Chronic Lyme Disease Clinical Trials

The Misdiagnosis Of Chronic Lyme Disease

Many patients referred for Lyme disease are ultimately found to have a rheumatologic or neurologic diagnosis. Rheumatologic diagnoses commonly misdiagnosed as Lyme disease include osteoarthritis, rheumatoid arthritis, degenerative diseases of the spine, and spondyloarthropathies.,, Some patients are found to have neurologic diseases, including multiple sclerosis, demyelinating diseases, amyotrophic lateral sclerosis, neuropathies, and dementia. Some CLD advocates have argued that these various conditions are simply manifestations of Lyme disease,, but these hypotheses are untenable. Lyme disease is transmitted quite focally, and there is no epidemiologic evidence that these alternative diagnoses cluster in regions with high Lyme disease transmission. There has been no association between diagnoses such as multiple sclerosis, amyotrophic lateral sclerosis, or rheumatoid arthritis and antecedent Lyme disease, these diagnoses do not arise concurrently with other recognized manifestations of disseminated Lyme disease , and there is no quality evidence associating any of these diagnoses with seroconversion to B burgdorferi. Although there can certainly be clinical overlap between Lyme disease and other conditions, objective findings and studies will generally allow them to be differentiated.

Priority : Conduct Additional Targeted Controlled Clinical Treatment Trials In Patients With Early And Persistent Lyme Disease Using Different Antibiotic Regimens And Longer Durations Of Treatment Than Those Used In Previously Conducted Trials

Assessment of the clinical presentation of patients with persistent Lyme disease involves a fre-quently complicated differential diagnosis that includes chronic fatigue syndrome and fibromyalgia, among other multi-symptom infectious and noninfectious diseases and disorders . Complicating support of the clinical diagnosis of persistent Lyme disease is the limited value of ex-isting laboratory tests, mostly serologic tests, which offer indirect evidence of exposure to B. burgdorferi. Other, more direct tests appear to be insufficiently sensitive, either because the remaining organisms are not in the traditional sites sampled for analy-sis, or because the bacterial load is too low to be detectable, or both. Therefore, a high priority to address this obvious gap in critical information is the development of direct detection tests, if that goal is possible to achieve, or other better indicators of ongoing infection or alternative causes of the persistent disease.

The subcommittee reviewed the results of prior published controlled studies of antibiotic treat-ment . As review of those stud-ies was included in the previous report of the Working Group, details of that discussion are not re-peated here. The subcommittee members noted shortcomings in those studies, including the types of antibiotics used, the numbers of patients, the duration of treatment, and interpretation of out-come results.

Possible Opportunities

Threats or Challenges

Meeting 7 October 9 2019

Agenda

Overview

The subcommittee heard a presentation from member Rex Carr, MD, on the successful use of antibiotics to treat persistent Lyme disease and potential mechanisms of action and discussed the implications of the findings.

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What Is Cdc Doing

CDC is currently conducting research to understand what concerns healthcare providers and the public may have about any potential Lyme disease vaccines. Once a Lyme disease vaccine is approved as safe and effective by the Food and Drug Administration , CDC will work with the Advisory Committee on Immunization Practices to develop recommendations about where in the U.S. the public might benefit from a Lyme disease vaccine. CDC will communicate these recommendations to increase awareness of a vaccine among the public and clinicians to prevent Lyme disease in the United States.

Treatment #: Acupuncture Points And Rationale :

LI 11 draining technique clear heatLI 4 draining technique Master command point for painUB 43 and UB 13 garlic moxibustion Back Shu of LU tonify backUB 23 and DU 4 tonify KD and alleviate back painPC 8 clear heat to help with anxietyDU 16 calm spirit and to eliminate sweating, headache and heaviness in bodySJ 5 and PC 6 strongly move qi to alleviate pain

Herbal Formulas:

Su He Tang + Zhi Bai Di Huang Wan + Modified Chai Hu Shu Gan Tang to spread LV qi, promote qi circulation, harmonize the blood and alleviate pain.

Instructions for Herbal Formula: Take Su He Tang if Jia Jian Su He Tang is not working after 2-3 weeks, but the patient must come back into the office and discuss how they are feeling after taking daily for a week to two weeks. Zhi Bai Di Huang Wan is to be taken for a week to see if it helps with the yin deficiency, while stopping the Jia Jian Su He Tang to address the Gu symptoms, and then possibly switched to a Modified Chai Hu Shu Gan Tang over the course of weeks or months after initial treatment. All must be managed and modified accordingly.

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Disulfiram: A Test Of Symptom Reduction Among Patients With Previously Treated Lyme Disease

• Study Details

There are several possible explanations for why patients may have persistent symptoms, including persistent infection and post-infectious changes triggered by the prior infection.

Scientists recently discovered that disulfiram is effective in the lab setting at killing the microbes that cause Lyme disease. Disulfiram is more commonly known as “Antabuse”. It is an FDA-approved compound used to assist alcoholics in resisting alcohol consumption. Most remarkable is that disulfiram was effective at killing not only the actively replicating Lyme bacteria but also the relatively dormant or quiescent Lyme bacteria – these latter spirochetes are the ones that may account for the development of chronic Lyme disease symptoms.

Patients will be randomly assigned to one of two groups:

Week 1: 250 mg every other day. Week 2: 250 mg daily .

Persistent Symptoms After Treatment For Lyme Disease

It is well-recognized that some patients experience prolonged symptoms during convalescence from Lyme disease, and a subset suffer significant functional impairment., The most common complaints among such patients are arthralgias, myalgias, headache, neck and backache, fatigue, irritability, and cognitive dysfunction .

A working definition was developed to categorize patients with post-Lyme disease symptoms , those patients with persistent clinical symptoms after treatment for Lyme disease, but who lack objective evidence of treatment failure, reinfection, or relapse . PLDS is not strictly speaking a coherent clinical diagnosis its primary value has been to define a patient cohort for further study. Nonetheless, it is worth considering how it conceptually differs from CLD. To meet criteria for PLDS, patients must have unequivocal documentation of appropriately treated Lyme disease, lack objective manifestations of Lyme disease, and have persistent symptoms that cannot be explained by other medical illnesses. Thus, of patients with chronic symptoms that have been attributed to Lyme disease, those meeting criteria for PLDS are those for whom infection with B burgdorferi is most plausible. This makes the studies of PLDS paradigmatic for the understanding of CLD.

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Extended Antibiotics For The Treatment Of Post

Three research groups have examined prospectively the effectiveness of prolonged antibiotic courses for post-Lyme disease syndromes., All trials had strict entrance criteria similar to the aforementioned definition of PLDS. The Klempner and colleagues study reported 2 parallel trials in which their cohort of 129 subjects was divided into seropositive and seronegative arms. Subjects randomized to treatment groups received 30 days of intravenous ceftriaxone followed by 60 days of oral doxycycline. Those randomized to the placebo arm received IV placebo for 30 days, followed by an oral placebo for 60 days. The primary outcome was health-related quality of life as assessed by standardized instruments . These instruments were administered at baseline, and then 30, 90, and 180 days. There was no difference in any outcome measure between placebo and treatment groups in either the seropositive or seronegative arm, or in a detailed battery of neuropsychological tests that was published subsequently. Although all patients had complained of cognitive dysfunction at baseline , objective measures of cognitive function, such as memory and attention, were normal compared with age-referenced normative data. Depression, anxiety, and somatic complaints improved in both the antibiotic and placebo arms groups between baseline and day 180.

Risk Factors For Persistent Symptoms After Treatment For Lyme Disease

Patients with the most severe symptoms on clinical presentation are the most likely to have persistent symptoms during convalescence. Severe headache, arthritis, arthralgias, and fatigue at presentation predicted persistent symptoms in a retrospectively examined cohort of 215 patients. In a prospective treatment trial for early Lyme disease, persistent symptoms at several late follow-up visits were more common in patients who had more symptoms, higher symptom scores and multiple erythema migrans lesions. Patients with a longer duration of symptoms may also be at greater risk of persistent symptoms: a review of 38 subjects who had been previously treated for Lyme disease found that persistent somatic and neuropsychological sequelae were strongly associated with prolonged illness before treatment.

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The Chronic Lyme Disease Controversy

Chronic Lyme disease is a poorly defined term that describes the attribution of various atypical syndromes to protracted Borrelia burgdorferi infection. These syndromes are atypical for Lyme disease in their lack of the objective clinical abnormalities that are well-recognized in Lyme disease and, in many cases, the absence of serologic evidence of Lyme disease as well as the absence of plausible exposure to the infection. The syndromes usually diagnosed as CLD include chronic pain, fatigue, neurocognitive, and behavioral symptoms, as well as various alternative medical diagnosesmost commonly neurologic and rheumatologic diseases. Perhaps the most recognized and contentious facet of this debate is whether it is effective, appropriate, or even acceptable to treat patients with protracted antibiotic courses based on a clinical diagnosis of CLD.

How Do Researchers Implement A Clinical Research Idea

Everything that happens in each phase of a clinical trial follows a plan detailed in a study plan, also referred to as a protocol, which describes the following:

• Purpose of the research
• Goals of the research such as the type of information to be learned from the clinical trial
• Eligibility requirements defines the population of people that can participate in the clinical trial .
• Details about tests, procedures, and/or treatments
• How long the clinical trial will last
• Potential benefits to participants
• Risks to participants and how the research team will minimize the risks

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Clinical Approach To Patients With A Chronic Lyme Disease Diagnosis

Even if CLD lacks biological legitimacy, its importance as a phenomenon can be monumental to the individual patient. This is because many if not most patients who believe they have this condition are suffering, in many cases for years. Many have undergone frustrating, expensive, and ultimately fruitless medical evaluations, and many have become quite disaffected with a medical system that has failed to provide answers, let alone relief.

Beyond this generalization, patients referred for CLD have heterogeneous medical, social, and educational backgrounds. Furthermore, there is great variation in their commitment to a CLD diagnosis. Some patients are entirely convinced they have CLD, they request specific types of therapy, and they are not interested in adjudicating the CLD diagnosis. By contrast, others are not particularly interested in CLD per se, and are content to move on to a broader evaluation. In the authors experience most patients fall somewhere in betweena certain amount of time must be spent reviewing past experiences and past laboratory tests, then explaining why Lyme disease may not account for their illnesses.

Fda Approves Investigational New Drug Application For Lyme Prep A Pre

UMass Medical School Communications

The first human clinical trial of Lyme PrEP, a seasonal shot to prevent Lyme disease, has begun enrolling volunteers to evaluate the safety and pharmacology of the treatment. A pre-exposure prophylaxis developed at MassBiologics of UMass Medical School, Lyme PrEP uses a monoclonal antibody that protects against the disease. Approximately 60 volunteers will be enrolled in the Phase I trial.

This is an exciting milestone, said Mark Klempner, MD, executive vice chancellor for MassBiologics and professor of medicine. There is a real unmet public health need for the prevention of Lyme disease. There are more than 30 years of clinical experience that says a monoclonal antibody will be safe. The bigger question we hope to answer is how long will the antibody last in the circulation so when a tick bites you will be protected from Lyme disease.

Lyme disease is the most common vector-borne disease in the United States. It is caused by the bacterium Borrelia burgdorferi and rarely, Borrelia mayonii, and is transmitted to humans through the bite of infected blacklegged ticks. When an infected tick bites someone and begins to feed on their blood, Lyme-causing bacteria can slowly travel from the ticks gut to its salivary glands and then transfer the bacteria to the site of the bite.

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Potential Treatment For Lyme Disease Kills Bacteria That May Cause Lingering Symptoms Study Finds

Screening thousands of drugs, Stanford scientists determined that in mice, azlocillin, an antibiotic approved by the Food and Drug Administration, eliminated the bacteria that causes Lyme disease.

Deer ticks are vectors of Borrelia burgdorferi, the bacteria that causes Lyme disease.Scott Bauer/USDA Agricultural Research Service

For decades, the routine treatment for Lyme disease has been standard antibiotics, which usually kill off the infection. But for up to 20% of people with the tick-borne illness, the antibiotics dont work, and lingering symptoms of muscle pain, fatigue and cognitive impairment can continue for years sometimes indefinitely.

A new Stanford Medicine study in lab dishes and mice provides evidence that the drug azlocillin completely kills off the disease-causing bacteria Borrelia burgdorferi at the onset of the illness. The study suggests it could also be effective for treating patients infected with drug-tolerant bacteria that may cause lingering symptoms.

This compound is just amazing, said Jayakumar Rajadas, PhD, assistant professor of medicine and director of the Biomaterials and Advanced Drug Delivery Laboratory at the Stanford School of Medicine. It clears the infection without a lot of side effects. We are hoping to repurpose it as an oral treatment for Lyme disease. Rajadas is the senior author of the study, which was published online March 2 in Scientific Reports. The lead author is research associate Venkata Raveendra Pothineni, PhD.

Basic Facts About The Studies

The studies are located in the Clinical Center on the NIH campus in Bethesda, Maryland.

Some travel costs may be covered.

There is no cost for study-related medical care or medicines.

People can be referred to a clinical trial by their personal physicians, or they can refer themselves.

Compensation is provided for participation in some of the studies.

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Priority : Educate Clinicians As To The Limitations Of Currently Available Tests In The Diagnosis And In The Monitoring Of Treatment Of Patients With Persistent Lyme Disease

There is a disparity between and among societal and government agencies and clinicians as to rec-ommendations regarding the use of existing tests in the diagnosis of persistent Lyme disease and of its treatment . In discussing potential actions to resolve these problems, there is a need to consider whether additional controlled treatment trials are feasible, given the absence of specific corroborative tests, the challenge of identifying sufficiently homogeneous clinical popula-tions, and the lack of consensus about the best antibiotic regimens to be tested. If and until re-search results are sufficiently conclusive to support recommendation of a specific regimen for gen-eral use, as part of educational efforts, health care providers should consider the use of currently available, apparently successful, treatment regimens, as previously noted.

Possible Opportunities

There is now updated information from the results of animal studies that the causative agent of Lyme disease, B. burgdorferi, can often resist innate and other host immune responses and can persist despite certain antibiotic treatments. Educating clinicians about these important results, along with information regarding the limitation of existing laboratory tests and of the limitations of previously conducted antibiotic treatment trials, should enable them to better manage and care for patients with persistent Lyme disease.

Threats or Challenges

First Clinical Trials Network For Lyme And Tick

The Cohen gift expands Lyme and tick-borne diseases research by establishing the first clinical trials network for multi-site clinical trials and pilot studies to assess treatments. Columbia will be the coordinating site for the trials. Experts at Johns Hopkins University School of Medicine and Childrens National Hospital are key members of the national network.

Academics, community physicians, and the general public will be invited annually to submit treatment study ideas to the clinical trials network for consideration.

Theres a critical need for effective therapies for patients with Lyme and tick-borne diseases, says Fallon. The clinical trials network will be a powerful engine to drive high-quality research in tick-borne diseases, including large-scale clinical trials and potentially transformational early stage research.

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Genomic Insights From Borreliaceae Lineages

Between 1982 and 2010, the B. burgdorferi species complex, known as B. burgdorferi sensu lato, steadily expanded from 1 to 18 species as isolates from tick vectors, their hosts, and patient samples were characterized . A subset of these species are associated with human disease. B. burgdorferi sensu stricto in the USA, as well as B. afzelii and B. garinii in Eurasia are the most common agents of LD in the Northern hemisphere. Cases of LD in Europe are also caused by Bb and B. bavariensis , but are less common. B. spielmanii , B. bisettiae , and B. lusitaniae have been identified in human specimens but their clinical importance is less clear. B. valaisiana has been identified in human specimens , but others have recently provided compelling reasons why existing evidence does not support it being considered a human pathogen . Additional species have been identified in tick vectors or their hosts, but not in patient samples.