7
Diagnostics and Diagnosis

Diagnostics and diagnosis, which are at the heart of the controversy surrounding tick-borne diseases (TBDs), have different connotations. Diagnostics provide a cluster of objective measures directed toward identifying the cause of a disease. After scientists discover the causative agent of an emerging infectious disease, such as Borrelia burgdorferi or Ehrlichia chaffeensis, they develop, evaluate, and refine diagnostic tests over time. Diagnosis, by contrast, rests on a patient’s history and symptoms and observed physical and laboratory findings. Ultimately, accurate diagnosis requires knowledge of the epidemiology, clinical manifestations, and diagnostic tests of a disease.

Lyme disease presents a significant challenge to this standard approach. The presentation of symptoms may not align directly with the diagnostic laboratory test results. Necessary and sufficient conditions for the diagnosis may not be met, and yet the constellation of findings might lead one to make a diagnosis. At the time of acute presentation to a health professional, serologies may not be definitive. Conversely, serology may be positive, but symptoms may not match the serological picture. This suggests opportunities to develop laboratory measures that are reliable, valid, and sensitive to change and that may help to define the phases/stages of Lyme disease, such as acute, post-acute, chronic, and recurrent.

In this chapter, three researchers explored the limitations of existing tests for Lyme borreliosis and other tick-borne diseases and suggested promising new approaches to diagnostics that can improve the diagnosis of those diseases, and four clinicians discussed the challenges and needs for improving diagnosis in the medical office.



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7 Diagnostics and Diagnosis Diagnostics and diagnosis, which are at the heart of the controversy surrounding tick-borne diseases (TBDs), have different connotations. Di- agnostics provide a cluster of objective measures directed toward identify- ing the cause of a disease. After scientists discover the causative agent of an emerging infectious disease, such as Borrelia burgdorferi or Ehrlichia chaffeensis, they develop, evaluate, and refine diagnostic tests over time. Diagnosis, by contrast, rests on a patient’s history and symptoms and observed physical and laboratory findings. Ultimately, accurate diagnosis requires knowledge of the epidemiology, clinical manifestations, and diag- nostic tests of a disease. Lyme disease presents a significant challenge to this standard approach. The presentation of symptoms may not align directly with the diagnostic laboratory test results. Necessary and sufficient conditions for the diagno- sis may not be met, and yet the constellation of findings might lead one to make a diagnosis. At the time of acute presentation to a health professional, serologies may not be definitive. Conversely, serology may be positive, but symptoms may not match the serological picture. This suggests opportuni- ties to develop laboratory measures that are reliable, valid, and sensitive to change and that may help to define the phases/stages of Lyme disease, such as acute, post-acute, chronic, and recurrent. In this chapter, three researchers explored the limitations of existing tests for Lyme borreliosis and other tick-borne diseases and suggested promising new approaches to diagnostics that can improve the diagnosis of those diseases, and four clinicians discussed the challenges and needs for improving diagnosis in the medical office. 125

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126 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES DIAGNOSTICS FOR LYME DISEASE: KNOWLEDGE GAPS AND NEEDS Maria Aguero-Rosenfeld, M.D., New York Medical College and Bellevue Hospital Center Microbiologists share some of the concerns that patients have about the current diagnostic tests for Lyme borreliosis and other tick-borne diseases. The laboratory diagnostic challenges stem from the organism’s complex antigenic composition and its variation in expression depending on the environment where the organism is located. Borrelia burgdorferi has both linear and circular plasmids along with chromosomal DNA, and, in con- trast to many other bacteria, a large portion of its genes are in plasmid DNA. The plasmid genes encode outer membrane components allowing the pathogen the flexibility of switching on and off antigens depending on the environment. This mechanism allows the pathogen to survive during the inactive tick stage (wintering) and to replicate during blood feeding on a suitable host. Unlike other spirochetes, B. burgdorferi can be cultured in vitro. How- ever, researchers are just beginning to understand the difference between immune responses to antigens expressed in vivo and antibodies detected using antigens from B. burgdorferi cultured in vitro. The Borrelia pathogen expresses some antigens as it first comes in contact with the host mammal leading to the early antibody response. Then, as more antigens are pre- sented, the mammalian host develops the corresponding immune response in a sequential fashion. The intensity and type of antibodies developed de- pend on the duration of disease prior to antimicrobial treatment, the host immune system, and, perhaps, pathogenetic properties of the microorgan- ism. Researchers have found that there are antigens expressed in vivo and others expressed in vitro. Therefore, the assays that are used to identify antibodies need to include those antigens expressed in vivo. Two methods are available for directly detecting the presence of the pathogen in humans: culturing and polymerase chain reaction (PCR). Both of these have had mixed results in detecting B. burgdorferi (Table 7-1). Cul- turing spirochetes from a patient’s blood or synovial fluid has been difficult because the concentration of spirochetes is low. The key to this approach would be to optimize the culture methods that could allow scientists to de- tect these spirochetes efficiently. Microbiologists attain the best results from culture when using skin from a patient’s erythema migrans rash. Modifications to the medium used to culture a patient’s blood have had mixed results. The sensitivity of the test depends on the volume of cultured blood and evidence of early disease dissemination, when the organism is most likely to be present in the bloodstream. However, only 40 percent

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127 DIAGNOSTICS AND DIAGNOSIS TABLE 7-1 Sensitivity of Direct Methods of Detection of Borrelia burgdorferi Disease Stage Sample Culture (%) PCR (%) Early disease— Skin >50 (up to 86) 69 (up to 88) Erythema migrans Blood >40 21 Early disseminated— CSF No data (US) 38-67 Neuroborreliosis Late disease— Synovium Anecdotal 78 (up to 96 of untreated Arthritis patients using 4 primer sets) SOURCES: Wang et al., 2002; Aguero-Rosenfeld et al., 2005; Mygland et al., 2010. of patients in the early stages of infection test positive for B. burgdorferi in their blood. European scientists can sometimes detect B. burgdorferi spirochetes in patients’ cerebrospinal fluid (CSF). The differences between being able to detect Borrelia in the blood or CSF may be a function of the Borrelia genotype. For example, the European Borrelia garinii is more neu- roinvasive, which means that it is more often present in the cerebrospinal fluid, where it can be detected in culture. The second technique for directly detecting Borrelia in patients is PCR, which amplifies specific sequences of spirochete DNA in samples of skin, synovial fluid, or blood. The efficiency of PCR depends on primers, number of sets used, sample type, and quality of the sample. In general, this detec- tion method is more successful for B. burgdorferi when several different genetic sequences are amplified on DNA extracted from the skin of patients with erythema migrans and synovial fluid from the joints of patients with untreated Lyme disease arthritis. Obviously, PCR will have a higher yield on those samples with more spirochetes. Only a few U.S. scientists have used PCR to examine for spirochete DNA in cerebrospinal fluid where evidence of borreliae was seen in up to 60 percent of patients with early neurobor- reliosis in one study. PCR is more sensitive in detecting infection in patients with untreated arthritis, as spirochete’s DNA is present in 78–96 percent of these patients. However, the high yield of PCR in CSF of patients with early neuroborreliosis and in synovial samples of patients with untreated arthritis was obtained when several PCR primer sets were used. Direct testing works well if applied to the best samples at the right time. Drawbacks are the un- availability of PCR in most clinical settings and the need to biopsy the skin or to perform a joint tap, which many primary care physicians do not do. Because of the drawbacks of those two methods for directly detecting B. burgdorferi, most clinicians continue to rely on detecting antibodies to the pathogen when testing patients for Lyme disease. The first generation of assays in the 1980s did not use antigens that were effective in detecting antibodies in patients’ sera. These tests often failed to confirm that patients

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128 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES were infected with B. burgdorferi or gave positive results in patients who did not have Lyme disease. In the mid-1990s, two-tier testing became the standard serological approach, and improvements were made on the antigen composition used in first- and second-tier tests, which produced better results. However, the two-tier approach is ineffective in detecting antibodies to B. burgdorferi during the acute phase of infection. Only 29 percent of patients later found to be infected with the pathogen have antibodies detected during the initial period. The sensitivity of the two-tier approach rises markedly during later stages of infection (Table 7-2). The first step in the two-tier approach, the enzyme-linked immuno- sorbent assay (ELISA) test, has high sensitivity, but low specificity. That is, patients infected with B. burgdorferi are very likely to yield positive results on that test. However, ELISA also produces false positives, suggesting that some people are infected with the pathogen when they actually are not. For this reason, microbiologists apply the second step to confirm the results for those patients who test positive on the ELISA test. The Western immuno- blot, by contrast, has high specificity: Most of the people who test positive for antibodies to B. burgdorferi are infected. The criteria for a positive result on this test are fairly stringent: Two of 3 specified bands on an IgM immunoblot or 5 of 10 specified bands on an IgG immunoblot must be de- tected for the specimens to be diagnostic. The IgM immunoblot should be used only within the first 4 weeks of illness, while the IgG immunoblot can be used at any stage in Lyme disease. If patients test positive on the ELISA but negative on the Western blot, they are considered not to have specific antibodies against B. burgdorferi. One of the most immunodominant antigens in early disease is outer surface protein C (OspC). Antibodies to this antigen are among the first to appear after infection occurs. Another key result is evidence of antibodies to VlsE, which shows reactivity as early as 8 days after patients become ill. The addition of VlsE to both first- and second-tier tests has improved their performance. An increment in immunoreactive bands is observed in TABLE 7-2 Performance of Two-Tier Testing Late Disease Early Disease Early Dissem. (arthritis, Erythema Migrans (neurological) neurological) Reference Acute 29–54% Acute 87% 97–100% Bacon et al., 2003 Conv. 65–88% Conv. 82% Acute 31% 63% 100% Branda et al., 2010 Conv. 64% 27.1–63.8% Acute 80% 94.7–100% Wormser (in preparation) Conv. 75%

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129 DIAGNOSTICS AND DIAGNOSIS the IgG immunoblots of sera of patients with neuroborreliosis and Lyme disease arthritis. One scientific gap is the testing of cerebrospinal fluid for antibodies. Europeans measure intrathecal production of antibodies by measuring an- tibodies in CSF and comparing these results against the concentration of antibodies in the serum to produce a ratio. U.S. scientists have not had a sufficiently large population in which to evaluate the efficacy of this approach because fewer cases of neuroborreliosis are documented in the United States as compared to Europe and CSF sampling is not routinely done in patients with Lyme disease. The absence of this type of testing is a gap in diagnostics for neuroborreliosis caused by B. burgdorferi in the United States. Besides the lack of sensitivity in detecting early Borrelia infection, the two-tier test cannot distinguish between active Lyme disease and past infec- tion or reinfection. Promising new tests to address this problem are on the horizon. European researchers have advanced the use of recombinant anti- gens. Furthermore, a combination of immunodominant antigens in a bead format could be used instead of whole-cell lysates. For example, scientists at the Centers for Disease Control and Prevention evaluated the use of VlsE and pepC-10 (a synthetic peptide derived from OspC) in a kinetic ELISA. More recently C6, a synthetic peptide based on a component of VlsE, has been approved as a source of antigen in first-tier enzyme immunoassay (EIA). Three studies (Bacon et al., 2003; Steere et al., 2008; Wormser et al., unpub.) compared the C6 testing protocol with the standard two-tier method. The C6 testing protocol has performed comparably in accurately detecting the presence of antibodies to B. burgdorferi in sera of patients with acute EM, but it was slightly less effective in the case of neurological Lyme disease. Overall, the specificity of C6 testing protocol is lower than that of the two-tier testing protocol. False positives remain a significant concern as U.S. laboratories now perform more than 2 million tests for Lyme disease annually, with at least 1 percent of these tests generating false positives. Thus, current test protocols produce approximately 20,000 false positives each year, a problem that may increase with wider adoption of the C6 testing protocol. In conclusion, education is crucial to the diagnostics for both the clini- cian and the community. The positive predictive value of a test relies on the test being applied to the appropriate patient. Furthermore, physicians need to be educated on the availability of the tests and their limitations. Clinicians sometimes order tests on patients with a low probability of infec- tion, making the results difficult to interpret. In the diagnostic laboratory, education and training are also important for laboratorians as individual interpretation of the test often results in over-reading of the Western blots, in particular IgM immunoblots.

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130 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES Knowledge Gaps and Research Opportunities Aguero-Rosenfeld identified a number of key areas for future work: • Development of programs to educate practitioners on the appropri- ate use of laboratory tests for Lyme disease. • Improvement of direct methods for detecting B. burgdorferi in samples from patients. For example, scientists could improve and automate culture techniques and use PCR to target several gene sequences. • Development of immunoassays containing a combination of recom- binant or peptide antigens of importance, such as VlsE and OspC, in a bead format or other comparable method that would allow measuring the quantity of antibodies to individual antigens. • Development and evaluation of assays on cerebrospinal fluid that can support a diagnosis of neuroborreliosis. • Development of an algorithm that enables laboratory tests for B. burgdorferi infection to determine the stage of disease or duration of infection. • Establishment of a repository of well-characterized samples from Lyme borreliosis patients for use in evaluating new assays. • Recombinant antigens and peptides such as C6, including variations in gene sequences, require further evaluation for sensitivity and specificity. IMPROVED DIAGNOSTICS AND NOVEL APPROACHES TO TICK-BORNE DISEASES Juan P. Olano, M.D., University of Texas Medical Branch Diagnosis of infectious diseases is based on the same techniques for nearly all infectious agents: antibody detection, antigen capture, and cul- ture and detection of nucleic acids with or without amplification. Antibody detection (serological techniques) is the most common diagnostic method used in infectious diseases, but as reiterated throughout the workshop, a serologic diagnosis is frequently rendered too late to be of clinical value for therapeutic decisions because the immune response requires time to develop so that pathogen-specific circulating antibodies can be reliably detected. More recently, great progress has been made following the development of PCR and other nucleic acid amplification techniques for detection of pathogens in blood and other tissues. Most types of diagnostic tests used to diagnose Lyme disease are also used to diagnose other tick-borne infections, including rickettsial diseases, ehrlichioses, and anaplasmosis. Rickettsia

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131 DIAGNOSTICS AND DIAGNOSIS disease differs pathologically from those of Ehrlichia and Anaplasma in that it infects the microvascular endothelium, and therefore levels of circulating rickettsiae are usually low, posing a challenge for diagnosing rickettsioses during the acute phase of the disease. The indirect immunofluorescence as- say (IFA) is considered the gold standard for diagnosis of rickettsial infec- tions due to its high sensitivity and specificity when paired serum samples obtained 2–3 weeks apart are tested. However, its sensitivity is very low when single serum samples obtained in the acute phase are used. As with the diagnostic tests for Borrelia burgdorferi, the presence of IgM antibodies can be detected 5 to 7 days after the onset of symptoms, but the specificity of these tests is low. They produce false positives as other bacterial, viral, and parasitic infections can cross-react with the antigens. Similarly, IgG antibodies have rising titers after 7–10 days, but there is cross-reactivity within the spotted fever and typhus group rickettsiae. Diagnostic titers continue to rise, and, by day 30, approximately 100 percent of the patients have detectable circulating antibodies. As a result of the delayed diagnosis, appropriate treatment may be delayed, and case-fatality ratios are higher in the absence of specific antibiotic therapy. There are a number of other diagnostic tests for rickettsial diseases. Western blots allow for early detection of IgM antibodies to lipopolysac- charide antigens, but they still have low specificity, and cross-reactions occur between the spotted fever and typhus group rickettsiae. Detection of diagnostic IgG bands parallels the IFA detection rates. Cross-adsorption studies can be used to distinguish between the various species, but the tests are cumbersome and expensive. Dot blot enzyme immunoassay has similar sensitivity as IFA but also allows for the use of multiple antigens. The rash associated with rickettsial disease is caused by infection of the endothelial cells lining the microvessels in the skin. When the rash is present in the acute phase of the disease, detection of rickettsiae by immunohisto- chemistry of skin biopsies has a sensitivity of ~60–80 percent. Nucleic acid amplification techniques (mostly DNA), including PCR and real-time PCR, are used in selected research laboratories around the world for detection of circulating rickettsiae (inside macrophages or cir- culating endothelial cells that have detached from their microvascular niche). These tests are not commercially available, and their sensitivity and specificity have not been evaluated systematically. The agents of human monocytic ehrlichiosis (HME), Ehrlichia ewingii ehrlichiosis (EEE), and human granulocytic anaplasmosis (HGA) infect mononuclear phagocytes, including circulating monocytes (HME) and neutrophils (EEE and HGA). Therefore, detection of these pathogens in blood is theoretically more sen- sitive compared to rickettsioses. However, the diagnosis of these diseases presents similar difficulties as described for rickettsiae. Direct observation of the pathogens in peripheral blood smears is usually insensitive (more so

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132 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES for HME than HGA) due to the lower abundance of circulating target cells for HME. Diagnosis relies primarily on IFA, and its sensitivity and speci- ficity is similar to the rickettsioses. Other serological tests include Western immunoblotting using native or recombinant antigens. Antibodies against tandem repeat protein (TRP) 120 and TRP 42 provide diagnostic bands to differentiate Ehrlichia chaffeensis from other Ehrlichia spp., while the 42, 44, and 49 kDa proteins help in distinguishing HGA from other ehrlichiae. Similar to Rickettsia, there are a number of other diagnostic approaches for ehrlichioses and anaplasmosis. Immunohistology is available, but not widely applied outside the research setting. Conventional and real-time PCR assays have been developed and evaluated in small series of cases. Sensitivity varies widely, from 50 to approximately 100 percent, depending on several factors including primers used, time of testing during the course of the disease, use of pre-test antibiotics, etc. Specificity for PCR is very high provided there is no amplification contamination. All amplification techniques are available at selected research laboratories and are not com- mercially available. Currently, several new technologies provide platforms for improving the performance of conventional serological assays and are based on antigen capture using pathogen-specific antibodies in microfluidic settings followed by different detection techniques, including electrochemi- luminescence and microretroreflectors. Electrochemiluminescence is a highly sensitive technique that uses ruthenylated antibodies that in the presence of tripropylamine and an electrical current release photons. For rickettsial pathogens, its analytical sensitivity in vitro and in vivo using animal models is ~1,250 to 1,500 organisms/mL. Microretroreflector detection is based on reflection of light off a gold-coated surface. As rickettsiae are captured by antibody-coated magnetic beads or nanogold particles, their deposition on a reflective sur- face dims the amount of light bouncing off that surface. This variations are detected using conventional optics. Other antigen-capturing systems being evaluated with microfluidic systems include the use of microporous substances to increase the capturing surface area. Improved serological assays using protein microarrays is another prom- ising technology. In short, all open reading frames of the R. rickettsii ge- nome have been cloned, expressed, and blotted onto microarray spots. The serological response is then analyzed and response patterns are delineated. This technique could improve both sensitivity and specificity for diagnosis of rickettsioses, ehrlichioses, and anaplasmosis. Promising preliminary re- sults have been observed with rabbit and dog sera and a few human samples available for testing. In conclusion, Olano noted that despite advances in antigen-capturing systems, detection technologies, automation, and nucleic acid amplifica- tion techniques, commercially available tests for the diagnosis of human

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133 DIAGNOSTICS AND DIAGNOSIS rickettsioses, anaplasmosis, and ehrlichioses by nucleic acid amplification have not been developed. Aside from IFA, all these tests are available only at selected research laboratories around the United States and the world. Thus, the gap between the laboratory bench and the patient bedside in diagnosing tick-borne diseases remains wide. As better detection platforms are refined and become increasingly available, microfluidic technology, au- tomation, nanotechnology, and point-of-care testing will result in accurate, fast, and inexpensive diagnosis of these diseases. POTENTIAL BIOMARKER APPLICATIONS FOR LYME DISEASE: ALIGNING MULTIPLE SYMPTOMS WITH BIOLOGICAL MEASURES Afton L. Hassett, Psy.D., University of Michigan Medical School Biomarkers are cellular, biochemical, and molecular characteristics by which normal and abnormal processes can be recognized or monitored. Their identification has numerous clinical applications, such as improving diagnostic accuracy; assessing disease activity, prognosis, and efficacy of treatment; and tailoring treatment to the individual. However, studies that fail to properly characterize the patients studied (i.e., phenotyping) ham- per progress. For example, a recent review of research on biomarkers for autoimmune diseases found that some investigators had failed to control for patients’ age or gender, while others had not controlled for medication use, other medical and psychological comorbidities, or the stage of disease (Tektonidou and Ward, 2010). These factors, and several others, must be accounted for as each can influence biological measures. Currently, there are no credible biomarkers for post-Lyme disease de- spite ongoing efforts in this area. For example, in a series of studies, re- searchers using the CD57 marker for natural killer cells found that patients with post-Lyme disease had fewer natural killer cells, suggesting that the marker could be used to assess treatment outcomes (Stricker and Winger, 2001, 2003; Stricker et al., 2002). However, a more recent study using a combination of CD56 and CD16 surface markers in conjunction with CD3 markers showed that natural killer cell counts did not differ between post- Lyme disease patients and healthy controls or patients who had recovered from Lyme disease after treatment (Marques et al., 2009). In another study, heightened anti-neural antibody reactivity was found in 49.4 percent of post-Lyme disease patients compared with control groups who had recovered from Lyme disease (18.5 percent) or were healthy (15 percent) (Chandra et al., 2010). The heightened reactivity was not greater compared to patients with systemic lupus erythematosus (73.3 percent). A similar reactivity was observed in an earlier study evaluating ongoing

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134 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES neurologic Lyme disease (Sigal and Williams, 1997). This antibody reactiv- ity supports the hypothesis that a sustained immune response may contrib- ute to persistent neurologic dysfunction in Lyme disease patients, even after the pathogens are eliminated (Sigal and Williams, 1997). Other ongoing and/or promising research includes • Immune system abnormalities (e.g., persistent activation, cytokine- induced sickness behavior); • Proteomics—proteins produced specific to post-Lyme disease; • Neuroendocrine dysfunction; • Neuroimaging (microglial activation, neural network differences); and • Genetic predisposition. Charting a scientific inquiry into the nature of post-Lyme disease may rely on understanding the symptoms of the condition, which include ar- thralgias, musculoskeletal pain, radicular pain, paresthesia, fatigue, neuro- cognitive impairment, and mood disturbances. These symptoms are the very same symptoms observed in conditions such as fibromyalgia and chronic fatigue syndrome, which are currently thought to result from disturbances in the central nervous system processing of sensory information. These con- ditions are frequently referred to as “central sensitivity” syndromes. Thus, to understand the persistent symptoms of post-treatment Lyme disease, there is a need to understand the commonalities between these symptoms and those associated with central sensitivity syndromes. Moreover, aspects of the underlying pathophysiology of central sensitivity syndromes will likely inform biomarker research. We begin with the most prominent symptom—pain. Findings from the past decade of neuroscience research suggest there are at least three types of pain. The first, peripheral pain, includes acute injury, osteoarthri- tis, rheumatoid arthritis, and cancer pain, and is “nociceptive,” meaning that a stimulus in the periphery (e.g., inflammation, mechanical malfunc- tion, or tissue damage) is causing the pain. This type of pain responds to interventional procedures, non-steroidal anti-inflammatory drugs, and opioids. Second, neuropathic pain stems from damage to or dysfunction of peripheral nerves and can include diabetic neuropathic pain and post- herpetic neuralgia. Neuropathic pain responds to both peripheral and cen- tral interventions. Third, “central,” or non-nociceptive, pain results from disturbances in central nervous system processing and leads to diffuse hyperalgesia (increased response to painful stimuli) and allodynia (painful response to normal stimuli). Examples of central pain conditions include fibromyalgia, interstitial cystitis, and irritable bowel syndrome. Individu- als can have a combination of these types of pain. For example, about 15

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135 DIAGNOSTICS AND DIAGNOSIS percent of patients with rheumatoid arthritis also have fibromyalgia: that is, they have both inflammatory pain and central pain. Even patients with well-controlled rheumatoid arthritis, as evidenced by a lack of inflamma- tion, may continue to have persistent pain. In these cases, it appears that augmentation of central nervous system pain processing accounts for the persistent experience of pain. Another common symptom in central sensitivity syndromes is fatigue, which is thought to have a peripheral or central origin. It has been proposed that peripheral fatigue is predominantly due to physical exhaustion and may be attributed to organ-system dysfunction (Silverman et al., 2010). This type of fatigue occurs commonly in patients with rheumatoid arthri- tis, cardio-respiratory diseases, and myasthenia gravis. By contrast, central fatigue is more cognitive in nature and is attributed to central nervous system dysfunction. Classic examples of central fatigue include chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome, although central fatigue can also accompany rheumatoid arthritis, lupus, and cancer. Importantly, the difficulty with memory and concentration reported by a myriad of patients with various systemic diseases may be a function of central fatigue. As with many other medical conditions, a stress-diathesis model for the etiology of central sensitivity syndromes is widely accepted. Such a model purports that genetic and environmental factors likely contribute to central sensitivity syndromes in equal measure. A series of case-controlled studies suggest that in predisposed individuals these syndromes can be triggered by peripheral pain conditions (e.g., rheumatoid arthritis and lupus [Clauw and Katz, 1995], physical trauma [Buskila et al., 1997; McBeth, 2005; Miranda et al., 2010], or catastrophic events, such as war [Clauw et al., 2003]) and infections. Pertinent to Lyme disease, infections in general have been shown to trigger central sensitivity syndromes in approximately 10 percent of pa- tients. More specifically, 5 to 30 percent of patients with enteric infections later manifest irritable bowel syndrome (Bayless and Harris, 1990; Saito et al., 2002; Thabane and Marshall, 2009). Similarly, urinary tract infections appear to later lead to interstitial cystitis and painful bladder syndrome (Warren et al., 2008). In the Dubbo population-based prospective cohort study of patients infected with three very different viruses—Epstein-Barr virus, Ross River virus, and Coxiella burnetii, the bacterium that causes Q fever—approximately 9 percent of infected patients continued to pres- ent with a chronic fatigue–like syndrome even after the agent was cleared (Nickie et al., 2006). More recently, there was a case report of a central sensitivity syndrome triggered by H1N1 influenza (Vallings, 2010). Similarly, various TBDs appear to trigger some central sensitivity syn- dromes. For example, approximately 39 percent of patients with human anaplasmosis developed chronic fatigue syndrome despite no serological

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144 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES Despite a large number of patients screened with persistent symptoms, few of them met the strict criteria for inclusion in the Columbia study. Only 1 percent had objective cognitive impairments, a positive IgG Western blot, prior intravenous therapy, and documentation of prior Lyme disease. We learned that a requirement of IgG Western blot positivity at time of enroll- ment for studies of patients with chronic symptoms following Lyme disease will exclude a large number of patients with good clinical histories, thus hampering enrollment and narrowing the generalizability of the findings. Ten percent of patients in the Lyme disease encephalopathy sample had a history of co-infections. There was no difference in the incidence of hu- man granulocytic anaplasmosis between the Lyme disease patients and the controls, but Babesia IgG was positive in 27 percent of the Lyme disease patients versus none of the controls. There was a high rate of Bartonella IgG positivity in the Lyme disease patients, but also in the controls, suggest- ing that exposure to Bartonella is common in the population. Cerebrospinal fluid findings across four studies of patients with persis- tent symptoms following Lyme borreliosis showed elevated protein in 25.8 percent, 7.3 percent, and 12.1 percent of the patients, respectively (Klemper et al., 2001; Krupp et al., 2003; Fallon et al., 2008). Brain imaging studies at the National Institutes of Health (NIH) re- ported that 55 percent of the patients with post-treatment Lyme disease exhibited hyperintensities on MRI (Morgen et al., 2001). Another study comparing the Lyme disease encephalopathy patients with controls well- matched for age, sex, and education showed no difference in the white matter hyperintensity density (DelaPaz et al., 2005). The study did find that the patients who had had Lyme disease were more likely to have blood flow deficits in their brains, as well as metabolic differences on positron emission tomography imaging, compared with the well-matched controls (Fallon et al., 2009). Prior work found the blood flow deficits to be reversible with intravenous ceftriaxone therapy (Logigian et al., 1997). With respect to pathophysiology, Borrelia act directly and can invade neural cells in vitro (Livengood and Gilmore, 2006); there are also indirect actions, such as the induction of local cytotoxins or inflammatory mediators (reviewed in Fallon et al., 2010). European studies show that pro-inflamma- tory cytokines are increased, and chemokines, excitotoxin, and quinolinic acid are increased in patients with neuroborreliosis (Weller et al., 1991; Halperin and Heyes, 1992; Widhe et al., 2004; Rupprecht et al., 2005). A rich field of research is psychoneuroimmunology, in which studies have suggested that individuals with risk factors for inflammatory disor- ders and for psychiatric disorders are more likely than those without them to experience chronic peripheral inflammation and chronic activation of the brain cytokine pathways following infections, leading to subjective health complaints similar to those in Lyme disease and a number of other

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145 DIAGNOSTICS AND DIAGNOSIS disorders (Dantzer et al., 2008). Anti-neural antibody reactivity is increased in patients with persistent symptoms following treatment for Lyme disease (Alaedini and Fallon, 2010; Chandra et al., 2010). Approximately 50 per- cent of patients enrolled in two independent studies (Klemper et al., 2001; Fallon et al., 2008) of patients with chronic, persistent symptoms had elevated levels of anti-neural antibodies, indicating there is an abnormally activated immunological process at work in some of these patients with chronic symptoms. A summary of the possible explanations for chronic, persistent symp- toms in patients following treatment for Lyme disease includes: persistent infection in some patients; reinfection from a later tick bite; reactivation of a latent, dormant infection; widely distributed effects from a small amount of physiologically active but attenuated spirochetes; or post-in- fectious phenomena, such as spirochete-triggered immune abnormalities, neurotransmitter/receptor changes, or damage from prior infection. The symptoms also could be related to an unrecognized concurrent process, such as another TBD, another non-tick-borne infection, or another disease (e.g., depression or hypothyroidism). There is a danger that persistent symptoms following treatment for Lyme disease will be labeled as somatoform. In part this may be due to clinicians’ assumptions that 2 to 4 weeks of antibiotic therapy is always curative and that any symptoms after minimal antibiotic treatment are due to other causes. It may also reflect a clinician’s failure to recognize that any infection may have a course of post-infectious symptoms that can continue for a year or more. In addition, some clinicians may experience hostility or frustration toward patients with chronic illnesses or may misinterpret the patient’s presentation with anxiety and multi-systemic, nonobjective symptoms as indicative of a psychiatric etiology. Richard F. Jacobs, M.D., University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute One of the challenges that clinicians face in the diagnosis and manage- ment of tick-borne diseases (TBDs) in children is a poor understanding of the true incidence and geographic distribution of the diseases. The more information is known about the different variations of these organisms, the greater the realization will be that what has been taught about geographic distribution is not true. Another challenge is the similarity in the multisystem presentation among the TBDs. In addition, diagnostics are limited in acute illness, and the rates of chronic illness and morbidity are unknown. There is information about neuroborreliosis in adults, but aside from a few studies in

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146 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES children, there are no data on any of the TBDs that are sufficiently reliable to tell parents what the potential chronic neurologic or other sequelae may be. Children are different; they are not little adults. They are still develop- ing, and they have a very different central nervous system from adults, as well as a developing immune system. For this reason, it is important to recognize and study children as a distinct population. Furthermore, it is also important to keep in mind that the duration of any long-term effects of disease in this population will last 50 to 70 years. Jacobs noted there is a need to provide enhanced educational infor- mation to clinicians—not only pediatricians, but also family physicians, advanced practice nurses, and physicians’ assistants—about the clinical manifestations of and other information regarding tick-borne illnesses. Conventional wisdom about spotted fever rickettsiosis (Rocky Mountain spotted fever) indicates that young children have a lower mortality rate, but a much higher infection rate, than do older adults (Dalton et al., 1995), although this generalization is not completely accurate. In addition, the fatality rate increases dramatically among cases in which treatment was not started until after the fifth day following the onset of symptoms (Dalton et al., 1995). Therefore, it is important to make treatment decisions presump- tively and empirically based upon a patient’s clinical presentation. Experience with Ehrlichia chaffeensis led to the recognition of a set of symptoms associated with ehrlichial infection. Fever and rash are common, but a host of other signs and symptoms occur as well: myalgia, headache, vomiting, diarrhea, and puffy eyes (Schutze and Jacobs, 1997). The physi- cal presentation of ehrlichiosis has a large differential diagnosis, including a significant overlap with Rocky Mountain spotted fever (Buckingham et al., 2007), but the clinical laboratory triad of thrombocytopenia, leukopenia with lymphopenia, and elevated hepatic enzymes suggests human mono- cytic ehrlichiosis and warrants doxycycline therapy at admission (Schutze and Jacobs, 1997), given the importance of prompt treatment in reducing mortality. Compounding the challenges of diagnosis and prompt treatment, dif- ferent pediatric diseases within the differential for tick-borne illnesses, such as Kawasaki syndrome and meningococcemia, require very different therapies, but on a similarly urgent time line. The clinical challenge is that the diagnostics and clinicians’ understanding about the ecosystem and the organism do not allow them to separate these clinically. Consider a child with a rash on her arms, legs, face, hands, and feet, along with fever, headache, and pleocytosis in her CSF. Rocky Mountain spotted fever and ehrlichiosis certainly are on the list of differential diag- noses. But the child had disseminated meningococcemia, which carries a 20 to 40 percent mortality rate had it not been treated with a third-generation

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147 DIAGNOSTICS AND DIAGNOSIS cephalosporin on admission. This example highlights both the difficulty and the urgency of separating these diseases clinically. The clinical challenge is compounded by the short incubation period of the TBDs. Antibody testing is not useful in the acute management of Rocky Mountain spotted fever or human monocytic ehrlichiosis. Both infections, as well as others, respond to treatment with doxycycline, however, so physi- cians are taught to administer doxycycline. In terms of knowledge gaps, more data and understanding are needed on the genetics, predisposing factors, and epidemiology associated with tick-borne illnesses. In addition, more information is needed about the organisms, acute and persistent infections, diagnostics, spectrum of dis- ease, and chronic manifestations and outcomes. In addition to the dearth of information in these areas for adults, there is virtually no knowledge of most of these infectious diseases as they relate to the unique attributes of children. Lessons have been learned about the different impacts of acute disease from babies exposed to herpes simplex virus, different disease manifesta- tions from children with tuberculosis, age-related immune responses to vaccinations, unknown central nervous system effects (autism-spectrum dis- orders), age-related exposures and adaptive immunity (Kawasaki’s disease), and central nervous system growth and development (use of folic acid to prevent neural tube defects). But much of the biology remains a mystery. Jacobs noted the United States needs a study group to explore tick- associated and tick-borne infections in children. Two models currently exist. The NIH/National Institutes of Allergy and Infectious Diseases Col- laborative Anti-Viral Study Group has operated for 30 years. Thirty-two sites now study rare diseases. The study of TBDs can follow the same model. The National Children’s Study, now NIH funded, involves randomly selected, geographically dispersed counties in the United States. that will follow pregnant women and their babies until the children are 20 years old. The study provides an opportunity to collect information in a reposi- tory, including biological samples and detailed historical information, and is charged to look at priority exposures and examples. Infectious agents are already listed as one of the study areas. The National Children’s Study provides a wonderful opportunity to use a currently NIH-funded, 20-year- long prospective study to focus some attention on TBD. Matthew H. Liang, M.D., M.P.H., Harvard Medical School and Harvard School of Public Health In unselected, non-specialty (primary care) practices, atypical manifes- tations of common illnesses are much more common than typical manifes- tations of uncommon illnesses. Primary care physicians build their practices

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148 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES on their patients’ trust in and access to them, both of which are necessary for fine-tuning a diagnosis or refining a treatment. The usual strategy is to identify treatable illnesses, make a working presumptive diagnosis, treat, and assess the outcome. If the treatment is not working, the physician may get more information, refine the diagnosis, and/or change the treatment. The process can be threatened, or lulled into complacency, by the primary care physician’s familiarity with the patient and the underlying probability that the illness is benign rather than serious. These factors sometimes make it difficult to keep an open mind about a patient with a persistent problem. The presentation of Lyme disease in clinical practice is variable. Thirty- nine percent of patients ultimately considered to have Lyme disease do not meet the Centers for Disease Control and Prevention (CDC) criteria, and approximately 40 percent had negative Lyme disease serology and an acute viral-like illness without objective findings. Nearly one-third of the patients had a rash that did not meet the criteria for EM, and only 19 percent of those with EM exhibited the stereotypical bull’s-eye appearance (Aucott et al., 2009). Given the variability, it is helpful when patients can provide the actual tick or a good description of a fed tick, as well as a time line to indicate how long the tick had been on them. A tick has to feed for 48 to 72 hours to transfer Borrelia to the host. The finding of a tick that is not well fed decreases the probability that it infected the patient. Clinicians also look for EM or forme-frustes, although EM can look like almost anything and is often mistaken for spider bites. Generally clinicians would treat empirically because of the importance of early treatment and the assumption that there is little to lose because treatment can always be stopped. This presupposes the treatment has mini- mal negative effects. As mentioned previously, doxycycline is a common default treatment for suspected tick-borne illness; however, there are some downsides, including dental staining. A prime area for intervention is educating people about prevention. Successful education requires understanding and reversing the thought barriers that prevent people from receiving and acting upon the message. There is, as already noted, a 48- to 72-hour time window within which to find a tick before it can infect the host, and a nightly shower provides ample opportunity to interrupt the life cycle. In theory, improved education will increase prevention and decrease the occurrence of Lyme disease. A 5-year study randomized 29,000 people traveling by ferry to Nan- tucket (Daltroy and Phillips, 2007). The study group was exposed to an entertainment-based information session about Lyme disease and steps to prevent it. Participants also received a card with a Braille dot on it the size of a tick and a plastic shower card similar to those used for breast self- exam, tweezers, and a map of the island where ticks were prevalent. The study showed a reduction in Lyme disease in the group who received the

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149 DIAGNOSTICS AND DIAGNOSIS message, both among year-round residents and among visitors, who con- stitute a high-risk population. A population-based retrospective cohort study of 38 patients in a particular location in Ipswich, Massachusetts, who had been treated for Lyme disease showed 13 patients with ongoing symptoms of arthritis or recurrent arthralgias, neurocognitive impairment, neuropathy, or myelopa- thy (Shadick et al., 1994). The individuals with these sequelae tended to have higher IgG antibody levels to the spirochete and also to have received treatment later following infection. One of the 13, a 76-year-old woman, had been worked up by Lyme disease experts, had received two courses of ceftriaxone, and was negative for objective central nervous system find- ings. She died and at post mortem a Dieterle silver stain demonstrated two spirochetes, one in the cortex and another external to a leptomingeal brain vessel (Shadick et al., 1994). Another study of approximately 6,000 year-round residents of Nan- tucket showed patients who had been diagnosed with Lyme disease and continued to be symptomatic following treatment, but the study presented few objective findings. This reinforces the challenges that clinicians face in the diagnosis and treatment of patients with chronic persistent symptoms following Lyme borreliosis. In treating such patients, it is important to ensure that a thorough history and physical exam are conducted and that they have received suf- ficiently long courses of the appropriate doses and types of antibiotics. Beyond that, at a certain point the diagnosis matters less than treating the symptoms in an effort to maintain and improve function. In addition, it sometimes is necessary to assist patients in revising their expectations as well. DISCUSSION Much of the discussion focused on the challenges associated with the diagnosis of TBDs, both in patients with acute illness and in those experi- encing persistent symptoms following an initial diagnosis of and treatment for Lyme disease. A second focus of discussion centered on the occurrence of Lyme borreliosis and other TBDs in children. One participant questioned the reliability of screening tests, such as white blood cell count and standard neurological exam, to evaluate patients with chronic symptoms. Liang felt that these tests are not particularly useful and noted that there is tremendous variation among practitioners in terms of their approach to patients with persistent symptoms. With regard to diagnosing TBDs in children, Jacobs noted that practitio- ners have come to rely on a clinical presentation of multisystem disease, in which the clinician must determine which systems are involved and create a differential diagnosis that is treatable. He reiterated the approach discussed

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150 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES by Krause, in which clinicians learn to look at particular presentations on screening tests (e.g., anemia, with thrombocytopenia) in acute infection to help make a diagnosis. The presence of multisystem disease and a specific picture of laboratory results together can generate a presumptive diagnosis and the initiation of treatment. Jacobs stressed, however, the need to develop better diagnostic testing that would permit more definitive diagnosis of TBDs. Another participant questioned the practice of those clinicians who use the absence of direct markers of an infecting organism following treatment as evidence of the treatment’s success given the absence of, or the current inability to identify and test for, markers for the presence of infecting organ- isms prior to treatment as well. With respect to cognitive dysfunction, one participant asked about the ability of brain SPECT scanning to distinguish hypoperfusion brain damage and cognitive dysfunction caused by TBDs from that caused by long-term excessive use of medication. Fallon agreed that certain medications can confuse the interpretation of SPECT scans. Cocaine use, although not a medication, can cause heterogenous hypoperfusion consistent with vascu- litis, which appears similar to that seen in Lyme disease patients who have had SPECT scans. He also stated that despite the power of such imaging tools for research purposes, the use of SPECT scanning as a clinical tool is of questionable reliability because rarely are systematic methods used to evaluate the scans against healthy populations, making variation in readings across clinicians likely and interpretations of clinical significance difficult. A question was posed about the implications of multiple phenotypes or strains of Borrelia and other organisms for the development of new, improved diagnostics. It has to do with moving forward into the new diag- nostics. Fallon reiterated that 17 different isolates of Borrelia in the United States have been sequenced and their antigens are now known. He mentioned the possibility of using that information to study a wide sample of patients and perhaps trying to correlate some of their clinical profiles, clinical histo- ries, and/or treatment outcomes with these actual antigenic profiles. Doing so would require a very large study of many patients followed up with good bioinformatics over a long period of time, but the ability is there to do it. With respect to the experience and impact of Lyme disease and chronic persistent symptoms in children, Jacobs emphasized how difficult it is to have to tell concerned parents that there is simply no solid information about the long-term effects and impact of the disease on the child. A participant observed that it seems as if the numbers of children experiencing symptoms and being diagnosed with illnesses such as fibro- myalgia or chronic fatigue syndrome have risen since the last generation and asked whether schools could be surveyed to obtain information on the school-age population and the kind of symptoms and difficulties they are experiencing. Jacobs discussed the current National Children’s Study as an

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151 DIAGNOSTICS AND DIAGNOSIS example of a study looking at the complex interactions among the envi- ronment, infectious agents, and genetics. He expressed the need to tap into the new area of bioinformatics, which can provide detailed information on participants, and combine that information with access to environmental samples from the National Children’s Survey, as well as human samples in a biorepository. Such a data repository would provide a very rich source of information to probe once there are better diagnostics, better biomarkers, or a better understanding of which imaging system or type of testing to do. A question was raised regarding concerns about privacy and confidenti- ality, among citizens and schools, as well as publicized knowledge of being located in a tick-endemic area. Jacobs acknowledged the possibility of such concerns, but that generally when members of a community are or become vested in a project, the schools and other community organizations follow. Another participant indicated that the interest level in participating in such a trial would be high in that community. Related to questions about the long-term impact of Lyme disease and other TBDs on children as they develop and mature, a request for greater consideration of gender differences and issues specific to women in these diseases was made by one participant. She specifically mentioned the impact of hormonal fluctuations (e.g., during adolescence and puberty, pregnancy, and menopause) on symptoms. Questions were also raised about congenital transmission of the diseases as well as their impact on fertility. Donta noted that there are changes in the severity of symptoms experienced by women not only with Lyme disease but also with various chronic conditions, such as chronic fatigue syndrome, as hormone levels fluctuate. In addition there is a gender difference in Lyme disease, perhaps related to the presence of es- trogen and progesterone receptors in glial and neural cells. Jacobs reiterated the need for a large-scale, long-term study, such as the National Children’s Study, involving bioinformatics, although he acknowledged that the results would not be available in time to help inform the parents of children cur- rently experiencing symptoms. Nevertheless, such a study would provide hope that the present large knowledge gaps will be filled in the future. CONCLUDING THOUGHTS ON DIAGNOSIS AND DIAGNOSTICS Lynn Gerber, M.D., Center for the Study of Chronic Illness and Disability, George Mason University David H. Walker, M.D., Department of Pathology, University of Texas Medical Branch at Galveston Many participants in this session noted that diagnosis of tick-borne dis- eases remains problematic. This could be ameliorated using a three-pronged

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152 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES approach: (1) education of clinicians about which diagnostic tests to use, when to use them during the course of the disease, and how to interpret these results; (2) developing and applying new technology for serological assays to close the gap between bench and bedside using microfluidic technology, automation, and nanotechnology to achieve accurate, fast, and inexpensive diagnostic tests; and (3) consensus building to establish criteria for clinical phases of disease in children and adults, possibly describing necessary and sufficient criteria for arriving at common nomenclature, such as in systemic lupus erythematosus, chronic fatigue syndrome, and fibromyalgia, among others. Clinicians need better education regarding the limitations of existing tests, and how to interpret the results. Some 10–20 percent of healthy people in some regions may already carry antibodies to a particular organ- ism, such as Rickettsia rickettsii or Ehrlichia chaffeensis. The antibodies might stem from exposure to a related organism that caused a subclinical infection. In that situation, a clinician who does not realize that a patient with acute febrile illness has had antibodies for a long period might wrongly diagnose rickettsiosis or ehrlichiosis on the basis of a single acute serologic test. In fact, clinicians often fail to do a follow-up serologic test to deter- mine whether the concentration of antibodies to a tick-borne disease in a patient is rising. Clinicians need to understand that testing patients with a low likeli- hood of a tick-borne disease strongly undermines the test’s positive predic- tive value. When clinicians do test such patients, a substantial proportion will be false positives. Lengthy menus of tests also present a barrier to effective diagnosis of tick-borne illness by clinicians who are not familiar with the advantages and disadvantages of many laboratory assays. Some clinicians also use serologic assays for IgM antibodies that have not been validated through well-documented series of cases. The soaring incidence of reported spotted fever rickettsial infections—few of which have been confirmed by methods specific to R. rickettsii—is one result. Some presenters in this session emphasized that patients with tick- borne diseases do not develop antibodies to an infectious organism until some time after the onset of illness, because of the nature of the immune response. That means existing tests that may be highly reliable later in the disease are insensitive early on. It also means that diagnosing a tick-borne infection requires knowledge of a patient’s geographic and seasonal expo- sure to ticks as well as the clinical manifestations of tick-borne diseases. Despite these diagnostic shortcomings, tick-borne diseases such as hu- man ehrlichioses and anaplasmosis likely have undiagnosed incidence equal to that of Lyme borreliosis. And they and Rocky Mountain spotted fever carry the threat of a fatal outcome, which Lyme disease does not.

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153 DIAGNOSTICS AND DIAGNOSIS New methods that can determine which species of Rickettsia or Babe- sia a person has encountered are particularly important. Some participants noted that investigators also need to develop tests that can shed light on the etiology of southern tick associated rash illness (STARI), whose erythema migrans resembles that of Lyme disease but is not caused by B. burgdorferi. Creating biorepositories and a network of clinical studies, such as those now supported by the National Institute of Child Health and Hu- man Development, would greatly enhance the opportunity to improve di- agnostics by providing wider access to stored specimens as well as clinical information. Sera from documented cases of tick-borne diseases—during both acute and convalescent phases—would enable scientists to validate new serologic tests. Such repositiories would aid in enabling investigators correlate symptoms and biological findings and help develop evaluative and treatment outcome criteria. It might help determine whether children, for example, have a different course of illness, given that their central nervous and immune systems are still developing. Samples of whole blood and cerebrospinal fluid, tissue biopsies, and other specimens would allow scientists to validate the use of PCR for ampli- fying nucleic acids and to identify and validate novel methods of detecting tick-borne pathogens. The recently sequenced genomes of different strains of B. burgdorferi also promise to allow scientists to develop new diagnos- tics and ultimately, preventive measures. The community affected by Lyme borreliosis and other tick-borne diseases seeks guidance on prognosis and treatment, and that has not yet been achieved. Throughout the workshop, during podium presentations and com- ments and questions from the floor, participants employed descriptive ter- minology pertaining to Lyme disease in different ways. This presented several challenges to discussants in that it was not always clear that the topic under discussion was addressing acute, chronic, recurrent phases of illness or other co-infections. Better descriptors would provide a uniform vocabulary for clinicians, researchers, and patients. They would also pro- vide a basis for building and validating a comprehensive, sensitive battery of tools for evaluating both objective and patient-reported outcomes for tick-borne diseases. Improved descriptors should include both signs and symptoms: that is, information that is both objective and self-reported, and that includes physical findings, serological measures, and psychological measures, among others. Further exploration of the stress response to tick-borne pathogens could help expand our understanding of the pathogenesis and natural history of Lyme disease. One approach is to investigate the role of the hypothalamic–pituitary–adrenal axis and the cortisol response in people

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154 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES with chronic Lyme disease symptoms that resemble those of other chronic fatigue or pain syndromes. Another would be to determine whether there is a genetic vulnerability to central sensitivity syndromes, which might of- fer a productive approach to better identify those at risk. Good biomarkers for post-Lyme disease are not yet available. However, conceptualizing the disease as having roots in central nervous system dysfunction could help chart the way.