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"

  • Kathleen
    07/03/2017 (1:34 pm)

    Mono at age 18. Lyme and Mono at age 55 and early onset Alzheimer’s symptoms at age 55. Lyme test was positive and I have been recovering my health since 2012. There are no more symptoms of early onset Alzheimer’s and I am grateful that my family doctor, at the time, was able to prescribe the right antibiotics for the necessary time to get me healed. I have also changed my diet, exercise and lifestyle around to be healthier, because thanks to Lyme and Mono, I can no longer take a break from staying on top of my health, or it all might come back

    • Debbie
      02/06/2018 (2:03 am)

      What antibiotic and how long were you on it?

      • Dr. Daniel Cameron
        02/07/2018 (12:30 am)

        Each case is different. The treatment depends in part on the response.

  • 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.

    • Joyce Dahlberg
      02/26/2018 (9:58 pm)

      #31 is staph aureus bacteria. More or less contaminated water. # 41 is the spirochete (not necessarily Lyme). # 45 I believe is osteomyelitis as I have that # as a previous infection/together with # 30 as a European strain. Yes I got osteomyelitis as a child after getting the BCG vaccine in France. Current infection is for me #31, #34 and # 41. This is chlamydophila C pneumonia from staph aureus infection. #34 is a deeper infection of lung and yes the infection affected my brain. This staph bacteria favors higher oxygen level. The #34 is a deeper fungal infection with elastic type protein production. It is possible you have bone infection as osteopenia which I have too. If I was you I would get tested for all mycoplasma and chlamydiaphila C pneumonia ( under chlamydia tests). Do not freak out this one is not a sexually transmitted disease although your kids will have the disease too because it is also contagious and transmitted to offsprings.

  • 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.

    • Anna
      07/06/2017 (6:42 am)

      Not all doctors are correct and when it comes to our children we know what is right and a lot of us go by our gut feeling because we know our children better then a 5 minute exam and a test or two. I pray you don’t accept the doctor’s answer and demand she be retested by another facility or by a doctor specializing in Lyme’s Disease. 18 months of symptoms is way too long for your little girl! Do not stop testing or seeing doctor after doctor until she is diagnosed. I wish you and your family the best and I will keep your daughter in my prayer’s. Anna

    • Carolyn
      02/24/2018 (3:56 pm)

      My daughter’s Ilad said the sicker or more chronic the Lyme disease the harder it is to test positive. Her IGenex test came back inconclusive for Lyme but positive for Babesio and other coinfections . Her blood was also sent to a lab in Germany where the Lyme was positive along with the coinfections. She also tested positive for EBV. She now has Chest port and receiving Iv antibiotics but improving.

      • Dr. Daniel Cameron
        02/25/2018 (8:53 pm)

        Thanks for sharing. Don’t forget Babesia as it differs from Lyme disease treatment.

    • Joyce Dahlberg
      02/26/2018 (9:49 pm)

      Did the test show #31 or even # 34. If #31 that is staph aureus USA strain 300, potentially USA strain 252. # 34 is a deeper infection. These two go together and favor lung and brain. #34 has elastic type protein that goes to brain an lung as it prefers higher oxygen levels.

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

      find out the other numbers. # 31 is staph aureus bacteria which is opsA and is USA 300 strain. Possibly even USA strain 252. # 34 (opsB)is also a deeper infection that goes together with the #31. #41 is the flagella and not necessarily a tick spirochete. Staph aureus is a spirochete too. Get the Igenex numbers. The mentioned #31 and #34 were like eliminated or manipulated by the CDC after the 2 bacteria (mycoplasma and chlamydophila C pneumonia) were accidently found to be bacteria. The smallest known bacteria to this day. The CDC does not want people to know that water contamination is the root of all inflammatory diseases. Yes it activates a lot of viruses. The lyme testing was changed after finding those viruses were found to be bacteria. It is easy to find info on the meaning of the numbers. Although the staph # 31 is not talked about nor made public. We all know why. SO to summarize. it is E coli and also being injected through vaccinations.

    • Christina Harrison
      03/19/2019 (2:39 pm)

      I’m 14 and my mom has severe late stage lyme disease and the epstein barr count was off the charts. She is 46 and has had lyme disease since she was in 7th grade. She is really depressed all the time and saying that she just wants to die. She hasn’t cooked in months and has quit her job. She is really sick and tired and her joints hurt. I want to try to help her get treatment but I don’t know how or what to do. I want to get a job to help but I don’t know where anyone would hire someone who is only 14. Any advice?

      • Dr. Daniel Cameron
        03/20/2019 (3:57 pm)

        It must be difficult for you to see your mother ill. I have focused my practice on the tick-borne problem. Keep working on it.

      • Christelle Maginot
        10/04/2019 (2:43 pm)

        I’m so sorry to hear your mom is sick. Lyme is difficult for everyone in the family. It took me 8 years to get to remission, and even though I relapse regularly, I have managed to keep things under control and go back to a “regular” life. So there is hope. The trick is to find a Lyme-literate doctor and be on the right mix of medication for your mom’s individual case. Recently, Disulfiram (a drug originally developed for alcoholism) has been proven to eradicate [chronic] Lyme. There’s a doctor in NY who has had over 90% of success with it. Scientist have also discovered a few months ago that chronic Lyme is real, finding Lyme protein in the brain of patients with chronic Lyme. According to statistics, 20% of Lyme patients get chronic Lyme. Nobody knows why. But now that its existence has been proven, maybe Main-Stream Medicine is going to concentrate on treating it vs. campaigning against patients and doctors who treat it. Meanwhile, the biggest support you can give your mom is to believe in her disease.

      • Gayle
        11/20/2023 (11:13 pm)

        It takes a team beginning with a solid proactive Primary Care Physician (PCP) along with Infectious Disease to address each system affected be it Cardiology, Neurology, Rheumatomology. Persist with referrals for assessment and potential treatment. If Arthritis, Lupus, or other illness is part or a result of the discovery then she may be eligible for federal and state disability benefits to cover medical and other financial support especiallyif shes worked 10 years or more SSDI seek a lawyer who could gat a case manager and process on application going. Be her best advocate to seek care and persist. Mental health is important with support most helpful coping with illness stress of it all. Good looking out for your Mom.

  • 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.

    • Destiney
      07/19/2017 (11:55 pm)

      That sounds exactly like me I was finally diagnosed yesterday with Lyme…as well as Babesia, Mono, Candida and numerous other things…i missed the last month of 7th grade due to mono???? And my physical and mental health continued to decrease…i wonder if it was Lyme the entire time…We were ALWAYS outside…sports camping playing…..i feel so overwhelmed

      • Dr. Daniel Cameron
        07/20/2017 (5:46 am)

        I am sorry to her you are overwhelmed. It can be hard to sort out when Lyme disease starts when other common illnesses are present.

        • Tina Vanderhoff
          08/04/2019 (8:11 am)

          My son approximately 9 years ago tested positive for mono & strep in June of that year. After a month he was better, but close to September started screaming his legs and head hurt so badly. We kept going to doctors whom kept telling us he didn’t have mono bad enough or long enough so it was a recurrence. Finally a Nurse Practitioner tested him for Lymes and it came back positive. He has been exhausted sometimes sleeping 12 hours or more a day ever since. Funny because when he was initially diagnosed with mono he barely slept more than 8 hours a day. We were told that our extremely healthy young teen had mono and lymes in the same summer, but given the exhaustion he usually has as well as body aches he complains of often (for a healthy slender 21 year old) I always wonder if something is up with those past diagnosis.

          • Dr. Daniel Cameron
            08/04/2019 (6:03 pm)

            It can be difficult to recognize Lyme disease if a child had Mono. It can also be more difficult to treat Lyme disease if there are delays. It may be the infection or coinfections have not resolved.

  • 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.

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