What is "chronic Lyme disease?"
Lyme disease is an infection caused by the bacterium Borrelia burgdorferi. In the majority of cases, it is successfully treated with oral antibiotics. In some patients, symptoms, such as fatigue, pain and joint and muscle aches, persist even after treatment, a condition termed “Post Treatment Lyme Disease Syndrome (PTLDS)”.
The term “chronic Lyme disease” (CLD) has been used to describe people with different illnesses. While the term is sometimes used to describe illness in patients with Lyme disease, it has also been used to describe symptoms in people who have no clinical or diagnostic evidence of a current or past infection with B. burgdorferi . Because of the confusion in how the term CLD is employed, and the lack of a clearly defined clinical definition, many experts in this field do not support its use.
How is Lyme disease treated?
For early Lyme disease, a short course of oral antibiotics such as doxycycline or amoxicillin is curative in the majority of the cases. In more complicated cases, Lyme disease can usually be successfully treated with three to four weeks of antibiotic therapy.
In patients who have non-specific symptoms after being treated for Lyme disease and who have no evidence of active infection (patients with PTLDS), studies have shown that more antibiotic therapy is not helpful and can be dangerous.
Has NIAID looked at the potential benefits of long-term antibiotic therapy on PTLDS?
Yes. NIAID has funded three placebo-controlled clinical trials on the efficacy of prolonged antibiotic therapy for treating PTLDS. The published results were subjected to rigorous statistical, editorial, and scientific peer review.
These trials were designed to ensure that several key parameters were addressed:
- The susceptibility of B.burgdorferi to the antibiotics used
- The ability of the antibiotics to both cross the blood-brain barrier and access the central nervous system and to persist at effective levels throughout the course of therapy
- The ability of the antibiotics to kill bacteria living both outside and inside mammalian cells
- The safety and welfare of patients enrolled in the trials
The first clinical trial, which included two multicenter studies, provided no evidence that extended antibiotic treatment is beneficial. In those studies, physicians examined long-term antibiotic therapy in patients with a well-documented history of previous Lyme disease but who reported persistent pain, fatigue, impaired cognitive function, or unexplained numbness. Those symptoms are common among people reporting PTLDS. Patients were treated with 30 days of an intravenous (IV) antibiotic followed by 60 days of an oral antibiotic.
These studies reinforced the evidence that patients reporting PTLDS symptoms have a severe impairment in overall physical health and quality of life. However, results showed no benefit from prolonged antibiotic therapy when compared with placebo in treating those symptoms.
In another study, published in 2003, researchers examined the effect of 28 days of IV antibiotic compared with placebo in 55 patients reporting persistent, severe fatigue at least six months following treatment for laboratory-diagnosed Lyme disease. Patients were assessed for improvements in self-reported fatigue and cognitive function.
In that study, people receiving antibiotics did report a greater improvement in fatigue than those on placebo. However, no benefit to cognitive function was observed. In addition, six of the study participants had serious adverse events associated with IV antibiotic use, four requiring hospitalization. Overall, the study authors concluded that additional antibiotic therapy for PTLDS was not supported by the evidence.
Another study supported by the National Institute of Neurological Disorders and Stroke again showed that long-term antibiotic use for Lyme disease is not an effective strategy for cognitive improvement. Researchers compared clinical improvement following 10 weeks of IV ceftriaxone versus IV placebo. The patients were treated for Lyme disease and presented with objective memory impairment tests. In a complicated statistical model, the ceftriaxone group showed a slightly greater improvement at 12 weeks, but at 24 weeks both the ceftriaxone and the placebo groups had improved similarly from baseline. In addition, adverse effects attributed to IV ceftriaxone occurred in 26 percent of patients. The authors conclude that because of the limited duration of the cognitive improvement and the risks involved, 10 weeks of IV ceftriaxone was not an effective strategy for cognitive improvement in these patients, and more durable and safer treatment strategies are still needed.
The results and interpretations of these studies have been reexamined since their publication, including by their own authors. While one team questioned the statistical interpretation of parts of these clinical trials, other researchers continue to support the studies’ initial conclusions.
In 2016, a clinical trial conducted in the Netherlands also concluded that in patients with persistent symptoms attributed to Lyme disease, longer term treatment with antibiotics did not provide additional benefits compared with shorter term regimens.
If long-term antibiotic therapy is not effective why do some people report improved symptoms following such treatment?
Carefully designed, placebo-controlled studies have failed to demonstrate that prolonged antibiotic therapy is beneficial. Although isolated success stories are always good to hear, such reports alone are not sufficient grounds to support a therapeutic approach.
A positive response to prolonged antibiotic therapy may be due to the placebo effect, which was reported as high as 40 percent in the studies described above.
Has NIAID looked at whether infection persists after antibiotic therapy?
Several recent studies suggest that B. burgdorferi may persist in animals after antibiotic therapy. In one study, NIAID-supported scientists found that remnants of B. burgdorferi remained in mice after antibiotic treatment. Another team of NIAID-supported investigators found that intact B. burgdorferi persist in nonhuman primates after antibiotic treatment. It was not possible to culture these bacteria and it is not clear whether they are infectious. More recent work by Hodzic et al. replicated the earlier finding of persisting DNA but non-cultivatable B. burgdorferi after antibiotic treatment using a mouse model. In 2017, scientists at the Tulane National Primate Research Centers, funded in part by an NIH research resources grant, reported evidence of persistent and metabolically active B. burgdorferi after antibiotic treatment in rhesus macaques.
In a first-of-its-kind study for Lyme disease, NIAID-supported researchers have used live, disease-free ticks to see if Lyme disease bacteria can be detected in people who continue to experience symptoms such as fatigue or arthritis after completing antibiotic therapy). This study remains underway.
NIAID has not limited its efforts to animal studies, and researchers have proposed the existence of drug-tolerant, persistor cells of B. burgdorferi in cell cultures. Additional research is needed and continues to be supported by NIAID to learn more about persistent infection in cell culture and animal models and its potential implication for human disease.