9
Closing Panels

The committee invited a panel of stakeholders to listen to the presentations and discussions during the course of the 2-day workshop and to share their observations regarding the research gaps and priorities in the science of tick-borne diseases (TBDs). The panel members were not to come to a consensus, but rather to reflect their own viewpoints. Panelists included a representative from a patient advocacy group, a clinician specializing in Lyme disease, a clinician researcher specializing in Ehrlichia and Anaplasma, a clinician researcher studying pathogenesis, and a clinician researcher from Europe to provide a global perspective. The member of the patient advocacy group worked with a number of members of his Lyme disease coalition during the workshop, but his perspective does not imply or represent a consensus of all patients or advocacy groups. Similarly, the physicians’ and researchers’ perspectives do not reflect a consensus of the scientific opinion of their fields, although many panelists had overlapping comments. The committee chose to summarize each panelist’s comments individually and to allow these redundancies to emphasize the various viewpoints. To broaden the discussion, the committee invited the general audience to comment following the panel discussion to elicit views or ideas that were not captured during the panel presentations.

After reviewing the presentations and comments in the listening sessions before the workshop and during the workshop, the committee noted that the language and terminology used to describe various facets and manifestations of Lyme disease and coinfecting conditions were inconsistently applied and have likely contributed to misunderstandings and even inaccuracies. Rather than offering its own interpretation of terms and definitions



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9 Closing Panels The committee invited a panel of stakeholders to listen to the presen- tations and discussions during the course of the 2-day workshop and to share their observations regarding the research gaps and priorities in the science of tick-borne diseases (TBDs). The panel members were not to come to a consensus, but rather to reflect their own viewpoints. Panelists included a representative from a patient advocacy group, a clinician special- izing in Lyme disease, a clinician researcher specializing in Ehrlichia and Anaplasma, a clinician researcher studying pathogenesis, and a clinician researcher from Europe to provide a global perspective. The member of the patient advocacy group worked with a number of members of his Lyme disease coalition during the workshop, but his perspective does not imply or represent a consensus of all patients or advocacy groups. Similarly, the physicians’ and researchers’ perspectives do not reflect a consensus of the scientific opinion of their fields, although many panelists had overlapping comments. The committee chose to summarize each panelist’s comments individually and to allow these redundancies to emphasize the various viewpoints. To broaden the discussion, the committee invited the general audience to comment following the panel discussion to elicit views or ideas that were not captured during the panel presentations. After reviewing the presentations and comments in the listening ses- sions before the workshop and during the workshop, the committee noted that the language and terminology used to describe various facets and mani- festations of Lyme disease and coinfecting conditions were inconsistently applied and have likely contributed to misunderstandings and even inaccu- racies. Rather than offering its own interpretation of terms and definitions 177

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178 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES used by the various presenters, the committee presented the terms exactly as transcribed reflecting the use by presenters and other participants. This does not imply that the committee believes that terms such as “post-Lyme disease,” “post-treatment Lyme disease,” “persistent Lyme disease,” and “chronic Lyme disease” are or are not interchangeable, differ in meaning or value, or have differing scientific validity. Similar confusion exists regarding terminology related to recurrent and relapsing Lyme disease with or with- out reinfection. As highlighted by many presenters, a commonly accepted lexicon of definitions that is consistently applied and understood would improve and advance research efforts regarding Lyme disease and other tick-borne diseases and likely improve patient care. Elucidation of the criti- cal issues of infection and pathogenesis remains to be definitively achieved. CRITICAL NEEDS AND GAPS IN UNDERSTANDING TICK-BORNE DISEASES: PRACTICING PHYSICIAN PERSPECTIVE John Aucott, M.D., Park Medical Associates Most clinicians are aware that an abundant literature exists on clas- sic untreated Lyme disease and its typical early and late manifestations. In contrast, the literature and clinicians’ experience with persistent symptoms following antibiotic treatment of Lyme disease are more limited. Regard- less of whether one names it chronic Lyme disease or post-Lyme disease syndrome, patients and clinicians are confused about how to proceed when patients report symptoms after a course of antibiotic treatment. A recent survey reported that 48 percent of Connecticut physicians are undecided as to whether chronic Lyme disease exists (Johnson and Feder, 2010). This controversy leaves clinicians uncertain about how to help patients who continue to report symptoms following antibiotic treatment. The Centers for Disease Control and Prevention (CDC) “definite cri- teria” for classical signs and symptoms of Lyme disease include: erythema migrans (EM) rash, joint disease with inflammatory synovitis, and neu- rological disease with objective findings. Even with these straightforward criteria, a gap exists between the textbook descriptions of the disease and clinical practice. Retrospective studies (Aucott et al., 2009) have shown that frequent misdiagnosis occurs in community practices. For example, 23 percent of EM rashes and 54 percent of patients who did not present with a rash were misdiagnosed. Further complicating the clinical practice, as noted throughout the workshop, are the gaps in understanding the serologic response to the disease—how to use the laboratory tests that exist and what the limitations of these tests are. The CDC has developed a “probable” case definition of Lyme disease that has a viral-like presentation. These patients present with symptoms and

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179 CLOSING PANELS a positive serologic test result, but without physical findings or signs of an EM rash. This area of Lyme disease is poorly understood. For example, it is not known whether a subset of late (or chronic) Lyme disease patients may lack physical signs or symptoms and only present with constitutional symp- toms such as fatigue. In the recent review by Feder and colleagues (Feder et al., 2007), this scenario would be equivalent to their category 3—“Patients do not have a history of objective clinical findings that are consistent with Lyme disease, but their serum samples contain antibodies against Borrelia burgdorferi, as determined by means of standardized assays that were or- dered to investigate chronic, subjective symptoms of unknown cause.” The question for the clinician is whether this category exists; no studies have been done on the treatment and the outcomes for early or late probable Lyme disease—a research gap. Another category is patients who experience persistent symptoms fol- lowing antibiotic treatment of confirmed Lyme disease. It is called different names, but for this discussion, it will be referred to as “post-treatment Lyme disease syndrome.” It is known that the visible, physical signs of early Lyme disease respond to appropriate antibiotic treatment, but 10 percent of late Lyme disease patients with Lyme disease arthritis still have joint disease after antibiotic treatment. In fact, in all stages of Lyme disease, persistent symptoms without the classic signs have been observed after an- tibiotic treatment. For this class of patients (post-treatment Lyme disease syndrome), there are more unknowns than knowns, such as the magnitude of the problem, and the range of severity of the illness. Some factors that increase the likelihood for poor treatment outcomes and post-treatment Lyme disease syndrome such as delayed diagnosis or treatment with nonideal antibiotics. Whether the combination of high rates of misdiagnosis and nonideal antibiotic therapy result in a population of patients who experience persistent symptoms is unknown. Furthermore, there is a gap in the clinicians’ ability to identify patients who have persis- tent symptoms following antibiotic treatment in part due to the insensitivity of serologic tests, the lack of biomarkers, the lack of pathological material, or the lack of a clinically useful definition. In my community-based clinical practice, when we tried to apply the Infectious Disease Society of America (IDSA) guideline definition for post-Lyme disease syndrome (Wormser et al., 2006) to our patient population, the definition did not match the patients we were seeing. Those patients who were most likely to have post-Lyme disease syndrome based on our clinical history and evaluation ultimately could not meet the IDSA case definition because they were misdiagnosed initially and had not received appropriate initial antibiotic treatment (both of which preclude inclusion in the IDSA case definition). One gap echoed repeatedly during the workshop is that gap between the existing research on the disease and the knowledge that clinicians need

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180 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES in order to care for patients in the clinical setting. One way to address this gap is to establish a multicenter network for clinical evaluation and treat- ment of Lyme disease and other TBDs. This network would follow a trans- lational clinical model as a way to link the laboratory study of pathogenesis to community-based patient care. The hallmark of this approach would be the use of a multidisciplinary, coordinated approach to patient evaluation. The goals would include • Formalizing reproducible case definitions or phenotypes of post- treatment Lyme disease syndrome; • Performing uniform evaluations of clinical symptoms and signs with validated instruments from a variety of medical disciplines; • Developing better tests for indentifying biomarkers that can be used for diagnosis, measuring the efficacy of therapy, and establishing prior exposure in patients being evaluated for post-treatment Lyme disease syndrome; • Establishing a biorepository of blood and tissue from patients with various stages or categories of Lyme disease; • Analyzing measurement tools and tests for sex-based differences in performance; and • Developing an evidence-based clinical guideline for post-treatment Lyme disease syndrome that is based on knowledge of the patho- physiology of the illness. CRITICAL NEEDS AND GAPS IN UNDERSTANDING TICK-BORNE DISEASES: PATHOGENESIS PERSPECTIVE Linda K. Bockenstedt, M.D., Yale University School of Medicine The workshop’s presentations and discussions underscored the com- plexity of Lyme disease and the difficulty from an academic and scientific point of view in understanding its various facets. For example, ticks are known to harbor a large number of microbial species, but the relevance of each of these microbes to veterinary and human disease is known only for a few. Scientists do not know the absolute risk for human infection following a tick bite, nor do they understand how coinfection in the tick influences the infectivity and virulence of tick-transmitted pathogens. These unknowns could be answered by applying a systems biology approach to a defined population of ticks. An ideal scenario for the prevention of tick-borne diseases would be a single vaccine against the tick-borne pathogens that have the greatest potential to cause human disease. This is not likely in the short term given the inherent difficulties with vaccine design, production, and evaluation

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181 CLOSING PANELS for safety and efficacy. A vaccine to interrupt tick feeding shows some promise and may be an alternative to pathogen-specific vaccines. All vac- cine prevention strategies require continued studies of tick-borne dis- ease pathogenesis to better understand the tick and pathogen life cycles and the response of the mammalian host to the tick and its pathogens. Bockenstedt noted that a demand for better diagnostic tests should not overshadow the need to educate clinicians on the use and limitations of the current diagnostic tests for tick-borne diseases. To meet this need, physicians should be aware of how tick-borne illnesses commonly present. For patients presenting with an acute illness, it is reasonable to consider empiric therapy for the most likely cause(s) of the illness while obtaining appropriate tests to validate or exclude the diagnosis. The approach should weigh risks of treatment against potential benefit. Indiscriminate testing raises clinical conundrums. Borrowing from the field of rheumatology, the prevalence of antinuclear antibodies (ANAs) in healthy people, which in the appropriate clinical setting can be a rheumatic disease marker, ranges from 5 to 30 percent depending on the age group. The clinical significance of this test requires placing results in the context of the patient’s symptoms. If the patient does not have an appropriate clinical history compatible with an ANA-related disease, the clinician is faced with deciding how to value the test: Should the clinician monitor the patient or proceed with therapy? For Lyme disease, Bockenstedt noted that spirochete persistence is an- other area in need of further research. Without antibiotic treatment, disease manifestations can resolve despite persistence of the spirochete. This area holds a number of unresolved questions in this area: (1) To what degree does the mammal expend immunologic energy when spirochetes are pres- ent, but clinically apparent disease is not? (2) Is there a pattern of host gene expression that is a signature of this stage of spirochete infection? (3) What happens to this immune signature with antibiotic treatment? Answering these questions will give us insights into how spirochetes persist in humans and may give us new tools for monitoring response to therapy. The challenge of “chronic Lyme disease” is that the term means dif- ferent things to different people. Designing a study to investigate “chronic Lyme disease” is difficult when there is no agreement on the precise defini- tion. Furthermore, there is no animal model has been found that is analo- gous to patients with “chronic Lyme disease” who do not satisfy the CDC interpretation of Lyme disease serology. All of the animal models, from mice to nonhuman primates, exhibit IgM and IgG antibodies to a broad ar- ray of the proteins, even when the animal has been treated with antibiotics and has culture evidence of persistent infection. Clinicians and researchers have not yet explained how a patient with protracted symptoms attributed clinically to “chronic Lyme disease” may fail to develop the expected evo- lution of antibody responses. Understanding pathogenesis is an important

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182 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES element in explaining some of these clinical disparities. However, it relies heavily on animal models and for some areas (e.g., neuroborreliosis) no animal model exists. There is a strong unmet need for stratifying for study those individuals who have illnesses or disease patterns that are considered “chronic Lyme disease,” including those who are being treated for this condition. The creation of a biorepository from well-defined patient popu- lations would be an important first step toward addressing mechanistically their pathobiology. The ultimate goal of research on disease pathogenesis is to inform us on the ways to ameliorate human disease. A study of the human immune system in normal adults—healthy young adults and healthy elderly—has demonstrated that alterations in immunity occur due to normal aging (van Duin et al., 2007; Panda et al., 2010; Shaw et al., 2011). Other factors, such as infections and comorbid chronic conditions (e.g., obesity), vaccina- tions, and antibiotic use, also can shape the immune system and immune response (Amar et al., 2007; Didierlaurent et al., 2008). Moreover, studies in animal models suggest that an individual’s microbiome contributes to how diseases are expressed (Sekirov et al., 2010). How these factors influ- ence the susceptibility to and clinical expression of tick-borne diseases is an area for further investigation. CRITICAL NEEDS AND GAPS IN UNDERSTANDING TICK-BORNE DISEASES: RESEARCHER SPECIALIZING IN EHRLICHIA AND ANAPLASMA J. Stephen Dumler, M.D., Johns Hopkins University School of Medicine The workshop presentations and the discussions offered considerable value. One way to approach the research gaps and opportunities is to use the traditional triad of medical science: prevention, identification (including coinfections), and treatments (including disease pathogenesis). In terms of prevention, many variables that determine the natural bur- den of disease, tick abundance, pathogen abundance, or pathogen transmis- sion are unknown. More information about these variables may result in prevention strategies that ultimately and substantially reduce the likelihood of transmission and infection. Simultaneously, Dumler noted that surveil- lance of both human and animal diseases, vectors, and their reservoirs needs to be improved. This research information could improve targeting of habitat or human behavior to reduce the burden of TBDs. Prevention also can be achieved through vaccines, but questions re- main as to whether they are reasonable and practical and, if so, for whom (humans, animals, or ticks). Vaccines are not currently available for tick- borne diseases, but they may be more useful with further research and

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183 CLOSING PANELS more refined approaches. For example, Dumler noted that scientists need to understand induction of protective immunity versus the induction of immunopathology before moving forward. Furthermore, discussions need to be held to determine the role of technologies, such as high-throughput analyses for facilitating vaccine development and target identification. Improving diagnosis is crucial, especially for early diagnosis of Eh- rlichia, Anaplasma, and Rickettsia infections. This would also facilitate reduction in the number of cases of Lyme disease with persistent man- ifestations and help curtail serious acute disease and the potential for long-lasting clinical sequelae. More sensitive diagnostics are needed in the earliest stages of disease without sacrificing specificity and increasing false positives. One avenue might be the use of systems biology, but analysis of the data is extremely challenging. A second avenue involves targets from the microbes themselves. Most of the advances in diagnosis have come from basic research, including the VlsE/C6 peptide diagnostics for Lyme disease, polymerase chain reaction (PCR) targets for identification of Ehrlichia, Anaplasma, and Rickettsia infections, and peptide immunoassays for new- generation diagnostics. The presentations underscored a need for research investments to be made on diagnostics. At the same time that the diagnostic research is continuing, Dumler suggested that the field needs to do a better job of educating physicians in the use of existing and newly developing diagnostic tools. Physician educa- tion results in more accurate diagnoses and appropriate treatment. Simi- larly, there is a need for better corroboration of infection with individual pathogens as well as coinfections. For treatment, Dumler noted that pathogenetic mechanisms need to be more fully defined so that interventions can be targeted directly at the level of pathophysiology. Animal models are needed to define cellular microbiol- ogy and immunology in vivo, in a system that will translate to human infec- tion and disease. As noted at different times during the workshop, animal models will show discrepancies. These discrepancies need to be resolved, or researchers need to understand how the results inform understanding of human infection and disease. The question also remains whether the whole-genome survey studies described in the pathogenesis chapter can be translated into human clinical studies that will allow scientists to identify those targeted areas in pathophysiology to create new interventions. Finally, Dumler noted that large-scale human clinical studies that have sufficient statistical power are needed. As discussed by previous panelists, such studies would allow the acquisition of large numbers of subjects and potentially bring together all of the involved communities—patients, advo- cate groups, physicians, academicians—to address research uncertainties on a large scale. These clinical trials for tick-borne diseases could easily be assimilated into modern high-throughput methods that may make whole

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184 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES genome surveys feasible. There would need to be some discussion on how many patients would be needed for a single-nucleotide polymorphism (SNP) analysis for neuroborreliosis. A large-scale clinical study would be intense and difficult, but it would rely on the communities coming together. These clinical trial groups could provide critical corroborated subjects and a biorepository of samples for pathogenesis studies. Within the group, one could create and validate the next generation of diagnostics. It would also provide a critical structure for the assessment of the new diagnostics, clini- cal interventions, and therapeutics. CRITICAL NEEDS AND GAPS IN UNDERSTANDING TICK-BORNE DISEASES: THE GLOBAL PERSPECTIVE Susan O’Connell, M.D., Southampton University Hospitals Trust One of the challenges that has bedeviled this field is the case definition and diagnostic criteria for Lyme disease and other TBDs. The challenge starts with the lack of agreement among stakeholders on the definitions of the various terms, including Lyme borreliosis, disseminated Lyme bor- reliosis, late Lyme borreliosis, chronic Lyme disease, and post-Lyme disease syndrome and symptoms. Agreeing upon a lexicon is crucial both for the diagnosis and the appropriate management of patients who are suffering now and for the basic research for the future. From a clinical and a laboratory perspective, improved diagnostic tests are needed for all TBDs. Encouraging progress has been made in the serological tests for Lyme disease, which have improved very significantly since the 1990s. However, now is the time to review the current state of the role of two-tier testing. For example, in-depth discussions are needed on the use of immunoblots versus the modern recombinant and peptide- based tests. Also, high volumes of sera are needed from a large number of well-characterized Lyme borreliosis patients, normal controls, and patients from other disease groups to produce a serum repository that can be used to evaluate new and existing tests. Currently, a relatively small serum panel is available. Scientists also need to review the performance of currently available Lyme borreliosis tests and ensure that maximum information is extracted from them, as exemplified by recent work of American and European groups (Dessau et al., 2010; Porwancher et al., 2011). IgM tests are problematic (Porwancher et al, 2011). The challenges associated with IgM assays are not unique to tick-borne diseases but occur in other infectious and autoimmune conditions, as IgM antibodies tend to be more polyreactive than other antibody isotypes (Schroeder and Cavacini, 2010). Sera from patients with conditions such as infectious mononucleo- sis or rheumatoid arthritis can give false-positive reactions in Borrelia

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185 CLOSING PANELS burgdorferi IgM tests and in many other IgM assays. The use of the IgM tests in the diagnosis of Lyme borreliosis should be limited to appropriate clinical circumstances (i.e., for patients with suspected recently acquired infection) and interpretive laboratory criteria strictly applied, including use of appropriate reaction cut-off controls to minimize overreading of immu- noblot reactions. Finally, as many panelists noted, clinician education about appropriate use of diagnostic tests for Lyme borreliosis, appreciation of pre- dictive values, and interpretation of clinical significance of results is needed. In the clinical arena, a number of questions remain unanswered, such as what proportion of people who get B. burgdorferi infections do poorly, and why. Recent prospective and retrospective studies indicated that outcomes were excellent for the great majority of enrolled patients. Early diagnosis and treatment are important factors affecting outcome, requiring increased public and healthcare professional education and awareness for early rec- ognition and management. To assist the effort into finding out why some patients have poor outcomes, scientists need to understand which borrelial strains are associated with infections with poor outcomes and the role that patients’ genetic makeup, immune system abnormalities, and other possible conditions (e.g., central pain syndrome) play in the disease manifestations of patients with prolonged symptoms following treatment. The term “chronic Lyme disease” encompasses several groups of pa- tients, including those with persistent symptoms following treatment; others with active late-stage infections because the diagnosis had been missed at an earlier stage; and some who had been misdiagnosed with Lyme disease but have other conditions. Ultimately, no matter the underlying diagnosis, they are a group of patients who are ill, some seriously incapacitated, who are looking to their clinicians for immediate help. One avenue for investigating some of these issues raised at the workshop is for a large long-term study of these patients to assess accuracy of diagnosis, investigate possible mecha- nisms of persistent symptoms, examine treatment and management through a multidisciplinary holistic approach, maintain support and assess the long- term outcomes of all recruits, regardless of their eventual diagnostic assign- ment. A central component of the study would be a biorepository similar to that which other panelists have suggested. Other areas where research is needed include pain research, cognitive studies, and basic pathogenesis studies, including the clearance of infection following treatment. Finally, O’Connell noted in terms of disease prevention, vaccines are not a viable option in the near future. More immediate options need to be developed to raise awareness among at-risk populations and their health- care providers. First, more research needs to be done to further our under- standing of the complex ecological factors involved, observing geographical changes in the tick range, and translating this information into prevention strategies. Second, there is a need to invest in targeted surveillance. Third,

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186 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES human behavioral factors are the key to prevention. The ideas of following everyday tick bite prevention meausures and removing attached ticks im- mediately need to be promoted to at-risk populations. Fourth, educational efforts for healthcare professionals and patients need to be increased. CRITICAL NEEDS AND GAPS IN UNDERSTANDING TICK-BORNE DISEASES: THE PATIENT PERSPECTIVE Greg P. Skall, J.D., National Capital Lyme and Tick-Borne Disease Association I would like to begin with an acknowledgment of Representative Frank Wolf (R-VA) for his part in making this workshop a reality. His work, to- gether with his colleagues on the House Appropriations Committee, led to the recognition that we face a serious national Lyme disease and tick-borne disease problem requiring study. When used by the patient advocate community, the term “Lyme” has become shorthand for all of the diseases that have been discussed at this workshop. So, when referenced in this discussion and going forward, “Lyme” is a label used to encompass all the tick-borne coinfections. Throughout the 2 days of this workshop, we have heard many im- portant and extraordinary observations and conclusions from the expert presenters. Some of the most salient were • We have a poor understanding of the true incidence and geographi- cal distribution of Lyme disease. One presenter ventured that, in this regard, we don’t have a clue of its magnitude. • The long-term effects of chronic Lyme disease can last 50–70 years. • Children cannot be considered little adults in either diagnosis or treatment. Many children have literally lost their childhood to this disease. • Underpowered studies that purport to demonstrate universal efficacy must be viewed with circumspection. • Everyone is studying the early stage of this infection; no one is study- ing the persistent phase of the disease. It is important that those studies occur. • Current testing and diagnosis is horribly inadequate; some of the declarations heard in this regard were: • A person does not require an antibody response to develop the disease! • How can you say that after 4 weeks of treatment a patient no longer has Lyme disease? The fact is we don’t know!

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187 CLOSING PANELS We need direct antigen detection; antibody tests are not suffi- • ciently reliable. • Treat the patient, not the test. • The bitterness of the debate does not serve science or the patient. One presenter stated: All the shouting drowns out all the complexity and the nuance and the work that needs to be done. A clear direction for future investigation and treatment options emerges from these observations. That direction must not be lost on the scientific and medical community, and the patient community expects it to be pur- sued. The presentations and discussions we have been privileged to witness in this workshop make it clear that Lyme disease is now recognized as a national epidemic. As a next step, it is crucial that Congress and the medi- cal community recognize the complexity of this disease and the burden it imposes on individuals. That case has been clearly established by these pre- sentations, many of which noted the persistence of the infection in animal models. Unfortunately, these presentations only detailed the work that has been done in mice and do not refer to primate studies. Medical progress depends on bridging this research gap. Furthermore, while this research is being done there must be support for the medical practitioners on the front lines, who are working directly with the patients and the family members burdened with this disease but with inadequate diagnostic tools. The data clearly demonstrate that the burden of TBDs is enormous on both adults and children. It is so debilitating that it often affects one’s livelihood, career, and family, and can wipe out a family’s life savings. New research directed to the effects of the disease and treatment of children is a necessity. Children are literally losing their childhood to this disease, and its long-term effects can last many years. Indeed, some patients are losing their lives to it. It is also clear, whether through healthcare costs or the social upheaval that comes from the effect of the disease on an individual’s ability to perform and provide for economic well-being, that society bears the final burden. Multiple presentations clearly demonstrated that Lyme disease is a complex disorder for which there is a critical need for improved diagnostic tools that will allow for better characterization of both the acute and the persistent manifestations of all tick-borne coinfections. The CDC case defi- nition of Lyme disease must be reviewed. That definition, designed specifi- cally and only for surveillance, is often misused as the definitive diagnostic criteria in the clinical setting, so its use is misunderstood in the general medical community. Patients, physicians, and scientists must have a better case definition, expanded to include the entire emerging spectrum of Lyme disease and tick-borne coinfections.

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188 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES The data presented about Lyme disease clearly indicate it is a grow- ing problem throughout the United States. Therefore, we must discard the often-heard regional biases about the existence and extent of Lyme disease. It is no longer solely a northeast U.S. phenomenon, if it ever was. Our na- tional consciousness must be expanded to include the study and treatment of all tick-borne diseases throughout the United States. The hallmarks of new studies and research must include • Developing an automated, standardized report or technique to assist in reporting compliance; • Developing consistent reporting criteria for all states; and • Reaching a broadened case definition for surveillance to recog- nize and include advanced late-manifestations of Lyme disease and coinfections. An enlightened approach to the various manifestations of Lyme disease is urgently needed. Although several presenters did highlight the significance of coinfections and their immune-suppressing properties, most of the sci- ence presented focused only on the acute condition and did not investigate or discuss chronic manifestations. If we are to stem the epidemic, chronic or disseminated Lyme disease must be taken seriously and researched. Physicians should be taught to include it in their differential diagnoses. Symptoms dismissed by some as “subjective” must be studied, quantified, and given clinical weight. They are presented too often and too consistently by too broad a patient population to be ignored. Finally, “post-Lyme disease syndrome,” a derogatory label that subtly suggests a patient no longer has a disease and more likely suffers a psy- chological condition, should be stricken from the diagnostic alternatives unless it can be proven with scientific accuracy that a statistically significant number of patients presenting with chronic Lyme disease symptoms are actually disease free. Critically important research for the 21st century should include • Research on the characterization of borrelia genotypes; • Informatics to create national databases that capture every aspect of the disease in the ecosystem, the vectors, and the patients; and • Nothing short of a “Manhattan-like project” all-out effort to ad- dress the tick-borne disease burden on patients and on society. Research for the 21st century should look at other models for guid- ance; one useful reference might be the Alzheimer’s Disease Neuro-Imaging Initiative (ADNI) for advancing research on biomarkers and the sharing of data. As suggested above, this research would focus on the complexity

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189 CLOSING PANELS of the disease, such as multiple pathogens, the role of mutations, immune system evasion and suppression, subspecies and strain variation, multiple mechanisms for persistence, and patient population heterogeneity. To accomplish these research goals, new approaches are needed that focus on persistent, post-treatment illness and that employ a broader sur- veillance case definition than presently used by the CDC study designs. The CDC criteria prejudice the research that relies on it because, by definition, it eliminates the possible inclusion of the vast majority of Lyme disease patients. Medical progress should no longer be impeded by the polarizing con- troversy that has characterized Lyme disease research in the past. The dialogue must continue and encourage mutually respectful collaboration across scientific disciplines and among researchers, clinicians, and patients, even when viewpoints differ, if we are to make progress. The National Insti- tute of Health Chronic Fatigue Committee might serve as another example of this type of collaboration. Finally, a number of state advocacy and support leaders across the country have emphasized areas of concern to them: • Physicians are not updated on the existence of Lyme disease in their state or the expanded list of symptoms presented by patients. Con- tinuing medical education courses must be designed to recognize and include them. • When physicians pursue testing, too many rely solely on the enzyme- linked immunosorbent assay (ELISA). The medical community must recognize that the ELISA is not sufficiently accurate to be relied on as the definitive first-stage screen. • The lack of physician knowledge and poor testing results in incom- plete surveillance data, and it leads to a lack of appropriate treat- ment, all of which must be improved. Finally, it cannot be overstated that until a highly accurate test is devel- oped and disseminated, Lyme disease is and will remain a clinical diagnosis that relies on the ability of physicians to practice the art of medicine as well as applying the craft of medical technology. PANEL DISCUSSION Diagnostics During the workshop, some speakers noted that the IgM Western blot is an unreliable indicator of the disease except for the first two months of illness. One clinician countered by noting that some patients who have a

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190 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES prolonged illness do not have positive ELISAs or their Western blots do not show IgG reactivity. Specimens from these patients may show IgM reactivity with many bands on Western blot; these patients also appear to respond to antibiotic therapy. However, among the panelists there was no consensus on the role and value of IgM tests and the likelihood for false positive IgM Western blots. The Role of Collaboration Collaboration was a major theme throughout the discussion. One par- ticipant noted that the various disciplines involved, the clinicians, and the patient advocacy community each have a piece of the puzzle. With more collaboration, the field would have advanced further in the past 30 years. Some participants noted that now is the time for the different factions to come together to focus on the disease and to work to help the patients. Another participant noted that many individuals echoed the call for partnerships among clinicians, patient advocates, and academics, but the list did not include veterinary colleges and medical entomologists. In ad- dition, community, state, and international collaboration will be essential to moving forward. If the goal is community-based preventive care, the mosquito abatement districts and vector-control programs need to be en- gaged. Finally, public–private partnerships were not discussed during the workshop. Some participants suggested the need to discuss how to encour- age the public and the private entities to work together. O’Connell raised the question of whether advocates, doctors who see early and late manifestations of Lyme disease, and researchers could design a research project that would meet the needs of the various groups. One participant noted that this workshop demonstrated that everyone could be in the same room and share some common ideas and goals. Instead of working toward one goal, it will be important to work toward two or three goals to meet the needs of various stakeholders. Furthermore, a clinical trial should not be owned by one stakeholder, but by a group of stakeholders. O’Connell expanded on this thought by suggesting that the trial should be a multi-specialty, multidisciplinary effort. It should also have a component that supports the patients within their family and societal structure. The participant further noted that the study should be more prospective and look at people who have a different diagnosis, such as fibromyalgia, chronic fatigue, or multiple sclerosis, and check them for Lyme disease. O’Connell agreed and noted the assertion in her original statement that patients who are found not to have Lyme disease should be kept within the cohort, rather than excluded, so that the long-term outcomes of the whole cohort can be assessed. The findings of such a study could have broader benefits to many patients with medically unexplained illnesses.

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191 CLOSING PANELS Clinical Management Team A question was raised about who should comprise a clinical manage- ment team to treat patients with long-term symptoms. O’Connell noted that Lyme disease affects a number of different systems, depending to some degree on the borrelial genospecies causing the infection. Borrelia burgdor- feri, which is the most common strain in the United States and also occurs in Europe, tends to cause Lyme disease arthritis. Borrelia garinii, which is strongly associated with neuroborreliosis, and Borrelia afzelii, mainly caus- ing skin manifestations, are more common causes of Lyme borreliosis in Europe. To address Lyme disease, O’Connell noted a need for participation by all the major specialties who normally would be involved in addressing the complications of Lyme disease patients. It is important to manage all of patients’ symptoms and help them to get their lives back. Rehabilitation is an important part of that process as well, requiring expert input from a variety of specialists working closely with patients and families. FINAL SUMMATION AND CLOSING REMARKS Lonnie King A character in an E. B. White novel said, “I see a great future for com- plexity.” For Lyme disease and other tick-borne diseases, this is certainly true. Participants need to consider our earlier discussions about looking at tick-borne diseases from 30,000 feet. There is a remarkable dynamic that involves the convergence of people, animals, and ecosystems. More than 7 billion people share space on Earth with rapidly increasing numbers of wildlife and domestic animals. Human–animal interfaces are both being amplified and intensified as our world becomes progressively intercon- nected. Thus, pathogens and vectors have new opportunities to spread, transmit, and create new niches and survival mechanisms. People live in an unprecedented time regarding new emerging infectious diseases, many of which are vector borne. The pathogens have a favorable environment to be- come resistant, undergo genetic modification, and move globally as people and products traverse the globe faster than the incubation period for any of these diseases. To address these current and emerging tick-borne diseases, scientists need to refocus their attention to achieve a greater understand- ing of the convergence of these factors and create greater possibilities for disease control and prevention, including intervention strategies targeted at the vectors, maintenance hosts, and environmental sites. The ecology of infectious diseases is a field where the available infor- mation is imprecise. In addition, significant gaps in knowledge exist that

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192 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES require new studies and research with better integration and the creation of a national research agenda to ensure that there is no duplication of effort and that researchers are properly linked and cohesively working together to leverage limited resources. Perhaps a new portfolio of research and a fresh focus of inquiry may advance the scientific process. A few observations from the presentations can be highlighted: • The philosopher Nietzsche once stated that “the most common form of ignorance is forgetting what it is that we are trying to do.” For Lyme disease and other tick-borne diseases, as noted by Pamela Weintraub, the goals are the reduction in the morbidity and the mortality of this group of diseases, the reduction of the burden of disease, and the creation of better strategies for prevention, control, and amelioration. • Weintraub noted that perhaps the number one problem that limits progress toward these goals is the polarity that exists between pa- tients and some of the medical community. This can be extended fur- ther to the polarization that exists between the medical community and the advocacy groups. • A number of individuals suggested the need for less hubris and more sensitivity to others’ points of view. People are suffering, and there is a need to reframe and refocus the research to generate new ways to reduce disease burden. As one researcher noted, it is about creating a better path forward and not maintaining the status quo. I believe that science could emerge as the mediator to define a new common ground to reduce the polarity between groups and focus on areas where there is agreement. Scientific research is the key to new knowledge, and the application of this knowledge is the key to reducing the burden of illness. It seems unlikely that any gains in reducing TBD illnesses and impact can occur without filling our gaps in knowledge and better under- standing the dynamics and complexities of these diseases through research. A critical review of the state of the science, such as that found in this sum- mary, is an essential first step.