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B. microti: Looks like malaria, smells like malaria, but isn’t malaria
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Babesiosis in humans is a tick-borne infection. In the United States, babesiosis is usually caused by the protozoan Babesia microti, an obligate intracellular parasite of erythrocytes. B. microti occasionally causes disease in Europe, Asia, Central America and Australia. Babesiosis is transmitted by different ticks throughout the world, mainly to wild and domesticated animals. Another species, Babesia duncani, has been the cause of babesiosis cases on the West Coast of the U.S. In Europe, most cases of human babesiosis are caused by Babesia divergens, which has also caused a limited number of cases in the U.S. Unlike B. microti, nearly all symptomatic cases caused by B. divergens are severe and occur in people without spleens. Babesia venatorum is another cause of babesiosis in humans and is found in Europe and China. This discussion will be limited to babesiosis caused by B. microti, which is responsible for the vast majority of cases of babesiosis in the U.S.
Epidemiology
Most cases of human babesiosis are asymptomatic, and clinical cases are uncommonly recognized. Between 2011 and 2015 — during the first 5 years of national surveillance for babesiosis in the U.S. — there were 7,612 cases reported from 27 states. The median age was 63 years. The great majority of cases were from the Northeastern U.S., including the offshore islands (parts of New England, New York and New Jersey) as well as Wisconsin and Minnesota. States outside of these areas reported very few cases. Most cases occurred during the months of June through August. Hospitalizations were particularly frequent in those who were asplenic and in the elderly.
In the U.S., most cases are acquired from the bite of the Ixodes scapularis tick (usually a nymph). In the wild, B. microti is a parasite of small mammals, and in particular the white-footed mouse. These mice have been found to be frequently coinfected with Borrelia burgdorferi (the cause of Lyme disease) and/or Anaplasma phagocytophilum, as well as B. microti, and the animals can transmit all three infections to ticks. Thus, one tick can become a transmitter of multiple diseases after biting one mouse. Infection with B. microti may also rarely occur via blood transfusion from an infected donor, and rarely by transmission from an infected mother to her baby during pregnancy or at delivery. Although white-tailed deer are an important host for I. scapularis and help amplify populations of the tick, they are not a reservoir for B. microti.
Pathogenesis
Following the tick bite, sporozoites are injected into the human host. The only cells infected in the human host are the erythrocytes. After the sporozoite enters the red cell, it divides and forms merozoites. With the growth and multiplication of merozoites, the red cell lyses, releasing merozoites that invade other red cells. As infection spreads from erythrocyte to erythrocyte, hemolytic anemia develops, which may result in tissue hypoxia. If complications occur, the organ most often involved is the lung, with acute respiratory distress syndrome (ARDS). Much of the end organ damage that occurs in severe disease is the result of excess cytokine release related to the immunological reaction.
For the tick to transmit babesiosis, it must be attached for over 24 hours, and probably even 36 hours or more.
Clinical manifestations
Following the bite of an infected tick, there generally is a prolonged incubation period (typically 1-4 weeks) before symptoms develop, if they are to occur. Following transfusion of infected blood, there is generally a 3- to 7-week incubation period, but it can be delayed by as much as 6 months.
After infection from a tick, most patients remain asymptomatic, but some develop symptoms and occasionally an infected patient becomes severely ill. Death may even occur. Risk factors for symptomatic and severe disease include asplenia, immunocompromise and old age. Infected patients, especially those who are severely ill, can develop parasitemia, which can last for months to years and can serve as a source of disease in patients transfused with their blood. They can also serve as a source of infection for the tick vectors. Additionally, clinical disease can be triggered in the asymptomatic patient who undergoes splenectomy or becomes immunosuppressed.
Some patients develop a viral-like illness with fever, fatigue, headache and other nonspecific symptoms. Splenomegaly or hepatomegaly may occur. Symptoms can last for weeks to months.
Patients with severe disease can experience prolonged, relapsing infection and complications such as disseminated intravascular coagulation, ARDS, heart failure and renal failure.
Source: CDC/James Gathany
Serological population studies in areas of high endemicity have demonstrated that asymptomatic infection is common. One study done in Block Island, Rhode Island, showed evidence of B. microti infection in 40% of children and 20% of adults.
Diagnosis
Babesiosis should be considered in anyone developing a viral-like illness during the tick season (summer and early fall) in an area where babesiosis is known to occur and when no alternative diagnosis is made. Of course, with climate change, these endemic areas will undoubtedly expand. Certainly, in anyone with Lyme disease or anaplasmosis in an area endemic for babesiosis, the possibility of the simultaneous presence of babesiosis should be considered.
Laboratory results may show evidence of hemolytic anemia with elevated indirect bilirubin, lactate dehydrogenase and reticulocyte count and decreased haptoglobin. Other laboratory results reflect damage in end organs, if any.
The diagnosis of babesiosis is made with microscopy using Giemsa- or Wright-stained thin or thick blood smears or by PCR testing. PCR testing is more sensitive than microscopy. The parasites are most often seen as ring forms with blue cytoplasm and red chromatin within erythrocytes, similar to that of Plasmodium falciparum. They may also appear as round, oval or pear-shaped forms. Multiple parasites may be present in one infected red blood cell. In severe cases. extra-erythrocytic forms may be seen. Tetrads of merozoites arranged in a “Maltese Cross” are said to be diagnostic of babesiosis but are rare. Serological tests are available but are considered only laboratory supportive rather than confirmatory for an active case of babesiosis.
Parasitemia is higher in sicker patients. Nonseverely ill patients generally have parasitemia of less than 4% of erythrocytes, whereas severely ill patients usually have parasitemias of 4% and even much higher.
Patients with babesiosis frequently are found to be concurrently infected with the organisms causing Lyme disease or anaplasmosis.
With the combination of fever, hemolytic anemia and microscopy showing ring forms in erythrocytes, there can be obvious confusion with malaria, specifically falciparum malaria.
Treatment
Most asymptomatic infections should not be treated. Symptomatic infections that are not severe can be treated for at least 7 to 10 days with an oral regimen of atovaquone 750 mg twice a day plus azithromycin 500 to 1,000 mg orally on day 1 and a total daily dose of 250 to 1,000 mg daily for the rest of the course. An alternative regimen is 600 mg three times daily of clindamycin taken orally or 300 to 600 mg IV clindamycin four times a day plus quinine 650 mg orally three times a day for at least 7 to 10 days. Severely ill patients should receive the long-recommended regimen of IV clindamycin plus quinine; however, a recent paper demonstrated that IV azithromycin (500 mg daily) plus oral atovaquone (750 mg twice a day) is effective and may be better tolerated.
If illness persists, the duration of therapy should be extended. Exchange transfusion has been used in severe cases. Therapy should be prolonged until the parasitemia is absent for at least 2 weeks. Relapse may occur after treatment, especially in those who are immunocompromised. Some of the risk factors for relapse are asplenia, malignancies, transplantation of organs or stem cells, immunosuppressive therapy and HIV infection. Therapy has been prolonged for as long as 6 weeks in immunocompromised patients to prevent relapse. Relapses are treated with the same regimens as the initial case.
The regimens recommended for treatment of babesiosis can be difficult to tolerate, and better, more tolerable regimens are needed. One possible promising drug is tafenoquine, recently approved by the FDA for use in prophylaxis of malaria. It has shown effectiveness in animal models of B. microti infection.
Prevention
Avoiding ticks is the main way of preventing babesiosis. People should avoid areas of uncut grass and brush, and use protective clothing to cover exposed skin and insect repellent (DEET on skin and clothing, permethrin on clothing). It is important for people to inspect themselves daily for the ticks and to remove them promptly.
People who serve as blood donors should be asked about previous babesiosis. In March 2018, the FDA approved the first B. microti blood donor screening tests. Appropriate use of this test should greatly diminish the chances of blood donor transmission of babesiosis. In May 2019, the FDA published new recommendations on screening for babesiosis. Medical screening has always been part of the blood donation process, but this recommendation from the FDA includes wholesale testing of donor samples in certain areas of the country for babesiosis.
- References:
- CDC. Parasites – babesiosis. https://www.cdc.gov/parasites/babesiosis/index.html. Accessed September 16, 2019.
- CDC. Babesiosis. https://www.cdc.gov/ticks/tickbornediseases/babesiosis.html. Accessed September 16, 2019.
- FDA. Guidance document. Recommendations for reducing the risk of transfusion-transmitted babesiosis. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reducing-risk-transfusion-transmitted-babesiosis. Accessed September 16, 2019.
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- For more information:
- Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Disclosure: Kaye reports no relevant financial disclosures.