When Lyme disease causes a positive test for mononucleosis

False positive serologies for Lyme disease have been previously reported in patients with acute infectious mononucleosis. However, a recent paper describes two cases in which Lyme disease was misdiagnosed as mono based on false positive serologies for the Epstein-Barr virus (EBV).

by Daniel J. Cameron, MD MPH

In the article, published in the journal Clinical Infectious Diseases, Pavletic, from the National Institute of Mental Health, reports “two cases of false positive Epstein-Barr virus (EBV) serologies in early-disseminated Lyme disease.”

In the first case, a 16-year-old male from Virginia developed fatigue, myalgias and three brief episodes of fevers over an 18-day period. He was diagnosed with acute infectious mononucleosis based on a positive viral capsid antigen (VCA) IgM and negative VCA IgG.

It was not until 17 days later with the onset of multiple erythematous rashes and right-sided peripheral facial nerve palsy that doctors diagnosed the young man with Lyme disease. Laboratory evaluation revealed a positive C6 peptide ELISA index of 6.02 and a positive IgM immunoblot. He was prescribed a 4-week course of doxycycline and recovered.

“Repeat VCA IgG, VCA IgM and EBNA were negative, indicating that the initial VCA IgM was falsely positive,” according to Pavletic.

In the second case, an avid biker from Maryland presented with a six-day history of fatigue, fever, myalgias and headache. Lyme disease was diagnosed the next day based on multiple erythematous rashes. Lyme serologies were positive by ELISA, IgG and IgM immunoblots.

Twelve days into her illness she tested positive for mononucleosis with a positive VCA IgM, VCA IgG, EBV early antigen, EBNA IgG, and positive monospot.

The fever resolved and the rashes faded with a 21-day prescription of doxycycline. The recovery was complicated by a right upper trunk brachial plexopathy. “The pain resolved and the weakness improved over the next six months,” according to Pavletic.

“Three and a half years later, repeat VCA IgG and EBNA were positive, and VCA IgM was negative.”

According to the authors, both cases were initially misdiagnosed. “Here we present two cases where early manifestations of Lyme disease were initially misdiagnosed as acute EBV infection due to positive VCA IgM results.”

The authors touched on the difficulties interpreting acute mononucleosis testing. “While isolated VCA IgM may indicate early acute mononucleosis, the test can be nonspecific, especially when the likelihood of acute EBV infection is low.” Pavletic adds, “Immune activation with other pathogens can also result in a false positive VCA IgM.”

The second case was difficult to interpret given the positive monspot, heterophile and VCA IgM tests. “In this case, we cannot exclude that the positive VCA IgM could be due to subclinical EBV reactivation, which has little clinical relevance in immunocompetent individuals,” states Pavletic, adding, “Heterophile antibody tests are known to have false positives due to acute infections, autoimmune diseases and cancer.”

In practice, Lyme disease and mononucleosis are common conditions that share similar symptoms. The authors’ two cases remind the reader of the need to consider Lyme disease even if initial serologies suggest mono.



  1. Pavletic AJ, Marques AR. Clin Infect Dis. 2017 Apr 4. doi: 10.1093/cid/cix298.

122 Replies to "When Lyme disease causes a positive test for mononucleosis"

  • Eli
    10/31/2022 (12:57 pm)

    Hello, this was an interesting article to read, because although I do not have EBV, every time blood tests are done, there are more positive lyme disease bands. The doctor also took a HHV6 blood test, which came back borderline positive for HHV6-A.
    I have been getting treated for lyme with alternating 2 antibiotics…3 weeks on doxycycline, then 3 weeks on clarithromycin…then repeat. The doc has also been using hydroxychloroquine, which I take everyday regardless of the antibiotic I happen to be on at the time. It has been 3 months and overall I feel as if I am improving, however I continue to experience “herxing” symptoms for about a week every time I alternate between the Doxy and Clarithromycin. It is frustrating, and I was curious about how HH6 can play into this? That is actually how I somehow found this article…when I did a google search for “HH6 ans Lyme Disease.” Now that it has been 3 months, the doctor thinks we should stop the ABX…however, because I still have symptoms (milder with every “herx”) I feel that I need to stay on them for now…but obviously do not want to continue doing so without medical supervision. I would be interested in your feedback. Thank you.

    • Dr. Daniel Cameron
      11/01/2022 (9:17 am)

      I am not a fan of pulse therapy. Some of my colleagues are. I treat based on response to treatment. BTW, I have patients who benefit from other antibiotics.

  • Tammy
    03/16/2022 (3:10 pm)

    I was diagnosed with Lyme in 2006 and was on doxycycline for two weeks and ended up with ulcers in my esophagus. I ended up using a holistic approach named Cowden protocol. It was a series of tinctures that I took for 2 months. I felt much better and only have had a few flare ups over the years. Now here I am at age 60 and was just diagnosed with Epstein Barr. They put me on amoxicillin for 10 days. I felt a little better but now a month later, all my joints hurt and I am exhausted. It feels like Lyme all over again. I live in Florida and the doctors here are awful. They just ignore everything you say and I can’t get them to give me any treatment because the Lyme test is negative. Is there a way to get anti-biotics through another source? Completely frustrated with the medical community here.

    • Dr. Daniel Cameron
      03/23/2022 (7:20 am)

      Doctors are divided. I have advised my patient with similar situations to consult a doctor with experience treating chronic manifestations of Lyme disease even if the test are negative in addition to their standard workup.

      • Renee Smith
        03/29/2022 (10:10 am)

        I’m at a loss. 50 years old, menopausal and just diagnosed positive for Mono. I however have felt terrible for over a year, and they keep saying “oh it’s menopause”.
        I literally have the symptoms of Lyme Disease. I saw the doc last June for a rash that was diagnosed as viral. I was given a topical cream and sent on my way.
        The one symptom that can’t be explained away is muscle twitches, and feeling of constant flu. I keep being told it’s anxiety and possible allergies.
        What kind of doc do I see that will do a Lyme test? Or take me seriously? My mental health is being affected and the aggrevation of no one listening is so tiring.

        • Dr. Daniel Cameron
          03/29/2022 (2:42 pm)

          I often see patients in my practice in New York who are diagnosed with multiple conditions before Lyme disease is considered. You may have to reach out to Global Lyme Alliance, LymeDisease.org or ILADS for doctor with experience treating chronic manifestations of Lyme disease if you remain ill.

  • Annette Paukovitz
    12/19/2021 (10:45 am)

    Very informative blog. I was diagnosed with Lyme’s years ago, recently had dibilitating tiredness, no appetite, joint and muscle pain. Testing determined I have Epstein Barr Syndrome, EBV VIRAL CAPSID AG (VCA) AB (IGG) – >750.00 *High*. I would like to know if Tinnitus and/or hearing loss can result from Lyme’s or EBS. My hearing specialist said highly unlikely, but if Lyme’s can cause nerve damage, why not your auditory nerve. This Tinnitus is driving me insane at times.

  • Leesa Osborne
    12/01/2021 (11:12 pm)

    I too have had negative Lyme disease results and positive ebv and Mycoplasma pneu. IgG/IgM Abs and high white count for years. I’ve been treated with doxy for a total of 61 days. I still am not well and ready to give up at times. My dr is LLMD but I feel like I’m not getting the treatment I need. She took me off the doxy after losing 10 pounds and being in bed herxing on it. I’m tired of the aches and pain, brain fog memory issues. I’m only 49 and feel 80. I have insurance and live in texas. Not many LLMD here. Any suggestions I feel like my dr is to busy and has so many patients. Nor tells me anything. She just fills my bp, anxiety meds, and orders labs every few months. I don’t know what else to do. I have this for almost 20 years now

    • Dr. Daniel Cameron
      12/02/2021 (7:38 am)

      You are not alone. There are so many doctors to see to rule out other illnesses. I have patients who have benefited from other treatment protocols for tick-borne illnesses such as Babesia.

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