C6 Peptide Test May Indicate Borrelia miyamotoi Infection

POSITIVE C6 TEST—BUT WESTERN BLOT IS NEGATIVE?
IT MAY NOT BE LYME DISEASE

Quick Answer: A positive C6 peptide test with a negative Western blot may suggest Borrelia miyamotoi infection rather than Lyme disease.

Clinical Insight: When laboratory results don’t match the clinical picture, alternative tick-borne infections should be considered.

Koetsveld and colleagues examined C6 reactivity in sera from mice infected with Borrelia miyamotoi and from 46 patients with PCR-confirmed disease. :contentReference[oaicite:0]{index=0}

Their findings suggest that the C6 peptide assay—commonly used in Lyme disease testing—may also serve as an indicator in a Borrelia miyamotoi testing strategy.

A positive C6 test with a negative Western blot may suggest Borrelia miyamotoi infection rather than Lyme disease and should prompt further evaluation.

This pattern reflects a broader issue in tick-borne illness: laboratory results do not always align with clinical presentation. This diagnostic gap is explored further in Why Lyme Disease Tests the Limits of Medicine.

It is also relevant when evaluating tick-borne coinfections, where overlapping infections may alter standard testing results.

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Positive C6 with Negative Western Blot: A Clinical Pattern

In clinical practice, a positive C6 result followed by a negative Western blot is often dismissed as a false-positive Lyme test.

However, emerging evidence suggests this pattern may reflect infection with Borrelia miyamotoi, particularly in patients with fever and recent tick exposure.

Recognizing this pattern can help avoid missed diagnoses and guide appropriate follow-up testing.

The authors recommend further evaluation when the Western blot is negative:

“We propose that a positive C6 EIA with negative immunoblot, especially in patients with fever several weeks after a tick bite, warrants further testing for B. miyamotoi.”

Testing for the glycerophosphodiester phosphodiesterase (GlpQ) gene may provide a more specific test, as GlpQ does not cross-react with Borrelia burgdorferi.

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What the Research Shows

Cross-reactivity against the C6 peptide was confirmed in most infected mice, and a C6 antibody response was present in the majority of patients.

In a separate study, the C6 ELISA was positive in more than 90% of convalescent-phase samples from patients with Borrelia miyamotoi disease.

Because Borrelia miyamotoi and Lyme disease occur in the same regions, caution is needed when interpreting C6-reactive results.

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Clinical Takeaway

A positive C6 test with a negative Western blot should not be dismissed outright.

In the appropriate clinical setting, this pattern may indicate Borrelia miyamotoi infection or another tick-borne illness.

Further evaluation is warranted.

Editor’s note: Some patients may have overlapping infections. In this study, a subset also showed Lyme Western blot reactivity, raising the possibility of co-infection or incomplete immune response.

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Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

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