Controversies Surrounding the Causes and Management of Persistent Symptoms Related to Lyme Disease

Although persistent symptoms have been observed in patients with a history of Lyme disease, the causes and management of these symptoms, as well as the challenges in conducting effective research studies, remain controversial among researchers. Improvements in research design and congenial collaboration among experts will be important for answering these questions, according to experts who participated in a recent Contagion^® Peer Exchange Panel.

LONG-TERM MANIFESTATION OF SYMPTOMS

Peter L. Salgo, MD, and Leonard Sigal, MD, noted that many patients who receive antibiotics soon after infection will have symptom improvement; however, Samuel Shor, MD, FACP, pointed out that 39% of patients in the SLICE study¹ treated early with antibiotics did not return to their pre-Lyme disease health status after 6 months. Dr. Shor noted that the findings in the SLICE study suggest persistence of symptoms after antimicrobial therapy in some patients, but whether they still harbor the Borrelia burgdorferi (B. burgdorferi) bacteria is controversial among scientists.

Some experts, including Robert C. Bransfield, MD, DLFAPA, suggest that patients carry the infection in a latent manner for several years and that an event, such as a coinfection with another pathogen, can re-activate the B. burgdorferi. “Co-infection is a complicated thing,” said Bransfield. “It can be a complex interactive infection, coinfection with other tick-borne or non—tick-borne pathogens that might be in the body and are opportunistic, like viruses.”

Dr. Sigal pointed out that past research has demonstrated that the proinflammatory B. burgdorferi—derived debris may persist after treatment with antibiotics, even if no live organism is present, and contribute to the persistent symptoms observed after treatment. Dr. Bransfield disagreed, stating that the persistent inflammatory reaction associated with symptoms likely lasts longer than the presence of the pathogen-derived debris. Bransfield also noted that patients who have received adequate treatment have relatively stable symptoms, whereas others have symptoms that worsen over time, likely caused by immune system provocation, although more research is needed to determine whether persistent infection is contributing to this immune system provocation.

MANAGEMENT CONSIDERATIONS

The panelists also debated the effective management of individuals with suspected Lyme disease, considering the notoriously inaccurate diagnostic laboratory testing, particularly for cases that have gone undiagnosed for several years. According to Dr. Bransfield, the 2-tiered system of serologic testing with an enzyme-linked immunosorbent assay (ELISA), followed by a confirmatory western blot test if the ELISA is positive, may be somewhat useful if a patient was infected a few months ago but is not standardized to test individuals who were infected 5 to 10 years ago. Furthermore, Dr. Sigal stated that the relationship between lingering symptoms and infection status is often unclear for many patients.

“I saw a gentleman15 years after an erythema migrans who came in with Lyme arthritis,” said Dr. Sigal. “He was very seropositive. If somebody comes in with something that is not clinically likely to be Lyme disease and you have the blood test that’s positive, you don’t know if there’s any relationship between the 2 or if this is one of those lucky individuals who get bitten by a tick, their immune response deals with [it], and they seroconvert because there is an organism inside and available to their immune system.”

Dr. Shor noted that although some experts state that the antimicrobials improve symptoms by providing an anti-inflammatory effect, they may also induce an inflammatory response, such as a Jarisch-Herxheimer reaction. He also described a recent study² in which researchers had Borrelia-naïve ticks feed off mice that had been infected with B. burgdorferi and subsequently treated with antibiotics and showed that the ticks transmitted the pathogen to a group of Borrelia-naïve mice, suggesting that antibiotics may not be sufficient to clear the infection.

RESEARCH CHALLENGES

The existence of chronic Lyme disease is a contentious debate among experts, and this controversy may be due to gaps in the types of research being funded, according to Patricia V. Smith. She stated that the lack of rigorous studies and the researchers that discount the relationship between persistent symptoms and Lyme disease is frustrating for many patients.

“After 33 years, I can say if it wasn’t for the International Lyme and Associated Diseases Society, most of the patients I have seen across the country…would not have anyone to turn to, to try to help them figure out just exactly what they do have,” she said.

To support the notion that funding for Lyme disease research is biased, she recalled her experience in 2012 at Congressional hearings of the House Foreign Affairs Committee, stating that a prominent researcher testified that there were “serious issues” with the grant process at the National Institutes of Health (NIH).

“If someone wanted to do a study and said they were looking at chronic Lyme, those grants were just not considered,” said Ms. Smith. “Apparently, those who sat in peer review didn’t really want to look at chronic Lyme because they had another bias. The same kinds of studies were funded year after year… instead of the kinds of research that really needed to be done; for example, research on new cutting-edge testing.” Dr. Sigal argued that the NIH grants were appropriately awarded and used by the recipients, but were rarely sufficient to conduct all needed research and consider multiple viewpoints. “There’s an undercurrent to many of these conversations that, somehow, there’s this nefarious self-interest amongst people who are getting funds for research,” said Dr. Sigal. “That’s really not true. These are scientists who are trying to do their best. There are other people who believe in a very different approach to Lyme disease…They are welcome to approach the NIH to get funds for their research as well. If…the paper is written properly, if the grant is written properly—they’ll be taken into consideration.”

REACHING A CONSENSUS

Most of the panelists agreed that a 2- to 4-week course of antibiotics for patients with suspected Lyme disease is an appropriate first step of treatment. However, they noted that the clinical response will likely vary among individuals, particularly if there is a complex infection, multiple pathogens, or life-threatening clinical manifestations, such as meningitis.

For the subset of patients who do not respond to 6 weeks of antibiotics, the panelists agreed that a careful differential diagnosis and empathetic review of a patient’s clinical picture should be performed. However, Dr. Shor pointed out that the secondary assessment will probably vary among clinicians based on their perception of the incidence of active Lyme disease. As for prolonging antibiotic use in patients who do not have symptom improvement at first, Dr. Shor stated that they should be continued if clinicians feel that there is still an active infection. “By not [continuing antibiotics], you potentially run the risk of not having adequate therapeutic gains.” The panelists also agreed that more collegial peer discussions among experts can help to reconcile differences in viewpoints and develop a specific universal definition of Lyme disease. However, several barriers have precluded these research projects and collaborations, including a climate of fear surrounding physicians, who have been subject to sanctions in the past for long-term treatment of patients with Lyme disease, and the reluctance of physicians and patients to participate in clinical trials due to poor responses to long-term antibiotic use in previous trials.

However, Dr. Sigal added that the duration of many of these long-term antibiotic trials was likely insufficient to see the desired outcomes and Shor noted that the trials had multiple confounding variables, such as the inclusion of patients with long-duration illness who had previously received the protocols being tested and the failure to identify co-infections. The panelists concluded that improving the quality of scientific research on clinical biomarkers and testing, along with a better consensus among experts about study design, goals, and endpoints, could help improve the perceived value among experts of study results in trials of persistent symptoms following Lyme disease infection.

References:

1. Aucott JN, Crowder LA, Kortte KB. Development of a foundation for a case definition of post-treatment Lyme disease syndrome. Int J Infect Dis. 2013;17(6):e443-9. doi: 10.1016/j.ijid.2013.01.008.

2. Hodzic E, Imai D, Feng S, Barthold SW. Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice. PLoS One. 2014;23;9(1):e86907. doi: 10.1371/journal.pone.0086907.