Babesiosis

Category: Vector-borne disease
Affected System: Circulatory System

Synonyms and related keywords:

Babesia species, Ixodes tick, parasitic infection, intraerythrocytic parasitic infection, tick bite, babesiosis, hemolytic anemia, thrombocytopenia, atypical lymphocyte formation, acute respiratory distress syndrome, ARDS

Introduction

Definition:

Babesiosis is an intraerythrocytic parasitic infection caused by protozoa of the genus Babesia and transmitted through the bite of the Ixodes tick. The disease most severely affects patients who are elderly, immunocompromised, or have undergone splenectomy. In the United States, Babesiosis is usually an asymptomatic infection in healthy individuals.



Causative Agent:

Babesiosis is caused by hemoprotozoan parasites of the genus Babesia. While more than 100 species have been reported, only a few have been identified as causing human infections. Babesia microti and Babesia divergens have been identified in most human cases, but variants (considered different species) have been recently identified.

Mode of Transmission:

Vector-borne.

Vector:

Ixodid ticks, in particular Ixodes dammini (Ixodes scapularis) and Ixodes ricinus.

Incubation Period:

5-33 days.

Signs and Symptoms:

The disease is a malaria-like syndrome characterized by fever, fatigue, and hemolytic anemia lasting from several days to a few months. Clinically, babesiosis may vary widely -- from asymptomatic infection to a severe, rapidly fatal disease. The first demonstrated case of human babesiosis in the world was reported in Europe in 1957. Since then, there have been at least 28 additional cases in Europe. Most European cases occurred in asplenic individuals; were severe, febrile, and fulminant; and were caused by B divergens, a cattle parasite. In the United States, there have been hundreds of cases of babesiosis (and, in contrast, mostly in people with intact spleens) caused by B microti, mainly from southern New England, and specifically from Nantucket, Martha's Vineyard, Shelter Island, Long Island, and Connecticut.

Differential Diagnosis:

Anemia, Acute
Bites, Insects
Malaria
Tick-Borne Diseases, Colorado
Tick-Borne Diseases, Ehrlichiosis
Tick-Borne Diseases, Introduction
Tick-Borne Diseases, Lyme
Tick-Borne Diseases, Q Fever
Tick-Borne Diseases, Relapsing Fever
Tick-Borne Diseases, Tularemia

Diagnosis:

Mild to severe hemolytic anemia and a normal to slightly depressed leukocyte count are common nonspecific findings in babesiosis. Usually, the diagnosis is based on typical morphologic picture on the blood smear in conjunction with epidemiologic information. A Wright- or Giemsa-stained peripheral blood smear is most commonly used to demonstrate the presence of intraerythrocytic parasites. Rarely, tetrads of merozoites are visible.

The organisms are intraerythrocytic ring forms closely resembling Plasmodium, the organism causing malaria. Three distinguishing features differentiate the two organisms. Babesial organisms usually form tetrads ("Maltese cross"), do not have hemozoin pigments within the affected red blood cells and have extracellular merozoites.

Serologic evaluation with the indirect immunofluorescent antibody test with use of B. microti antigen is available in a few laboratories. The cutoff titer for determination of a positive result varies with the particular laboratory protocol used, but in most laboratories, titers of more than 1:64 are considered consistent with B. microti infection. Tenfold to 20-fold higher titers can be observed in the acute setting, with a gradual decline over weeks to months. The correlation between the level of the titer and the severity of symptoms is poor.

Detection of B. microti by polymerase chain reaction (PCR) was first described in 1992. A more recent study, in which PCR was used prospectively for diagnosing suspected cases in the northeastern United States has shown that PCR is more sensitive and equally specific for the diagnosis of acute cases, in comparison with direct smear examination and hamster inoculation. PCR-based methods may also be indicated for monitoring of the infection.

Pathogenesis:

Of the more than 100 species of Babesia, Babesia microti (in the United States) and Babesia divergens and Babesia bovis (in Europe) cause most infections in humans. B. microti also infects various small mammals and primates, while B. divergens has been found to infect rats and gerbils as well as its main bovine host. Recently, a previously unknown species of Babesia (WA-1) was isolated from an immunocompetent man in Washington state who had clinical babesiosis. Researchers also described another probable new babesial species (MO1) associated with the first reported case of babesiosis acquired in the state of Missouri. MO1 is probably distinct from B. divergens but the two share morphologic, antigenic and genetic characteristics.

Ixodid (or hard-bodied) ticks, in particular Ixodes dammini (Ixodes scapularis) and Ixodes ricinus, are the vectors of the parasite. Ticks ingest Babesia while feeding off the host, and the parasite multiplies within the tick's gut wall. The parasites then spread to the tick's salivary glands. Inoculation into a vertebrate host occurs by a tick larva, nymph or adult. Infection in humans usually occurs from late spring to early fall.

After an infectious tick bite, the parasites invade red blood cells and a trophozoite differentiates, replicating asexually by budding with the formation of two to four merozoites. A second type of undifferentiated trophozoite is also formed that does not replicate but enlarges and differentiates into gametocyte-like forms similar to that seen in Plasmodium species. Merozoites eventually disrupt infected erythrocytes and reinvade other red blood cells.

Pathophysiology:

The parasite only infects red blood cells (RBCs). This significantly affects the hematological system, causing hemolytic anemia, thrombocytopenia, and atypical lymphocyte formation. Alterations in RBC membranes cause decreased conformability and increased red cell adherence, which can lead to development of acute respiratory distress syndrome (ARDS) among those severely affected.















Babesia parasites reproduce in red blood cells, where they can be seen as cross-shaped inclusions (4 merozoites asexually budding but attached together forming a structure looking like a "Maltese Cross") and cause hemolytic anemia, quite similar to malaria.

Note that unlike the Plasmodium parasites that cause malaria, Babesia species lack an exo-erythrotic phase, so the liver is usually not affected.

Frequency:

In the US: Babesiosis is limited to those who live in, or have recently traveled to, the northeastern United States. Few cases have been reported in California, Washington, Wisconsin, and Georgia. Hundreds of cases have been reported since the first domestic case of human babesiosis was reported in 1966. An increasing trend over the past 30 years may be the result of restocking of the deer population, curtailment of hunting, and an increase in outdoor recreational activities. Although the most life-threatening cases occur in patients who are elderly, immunocompromised, HIV infected, or have undergone splenectomy, most patients with babesiosis are asymptomatic, which may result in underreporting of the disease across all age groups.

Internationally: Babesiosis in Europe, caused by a different species of Babesia, is a more devastating disease. Although rare, it is symptomatic and often fatal. Like its US counterpart, babesiosis in Europe is also seen in patients who have undergone splenectomy. Anecdotal reports of babesiosis in China, Mexico, South Africa, and Egypt have been documented.

Epidemiology:

Babesiosis is a vector-borne illness usually transmitted by ticks. (Babesia microti uses the same tick vector, Ixodes scapularis, as Lyme disease does.) In babesia-endemic areas, the organism can also be transmitted by blood transfusion.

Infection with Babesia parasites can be asymptomatic or cause a mild non-specific illness, and therefore many cases go unnoticed. Most diagnosed cases occur in the very young, very old, or persons with underlying medical conditions (such as immunodeficiency). Some cases are identified when patients with another tick-borne illness are screened for babesiosis.

Little is known about the occurrence of Babesia species in malaria-endemic areas, where Babesia can easily be misdiagnosed as Plasmodium.

Mortality/Morbidity:

The US mortality rate is low.

· Most cases are asymptomatic and improve spontaneously without treatment.

· Approximately 25% of patients with babesiosis are co-infected with Lyme disease. These patients experience more severe symptoms for a longer duration than those with either disease alone.

In Europe, babesiosis is a life-threatening disease.

· Of patients with babesiosis, 84% are asplenic, and 53% become comatose and die.

· Of those rare reported cases of subclinical infection, all patients were infected by the same Babesia species that affects patients in the northeastern United States.

Race:

All races.

Age:

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

· No difference in seropositivity exists among age groups.

· Adequate reporting is a major problem, especially in children, because of masking by other infections and the disease's history of occurrence in elderly patients.

Sex:

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

Clinical

History:

Patients report a history of travel to an endemic area between the months of May and September. This is the period during which the Ixodes tick is in its infectious nymph stage; however, most do not recall being bitten by a tick. Incubation period is from 1-4 weeks.

Symptoms:

o Fatigue

o Anorexia

o Arthralgia and myalgia

o Depression

o Dark urine

o Nausea and vomiting

o Cough

o Dyspnea

Physical Assessment:

o Fever

o Shaking chills

o Hepatosplenomegaly

o Jaundice

o Myalgia

o Malaise

Causes:

The causative agent of babesiosis varies according to geographical region.

· In the northeastern United States, infections are caused by Babesia microti, transmitted by the same Ixodes tick that transmits Lyme disease.

· In California and Washington, WA-1, which is similar to Babesia gibsoni, is the causative agent. The arthropod vector has yet to be identified.

· In Europe, the Ixodes tick transmits the infectious agent, Babesia divergens.

· Occasionally, cases of infection via blood transfusion from a donor who lived in or traveled to an endemic area are reported.

Tests/Studies

Lab Studies:

· In individuals who are asymptomatic, lab studies may be unremarkable.

· Giemsa-stained peripheral blood smear

- This test reveals intraerythrocytic parasites (ie, ring forms, no pigment, pathognomonic tetrads [Maltese cross]).

- Smear may be negative in individuals with asymptomatic infection.

- Level of parasitemia does not correspond to severity of disease, although patients who are mildly ill may have less than 1% parasitemia and patients who are severely ill may have greater than 85%. This high level of parasitemia is especially seen in asplenic patients.

· Complete blood count (CBC) with differential indicates hemolytic anemia, thrombocytopenia, atypical lymphocytes, and leukopenia.

· Liver function tests often reveal mildly elevated hepatic transaminases, elevated erythrocyte sedimentation rate (ESR), lactic dehydrogenase (LDH), and serum bilirubin.

· Urinalysis: Hemoglobinuria, proteinuria, and a dark color may be present.

· Direct Coombs test may or may not be positive.

· Pulse oximetry: Hypoxia may be present in patients with severe disease.

Imaging Studies:

· Chest x-ray may be indicated for patients with respiratory complications including pneumonia or ARDS.

Other Tests:

· Immunofluorescence antibody testing

- Use this test to confirm diagnosis when peripheral blood smear is negative.

- Titer of greater than 1:64 is positive.

- A 4-fold rise in titer or a single titer greater than 1:256 is suggestive of acute infection.

- Differentiation of acute and chronic infection may be difficult because titers may increase to very high levels then decrease slowly. This is especially true in endemic areas such as the Northeastern US.

· Enzyme-linked immunosorbent assay (ELISA) immunoglobulin M (IgM) Lyme titer

- This test is used because of the high percentage (25%) of patients co-infected with Lyme disease.

- Co-infection increases the severity of disease; therefore, it is important to diagnose and treat both infections.

· Polymerase chain reaction (PCR) is a highly specific test that can be used to confirm diagnosis.

· Inoculation of a golden hamster with the patient's blood and subsequent antibody analysis of the animal's blood is used to confirm diagnosis when peripheral blood smear and lab tests are equivocal.

· Immunoblot antibody test

- Babesial infection causes a significant antibody response even at low levels of parasitemia.

- The assay is specific for anti–B microti antibodies when at least 2 or more bands on the assay are positive.

- This test has similar sensitivity and specificity for diagnosing babesiosis as that of IFA.

- Potential advantages over IFA include the lack of need for concentrated serum samples and ease of use, as immunoblot assays can be performed by generalist technicians versus trained microscopists.

Procedures:

· Because of the possibility of hemophagocytic syndrome, bone marrow biopsy is indicated in patients whose lab studies reveal pancytopenia and whose physical examination reveals lymphadenopathy.

Treatment/Management

Emergency Department Care:

· Suspicion of babesiosis in a patient with a history of tick bite, fever, chills, and fatigue is crucial.

· Peripheral blood smear or immunologic testing as described is needed to make the diagnosis.

· CBC with differential is important to determine the severity of infection.

· Immediately start patients who are elderly, immunocompromised, or asplenic on a treatment regimen of clindamycin IV and quinine PO or atovaquone IV and azithromycin IV to avoid acute renal failure.

· If the patient is otherwise healthy, supportive care is the only treatment required.

· Intubation and mechanical ventilation may be required for patients who develop respiratory distress or failure.

Consultations:

Consult infectious disease and internal medicine services if admission is indicated.

Medication

Antibiotic and antimalarial therapy should begin immediately after diagnosis to reduce the level of parasitemia. Treatment has historically been with clindamycin and quinine, but a promising first-line alternative may be atovaquone and azithromycin. Patients may have less side effects with the latter combination including decrease tinnitus, vertigo, and gastrointestinal upset. Parasitemia may persist despite treatment with either of the described drug regimens.

Drug Category: Antibiotics -- Therapy should cover all likely pathogens in the context of this clinical setting.

Drug Name	Clindamycin (Cleocin) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	300-600 mg IV tid for 7 d
Pediatric Dose	20-40 mg/kg/d PO tid for 7 d
Contraindications	Documented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

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

Drug Category: Antiprotozoals -- May contribute to the eradication of the parasite.

Drug Name	Atovaquone (Mepron) -- May inhibit metabolic enzymes, which in turn inhibits growth of microorganisms. Administer in combination with azithromycin.
Adult Dose	750 mg PO q12h for 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease atovaquone levels; atovaquone may decrease levels of TMP-SMZ
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly and in hepatic and renal impairment

Drug Category: Anti-malarials -- These agents are effective in eradicating the parasite.

Drug Name	Quinine sulfate (Formula Q) -- Inhibits growth of parasite by increasing the pH within intracellular organelles and possibly by intercalating into DNA of the parasites.
Adult Dose	650 mg PO tid for 7 d
Pediatric Dose	10-25 mg/kg/d PO for 7 d
Contraindications	Documented hypersensitivity; optic neuritis, tinnitus, G-6-PD deficiency, or history of black water fever
Interactions	Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates the 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
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidine-like activity and thus can cause cardiac arrhythmias

Follow Up Treatment/Management

Further Inpatient Care:

* Monitor level of oxygenation and watch for development of respiratory complications that present with dyspnea after initiation of treatment.

* Chronology of respiratory distress may be due to endotoxin sensitivity; endotoxin release results from the medication-induced intraerythrocytic death of the parasites.

* In severe cases, exchange transfusion may be the only means of reducing the level of parasitemia. Mechanical ventilation may be necessary should the patient continue to deteriorate.

* Monitor CBC for development of hemophagocytic syndrome. Examine lab results for pancytopenia and examine patient for lymphadenopathy.

* If the patient does not respond to or can not tolerate treatment with clindamycin and quinine, commence alternative treatment with atovaquone and azithromycin.

Deterrence/Prevention:

* Exposure to endemic areas

o Those at risk of severe infection should avoid endemic areas between the months of May and September.

o Cover skin with appropriate clothing, including tucking long pants inside socks.

o Examine skin and pets every day (takes 24 h for infection to be transmitted).

o Wear tick repellent, such as diethyltoluamide and dimethyl phthalate, on skin and clothes.

o People from endemic areas who report a fever within the last 2 months or a history of tick bite are not allowed to donate blood.

Complications:

* Respiratory problems

o Patients who have undergone splenectomy are unable to clear infected RBCs to reduce the level of parasitemia, leading to hypoxemia and subsequent risk of cardiopulmonary arrest.

o In severe cases, damage to RBC membranes, decreased deformability, and cytoadherence to capillaries and venules lead to pulmonary edema and respiratory failure.

o These respiratory problems begin after treatment has been initiated when intraerythrocytic death of parasites has been postulated to cause sensitivity to endotoxin.

o Noncardiogenic pulmonary edema

o ARDS is possibly due to mechanisms such as endotoxemia, complement activation, immune complex deposition, cytoadherence, microemboli, and disseminated intravascular coagulation.

* Relapses

* Postsplenectomy patients may develop hemophagocytic syndrome, acute renal failure, and generalized seizure.

* Coma can occur, possibly due to severe sepsis, ARDS, or multisystem organ failure.

* Co-infection with Lyme disease

Prognosis:

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

* In Europe, most symptomatic patients are asplenic, which contributes to a poor prognosis. Over 50% become comatose and die.

Patient Education:

Early removal of ticks is important; the tick must remain attached for at least 24 hours before the transmission of B. microti occurs. Therefore, daily self-examination is recommended for persons who engage in outdoor activities in endemic areas. Pets also must be examined for ticks because they may carry ticks into the home.

Miscellaneous

Medical/Legal Pitfalls:

* Failure to consider diagnosis in children

* Failure to initiate immediate therapy in individuals considered at high risk (ie, asplenic, elderly, immunocompromised)

* Administration of quinine therapy to a patient who is pregnant

Special Concerns:

* Pregnancy

o Do not give quinine to a patient who is pregnant.

o If the infection is subclinical, no drug therapy is needed.

o Combination therapy with clindamycin and quinine or atovaquone and azithromycin is more effective than either atovaquone and azithromycin alone.

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

References

eMedicine
Wikipedia
aafp.org

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