Babesia

Babesia microti – Blood protozoan

Antimicrobial therapy must be considered for:

• Symptomatic patients if Babesia is detected on blood smear or by polymerase chain reaction (PCR).

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• Asymptomatic individuals if Babesia has been detected on blood smear or by PCR for longer than 3 months.

Antimicrobial therapy should not be considered when:

• Babesia is not detected on blood smear or by PCR.

• Babesia has been detected on blood smear or by PCR for less than 3 months in an asymptomatic individual.

Initial therapy of mild babesiosis should consist of a 7-10-day course of the following:

• Adults – oral azithromycin (day 1: 500 mg/d; day 2 on: 250 mg/d) plus oral atovaquone (750 mg every 12 hrs). This regimen is preferred to clindamycin plus quinine, as the latter combination is associated with frequent adverse effects (including diarrhea, tinnitus, decreased hearing, and vertigo).

• Children – oral azithromycin (day 1: 10 mg/kg/d, max 500 mg/dose; day 2 on: 5 mg/kg/d, max 250 mg/dose) plus oral atovaquone (20 mg/kg every 12 hrs, max 750 mg/dose).

Symptoms should begin to abate within 48 hours of initiation of therapy and be fully resolved within 1-3 months. If symptoms persist and if Babesia organisms remain detected, antimicrobial therapy should be extended to at least 6 weeks, including 2 weeks after Babesia organisms are no longer detected. If symptoms persist but Babesia organisms are no longer detected, one should consider the possibility of addition concurrent Lyme disease (caused by the spirochete Borrelia burgdorferi sensu stricto in the USA) and/or concurrent human granulocytic anaplasmosis (caused by the obligate intracellular bacterium Anaplasma phagocytophilum). Addition of doxycycline will address both infections. Other tick-borne pathogens, although of lesser incidence, include Borrelia miyamotoi, the deer tick virus (Powassan virus type II) and an Ehrlichia muris-like agent.

Always investigate and consider treating co-infection with B. burgdorferi and Anaplasma in every patient treated for Babesiosis unless transfusion-associated.

Initial therapy of severe babesiosis should consist of a 7-10-day course of the following:

• Adults – intravenous clindamycin (300-600 mg every 6 hrs) plus oral quinine (650 mg every 6-8 hrs). Oral clindamycin (600 mg every 8 hrs) may be considered.

• Children – intravenous clindamycin (7-10 mg/kg every 6-8 hrs, max 600 mg/dose) plus oral quinine (8 mg/kg every 8 hrs, max 650 mg/dose). Oral clindamycin (7-10 mg/kg every 6-8 hrs, max 600 mg/dose) may be considered.

Parasitemia and hematocrit should be monitored every day or every other day until symptoms abate and parasitemia recedes below 5%. If symptoms persist and if Babesia organisms remain detected, antimicrobial therapy should be extended to at least 6 weeks, including 2 weeks after Babesia organisms are no longer detected. If symptoms relapse, Babesia organisms should be investigated by blood smear or PCR. If Babesia organisms are detected, a second course of antimicrobial therapy should be initiated and should last for at least 6 weeks, including 2 weeks after Babesia organisms are no longer detected.

In immunocompromised individuals, higher doses of azithromycin (600-1000 mg/d) are recommended, as is a longer course. In some immunocompromised patients with relapsing babesiosis due to premature interruption of therapy, resistance to a second course of azithromycin plus atovaquone has been noted. Mechanisms underlying this resistance are unknown.

When quinine is discontinued due to serious adverse effects, clindamycin can be combined with the azithromycin plus atovaquone regimen. In severely ill patients with persistent or relapsing babesiosis, several multidrug regimens have been used, but no particular regimen appears to be superior. In addition to the recommended standard regimens, alternative regimens have consisted of atovaquone plus clindamycin and azithromycin plus quinine. In some, albeit few, cases antimicrobial therapy has included other drugs, such as:

• atovaquone-proguanil

• artemisinin derivatives

• interferon gamma

• Symptoms include a gradual onset of fatigue, malaise, and weakness. Fever is intermittent or sustained and is accompanied by one or more of the following: chills, sweats, headache, myalgia, arthralgia, and anorexia. Less frequent symptoms include sore throat, dry cough, neck stiffness, shortness of breath, left upper quadrant pain or “heaviness”, nausea, vomiting, weight loss, diarrhea, and dark urine.

• The main physical finding is fever. Mild splenomegaly and hepatomegaly are occasionally noted, but lymphadenopathy is absent. Jaundice is rare. Pharyngeal erythema, retinopathy with splinter hemorrhages, and retinal infarcts have been reported.

• Owing to non-specific symptoms, such as fever, chills, sweats, headache, myalgia, arthralgia, and anorexia, babesiosis may be mistaken for a viral illness and has been referred to as the “summer flu”. Other illnesses that may resemble babesiosis include Lyme disease (in the absence of an erythema migrans rash), anaplasmosis, rickettsial disease, and even bacterial endocarditis.

• In travelers who return from tropical regions but have been infected with Babesia in temperate climates, babesiosis has been mistaken for malaria.

• Patients who experience babesiosis may present with an erythema migrans cutaneous rash, but this sign is indicative of concurrent Lyme disease and is not pathognomonic of babesiosis.

Results consistent with the diagnosis

Anemia is common. Low haptoglobin and elevated lactate dehydrogenase are consistent with the hemolytic nature of anemia. Reticulocytosis is indicative of increased erythropoiesis. In severe disease, schistocytes and helmet cells may be seen on blood smear.

Thrombocytopenia is common.

White blood cell (WBC) counts are normal or mildly decreased. Elevated WBC counts (>5×10⁹/L) are associated with severe babesiosis.

Elevated alkaline phosphatase (>125 U/L) is predictive of severe babesiosis. Elevated bilirubin, aspartate aminotransferase, and alanine aminotransferase also indicate liver involvement.

Elevated blood urea nitrogen (BUN) and serum creatinine indicate renal compromise, and severe disease.

Urinalysis may reveal hemoglobinuria, excess urobilinogen, and proteinuria.

Results that confirm the diagnosis

• Definitive diagnosis is made by microscopic visualization of parasites on Giemsa (or Wright’s) stained thin blood smears (under oil immersion) or by amplification of parasite DNA by PCR.

  B. microti trophozoites often appear as rings with a pale blue cytoplasm and one or two red chromatic dots. Rings are pleomorphic (i.e., round, oval, pear-shaped, or amoeboid).

  B. microti merozoites are arranged in tetrads, also referred to as “Maltese Cross”. These forms are rarely seen on smear. Tetrads also can be observed in human red blood cells invaded by Babesia duncani or Babesia divergens.

  B. microti rings may be mistaken for Plasmodium falciparum early stage trophozoites, but malaria can be ruled out by travel history and careful microscopy. Distinguishing features of B. microti are: pleomorphic ring forms, extracellular merozoites, absence of visible gametocytes, and lack of a brownish hemozoin deposit.

• PCR is useful to diagnose babesiosis when parasitemia is low (i.e., at the onset of symptoms and during convalescence).

  The advent of real-time PCR has greatly lowered the limit of detection, and offers the possibility of speciation.

  Persistence of babesial DNA has been associated with persistence of symptoms and is shortened by standard antimicrobial therapy.

• Serology typically confirms the diagnosis made by microscopy or PCR. Antibodies are detected by indirect immunofluorescent antibody testing (IFA). Antibodies against B. microti antigen do not cross-react with antigen from B. duncani, B. divergens or Babesia venatorum.

  Reciprocal IgG titers greater than or equal to 1024 indicate active or recent infection.

  Titers decline within 6-12 months and are considered negative when less than 64.

  Given that antibodies persist beyond resolution of symptoms, serology and symptoms are poorly correlated.

  The persistence of antibodies is useful for the identification of asymptomatic carriers, in particular of those implicated in transfusion-transmitted babesiosis.

• No imaging studies are needed.

Complications of severe babesiosis

• Severe babesiosis has been associated with parasitemia greater than 4% and requires hospitalization. Risk factors for severe babesiosis include age (>50 years), splenectomy, and immunosuppression.

• Nearly one-half of hospitalized patients develop complications. Risk factors for complications are severe anemia (hemoglobin <10 g/dL) and high parasitemia (>10%).

• The most common complications are adult respiratory distress syndrome and disseminated intravascular coagulation. Less common complications include congestive heart failure and renal failure. Splenic infarcts and splenic rupture have been documented.

• Among patients hospitalized for babesiosis, the fatality rate has ranged from 6-9%. Among immunocompromised patients and those who contracted the infection through transfusion of contaminated blood products, the fatality rate is approximately 20%.

Adjunctive therapy

• Partial or complete RBC exchange (RCE) transfusion is recommended for patients with parasitemia greater than 10%, severe anemia, or pulmonary, hepatic, or renal compromise. Also consider RCE for any patient who is severely ill and has a parasitemia greater than 5%.

• A 90% reduction in parasitemia should be the desired target of RCE and is likely achieved by exchanging 2.5 times the patient’s calculated RBC volume.

Parasite life cycle

• B. microti is a parasite of small rodents.

  The primary reservoir is the white footed mouse (Peromyscus leucopus). Other competent reservoirs include shrews, chipmunks, voles, and rats.

  B. microti invades RBCs only. More than one parasite may invade a single host cell.

  Following entry, parasites mature into trophozoites that freely move in the cytoplasm. Asexual replication yields four merozoites.

  As merozoites egress, the host cell lyses. Free merozoites quickly attach to nearby RBCs, re-orient themselves, and invade these host cells.

• The Ixodes scapularis tick maintains B. microti in its enzootic cycle.

  In late summer (year 1), tick larvae take a blood meal on white footed mice. In endemic areas, a significant fraction of these mice harbor B. microti. As larvae feed, Babesia infected RBCs accumulate in their gut. Babesia gametocytes eventually egress from RBCs and differentiate into gametes. Gametes fuse to form zygotes that translocate across the tick gut epithelium. At the basal lamina, zygotes become ookinetes, which enter the hemolymph and reach salivary acini. Once in the secretory and interstitial cells of the acini, ookinetes hypertrophy into sporoblasts that stay dormant.

  Larvae overwinter and molt into nymphs in the following spring (year 2). If larvae are infected with B. microti, the resulting nymphs harbor the parasite (trans-stadial transmission). In late spring and early summer (year 2), nymphs take a blood meal on warm-blooded vertebrates. As nymphs stay in close contact with such vertebrate, sporogony is initiated. Each sporoblast yields up to 10,000 sporozoites. When tick feeding is nearly completed (i.e., within 48-72 hours of tick attachment), sporozoites are delivered into the dermis of the vertebrate host. Sporozoites eventually reach the bloodstream and invade RBCs.

  In the fall (year 2), nymphs molt into adults that feed on white-tailed deer (Odocoileus virginianus). Deer are not competent reservoirs for B. microti, but provide a blood meal to adult ticks which then mate. Adult female ticks lay eggs in the following spring (year 3). Even if adult female ticks harbor B. microti, their eggs do not (no transovarial transmission).

  Larvae hatch from the eggs in early summer (year 3), and feed on white-footed mice in late summer.

• Modes of transmission of B. microti to humans.

  Tick bite is the primary mode of transmission to humans. Ixodes scapularis nymphs are the primary vector, although adult ticks can also feed on humans. The incubation period (from tick bite to symptoms) typically lasts from 1-6 weeks.

  Transfusion of blood products obtained from asymptomatic carriers is the second most frequent mode of transmission. The incubation period typically lasts from 1-9 weeks.

  Transplacental (vertical) transmission is rare.

• Seasonal differences in the incidence of infection are observed.

  Owing to the fact that nymphs feed in late spring and early summer and that the incubation period lasts from 1-6 weeks, most cases of tick-transmitted babesiosis occur from May through September. Three-fourths of such cases are diagnosed in July and August.

  As asymptomatic infection may persist for more than 1 year, transfusion-transmitted babesiosis can be acquired at any time during the year. Given the seasonality of tick-transmitted babesiosis, however, most cases of transfusion-transmitted babesiosis occur from June through November.

• Environmental conditions that predispose to babesiosis include a large deer population (as deer are required for survival and mating of adult ticks) and areas with tall grass, brushes, and foliage (where ticks and white-footed mice thrive).

• Babesiosis caused by B. microti is highly endemic in the United States.

  In the United States, long established endemic areas include southern Massachusetts (Cape Cod, Nantucket, and Martha’s Vineyard), southern Rhode Island (including Block Island), coastal Connecticut and offshore islands (Long Island, Shelter Island, Fire Island), the Lower Hudson Valley, and central New Jersey. Highly endemic counties are also found in Wisconsin and Minnesota.

  The geographic distribution of babesiosis has recently expanded. Cases have been reported from southern Maine, southern New Hampshire, western and northeastern Massachusetts, Pennsylvania, Delaware, and Maryland.

  Outside of the United States, B. microti infection is rare. One such case has been diagnosed in Canada and another Germany. Two cases in Taiwan and one in Japan have been attributed to B. microti-like organisms. Several cases of B. microti infection have been documented in southwestern China. One case was reported from Australia.

• Babesia species other than B. microti may cause human babesiosis.

  Three cases (Kentucky, Missouri and Washington State) have been attributed to B. divergens-like organisms that are found in eastern cottontail rabbits.

  Several cases in Washington State and northern California have been caused by B. duncani and B. duncani- type parasites that are found in wildlife animals in the West of the United States.

  Most cases in Europe have been attributed to B. divergens, a pathogen of cattle, and occur in France, Great Britain, and Ireland. A case of B. divergens-like infection was reported from the Canary Islands. Four cases (Italy, Austria, and Germany) have been caused by B. venatorum, a parasite commonly found in roe deer.

  Cases of B. venatorum infection have been recently recognized in a northeastern province of mainland China.

  Cases reported from Africa, South America, and India have been attributed to Babesia, although the causative agents were not molecularly characterized.

• Risk factors for severe babesiosis are age (>50 years), gender (male), splenectomy, HIV/AIDS, and immunosuppressive therapies for cancer and transplantation.

  Age-acquired susceptibility to babesiosis is not fully understood but is attributed to a decline in host immune functions.

  The higher proportion of men among symptomatic cases remains unexplained, although men may engage more often than women in outdoor occupations, such as lawn mowing, landscaping, and property management.

  The susceptibility conferred by asplenia, often due to splenectomy, is consistent with the observations that the spleen is critical for removal of Babesia-infected RBCs. The spleen is also the immunodominant organ and the site of extramedullary erythropoiesis in babesiosis.

  The susceptibility of HIV/AIDS individuals is consistent with the central role of CD4⁺ T-cells in host resistance to babesiosis. This observation is corroborated by the susceptibility of transplant patients while under immunosuppressive therapy.

  Patients who experience B-cell lymphoma and are treated with rituximab (anti-CD20) are prone to persistent or relapsing babesiosis, indicating that humoral immunity is essential for complete resolution of symptoms and parasitemia, at least in some hosts.

• Babesiosis is an emerging infectious disease in the United States.

  The incidence of babesiosis caused by B. microti has increased over the last 2 decades, particularly along the northeastern seaboard.

  In January 2011, the CDC declared babesiosis a nationally notifiable disease.

  Increased incidence has been attributed to: an expansion of the deer population, the encroachment of humans onto wildlife habitat, the increased awareness of local physicians and communities, a better reporting to public health authorities, and the increased mobility/exposure of vulnerable individuals, including the elderly and the immunocompromised.

Infection control issues

• Anti-infective prophylaxis has never been tested.

• A vaccine for human babesiosis is not available.

• Strategies for avoiding exposure to the tick vector include: avoid areas with tall grass, brushes, and foliage, particularly from May through September; cover parts of the body that may be exposed to ticks; and impregnate or spray clothing with tick repellents, such as diethyltoluamide (DEET) or permethrin.

• The current strategy for avoiding transmission of babesiosis through the blood supply relies on the use of a questionnaire. Prospective donors who report a history or symptoms of babesiosis are barred from donating blood indefinitely. Donors involved in cases of transfusion-transmitted babesiosis are deferred indefinitely, and their blood units or blood products are discarded.

• Acarides may be targeted to rodents (Damminix or fipronil) or to deer. Culling of the deer population is more difficult but has been proven effective in reducing tick density in an island setting. Individuals who reside in or travel to endemic areas should search their body for ticks. Attached ticks should be promptly and carefully removed using tweezers.

• Virulence factors have been identified:

  Variable merozoite surface antigens (VMSA) have been identified as surface coating molecules on Babesia bovis merozoites and sporozoites and are involved in their attachment to RBCs.

  BMN proteins are GPI-anchored proteins that are highly immunogenic and are thought to be involved in the attachment to, and/or invasion of RBCs by B. microti.

  Several proteins located in the apical complex have been implicated in the invasion process:

  RAP-1 is secreted from the rhoptries of both B. bovis merozoites and sporozoites.

  BbAMA-1 and BbTRAP are microneme proteins secreted by B. bovis merozoites.

  BdSUB-1, a subtilisin-like serine protease stored in the dense granules, has been involved in the invasion of RBCs by B. divergens merozoites.

• No direct relationship has been established between virulence factors and clinical manifestations.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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