Identifying the methodology gap that prevents treatment of infection-triggered chronic diseases

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?"

Steven Schutzer, Study Corresponding Author, Physician-Scientist and Professor, Rutgers New Jersey Medical School, Rutgers University

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."