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"

  • Dacia
    02/24/2018 (9:42 am)

    Interesting blog– I’ve never made that link, although like others posting here, I’ve had both mono and Lyme/Babesia. When I was a first-year student in college, my roommate and her boyfriend both came down with mono. I wasn’t surprised when a couple of weeks later I came down with something awful: 10 days of drenching night sweats, 103-104 fever, extreme muscle weakness. But I tested negative for mono. A few months later, a circular rash appeared on the back of my thigh: this time the doctor told me it was ringworm, and sent me home with a fungicide cream. The circular rash continued to grow until it stretched from knee to top of my thigh, and took 7 months to go away. The following year I began having painful heart palpitations, I had extreme difficulty breathing, debilitating panic attacks, and was suffering from ‘tendinitis’ in my elbows, my knees, my shoulders. No testing done, no explanations given. Fast forward to 1997: between 1997 and 2000 we had three children. The first had and still has difficulty breathing, with unexplained seizures and temporary paralysis on one side of his body at 8 years; the second had and still has difficulty breathing, Asperger’s as well as intense social phobia and at the age of 12 became increasingly violent with bipolar tendencies; he was forcibly ejected from the school system and was on his way into the judicial system when in 2014 he was diagnosed with Lyme, Babesia, mono and strep (positive blood tests). Our youngest became ill at about the same time, tested positive for mono, but negative for Lyme and Babesia. I was also tested as I was very ill at this point: now I was positive for mono, as well as for Babesia and clinically for Lyme. It’s now been six years and all I can say is that these diseases and their after-effects have destroyed my two youngest children’s lives.

    • Dr. Daniel Cameron
      02/25/2018 (8:50 pm)

      My All Things Lyme Blog series, book, and live #LymeHangout should encourage a dialogue. Thanks for sharing your challenges.

  • Dawn
    02/24/2018 (2:48 am)

    I read mixed rewiews regarding the use of antibiotics for chronic lyme. Any one have experience using long-term antibitotics?

    • Joyce Dahlberg
      02/26/2018 (10:42 pm)

      Yes I am. I personally do not believe you can get better without some. The biofilm is key in killing this smart and stubborn bacteria. Must also use supplements, healthy eating and so much more. There is no one simple cure it is a combination of lots including detoxing like crazy. I know too many that are on herbs only and they so not seem to get better. I do know one that did but I think it is before she caught it right away. How long before starting treatment is the key. I knew mine needed to include antibiotics as it has been decades.

      • Dr. Daniel Cameron
        02/27/2018 (12:37 am)

        The biofilm research in tick borne illness is still understood. Most of the research on biofilms are from other infections e.g. staph and strep

    • Jennifer
      12/30/2018 (10:45 pm)

      When I was 20 I was diagnosed with mono. The pediatrician said it was the worst case he had ever seen. I could barely get out of bed for a month. After that could no longer stay awake late at night like I was accustomed to. In my early 20’s I developed arthritic symptoms. I came to accept that my joints would always hurt. In my 30’s although I seemed otherwise healthy, I could not kneel down to play with my kids. In my 40’s I was diagnosed with Lyme. I had all sorts of neurological problems including not being able to walk up stairs, when i regularly could jog up several flights. I developed breathing problems and heart problems. I was in the ER with SVT and developed pretty severe anxiety. After being treated with oral antibiotics (mostly doxycylcline) for nine months, not only have all these problems cleared up, but the arthritis that started in my early 20’s also went away!

  • James
    02/24/2018 (1:56 am)

    When I finally tested positive for lyme in 2010 I also tested positive for EBV

  • ilene
    01/25/2018 (5:22 pm)

    My daughter, 13 years old now, was recently diagnosed with mono after high fever and swollen glands for weeks at a time. 3 summers ago she was diagnosed with lyme after coming home from summer camp with muscle and joint aches, severe weakness and a bulls eye rash. After a day of docyclone, she threw up and it threw her into a long term panic attacks for the fear of throwing up again. After therapy. After the recent diagnosis of mono, I insisted the Dr to run the lyme test while they were running the other levels after coming across Dr. Cameron’s website. It is positive as well. I am so torn if we should treat her for lyme again since her past experience was so tramatic or if it could be a false positive.

    • Dr. Daniel Cameron
      01/26/2018 (8:16 pm)

      Doxycycline can be hard on the stomach even if she takes it with food. It also may have been a Herxheimer reaction where the symptoms get worse before they get better. There are other antibiotics that she may tolerate. It would be reasonable to include a tick borne illness in her evaluation if she remains ill.

  • Rita Shaw
    12/30/2017 (5:04 am)

    I dont understand I was tested in 2009 2 different times and my Elisa-Lyme reactive was high positive both times…but western Igg and Igm were negative..with comment
    Antibodies to less than 2 of 3 significant B.burgdorfebe. proteins detected additional specimen should be submitted in 2-4 weeks..
    Rheumatoid factor was
    20.0 normal 0.0-20.0
    I had all lyme symptoms for 2 yrs after camping tripin 2007…in 2012 high ebv tilters? Also get flu like symptoms, though I was diagnosed fibromyalgia and chronic fatigue after lyme was negative. I have also been diagnosed Anterior Pituitary disorder..migraines, and now no false tb skin test..in 2007 , myalgia and Myostitis, Joint pain, and hearing loss due to chronic ear infection…Perineurophy.
    its all the cormorbid illnesses, symptoms,that drive me crazy.
    I don’t know if I should be tested a 3rd time? Is it to late to treat? Been 10 years?
    Why would elisa/reflex be high positive both times and western be negative?
    I wish I could find some answers..

    • Dr. Daniel Cameron
      01/10/2018 (1:45 pm)

      The tick borne tests leave something to be desired. Your doctor may have to use clinical judgment rather than a test if you remain ill without another answer.

    • Joyce Dahlberg
      02/26/2018 (10:47 pm)

      Never too late. for me 37 years untreated. Do not go by the regular offered testing. Too many numbers were purposefully eliminated as too many people would test pos. This occurred in 1994 after 2 viruses were determined to be bacteria. Get the IGENEX test that gives the numbers that you can evaluate and research yourself too. CDC and many others do not want people to get diagnosed to start out with. You have to be your own advocate. DO NOT RELY ON TRADITIONAL MEDECINE.

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