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Metabolic biosignature aids in detection of early Lyme disease

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March 23, 2015

A metabolic biosignature may detect early Lyme disease before patients have a detectable antibody response to Borrelia burgdorferi, according to data published in Clinical Infectious Diseases.

“Current diagnostic tests for early Lyme disease have excellent specificity, but relatively poor sensitivity,” John T. Belisle, PhD, professor in the department of microbiology, immunology and pathology at Colorado State University, told Infectious Disease News. “Thus, we wanted to test whether a new technology — metabolomics — that allows for the detection and measurement of a large number of analytes in a single sample, could be used to improve Lyme disease diagnostics.”

Belisle and colleagues used liquid chromatography-mass spectrometry to analyze retrospective serum samples from patients with early Lyme disease, other diseases and healthy controls for small molecule metabolites. They selected a biosignature for early Lyme disease, which then was used as an experimental diagnostic tool for additional patient sera. The accuracy of the method was compared with the two-tier serology method.

The initial biosignature included 95 molecular features that were specific to early Lyme disease, but further statistical modeling narrowed the signature to 44 molecular features.

When the researchers tested the biosignature in additional sera that were not used to develop the biosignature, the average accuracy was 88% for identifying early Lyme disease and 95% for healthy controls. There were five independent liquid chromatography-mass spectrometry runs conducted on all these samples. For all the tests, the sensitivity ranged from 84% to 95%, and the specificity ranged from 90% to 100%. The researchers said that the sensitivity of two-tier testing for the same early Lyme disease samples ranged from 43% to 48%, and the metabolic profiling identified 77% to 95% of the early Lyme disease samples that were negative by two-tier testing.

“This proof-of-concept study demonstrates that technologies beyond antibody-based serological tests can be developed and applied for the early diagnosis of Lyme disease,” Belisle said. “However, in its current form, this test cannot yet be directly applied to clinical practice. With continued development, this technology does hold potential for improved diagnosis of early Lyme disease.”

Belisle said his team is currently evaluating the technology with other specimen types, such as urine. They are also mapping metabolic biosignatures for other stages of Lyme disease. – by Emily Shafer

Disclosure: The researchers report no relevant financial disclosures.

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PERSPECTIVE
Eugene Shapiro

Eugene Shapiro

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.


Eugene Shapiro, MD
Infectious Disease News Editorial Board member

Disclosure: Shapiro reports no relevant financial disclosures.