C6 peptide test may indicate Borrelia miyamotoi infection

Koetsveld and colleagues examined C6 reactivity in sera from both mice infected with Borrelia miyamotoi and from 46 patients with PCR-confirmed Borrelia miyamotoi disease (BMD). Their findings suggest that the C6 peptide assay—commonly used in Lyme disease testing—may also serve as an indicator in a Borrelia miyamotoi test 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 highlights a broader issue in tick-borne disease: laboratory results do not always align with clinical presentation. This diagnostic gap is explored further in Why Lyme Disease Tests the Limits of Medicine.

This diagnostic pattern is particularly relevant when evaluating tick-borne coinfections, where overlapping infections may alter standard testing results.

They found, “Cross-reactivity against the C6-peptide was confirmed in 21 out of 24 mice experimentally infected with B. miyamotoi,” and a C6 antibody response was present in 39 of 46 patients.¹

In a separate study, investigators reported that “in a set of 43 sera from 24 patients with Borrelia miyamotoi disease in the United States, the C6 ELISA was positive in the vast majority (>90%) of convalescent-phase samples.”²

Koetsveld cautions, however, that because Borrelia miyamotoi disease and Lyme borreliosis occur in the same geographic regions, “caution should be used when relying solely on C6-reactivity testing.”

[bctt tweet=”The C6 peptide test used for Lyme disease may also help identify Borrelia miyamotoi infection.” username=”DrDanielCameron”]

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 Borrelia miyamotoi test, as GlpQ does not cross-react with Borrelia burgdorferi.

“Our results demonstrate that cross-reactive antibodies against the C6 peptide regularly occur in patients with Borrelia miyamotoi disease,” writes Koetsveld.

He adds that “as many as 90% (95% CI 68.3–98.8) of patients were C6-reactive in samples obtained 10 to 19 days after symptom onset.”

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 and warrants further evaluation.

Editor’s note: Some patients may have concurrent or overlapping infections. In this study, 10 of 39 patients demonstrated Western blot reactivity for Lyme disease, raising the possibility of co-infection or incomplete serologic responses. This further complicates interpretation of standard Lyme testing.

Koetsveld and colleagues examined C6 reactivity in sera from both mice infected with Borrelia miyamotoi and from 46 patients with PCR-confirmed Borrelia miyamotoi disease (BMD). Their findings suggest that the C6 peptide assay—commonly used in Lyme disease testing—may also serve as an indicator in a Borrelia miyamotoi test 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 highlights a broader issue in tick-borne disease: laboratory results do not always align with clinical presentation. This diagnostic gap is explored further in Why Lyme Disease Tests the Limits of Medicine.

This diagnostic pattern is particularly relevant when evaluating tick-borne coinfections, where overlapping infections may alter standard testing results.

They found, “Cross-reactivity against the C6-peptide was confirmed in 21 out of 24 mice experimentally infected with B. miyamotoi,” and a C6 antibody response was present in 39 of 46 patients.¹

In a separate study, investigators reported that “in a set of 43 sera from 24 patients with Borrelia miyamotoi disease in the United States, the C6 ELISA was positive in the vast majority (>90%) of convalescent-phase samples.”²

Koetsveld cautions, however, that because Borrelia miyamotoi disease and Lyme borreliosis occur in the same geographic regions, “caution should be used when relying solely on C6-reactivity testing.”

[bctt tweet=”The C6 peptide test used for Lyme disease may also help identify Borrelia miyamotoi infection.” username=”DrDanielCameron”]

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 Borrelia miyamotoi test, as GlpQ does not cross-react with Borrelia burgdorferi.

“Our results demonstrate that cross-reactive antibodies against the C6 peptide regularly occur in patients with Borrelia miyamotoi disease,” writes Koetsveld.

He adds that “as many as 90% (95% CI 68.3–98.8) of patients were C6-reactive in samples obtained 10 to 19 days after symptom onset.”

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 and warrants further evaluation.

Editor’s note: Some patients may have concurrent or overlapping infections. In this study, 10 of 39 patients demonstrated Western blot reactivity for Lyme disease, raising the possibility of co-infection or incomplete serologic responses. This further complicates interpretation of standard Lyme testing.

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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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