Widespread Borrelia miyamotoi Tick-borne Fever Found in US

Janis C. Kelly

June 12, 2015

Borrelia miyamotoi disease (BMD), a tick-borne infection that can cause more severe symptoms than Lyme disease, was first reported in the northeastern United States in 2013 but is becoming more common and should be considered in all areas where deer tick–transmitted infections are endemic, according to a case-series published online June 9 in the Annals of Internal Medicine.

The researchers suggest that BMD might be almost as common as human anaplasmosis among tick-exposed patients who present with fevers in the endemic areas, and they recommend that it be included in routine differential diagnosis protocols.

The timing of BMD peak incidence suggests that, unlike the transmission of Lyme disease pathogen Borrelia burgdorferi, the new infection might be transmitted by unfed larval ticks, who acquire it by transovarial transmission from the infected female tick. This has immediate clinical and public health implications.

In an accompanying editorial, Peter J. Krause, MD, from the Yale School of Public Health and Yale School of Medicine, New Haven, Connecticut, and Alan G. Barbour, MD, from the University of California, Irvine, write, "Bites from larval deer ticks have not been considered as a health threat, but this needs to be reevaluated. Larval transmission of B. miyamotoi has implications for checking for ticks and continuing tick precautions even after the risk for Lyme disease has abated."

The case series report was prepared by a research team led by Philip J. Molloy, MD, medical director of IMUGEN, a commercial laboratory that performs specialized testing of clinical specimens for tick-borne diseases. Cases were acutely febrile patients from the northeastern United States who presented to primary care offices, emergency departments, or urgent care clinics and for whom clinicians ordered testing for tick-transmitted infections. Between April 1, 2013, and October 31, 2014, the researchers identified 97 patients whose blood samples contained B miyamotoi DNA. Clinical information was available for 51 of the 97.

Patients Appeared "Toxic," Were Suspected of Having Sepsis

Presenting symptoms typically included fever, myalgia, influenza-like illness, headache, or rash. The authors write, "Patients presented with acute headache, fever, and chills and were often found to have leukopenia, thrombocytopenia, and elevated aminotransferase levels, mimicking human anaplasmosis infection. Patients were commonly described as appearing 'toxic'; more than 50% were suspected of having sepsis, and 24% required hospitalization. The headaches were most commonly described as severe, resulting in head computed tomography scans and spinal taps in 5 patients."

Initial screening used a whole-blood polymerase chain reaction for specific DNA sequences of a number of common tick-borne infections, including BMD. Because there is not yet an established test for BMD, the researchers used a recombinant B miyamotoi glycerophosphodiester phosphodiesterase enzyme-linked immunosorbent assay to detect antibody to B miyamotoi. Interestingly, only 16% of patients (8/51) had a detectably immune response to recombinant B miyamotoi glycerophosphodiester phosphodiesterase during the acute disease phase, but 86% of the case patients for whom convalescent sera (drawn 5 or more days after the beginning of treatment) were available demonstrated seroconversion.

The authors recommend that, in cases where BMD is suspected but the index specimen is negative by polymerase chain reaction, blood samples from the convalescent period should be tested. In this series, two such cases were identified.

Most cases began in July and August. The authors comment, "[O]ur findings suggest that it may not be a rare infection in the northeastern United States. The months during which cases were identified are consistent with transmission of B. miyamotoi by deer ticks. However, unlike acute Lyme disease, the majority of cases occurred in July and August, perhaps suggesting transmission by larval ticks, which have their peak activity during these months.... These considerations should prompt enhanced public education about the need to continue personal protection measures during the late summer, which is usually believed to be a less risky period because the agents of Lyme disease, babesiosis, and human anaplasmosis are not transmitted by larval deer ticks."

Doxycycline Recommended as First-line Treatment of Suspected BMD

Forty of the 51 patients had received 2- to 4-week courses of oral doxycycline, seven had received amoxicillin (including three patients treated with one or two doses of ceftriaxone beforehand), and one received levofloxacin. Symptoms resolved in from 2 days to 1 week in 40 of the 42 patients for whom outcomes information was available.

In the editorial, Dr Krause and Dr Barbour write, "Doxycycline, amoxicillin, and ceftriaxone seem to be effective in alleviating symptoms and preventing complications. Such therapy would also be effective against co-infection with B. burgdorferi. Doxycycline is the preferred initial therapy in patients with suspected B. miyamotoi infection because it effectively treats Lyme disease and human granulocytic anaplasmosis, which may be the cause of illness or co-infection with B. miyamotoi."

Laboratory investigations showed that 14% of the patients with BMD were coinfected with B burgdorferi. The study authors comment that although sera from patients with acute BMD often show reactivity to B burgdorferi on enzyme immunoassay testing, this is rarely confirmed by immunoblot. They write, "This finding is clinically relevant because a patient presenting with an acute 'summer fever' and no rash and testing positive by whole cell antigen serologic test for Lyme disease could actually be infected with B. burgdorferi, B. miyamotoi, or both. However, sera from patients with BMD generally do not react to B. burgdorferi antigens in [immunoglobulin G or immunoglobulin A] tests, which is partly consistent with what has been previously reported for a small number of case patients with BMD."

Since many cases presented in July and August, when transmission by larval ticks is suspected because of their peak activity during these months, the authors conclude that infection with BMD should be considered in areas where deer tick–transmitted infections are endemic.

The study was funded by IMUGEN. Dr Molloy is the paid medical director of IMUGEN. One coauthor has disclosed receiving personal fees from IMUGEN, Immunetics, Meridian Bioscience, and Fuller Laboratories. Five coauthors are employees of, board members of, or own stock in IMUGEN. The other authors, Dr Krause, and Dr Barbour have disclosed no relevant financial relationships.

Ann Intern Med. 2015; Published online June 9, 2015. Article abstract, Editorial extract

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