Review Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses, 2026, Arnaboldi et al

[Nightsong]

Abstract​

Infection-associated chronic illnesses (IACIs) encompass a spectrum of poorly understood syndromes often marked by significant neurologic and multisystem symptoms following an infectious event.

This review focuses on several diseases representative of the IACI spectrum. These are post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). Their clinical and biological complexity, combined with a lack of clear diagnostic criteria and objective available laboratory biomarkers, makes them difficult to distinguish from conditions with overlapping features. This presents challenges for research studies, as well as diagnosis and clinical management. This diagnostic ambiguity, coupled with heterogeneous patient presentations, has led to challenges in research, including misclassification of study participants and inconsistent or irreproducible findings. Some PTLDS research exemplifies these issues, which also extend to other IACIs.

To advance the field, we highlight key methodological refinements and approaches for studying IACIs, including rigorous participant selection, standardized sample collection protocols, and the use of appropriate control groups, including those with microbiologic proof of the initial infection when known and technologically feasible. We also address broader influences on research quality, such as stigma, historical neglect, and the urgency to find treatments, which have contributed to the proliferation of poorly controlled studies and questionable practices. Drawing lessons from past challenges, we propose a path forward grounded in fit-for-purpose methodological rigour to improve scientific understanding and support evidence-based therapeutic development for IACIs.

Link | PDF (Brain, May 2026, open access)

 

[duncan]

Some heavy hitters from the Lyme field (Patricia Coyle, Maria Gomes-Solecki; some of you will recall Steven Schutzer when he compared Lyme with CFS several years back).

Why anyone would lead a research-methodological guideline with Lyme - arguably one of the most politically contentious and polarizing diseases, at least within the US - is beyond me. Forget about diagnostics or treatments - definitions alone can be a quagmire.

Within two paragraphs following the abstract, they earn my distrust, although I did read the entire thing as it also invokes ME/CFS and Long Covid, with people like Avindra Nath and Jonas Bergquist listed as contributing authors.

 

[dave30th]

definitions alone can be a quagmire.

I've just scanned the opening, but it seems like they're discussing post-treatment Lyme disease, which is pretty well-documented and is a different thing than chronic Lyme disease, in which there might be no evidence of initial Lyme infection.

 

[duncan]

I've just scanned the opening, but it seems like they're discussing post-treatment Lyme disease, which is pretty well-documented and is a different thing than chronic Lyme disease, in which there might be no evidence of initial Lyme infection.

See? Definitions.

There absolutely can be evidence of initial Lyme infection in chronic Lyme, certainly when it comes to formal research. I was enrolled in an NIH chronic Lyme study about 15 years ago, and you had to have documented evidence of a Lyme infection in order to participate.

Some folks played with the definition. Just as they did with PTLDS, which used to be post-Lyme disease syndrome, but PLDS became too much of a hot potato because of the backlash. I would suggest there are plenty of people diagnosed with PTLDS that never had antibody proof since that can be abrogated if treatment is rendered early.

ETA: I was in that chronic Lyme NIH study for three or four years, and I tested 2T positive through NIH researchers something like 10 out of 11 times.

 

[duncan]

This should not be about the chronic Lyme label, but they introduced it into their screed. So I just want to point out how frequently chronic Lyme was discussed and researched and acknowledged prior to the 1990's - when vaccines started to come into play.

We can thank the Bayh-Dole Act for much of what happened.

Eh. These authors are correct when they say we need better research methodology and practices, I will give them that.

 

[duncan]

One last observation about definitions:

In 1980's in the US, if you had documented Lyme, and were treated, and symptoms persisted, you were categorized as having chronic Lyme. Period. Definition back then of chronic Lyme: Lyme disease that cannot be resolved with "suggested" treatment protocol. You had a Bb case that would not resolve, most likely because treatment had been delayed ( this is similar to syphilis, a sister spirochetal disease). You had Lyme that would persist, even in the face of what some thought was an adequate treatment protocol for acute cases, but not so much for late stage disseminated. In other words, Lyme that went chronic.

There is an argument that the allure of vaccine $'s changed all that. A stubborn and intractable infection, in theory, would make getting a vaccine vetted and approved virtually impossible.

So the definition of Lyme had to change. Hello acute Lyme, and simply by virtue of a nagging patient community, PTLDS. Bye-bye chronic Lyme. You can add to the chaos TBD tandems, which complicated everything, i,e., is Lyme Lyme, or Lyme +?

To refine the definitions, you really needed better diagnostics, and that's where the Bayh-Dole wall slammed on the breaks: patent dollars were involved, and this was big money. Moreover, vaccine revenue was within a decade of the Bayh-Dole act creating a whole new frenzy into the mix, and incenting a different breed of inventive defintions.

 

[Jonathan Edwards]

This looks like someone interested in Lyme wanting to get some oxygen of publicity borrowed from the Long Covid 'IACD' bandwagon.

The introduction uses lay ideas of 'disease' or 'distinct condition' that get you nowhere if you are wanting to do real medical research. The group of diagnostic categories chosen to include makes no great sense - MS has nothing much to do with the others.

The relevant definitions are a mess, more because they should never be proposed as 'distinct conditions' than anything.

And you will never get that number of people to agree to anything cutting edge.

The proverbial camel, I think.

 

[duncan]

In LymeWorld. the Rat Fink factor wields a lot of influence.

It's like Clavell's King Rat: Money rules.

Medicine has been breached, and the Marginot line is/was Lyme and babs and rickettsia. And yes, ME/CFS.

 

[duncan]

By my sloppy math, at least one third of these Lyme authors has a vested or historic interest in Lyme vaccines.

When money matters in medicine, we should watch.

BTW: What happened to all those Lyme diagnoses in the late 1980's that got undone by 1995? Many, by virtue of Lyme leaders at that time, became, specifically, CFS patients.

 

[Dolphin]

Flawed but correctable research hindered progress in infection-triggered chronic conditions, including Lyme disease and Long COVID

Scientists, including Rutgers Health researchers, say studies of chronic symptoms after infections have been undermined by unproven diagnoses.

www.eurekalert.org

NEWS RELEASE 18-MAY-2026

Flawed but correctable research hindered progress in infection-triggered chronic conditions, including Lyme disease and Long COVID​

Peer-Reviewed Publication
RUTGERS UNIVERSITY


FacebookXLinkedInWeChatBlueskyMessageWhatsAppEmail

Thousands of Americans develop chronic persistent symptoms—such as fatigue, cognitive difficulties ("brain fog"), and other debilitating issues—each year following acute infections from Lyme disease, COVID-19, and other pathogens. Efforts to identify causes and produce treatments have failed. However, 16 leading researchers think they know part of the problem: study design.

In an article in Brain, researchers from Rutgers University, the National Institutes of Health, Rockefeller University, New York Medical College, the Icahn School of Medicine at Mount Sinai, Stony Brook University, Cold Spring Harbor Laboratory and other institutions contend that studies of infection-associated chronic illnesses suffer recurring problems such as the failure to prove participants have the relevant pathogen.

Key Challenges in Lyme Disease Research

Up to 20% of the roughly 476,000 Americans diagnosed with Lyme disease each year develop chronic, persistent cognitive impairment, fatigue and pain known as post-treatment Lyme disease syndrome. Researchers have spent decades looking for causes and cures, but many of their studies included anybody with only Lyme antibodies or bull’s-eye rashes rather than documenting Borrelia burgdorferi, the bacterium that causes Lyme disease. Unfortunately, Lone Star tick bites, drug reactions and other conditions can produce identical rashes, and antibody tests detect only past exposure, not active infection. The result is that studies may include people with entirely different diseases.

“How can studies produce concrete conclusions about Lyme when you don’t know if patients really had Lyme disease or if they had a mimicking condition?” asked the paper’s corresponding author, Steven Schutzer, a physician-scientist and professor at Rutgers New Jersey Medical School.

The authors also identified additional methodological shortcomings in prior research regarding control groups and sample handling.

Parallels with Long COVID and Broader Implications

Studies of Long COVID, which affects an estimated 9 million Americans, face similar challenges, particularly the tendency to group patients with possible different underlying mechanisms into a single population. Research into myalgic encephalomyelitis/chronic fatigue syndrome is even more difficult because no causative pathogen has been identified.

Yet progress is possible, even without knowledge of the underlying infection. The authors point to multiple sclerosis (MS) as evidence that rigorous study design has yielded helpful FDA-approved treatments.

Looking Ahead

“The framework we advocate is a major step forward since it provides rigorous and well-thought-out guidelines for every aspect of conducting clinical trials in this patient population,” said coauthor Avindra Nath, physician-scientist and clinical director of the NIH’s National Institute of Neurological Disorders and Stroke.

“Patients with post-infectious conditions have been waiting far too long for answers,” said Jacqueline Becker, a neuropsychologist at the Icahn School of Medicine at Mount Sinai, and a coauthor on the paper. “If we want clinical trials that actually lead to treatments, we have to get the fundamentals right: we must confirm diagnoses, choose the right comparison groups, and treat patient populations as distinct rather than lumping everyone together. Patients deserve that rigor.”

JOURNAL​

Brain

DOI​

10.1093/brain/awag016

METHOD OF RESEARCH​

Systematic review

SUBJECT OF RESEARCH​

Not applicable

ARTICLE TITLE​

Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses

ARTICLE PUBLICATION DATE​

18-May-2026

COI STATEMENT​

P.M.A. is also employed by Biopeptides, Corp., which has received NIH grant funding and has patents for diagnostic technologies for Lyme disease and other tick-borne diseases, not relevant to the contents of this paper. Other authors report no competing interests.

 

[duncan]

Flawed but correctable research hindered progress in infection-triggered chronic conditions, including Lyme disease and Long COVID​

Researchers have spent decades looking for causes and cures, but many of their studies included anybody with only Lyme antibodies or bull’s-eye rashes rather than documenting Borrelia burgdorferi, the bacterium that causes Lyme disease.

“How can studies produce concrete conclusions about Lyme when you don’t know if patients really had Lyme disease or if they had a mimicking condition?” asked the paper’s corresponding author, Steven Schutzer, a physician-scientist and professor at Rutgers New Jersey Medical School.

No shit. This has been a defining problem in LymeWorld for half a century.

ETA: I'm curious to find out how they propose to resolve this dilemma what with the diagnostic logjam that's beset the community since the '80's. Patents pose serious hurdles.

 

[duncan]

From the study:

" ME/CFS also shares key neurologic features with PTLDS, particularly in its hallmark symptoms of profound fatigue, post-exertional malaise and cognitive impairment.

ME/CFS is now strongly suspected to be an IACI, and research has identified possible underlying mechanisms that align with other IACIs. Its onset has also been linked to immune dysfunction, environmental factors and traumatic events. "

This idea that PEM is tied into Lyme or a Lyme derivative is, to me, disconcerting.

Just as disconcerting is to tie ME/CFS to traumatic events.

There is a lot more that I take issue with, but my brain is fading.