His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.