Mono and Lyme Disease: Can They Occur Together?

Can a patient have both infectious mononucleosis (mono) and Lyme disease at the same time? Although these illnesses are often considered separate conditions, they can occur together.

Several published reports have described Lyme disease mimicking infectious mononucleosis and infectious mononucleosis mimicking Lyme disease. However, a study by Koester and colleagues was the first published report describing children with evidence suggesting acute Lyme disease and Epstein-Barr virus (EBV) infection occurring concurrently.

Koester and colleagues wrote, “We describe the clinical presentation of two children with confirmed early Lyme disease and features suggestive of infectious mononucleosis, including one case of probable Lyme and EBV co-infection.”

These cases remind clinicians that the presence of one diagnosis should not automatically exclude the other, particularly in Lyme-endemic regions.

Case 1: Five-Year-Old Boy

A 5-year-old boy living in a Lyme-endemic region developed abdominal pain, intermittent fevers, neck pain, fatigue, and a sore throat. He had no known tick bite and no erythema migrans rash.

Because his heterophile antibody test was positive, physicians initially favored a diagnosis of infectious mononucleosis. His positive Lyme IgM immunoblot (bands 23, 39, and 41 kDa) was thought to represent cross-reactive antibodies rather than true Lyme disease.

Two days later, however, the boy returned with multiple erythema migrans lesions, confirming early disseminated Lyme disease.

He was treated with amoxicillin for 14 days. Within four days of starting antibiotics, his symptoms had almost completely resolved.

This case highlights an important diagnostic pitfall. It may be tempting to dismiss positive Lyme serology when infectious mononucleosis is suspected because cross-reactivity between EBV and Lyme antibody testing is well recognized.

As Koester explained, significant cross-reactivity can occur between Lyme disease and EBV serologic assays, making interpretation more difficult.

The authors also noted that delayed recognition of Lyme disease can have serious consequences. Previous reports have described patients who developed Lyme carditis and brachial plexopathy after Lyme disease was initially dismissed because infectious mononucleosis appeared more likely.

Clinicians should therefore avoid assuming that a positive heterophile antibody test excludes Lyme disease, particularly in patients living in Lyme-endemic areas or those with clinical findings suggestive of tick-borne infection.

Case 2: Eight-Year-Old Boy

An 8-year-old boy living in a Lyme-endemic region developed fever, headache, sore throat, abdominal pain, fatigue, muscle aches, and joint pain. Like the first patient, he had no history of a tick bite or erythema migrans rash.

Initial testing for Group A streptococcal pharyngitis and heterophile antibodies was negative.

Because Lyme disease remained a consideration, the child underwent Lyme testing. He had a positive enzyme immunoassay (EIA) followed by a positive IgM Western blot and was started on amoxicillin.

One week later, however, he continued to experience fevers with worsening abdominal pain and joint pain.

The presence of a sore throat, marked cervical lymphadenopathy, ultrasound-confirmed splenomegaly, and atypical lymphocytes strongly suggested concurrent Epstein-Barr virus (EBV) infection.

Additional testing confirmed infectious mononucleosis with positive viral capsid antigen (VCA) IgM and early antigen diffuse (EA-D) IgG antibodies. Repeat Lyme serology also demonstrated seroconversion with additional Western blot bands (28, 39, 41, 58, 66, and 93 kDa), further supporting the diagnosis of Lyme disease.

After completing a 21-day course of amoxicillin, the child made a complete recovery.

Why These Cases Matter

These cases demonstrate that infectious mononucleosis and Lyme disease are not necessarily competing diagnoses. Some patients may have evidence of both illnesses at the same time.

Koester and colleagues also reviewed laboratory records from the Marshfield Clinic Health System between 1999 and 2017 and identified 52 patients with positive Lyme IgM testing together with either a positive heterophile antibody test or positive EBV viral capsid antigen (VCA) IgM within a two-week period.

Although these findings do not prove simultaneous acute infection in every patient, they suggest that concurrent positive Lyme and EBV testing occurs more often than many clinicians appreciate.

Because fatigue, sore throat, fever, headache, lymphadenopathy, muscle aches, and joint pain can occur with both illnesses, clinicians should rely on the entire clinical picture rather than a single laboratory result when evaluating patients from Lyme-endemic regions.

Another important challenge is that acute EBV infection may lead to false-positive Lyme IgM results because of serologic cross-reactivity. Conversely, assuming that all positive Lyme serology is falsely positive may delay recognition and treatment of genuine Lyme disease.

For that reason, heterophile antibody testing or EBV serology should not be used by themselves to exclude Lyme disease in patients with compatible symptoms or epidemiologic risk factors.

The authors also raised an interesting unanswered question: could one infection temporarily increase susceptibility to the other, particularly in patients treated with corticosteroids for infectious mononucleosis? At present, there are insufficient data to answer this question.

Frequently Asked Questions

Can someone have mono and Lyme disease at the same time?

Yes. Although uncommon, published case reports describe patients with evidence of both infectious mononucleosis caused by Epstein-Barr virus and Lyme disease occurring concurrently.

Can Epstein-Barr virus cause a false-positive Lyme test?

Yes. Acute EBV infection may produce false-positive Lyme IgM antibody results because of serologic cross-reactivity. Test results should always be interpreted together with the patient’s symptoms, physical examination, and exposure history.

Does a positive mono test rule out Lyme disease?

No. A positive heterophile antibody or EBV test does not exclude Lyme disease. In endemic areas, clinicians should consider both diagnoses when the clinical presentation is compatible.

Can Lyme disease reactivate Epstein-Barr virus?

Some investigators have proposed that physiologic stress or immune dysregulation associated with Lyme disease may contribute to Epstein-Barr virus reactivation in certain patients. However, current evidence is limited, and a causal relationship has not been established.

What symptoms overlap between mono and Lyme disease?

Both illnesses may cause fever, fatigue, headache, muscle aches, joint pain, sore throat, and enlarged lymph nodes, making the diagnosis more challenging.

Why is an erythema migrans rash important?

The appearance of erythema migrans strongly supports early Lyme disease, even when other laboratory findings suggest infectious mononucleosis.

Clinical Takeaway

Mono and Lyme disease can occur together. While Epstein-Barr virus infection may complicate the interpretation of Lyme serology, clinicians should avoid assuming that one diagnosis excludes the other.

Recognizing that infectious mononucleosis and Lyme disease can occur together may help prevent delayed diagnosis, inappropriate reassurance, and potentially avoidable Lyme disease complications.

Related Articles

When Lyme Disease Causes a Positive Test for Mononucleosis
Lyme Disease Misdiagnosis: Why It Happens
Early Disseminated Lyme Disease
Lyme Disease Symptoms Guide
Epstein-Barr Virus and Lyme Disease

References

1. Koester TM, Meece JK, Fritsche TR, Frost HM. Infectious Mononucleosis and Lyme Disease as Confounding Diagnoses: A Report of 2 Cases. Clin Med Res. 2018;16(3-4):95-99.

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

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention