When patients ask how to test for Lyme disease, they’re often surprised by the complexity—and the limitations—of the current testing system. While laboratory tests can be helpful, they do not tell the whole story. Clinical judgment is often just as important, especially when symptoms persist despite negative results.
This article explains how to test for Lyme disease, why results can be misleading, and when clinical judgment matters most.

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How to Test for Lyme Disease: The Standard Two-Tiered Approach

This is the testing pathway most patients encounter first and where confusion often begins.

The Centers for Disease Control and Prevention recommends a two-step testing approach for Lyme disease.

1. ELISA (Enzyme-Linked Immunosorbent Assay)

1. A screening test that looks for antibodies to Borrelia burgdorferi

2. If negative, testing often stops—even when symptoms strongly suggest Lyme disease

2. Western Blot (If ELISA Is Positive or Equivocal)

1. Detects specific IgM and IgG antibodies by evaluating antibody “bands”

2. IgM bands tend to appear earlier in infection

3. IgG bands typically develop later

Under CDC criteria, a positive IgG Western blot requires 5 of 10 specific bands. This threshold was developed for public health surveillance, not for diagnosing individual patients. Applying it too rigidly can result in missed diagnoses, particularly in chronic or late-stage disease.

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Limits of CDC Criteria in How to Test for Lyme Disease

Several factors complicate how to test for Lyme disease:

1. Antibodies can take weeks to develop, leading to false negatives in early infection

2. Some patients mount a weak immune response and never test positive

3. In late Lyme disease, antibody levels may wane and fall below detection

4. Co-infections such as Babesia or Bartonella are not detected by standard Lyme tests

5. Band interpretation may exclude potentially meaningful markers, including bands 31 and 34

These limitations can delay diagnosis and, in some cases, lead to patients being dismissed altogether.

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What If Only IgM Is Positive?

Some patients develop IgM positivity without ever progressing to IgG. This result is often dismissed, but in clinical settings—particularly when patients have hallmark symptoms—it may warrant further evaluation in appropriate clinical contexts.

I have seen many patients with IgM-only results and clear clinical features improve with appropriate treatment, even when their testing did not meet CDC reporting criteria.

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Why Bands 31 and 34 Deserve a Second Look

Two antibody bands—31 (OspA) and 34 (OspB)—are highly specific to Lyme disease. They were excluded from CDC criteria during Lyme vaccine trials in the 1990s for surveillance reasons, not because they lacked clinical relevance.

Today, these bands:

1. Are still reported by some specialty laboratories

2. May offer valuable diagnostic information

3. Can strengthen the case for Lyme disease when other bands are borderline or absent

Clinicians familiar with Lyme disease may consider these findings within the broader clinical picture.

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How to Test for Lyme Disease Beyond the Western Blot

Several newer testing approaches aim to address limitations of traditional Lyme diagnostics, including:

1. C6 peptide ELISA

2. VlsE-based assays

3. Modified Two-Tier Testing (MTTT)

These methods seek to improve early detection and simplify interpretation. While promising, they do not replace careful clinical evaluation and should be viewed as supportive tools, not definitive answers.

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Specialty Laboratory Testing: A Word of Caution

In response to the known limitations of standard Lyme testing, a growing number of specialty laboratories have developed alternative or adjunctive testing approaches. These may include expanded antibody panels, different antigen targets, or modified interpretation criteria intended to capture immune responses that standard tests may miss.

While these tests may provide additional information in select cases, they are not universally standardized, and their results should be interpreted cautiously and always in clinical context. No laboratory test—standard or specialty—can substitute for a careful assessment of exposure history, symptom patterns, and disease progression.

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Why Clinical Judgment Still Matters

I frequently see patients with:

1. Known or likely tick exposure

2. Fatigue, joint pain, neurologic symptoms, or cognitive decline

3. IgM-only results or partial IgG bands

4. Negative tests despite classic Lyme features

5. Symptomatic improvement with appropriate antibiotics

In these cases, testing alone should not determine care. History, symptom patterns, and response to treatment remain critical.

This diagnostic uncertainty underscores why early recognition is central to preventing chronic Lyme disease:

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What to Do If You Suspect Lyme Disease

Not every step applies to every patient, but taken together, these considerations can help clarify next steps.

Testing and Timing Considerations

1. Ask for a full Western blot, not just an ELISA

2. Consider the timing of testing—early tests may miss infection

3. Re-test if symptoms persist or evolve

4. Review prior test reports carefully for dismissed bands

5. Be aware that prior antibiotics may suppress antibody formation

6. Recognize that different Borrelia species may not be detected by standard tests

Clinical Context and Next Steps

1. Seek a second opinion from a clinician experienced in tick-borne illness

2. Evaluate for co-infections (Babesia, Bartonella, Ehrlichia)

3. Avoid steroids until infection has been reasonably excluded

4. Discuss empirical treatment trials when clinical suspicion remains high

5. Consider neurologic, cardiac, or rheumatologic referral when appropriate

6. Acknowledge the emotional toll of medical dismissal

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Final Thoughts

Laboratory tests are useful—but they are imperfect. Many patients with Lyme disease never meet CDC testing thresholds and are left untreated. Others test positive yet are told their results are insignificant.

When symptoms persist or testing is incomplete, clinical experience must guide decision-making. Lyme disease is a clinical diagnosis, and testing should support, not override, that process.

When test results and symptoms diverge, timing and clinical context should guide decisions—not a single laboratory threshold.

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Frequently Asked Questions About Lyme Disease Testing

Can Lyme disease tests be negative even if someone is infected?
Yes. Early in infection, antibodies may not yet be detectable, which can result in false-negative test results.

How soon after a tick bite should Lyme testing be done?
Testing too early can miss infection. Antibodies often take several weeks to develop, so timing plays an important role in interpretation.

Does a negative ELISA rule out Lyme disease?
No. A negative screening test does not always exclude Lyme disease, especially when symptoms and exposure history are suggestive.

What does an IgM-only positive Lyme test mean?
In some clinical contexts, IgM positivity without IgG may warrant further evaluation rather than dismissal.

Why do some people never test positive for Lyme disease?
Some individuals mount a weak or atypical immune response, and infection may not be captured by standard blood-based testing.

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Have you struggled with confusing Lyme test results?
Share your testing story in the comments—your experience may help others navigate this complex diagnostic landscape.

Resources

1. CDC – Lyme Disease Diagnosis and Testing
2. Why Some Lyme Patients Stay Sick – Dr. Daniel Cameron
3. Symptoms on Long-Term Follow-Up – Dr. Daniel Cameron