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Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop (2024)

Chapter: 4 Potential Research Priorities and Opportunities in Diagnostics

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Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
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4

Potential Research Priorities and Opportunities in Diagnostics

Key Points from Individual Speakers and Participants1

  • There is the potential for inflammatory mediators to act as biomarkers that predict the risk of persistent symptoms of Lyme disease. (Aucott)
  • Future opportunities for diagnostic tests include the measurement of host responses, including inflammatory processes and gene regulation, metabolic changes, and epigenetic signatures. (Aucott)
  • Multiple sclerosis (MS) is a rare complication of Epstein-Barr virus (EBV) infection. Evidence shows EBV reactivation in the brain is likely the leading cause of the pathology for MS. (Ascherio)
  • The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger platelet hyperactivation as well as microclot formation. Microclotting and platelet hyperactivation are also seen in myalgic encephalitis/chronic fatigue syndrome patients but at lower levels. (Pretorius)
  • Metagenomic sequencing can provide more diagnoses compared to conventional clinical testing and could be a powerful

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1 This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants.

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
  • tool for investigating emerging infections. Additionally, using host-response profiling, biomarkers can be identified to diagnose disease and monitor chronic disease. (Chiu)
  • There are commonalities between various types of postinfectious syndromes, suggesting a shared pathophysiology, though likely through different mechanisms. The individuality of each person’s immune response also plays an important role. (Nath)

A significant challenge in addressing infection-associated chronic illnesses is that they are difficult to diagnose or predict in the acute stages of the infection. This can lead to confusion for patients, dismissal from providers, misdiagnoses, or correct diagnosis only after years of suffering. Speakers presented on their research and suggested priorities in diagnostics, including the use of biomarkers, microclots, and high-throughput or next-generation and metagenomic sequencing. Similar to other chapter discussions, speakers highlighted lessons and findings that can be applied to different but related conditions given their overlap in symptoms.

USING BIOMARKERS FOR DIAGNOSIS

This section features speakers discussing the specifics of biomarkers for Lyme disease and EBV infection.

Lyme Disease

Lyme disease manifests in stages, said John Aucott, Johns Hopkins University, and can develop into a chronic illness. The first stage starts from the tick bite and transmission of the bacterial pathogen, which begins replication in the skin and sometimes results in the characteristic round red rash. Stage two is where manifestations of disseminated infection are present, with approximately 15 percent of people experiencing symptoms of neurologic disease and sometimes cardiovascular involvement such as carditis. When left untreated, he said about 60 percent of people develop arthritis in the third stage of disease progression. Aucott added that not all those with Lyme disease go through the three stages with identical symptoms, and that patients may seek care at either first-, second-, or third-stage of the disease. Others may be misdiagnosed or have a delayed diagnosis, and many might just have persistent symptoms but not an advanced stage of the disease. Aucott’s research center specifically studies posttreatment Lyme disease syndrome (PTLDS) because it is a defined condition, which facilitates the research process.

Aucott noted that the clinician’s ideal diagnostic test would have high sensitivity and specificity and be accurate at all disease stages. Tests that

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

could identify a marker of past exposure or determine whether the patient is responding to treatment or has improved would be particularly useful, as it would guide clinical decisions on whether the patient has been cured or is in need of additional treatment. Unfortunately, current test options have limitations in their sensitivity and specificity.2 Diagnostic tests for Lyme disease fall into two main categories: direct tests that detect presence of the pathogen, and indirect tests that gauge the host response. Indirect tests pose exciting opportunities, especially for the PTLDS population, as they can potentially provide insights into the host-microbe interaction and pathogenesis mechanism. This information could help clinicians decide which treatments to use for a particular patient.

Diving deeper into the effect of inflammation on neural network alterations, Aucott said dysautonomia and postural orthostatic tachycardia syndrome (POTS) may be linked to inflammation that affects the nervous system. The manifestations of these symptoms may also play a role in chronic fatigue syndrome (CFS) and PTLDS. To study potential connections between these conditions, Aucott’s team categorized patients into subgroups with similar symptoms, like autoimmunity or dysautonomia. Some of his research findings suggested that the peptidoglycans in B. burgdorferi are present in the synovial fluid of patients with late Lyme arthritis, even in individuals who have been treated aggressively by antibiotics and have no signs of active infection.

Shifting to inflammatory mediators, Aucott referenced the Study of Lyme disease Immunology and Clinical Events (SLICE), which was a longitudinal cohort study that has provided researchers with insights into the immune inflammatory mediators in acute Lyme disease. He presented a finding that a subgroup of people with acute Lyme disease had very high levels of inflammatory mediators, while Lyme disease patients had low levels of these mediators. This correlates with another study, where serum levels of IL-23, an inflammatory mediator, was high at acute infection and did not return to normal levels over 12 months in patients who went on to develop PTLDS. This was the first evidence that showed the potential for proinflammatory cytokines to be used as predictive markers of who might go on to develop persistent symptoms. For example, if a patient’s IL-23 is still high after treatment at month 2, they may be likely to have PTLDS (Strle et al., 2014).

Aucott’s team conducted a similar study that showed sustained elevation of the proinflammatory mediator CCL19 in the serum of a subgroup of Lyme disease patients (see Figure 4-1). For those who would eventually return to full health, the serum level of CCL19 decreased at their first follow-up appointment 1 month posttreatment. In fact, he continued, if a patient’s CCL19 was still elevated at that first visit, researchers observed a 14-fold higher risk of that patient developing PTLDS 6 months later. This

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2 See footnote 18 for additional background on currently available diagnostic tests.

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
A range bar chart shows CCL19 levels in patients as they progress from pre-treatment to one year post-treatment. Vertical bars at each time interval represent patient groups with posttreatment Lyme disease syndrome in green, symptoms in purple, and return to health in orange. The chart shows that CCL19 is detected throughout treatment in the PTLDS group at higher levels than in both other tested groups.
FIGURE 4-1 Serum CCL19 levels over time correlated to clinical outcome status.
NOTE: PTLDS = posttreatment Lyme disease syndrome; the median control values (79.3 pg/mL for CCL19) is represented by a triangle in the graph; the red boxes highlight the significantly elevated levels of CCL19 in the group of study participants who developed PTLDS following pretreatment assessment; *p≤0.05, **p≤0.01 for comparison of each group to controls.
SOURCE: John Aucott presentation, June 29, 2023, Aucott et al., 2016.

offered an option for an intervention at the time of elevated CCL19 detection rather than waiting to see whether symptoms persisted for several more months. A third, recently published study also showed correlation between interferon alpha levels and developing persistent symptoms (Hernández et al., 2023). Aucott noted that there are other interesting inflammatory cytokines being identified that could serve as biomarkers to predict which patients are most at risk for long-term symptoms. There are also autoantibodies being investigated that could play a similar role.

Aucott briefly touched on a couple of potential new diagnostic approaches. In terms of metabolomics, which examines small molecules (e.g., fatty acids) by mass spectrometry, Aucott found that the metabolic profile for people who will develop PTLDS 6 months after initial infection is different from those who will return to health (Fitzgerald et al., 2021). Another area of exploration is the study of epigenetics to characterize host DNA modification in response to environmental insults such as infectious disease. Aucott shared information about a project he is working on with the Defense Advanced Research Projects Agency called ECHO that seeks to examine potential threats to DNA epigenetics from the effects of B. burgdorferi.3

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3 For additional information on the ECHO project, see https://www.darpa.mil/program/epigenetic-characterization-and-observation (accessed December 10, 2023).

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

The last area Aucott outlined as a potential for diagnostics development in Lyme disease is central nervous system imaging. The translocator protein (TSPO) binds glial cells that are activated and inflamed and can be used as a marker of inflammation, he explained. Positron emission tomography (PET) imaging revealed that the brains of people with chronic Lyme symptoms have more microglial activation compared to healthy controls (Coughlin et al., 2018). Using functional magnetic resonance imaging (fMRI), researchers have found that people with persistent Lyme disease symptoms had lower blood flow in their grey matter compared with control groups. However, some regions in the white matter appeared more highly activated compared with the control group, suggesting potential compensatory mechanisms in neurocognition (Marvel et al., 2022). Researchers are working to study this further to elucidate whether this pattern of white matter activation aligns with the brain fog of persistent Lyme. To Aucott’s understanding, no one has yet examined this in PTLDS. Since brain scans can be done and is not an invasive procedure, this could be developed and used as a diagnostic test.

In conclusion, Aucott called for improved diagnostics for acute Lyme disease and its infection-associated chronic illness. He shared that future opportunities for diagnostic tests include imaging approaches as well as measurement of host responses, including inflammatory processes and gene regulation, metabolic changes, and epigenetic signatures.

Epstein-Barr Virus and Associations with Multiple Sclerosis

Alberto Ascherio, Harvard T.H. Chan School of Public Health, presented on the study linking EBV to MS, referenced in Chapters 2 and 3, explaining that his research team sought to estimate the risk of developing MS before and after EBV infection. Researchers found that risk of developing MS was extremely low before EBV infection but increased by 32-fold following EBV infection (Bjornevik et al., 2022). In contrast, individuals who were already positive for cytomegalovirus (CMV) at the beginning of the study were found to have a reduced risk of developing MS. Furthermore, the study demonstrated that EBV infection preceded not only the first clinical symptoms of MS, but also the elevation of serum neurofilament light chain (a marker of MS onset and progression) by up to 6 years (Bjornevik et al., 2020). He clarified that MS is a rare complication of EBV infection, but other factors at play that can increase risk aside from family history include vitamin D deficiency, tobacco smoking, obesity during adolescence, and low intake of alpha-linolenic acid.

Focusing on biomarkers, Ascherio referenced work that began more than 20 years ago studying antibody titers against EBV and CMV before the onset of any neurological symptoms of MS. The results of these studies support that EBV plays a role in the etiology of MS by showing that the serum levels of Immunoglobulin G (IgG) antibodies to EBV nuclear antigens

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

(EBNA) are a strong predictor of MS (Levin et al., 2005). He also noted that anti-EBNA titers may be a marker of a strong cellular immune response against EBV, which could complement the hypothesis of the antibody’s molecular mimicry. However, he did not think the anti-EBNA titers could be used for diagnostic purposes. Another characteristic of these antibodies is that elevated levels are seen up to 16–20 years before the onset of MS, said Ascherio. However, he noted, these antibodies do not seem to predict the disease severity or progression, and there does not seem to be any evidence that higher antibody titers are associated with faster disease progression.

In contrast to what is known in humoral immunity, Ascherio said, comparable data on cellular immunity are not available. A dataset comparable to what has been assembled for humoral immunity would be the best way to study cellular immunity against EBV before the onset of MS. He pointed to a study done in individuals with clinical MS showing that the frequency of cytotoxic CD8 T cells against EBV is higher in the MS patients than controls–this increase was of similar magnitude to the increase in CD8 T cells against SARS-CoV-2 observed in individuals with COVID 19 (Schneider-Hohendorf, 2022). According to Ascherio, this is consistent with the hypothesis that EVB not only causes MS, but also drives the long-term disease process. Based on the currently available evidence, he surmised that EBV reactivation in the brain is likely the leading cause of the pathology for MS.

USING MICROCLOTS AS INDICATORS OF DISEASE

Resia Pretorius, Stellenbosch University, emphasized the relevance of cellular receptor and inflammatory marker interactions in driving various disease pathologies. Her lab has spent years looking at how inflammatory molecules may cause pathological blood clotting, including effects on platelets, red blood cells, and the clotting protein fibrinogen.4 They have focused on the numerous membrane receptors on platelets that can cause platelet hyperactivation when these inflammatory molecules are in circulation. In the context of COVID-19, Pretorius said, it is important to remember that platelets can form complexes with not only other platelets, but also immune cells. These platelet–immune cell complexes can then influence autoimmunity and immunity. When you are healthy, she explained, fibrinogen is a soluble protein, but when it interacts with a circulating inflammatory molecule, it can change its shape (see Figure 4-2). A typical protein has lots of alpha coils and beta sheets, she explained, but when they interact with inflammatory molecules, the alpha coils untwist into large beta sheets, which causes the clotting.

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4 For more information on inflammatory molecules and chronic inflammation, see https://www.nature.com/articles/s41574-018-0059-4 (accessed November 30, 2023).

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
An image depicts the effect of inflammatory molecules on fibrinogen. At the top of the image is an image of fibrinogen, with the strands made of three shades of blue. Below on the left, healthy fibrin polymerization is depicted with tight alpha coils. In the middle, inflammatory molecules depicted in red bind to the fibrinogen protein. On the right, fibrinaloid formation is depicted with the alpha coils untwisted into beta sheets, showing the structural changes that result from inflammation.
FIGURE 4-2 Pathological clotting.
SOURCE: Resia Pretorius presentation, June 29, 2023; created with BioRender.com.

Pretorius’ team was already studying clotting pathologies in South Africa using scanning electron microscopy when COVID-19 emerged. It became clear to her that the cohort of patients with acute infection had significantly hyperactivated platelets. Pretorius and her team found there was also significant microclot formation in samples from intensive care unit (ICU) patients, much more than previously found in patients with type II diabetes or healthy controls. After the initial studies on acute COVID-19, her team also examined and found that the spike protein can trigger significant platelet hyperactivation as well as microclot formation. This finding is also supported by studies in Sweden, she noted, where researchers found that the spike protein itself is an amyloidogenic protein (Nyström and Hammarström, 2022).

Pretorius explained that she and her collaborators began studying long COVID in early 2021, as it became clear that many patients were not fully recovering from the acute infection and had significant symptoms. They found significant platelet hyperactivation in these patients as well, with platelets clotting together and binding to each other forming different protein complexes (Laubscher et al., 2021). Because diagnosis was difficult with the research methods they used in the lab, they developed a platelet grading system to show how they anticipated the platelets in a person with long COVID may look (see Figure 4-3). The first row represents healthy platelets, the second and third row is what platelet hyperactivation may look like in someone with diabetes or rheumatoid arthritis, and the fourth row is what platelets in individuals with acute and long COVID may look like. Examples of stage 4 microclots are depicted in the bottom row as detected by (A) bright-field microscopy, (B) fluorescence microscopy, and (C) an overlay of fluorescence and bright-field microscopy (Laubscher et al., 2021).

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
A grid of 15 images depicting platelets in a variety of patients shows a grading system moving from healthy platelets at the top to microclot formation at the bottom. Each tile in the grid consists of a black background with platelets in neon green. From the top down, each row contains more neon green as microclotting occurs.
FIGURE 4-3 A microclot grading system.
SOURCE: Resia Pretorius presentation, June 29, 2023; Laubscher et al., 2021.

Pretorius and colleagues employed proteomics to try and understand what was inside the clots, but they were surprised when a basic enzymatic process was unable to digest the clots and prepare samples for proteomics analysis, Pretorius said. Eventually, they were able to conduct the analysis and found numerous inflammatory molecules trapped inside the microclot complexes. These included von Willebrand Factor, fibrinogen molecules, and a molecule called alpha two antiplasmin, which prevents the clot breakdown (Pretorius et al., 2021). This result was replicated in a larger cohort study. Pretorius shared a paper that documents a novel cell-free methodology to detect microclots inside plasma from patients with long COVID (Turner et al., 2023). She noted that microclotting and platelet hyperactivation were also found in ME/CFS patients, though not to the extent they saw in long COVID patients. In both ME/CFS and long COVID patients,

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

she added that they recently found endothelial debris in their platelet-poor plasma, which confirmed an endothelial origin.

In summary, Pretorius said, ischemic reperfusion injury has been found in all the long COVID patients that her group studied. With the current evidence, she posited that long COVID is possibly a form of thrombotic endothelitis. She noted that there is a relevance of receptor-inflammatory marker interactions that drive disease and advocated for looking at protein–protein interactions when considering new methodologies for diagnosis.

NEXT-GENERATION AND METAGENOMIC SEQUENCING

Charles Chiu, University of California, San Francisco, discussed metagenomic sequencing for potentially aiding in diagnoses. Infectious disease doctors often faced with major diagnostic challenges, he said. For example, in as many as 62 percent of pneumonia patients who present to the hospital, providers are unable to diagnose an infection despite testing for bacterial and viral pathogens (Jain et al., 2015). Meningitis and encephalitis are neurological diseases thought to have infectious etiology, but the cause remains unknown in roughly half of meningitis or encephalitis cases (Glaser et al., 2006). Even in patients with well-characterized infectious syndromes like sepsis, he continued, doctors are unable to make a definitive diagnosis based on currently available tests in approximately 20 percent of the cases. Failure to make an accurate and timely diagnosis delays therapy, increases mortality, and increases health care costs.

Chiu noted that the only major indirect test available is antibody detection to diagnose infections. His laboratory has been working to develop clinical metagenomic sequencing as a way to diagnose acute illnesses, and potentially applying it to associated chronic illnesses. Metagenomic sequencing provides a way to comprehensively characterize the genomic material in a clinical sample by sequencing all of the DNA and RNA present, he explained. In theory, one would then be able to identify any causative organism in that clinical sample, potentially making this a powerful tool for investigating emerging infections. Chiu and his collaborators have validated this sequencing process in the laboratory as well as in clinical studies, and they contend that they can run the same assay on a variety of body fluids. However, how best to analyze the data and gather results remains a challenge. His team developed an automated pipeline that is compliant with the Health Information Portability and Accountability (HIPAA) Act and produces results that can be interpreted by a lab director, even without bioinformatics expertise.

Furthermore, Chiu said that parallel metagenomic sequencing of multiple samples can provide more throughput in diagnoses compared to conventional clinical testing approaches (Wilson et al., 2019). He and col-

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

laborators are currently working to enable any clinical lab to use their test; they have been able to reduce the metagenomic next-generation sequencing assay procedure from 2 or 3 days of processing with 300 steps, down to same-day results with just about 20 steps. He sees this test being used more routinely in the near future as part of clinical laboratory operations.

Application to Chronic Illnesses

Considering the application of metagenomic sequencing in infection-associated chronic illnesses research, Chiu revealed that most of what is sequenced is actually not the pathogen, but the patient’s own DNA and RNA. This has major implications for precision medicine, as it can provide significant insights into host response, which then inform a doctor in personalizing medicine and treatment to best suit the patient. The host response to various infections can be different for each individual. For example, some patients with West Nile virus infection are asymptomatic while others develop fatal encephalitis. Similar variation in outcomes was seen with COVID-19 as well. Chiu shared a vision of the future in which instead of researchers selecting major disease-specific pathways for an illness like Lyme disease, artificial intelligence (AI) selects them based on a machine learning algorithm, identifying the specific features or genes for a given disease. For example, he took data from 1,000 spinal fluid samples representing various infections and syndromes, and divided them into four major categories: bacterial, viral, fungal, and autoimmune. After exposing the machine learning model to the training set of well-categorized samples, it was able to then classify a test set with 90 percent accuracy for each of the four comparisons.

In another example of acute flaccid myelitis (AFM) in children, Chiu shared that it is often difficult to identify the potential causative agent, enterovirus D68, in spinal fluid and the diagnosis is usually made incidentally when examining other secretions. However, researchers found a signature for AFM in spinal fluid samples that were otherwise microbiologically negative if the disease is associated with infection by enterovirus A71 or D68. What the researchers hope to obtain in addition to a metagenomic sequencing result, said Chiu, is a host-response classifier that can identify specific types of infections and potentially noninfectious causes. Using the algorithm to cluster these signals, the clinician can see what diagnoses may be most closely tied to a cause based on the host response, such as autoimmune diagnosis being related to viral infection, he explained. Chiu’s team is also working to identify signatures specific to neurologic syndromes by taking the samples that were most well characterized and successfully identifying signatures for cancer, amyloidosis, and MS to develop a classifier tool.

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

Applying this approach to Lyme disease, Chiu and colleagues were able to show that host response can be used to identify infections (Servellita et al., 2022). Chiu anticipated that the ability to run this type of assay longitudinally allows for the development of tests that can diagnose infection and even potentially monitor the course of a chronic illness related to infection. Using Lyme disease patients as an example, he presented data from longitudinal host-response analyses showing the Lyme disease classifier was persistent in samples for as long as 6 months after early Lyme presentation. In the future he hoped to generate differential classifiers that can monitor the course of any given chronic disease.

In conclusion, Chiu said that metagenomic sequencing is a promising approach for diagnosis of infectious diseases. By using the host-response profiling he and his team developed, biomarkers can be identified to help with diagnosis and monitoring chronic disease progression. Chiu noted that advancement of this new technology will require close coordination with regulatory statues and bodies such as Clinical Laboratory Improvement Amendments and the Food and Drug Administration in order to develop useful reference standards and validation measures that could streamline the path to use in clinical practice.

DISCUSSION

The discussion focused mainly on the potential for future diagnostic tests and biomarker profiling. Regarding the validation of AI tools, Chiu said there has been increasing interest from the National Institutes of Health and other government agencies in developing guidelines for how these types of tests would be validated, and how to ensure they are being correctly indicated. He is hopeful that the ultimately approved tests will be disease agnostic and can be applied to diagnose a variety of different conditions.

Another question was in response to data Chiu presented that show markers of the host response for Borrelia clustering more closely with host responses to viruses than to other bacterial infections. The workshop attendee asked what markers might be used to distinguish between these pathogens. Chiu pointed out that infection by each pathogen may have very distinct features, so gene expression profiling can potentially be used to identify specific diagnostic markers in each case. An audience member highlighted the latency in symptom emergence experienced by many patients, who do not realize or make the connection between the initial infection until chronic symptoms manifest. From a diagnostic perspective, she asked, could technology reach a scale where it could become a preventive tool so diseases can be identified earlier, avoiding the long-term chronic illnesses that many are suffering from? Chiu noted that there has been increasing

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×

interest in shifting the focus away from disease and more on health. Technology exists that can do comprehensive -omics profiling of anyone, he said, so this could be a powerful tool for evaluating a person’s status and whether they are at risk of developing disease in the future. Beyond just diagnostics, metagenomic profiling could have a role as a predictive tool as well.

Avindra Nath, National Institute of Neurological Disorders and Stroke, shared emerging themes that he took away from the session’s presentations, beginning with the realization that there is a commonality between various types of postinfectious syndromes suggesting a shared pathophysiology though likely through different mechanisms. Secondly, he said, is the importance of the immune response, which several panelists have highlighted in their remarks. Even if a patient does have a persistent antigen, what is really driving the symptomatology could be an aberrant immune response. Lastly, many of these conditions seem to be diseases of the brain—but they are all interrelated, and there is a clear need to improve the ability to interrupt the negative cycles of pathology. With so many people already affected, he argued, we cannot afford to wait another decade to figure out all of the mechanisms before taking action to help the patients. Instead, he emphasized the need to start clinical trials now with the information available, and then continue to study the pathophysiology in the context of these trials.

Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 41
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 42
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 43
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 44
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 45
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 46
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
Page 47
Suggested Citation:"4 Potential Research Priorities and Opportunities in Diagnostics." National Academies of Sciences, Engineering, and Medicine. 2024. Toward a Common Research Agenda in Infection-Associated Chronic Illnesses: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27462.
×
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The National Academies Forum on Microbial Threats and Forum on Neuroscience and Nervous System Disorders hosted a hybrid public workshop in June 2023 to explore opportunities to advance research and treatment of infection-associated chronic illnesses. The illnesses discussed in this workshop, including COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), persistent or posttreatment Lyme disease syndrome (PTLDS), and multiple sclerosis (MS), share overlapping mechanisms and symptoms and have been inadequately researched. Recognizing these commonalities, speakers identified the need to advance research more comprehensively, translating to improved diagnostic and treatment options for patients across multiple conditions.

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