Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.
Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.
Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “.”
(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)
All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
Move toward combination therapy research
Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.
“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.
Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.
The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that“leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”
The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.
“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthoredof B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.
Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.
Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.
Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, haveof antibiotics and other compounds, identifying candidates for further testing.
During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”