Metabolic biosignature aids in detection of early Lyme disease

Eugene Shapiro, MD

The diagnosis of early Lyme disease has been somewhat problematic because patients often develop symptoms and signs of early Lyme disease 7 to 14 days after a tick transmits the B. burgdorferi. Standard methods for diagnosing bacterial diseases, such as culture or PCR, have poor sensitivity. Likewise, tests for circulating antibody are not generally recommended because they typically do not become positive until 3 to 4 weeks after infection. Thus, while serologic tests have excellent sensitivity for late manifestations of Lyme disease, like arthritis, sensitivity is poor for early Lyme disease.

In this study, the investigators tried a different approach. They performed metabolomics on samples of sera from patients with early Lyme disease and on controls without Lyme disease. They found that, in a discovery process that has a number of limitations (eg, inherent variability in different runs of the procedure) that the authors acknowledge in the paper, a specific group of small molecules, together, could be used as a metabolic signature to identify patients with early Lyme disease with better sensitivity than standard two-tier antibody tests. Is this important? Perhaps. First, as the authors acknowledge, this is a long way from being a clinically useful test for technical reasons. Moreover, although sensitivity was better than standard serology, it was far from perfect. There is no discussion of the cost of such a test in the paper. In addition, since virtually all of the patients had erythema migrans (EM), one could question whether there is any reason for a blood test to make the diagnosis. While one may not always be able to be certain that a rash is EM at a single point in time, with follow-up, one is likely to be able to make this diagnosis clinically with pretty good sensitivity and specificity.

The symptoms of early Lyme disease in the absence of EM (eg, fatigue, arthralgia, myalgia, fever) are extremely non-specific, and very common. In a patient with only non-specific symptoms, the probability that symptoms are due to Lyme disease is so low, even in a highly endemic area, that any test is not likely to be useful unless it is close to 100% specific. While a search for a simple, accurate and clinically useful diagnostic test for early Lyme disease goes on, one can reasonably question whether such a test is needed and whether there is any reasonable chance that one will be accurate enough to be clinically useful. The need is primarily to prove that someone with symptoms but no rash does NOT have Lyme disease. It is very difficult to prove a negative. There may be situations, such as distinguishing patients with Southern tick-associated rash illness from those with early Lyme disease, or identifying those with atypical EM, in which such a test would be useful.  It is a noble quest, but I am skeptical that a test that is sufficiently sensitive and specific to be clinically useful will be available anytime soon.

That said, while using metabolomics as an approach to diagnosing early Lyme disease likely will not prove to be clinically useful in the near future, this approach is relatively novel for diagnosis in infectious diseases and may hold promise, especially if applied in other areas. For example, might a metabolic biosignature be useful as a way to distinguish active from past Lyme disease.