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.

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

  • Elysa
    05/09/2017 (4:12 pm)

    3 weeks after a tick bite, I went to the doctor with fever, aches, chills, joint pain and exhaustion. ELISA came back negative but the MonoSpot lit up like a christmas tree. For the next 5 years I was told I had Post Mononucleosis Syndrome, Fibromyalgia, MS, Cancer, Depression… I was able to find an LLMD through ILADS.org who ran a Western Blot among other tests. They came back postive for Lyme and Babesia. I’m now going on my 9th month of treatment but I’ll be living with the damage for the rest of my life.

  • Julie
    05/09/2017 (5:51 pm)

    I always wondered if my EBV diagnosis when I was 16 could have been Lyme’s, since, it was so severe I was sick for years and my fatigue, neurological problems continued up to and have continued thru & after I diagnosed w Lyme’s and co-infections at age 35.

  • Becca
    06/16/2017 (1:13 am)

    So interesting! My daughter is 9 and had tests run through IGenex. Showed ++ on 41 band of IgG and IgM but gave a negative overall result. Doctor tested her for EBV and it came back positive. She has severe joint pain, tummy aches, fatigue, weight loss, and random fevers on occasion. When I asked him what to do with the EBV result, he said “Lots of rest.” He assured me she did not have Lyme and that she has had EBV for “quite some time.” Her symptoms have been going on for 18 months. No known tick bite but she did have lice right before symptoms started.

    • Dr. Daniel Cameron
      06/16/2017 (6:16 am)

      It would be reasonable to revisit the cause of symptoms beyond 6 weeks even if the EBV were well documented. It is also possible someone can have EBV and a tick borne illness since they are common in children.

  • Lynne
    06/20/2017 (4:41 pm)

    Interesting indeed. I have an Igenex IgM result with 31+, 41++ and 45+ And have been told I am negative for Lyme disease. Of course that is CDC negative. I still have unbelievable fatigue and joint pain that is nearly unbearable 24 hours a day. The fact that I live in NY makes it that much more difficult. No one seems to want to treat this and all I want is to feel better.

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