levels of haptoglobin or elevated levels of lactate dehydrogenase are consistent with hemolysis.
  • Thrombocytopenia: Severe anemia often is preceded by severe thrombocytopenia.
  • WBC Count: The white blood cell (WBC) count is reduced, unchanged, or elevated.
  • Liver Enzymes: Elevated levels of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase signify hepatocyte injury.
  • Bilirubin: Elevated total bilirubin levels result from hemolysis but may also denote hepatic compromise.
  • Renal Function: Elevated levels of blood urea nitrogen and serum creatinine indicate renal compromise.
  • Urinalysis: May reveal excess urobilinogen, hemoglobinuria, and/or proteinuria.

Predictors of Severe Disease

  • In a study of severe disease as defined above (see Clinical Manifestations), a total bilirubin level of >1.9 mg/dL was highly predictive of severe disease.
  • WBC counts of 10 × 103/μL and creatinine levels of >1.2 mg/dL.
  • An earlier study identified alkaline phosphatase levels of >125 IU/L and WBC counts of >5 × 103/μL as strong predictors of severe disease, in this case defined as a hospital stay of >2 weeks, an ICU stay of >2 days, or death.

Specific Testing

  • Microscopy: A definitive diagnosis of babesiosis is made by microscopic examination of Giemsa-stained thin blood smears. B. microti is an obligate parasite of erythrocytes. Trophozoites may appear as ring forms or as ameboid forms. Merozoites can be arranged in tetrads that are pathognomonic. Extracellular parasites can be noted, particularly when parasitemia is high.
  • Parasitemia: Parasitemia typically ranges from 0.1 to 10% in immunocompetent patients but has reached 30–40% in immunocompromised patients. Parasitemia of >4% is a risk factor for severe, complicated disease.
  • PCR: If parasites cannot be identified by microscopy and babesiosis is still suspected, amplification of Babesia DNA is recommended. Real-time polymerase chain reaction (PCR) assays, which amplify the parasite 18S rRNA gene, detect as few as 1–10 parasites/μL of blood. Use of a fluorescent probe allows for speciation of the causative agent.
  • Serology: A single positive serologic result is not sufficient to establish a diagnosis of babesiosis because antibodies can persist for >1 year after the illness has resolved and the parasite has been cleared. An indirect fluorescent antibody test is most commonly used. For B. microti, IgM titers of ≥1:20 and IgG titers of ≥1:64 are considered positive. IgG titers of ≥1:1024 suggest active or recent infection. Antibodies to B. microti do not react with B. duncani or B. divergens antigen. Sera from patients infected with B. venatorum or B. crassa–like organisms react with B. divergens antigen.
  • Malaria Differentiation: The presence of extracellular merozoites, particularly when parasitemia is high, and the absence of gametocytes and schizonts also distinguish babesiosis from malaria. Merozoites are arranged in pairs and occasionally in tetrads (the "Maltese cross"). Tetrads are pathognomonic of babesiosis and can be seen in human erythrocytes infected with B. microti, B. duncani, B. venatorum, or B. divergens–like organisms.

7. MANAGEMENT & TREATMENT

  • Mild to Moderate B. microti Illness: Mild to moderate babesiosis caused by B. microti is treated with atovaquone plus azithromycin administered orally for 7–10 days. Symptoms usually abate within 48 h after initiation of therapy and resolve within 1–2 weeks.
  • Severe B. microti Illness: The preferred regimen for the treatment of severe babesiosis caused by B. microti is oral atovaquone plus IV azithromycin. Use of this combination is supported by a retrospective study of 40 patients who were admitted for severe babesiosis, including 11 who were admitted to the ICU. All but 1 of the 40 patients improved following initiation of treatment with atovaquone plus azithromycin, and were discharged.
  • Alternative Regimens: Clindamycin plus quinine, the first regimen to ever bring cure to a babesiosis patient, is an alternative choice. Use of quinine is impeded by a risk for QTc prolongation and cinchonism, including tinnitus; these adverse events often require premature discontinuation.
  • Exchange Transfusion: RBC exchange (RCE) is recommended when parasitemia is high and the clinical status of the patient deteriorates in the context of complications such as severe hemolysis or critical organ dysfunction, particularly renal or pulmonary compromise. The primary purpose of RCE is to rapidly reduce parasite burden; RCE also corrects anemia.
  • Splenic Rupture: Splenic rupture typically occurs in young, healthy patients with low-grade parasitemia. If the patient is hemodynamically unstable, emergent splenectomy should be performed. If the patient is hemodynamically stable but bleeding persists, splenic arterial embolization should be considered. In the absence of hemoperitoneum, splenic rupture should be managed without surgery but with careful hemodynamic monitoring.

Drug Therapy: Mild to Moderate Infection

  • Regimen: Atovaquone plus azithromycin administered orally for 7–10 days.
  • Dosage (Adults): Atovaquone 750 mg q12h PO; Azithromycin 500 mg/d PO on day 1 followed by 250 mg/d PO on subsequent days.
  • Dosage (Children): Atovaquone 20 mg/kg q12h PO; maximum 750 mg/dose; Azithromycin 10 mg/kg qd PO on day 1 followed by 5 mg/kg qd PO thereafter [maximum 250 mg].
  • Monitoring: Symptoms usually abate within 48 h after initiation of therapy and resolve within 1–2 weeks.
  • Follow-up: Parasite DNA can be detected for as long as 3 months, but follow-up PCR testing is not recommended because relapse of infection in immunocompetent individuals is unlikely.
  • Persistence of Symptoms: If symptoms persist despite therapy for babesiosis, initiating doxycycline while testing for B. burgdorferi or other tick-borne pathogens such as A. phagocytophilum and B. miyamotoi is essential.
  • Fatigue: Fatigue may persist for weeks to months but does not warrant, on its own, that treatment be extended or resumed.

Table 1 — Table 232-1 Treatment of Human Babesiosis

Condition Adults Children
Mild to Moderate B. microti Infection Atovaquone (750 mg q12h PO) plus Azithromycin (500 mg/d PO on day 1 followed by 250 mg/d PO on subsequent days) Atovaquone (20 mg/kg q12h PO; maximum, 750 mg/dose) plus Azithromycin (10 mg/kg qd PO on day 1 followed by 5 mg/kg qd PO thereafter [maximum, 250 mg])
Severe B. microti Infection Preferred: Atovaquone (750 mg q12h PO) plus Azithromycin (500 mg qd IV plus followed by 250–500 mg qd PO). Alternative: Clindamycin (600 mg q6h IV followed by 600 mg q8h PO) plus Quinine (650 mg q6–8h PO). Consider exchange transfusion. Preferred: Atovaquone (20 mg/kg q12h PO; maximum, 750 mg/dose) plus Azithromycin (10 mg/kg qd IV followed by 10 mg/kg qd PO [maximum, 500 mg]). Alternative: Clindamycin (7–10 mg/kg q6–8h IV followed by 7–10 mg/kg q6–8h PO [maximum, 600 mg/dose]) plus Quinine (8 mg/kg q8h PO; maximum, 650 mg/dose). Consider exchange transfusion.
B. divergens Infection Immediate complete exchange transfusion plus Clindamycin (7–10 mg/kg q6–8h IV; maximum, 600 mg/dose) plus Quinine (650 mg q8h PO). Immediate complete exchange transfusion plus Clindamycin (600 mg q6–8h IV) plus Quinine (8 mg/kg q8h PO; maximum, 650 mg/dose).

Drug Therapy: Severe Infection

  • Preferred Regimen: Oral atovaquone plus IV azithromycin.
  • Dosage (Adults): Atovaquone 750 mg q12h PO; Azithromycin 500 mg qd IV plus followed by 250–500 mg qd PO.
  • Dosage (Children): Atovaquone 20 mg/kg q12h PO; maximum 750 mg/dose; Azithromycin 10 mg/kg qd IV followed by 10 mg/kg qd PO [maximum 500 mg].
  • Duration: Treat for 7–10 days, but extend duration if symptoms persist.
  • Immunocompromised Patients: For severely immunocompromised patients, antimicrobial therapy should be given for at least 6 consecutive weeks, including 2 final weeks during which parasites are no longer detected on blood smear.
  • IV Azithromycin Initiation: Intravenous azithromycin should be initiated at 500 mg/d, along with atovaquone. Laboratory parameters should be monitored daily until symptoms abate and parasitemia is <4%.
  • Oral Conversion: Thereafter, azithromycin can be administered orally. If the patient has an intact spleen and is not immunocompromised, the dosage can be reduced to 250 mg/d.
  • Duration Extension: The regimen is administered for 7–10 days, but the duration should be extended if symptoms persist.
  • Asplenic/Immunocompromised: If the patient is asplenic or immunocompromised, azithromycin should be maintained at 500 mg/d. Given the risk for prolonged or relapsing babesiosis in such patients, the regimen should be administered until symptoms have resolved and parasites are no longer seen on blood smear for at least 2 weeks.
  • Alternative Regimens: If the risk of QTc prolongation or allergy associated with use of azithromycin is a concern, clindamycin can be substituted for azithromycin. For severely immunocompromised patients, IV clindamycin can be added to atovaquone plus azithromycin at initiation of treatment.
  • Clindamycin Plus Quinine: Clindamycin plus quinine is no longer the preferred regimen because quinine often is discontinued due to QTc prolongation or other side effects, including tinnitus. This regimen can be considered for cases that respond poorly to atovaquone plus azithromycin.
  • Atovaquone-Proguanil: If quinine toxicity is a concern, atovaquone can be substituted for quinine. For cases that respond poorly to atovaquone plus azithromycin, atovaquone-proguanil can be added to the two-drug regimen or can be substituted for atovaquone.
  • Tafenoquine: Tafenoquine, which acts by inducing reactive oxygen species, is well suited to substitute for drugs that target a particular gene product. Tafenoquine should not be prescribed to patients with glucose-6-phosphate dehydrogenase deficiency because their RBCs have reduced antioxidant capacity and would not sustain the oxidative stress caused by tafenoquine. Following initiation of tafenoquine at the loading dose of 600 mg (given over 3 consecutive days), parasitemia rapidly declined. Maintenance therapy, which consisted of a 300-mg weekly dose of tafenoquine, was discontinued 5 weeks after the last positive B. microti PCR test.

Antimicrobial Resistance

  • Parasitologic or clinical relapse has been documented in highly immunocompromised patients, particularly when antimicrobial therapy is interrupted or administered at a reduced dosage.
  • Some patients who relapse while or after being treated with atovaquone plus azithromycin have been managed with clindamycin plus quinine.
  • When quinine toxicity is a concern, clindamycin has been added to atovaquone plus azithromycin.
  • An informed approach is to identify mutations that have arisen in the parasite genome and may explain antimicrobial resistance.
  • Atovaquone Targets: Atovaquone targets the parasite cytochrome b (Cytb). When resistance to atovaquone is predicted to be partial, atovaquone-proguanil can be substituted for atovaquone.
  • Azithromycin Resistance: Resistance to azithromycin has been attributed to missense mutations in the ribosomal protein subunit L4 gene (RLP4) and to a mutation in domain V of the 23S rRNA gene, which carries the peptidyl transferase activity of the parasite ribosome. Domain V is also the target of clindamycin.
  • Dual Resistance: A mutation in domain V that prevents binding of azithromycin and clindamycin precludes substitution of one for the other. Such mutation was recently identified in a patient who relapsed while being treated with a three-drug regimen that included azithromycin and clindamycin.
  • Post-RCE Parasitemia: Post-RCE parasitemia (mean, 3.4%; 95% CI, 1.9–4.9) was associated neither with post-RCE length of hospital stay nor with mortality; this finding advocates against the use of repeat RCE.

Exchange Transfusion

  • Indications: RCE is recommended when parasitemia is high and the clinical status of the patient deteriorates in the context of complications such as severe hemolysis or critical organ dysfunction, particularly renal or pulmonary compromise.
  • Primary Purpose: The primary purpose of RCE is to rapidly reduce parasite burden; RCE also corrects anemia.
  • Criteria: The criteria for RCE are not strictly defined. It is common practice to initiate RCE when parasitemia is >10%, although no study has been conducted to identify the threshold above which RCE provides greatest benefit.
  • Limitations: A recent case series illustrates the limitation of using parasitemia as the sole criterion to initiate RCE in the hope of preventing death. In this study of 19 patients, pre-RCE parasitemia (mean, 12.9%; 95% CI, 9.4–16.4) was a predictor of post-RCE length of hospital stay but not of mortality.
  • Post-RCE Outcomes: Post-RCE parasitemia (mean, 3.4%; 95% CI, 1.9–4.9) was associated neither with post-RCE length of hospital stay nor with mortality; this finding advocates against the use of repeat RCE.
  • Plasma Exchange: Plasma exchange seldom is used in severe, complicated babesiosis although it removes circulating inflammatory mediators and byproducts of hemolysis such as free hemoglobin, free heme, and unconjugated bilirubin.
  • Consultation: Therapeutic apheresis is performed in close consultation with transfusion medicine services.

Splenic Rupture Management

  • Typical Presentation: Splenic rupture typically occurs in young, healthy patients with low-grade parasitemia.
  • Hemodynamically Unstable: If the patient is hemodynamically unstable, emergent splenectomy should be performed.
  • Hemodynamically Stable: If the patient is hemodynamically stable but bleeding persists, splenic arterial embolization should be considered.
  • No Hemoperitoneum: In the absence of hemoperitoneum, splenic rupture should be managed without surgery but with careful hemodynamic monitoring.
  • Outcome: Removal of the spleen leaves patients at risk for overwhelming post-splenectomy infection (OPSI).

8. PROGNOSIS & COMPLICATIONS

  • Mortality: Despite therapy, babesiosis can be fatal. Since atovaquone plus azithromycin has become the first-line therapy, a fatal outcome is rare.
  • CDC Data: Of the 7612 cases of babesiosis reported to the CDC in 2011–2015, 46 (0.6%) ended in death.
  • Age Factor: Death is more frequent among those ≥65 years of age.
  • Medicare Data: A review of claims for 10,305 Medicare recipients who were diagnosed with babesiosis between 2006 and 2013 revealed that 1% had died within 30 days.
  • Hospital Admission: Among those admitted to a hospital, the fatality rate was 3%.
  • High Risk Groups: Fatality is high in immunocompromised patients (~20%) and those with splenic rupture or splenic infarction (6%).
  • Complications: The leading complication is acute renal failure (20%). The second most common complication is acute respiratory failure (7%). Less common complications include supraventricular arrhythmia, heart failure, disseminated intravascular coagulation, and shock.
  • Hospital Stay: The median length of hospital stay is 4 days (interquartile range, 3–7).

9. SPECIAL CONSIDERATIONS

  • Pregnancy: Given that babesiosis is an imitator of HELLP syndrome, a diagnosis of babesiosis should be considered for pregnant women who are at risk of tick exposure and have laboratory abnormalities that define this syndrome.
  • Pediatrics: Infants (<1 year of age) account for <1% of the annual number of cases of babesiosis reported to the CDC. Most cases of neonatal babesiosis, however, are acquired through blood transfusion or tick bite.
  • Immunocompromised: Highly immunocompromised patients and asplenic individuals are at risk of persistent infection and should be treated for a longer duration. Persistent, relapsing babesiosis often occurs in patients treated with rituximab for a cancer or an autoimmune disorder.
  • Tafenoquine Contraindication: Tafenoquine should not be prescribed to patients with glucose-6-phosphate dehydrogenase deficiency because their RBCs have reduced antioxidant capacity and would not sustain the oxidative stress caused by tafenoquine.

10. KEY PEARLS & CLINICAL TRAPS

  • Pathognomonic Finding: Merozoites arranged in tetrads (the "Maltese cross") are pathognomonic of babesiosis and can be seen in human erythrocytes infected with B. microti, B. duncani, B. venatorum, or B. divergens–like organisms.
  • Risk Factor: Asplenia is a major risk factor for severe disease because the spleen is the immunodominant organ in babesiosis.
  • Diagnosis Trap: A single positive serologic result is not sufficient to establish a diagnosis of babesiosis because antibodies can persist for >1 year after the illness has resolved and the parasite has been cleared.
  • Malaria Differentiation: For travelers who have returned from P. falciparum–endemic areas and reside in a Babesia-endemic area, a negative result in the BinaxNOW malaria test readily rules out falciparum malaria when microscopy cannot.
  • Treatment Trap: Clindamycin plus quinine is no longer the preferred regimen because quinine often is discontinued due to QTc prolongation or other side effects, including tinnitus.
  • Exchange Transfusion Trap: Post-RCE parasitemia was associated neither with post-RCE length of hospital stay nor with mortality; this finding advocates against the use of repeat RCE.
  • Emerging Treatment: Tafenoquine is an emerging treatment option for relapsing cases but is contraindicated in G6PD deficiency.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Geographic distribution of human babesiosis and associated tick (defined by...

Caption: FIGURE 232-1 Geographic distribution of human babesiosis and associated tick (defined by ≥5 cases). Light colors indicate areas where tick vectors are present but single cases except in six locations (Colombia, Mexico, Montenegro, Poland, and the at one hospital or identified via survey in one location. Colors distinguish the etiologic B. divergens–like, green for B. venatorum, pink for B. crassa–like, brown for B. bovis and uncharacterized Babesia isolates or by isolates for which the full sequence of the 18S Asymptomatic infections and cases of travel-associated babesiosis are omitted. — FIGURE 232-1 Geographic distribution of human babesiosis and associated tick vectors. Dark colors indicate areas where human babesiosis is endemic or sporadic (defined by ≥5 cases). Light colors indicate areas where tick vectors are present but human babesiosis is rare (<5 cases), undocumented, or absent. Circles depict single cases except in six locations (Colombia, Mexico, Montenegro, Poland, and the provinces of Gansu and Shandong in China) where all patients were diagnosed at one hospital or identified via survey in one location. Colors distinguish the etiologic agents: red for Babesia microti, orange for B. duncani, blue for B. divergens and B. divergens–like, green for B. venatorum, pink for B. crassa–like, brown for B. bovis and B. bigemina, and black for B. motasi–like. White circles depict cases caused by uncharacterized Babesia isolates or by isolates for which the full sequence of the 18S rRNA gene was not available or ruled out all of the Babesia species listed above.

Figure 2

Giemsa-stained thin blood films showing Babesia microti parasites

Caption: FIGURE 232-2 Giemsa-stained thin blood films showing Babesia microti parasites. B. microti is an obligate parasite of erythrocytes. Trophozoites may appear as ring forms (A) or as ameboid forms (B). Merozoites can be arranged in tetrads that are pathognomonic (C). Extracellular parasites can be noted (D), particularly when parasitemia is high. (Reproduced with permission from E Vannier, PJ Krause: Human babesiosis. N Engl J Med 366:2397, 2012.) — FIGURE 232-2 Giemsa-stained thin blood films showing Babesia microti parasites. Trophozoites may appear as ring forms (A) or as ameboid forms (B). Merozoites can be arranged in tetrads that are pathognomonic (C). Extracellular parasites can be noted (D), particularly when parasitemia is high. B. microti is an obligate parasite of erythrocytes.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.