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"

  • Kelly Kutrufis-Lee
    10/25/2017 (9:54 pm)

    Good Afternoon,

    I was recently diagnosed with mono- EBV Ab VCA, IgG = 559.0 on 9-21-17 and tested negative for Lyme total An test/Reflex-lyme IgG/IgM Ab= <.91 on 8-9-17. I am still having problems and I'm very frustrated and worried that my diagnosis is wrong. I would like to know where everyone was finally diagnosed with Lyme's? Or what steps I should take next? Currently I'm seeing my general practitioner.
    Thank you for your help!!

    • Dr. Daniel Cameron
      10/26/2017 (6:32 pm)

      Both EBV and tick borne illnesses are common. It is reasonable in practice look a second time at a tick borne infection if the illness is atypical or persists beyond the 4 6o 6 weeks typical of mono.

  • Susan
    09/15/2017 (12:25 am)

    So my son had mono in early 2015. He had a very bad case that was undiagnosed because he didn’t have sore throat or swollen lymph nodes, just crazy fever, drenching sweats for 9 days and fatigue, which doctors ignored. He got sort of better, played basketball and wound up in the hospital where they finally diagnosed him with mono after a positive monospot, atypical lymphocytes =31, and a very enlarged spleen (19cm). He was very sick with fevers for another two weeks did get the awful sore throat and lost 20 pounds. He’s never been well since and seems to always have something wrong going on… In the fall of his freshman year (2016), he suffered a concussion, from which he recovered by Christmas break. Since then, he has had lymphangitis in his arm, eustachian tub dysfunction, a sinus infection, two very severe febrile episodes that I could have sworn was mono all over again. Sometime in February when he had the sinus infection and eustachian tube dysfunction he became dizzy, unable to focus, foggy, couldn’t read with overall clogged feeling in the head and tired. We found out recently that he has a vision/vestibular saccades issue. We have been going down the road that he has post concussion syndrome causing the dizziness and have been to ENT to check for peripheral vestibular problem, MRI, PT, Chiro, and vestibular rehab. It’s never-ending. To rule everything out, he has also been tested for lyme and are awaiting the results. In the meantime we got back EBV tests that showed EBV EA at 6x the norm and VCA IGg 10x the norm. We’ve been told he has reactivated mono. Can lyme cause both of those tests to be elevated and can lyme cause problems with saccades and make him unable to focus? Has mono been reactivating over and over again or is it possibly been lyme all this time? Can a concussion bring out lyme or EBV? At my wits end with this…

    • Dr. Daniel Cameron
      09/15/2017 (5:00 am)

      I am sorry to hear your son remains ill. EBV titer can be hard to interpret if they are elevated. It is difficult to tell the difference between chronic fatigue, Lyme and a concussion. I have seen Lyme disease cases that have been difficult to identify since they started with mono, an elevated EBV or concussion. I would prefer a tick borne illness evaluation be included even if the tests are negative.

  • Laura
    08/28/2017 (5:48 am)

    Wow, this is an informative article and I appreciate the responses from your readers as well. Based on my incapacitating fatigue, my Nurse Practioner had me tested for EBV when I was getting labs to check my thyroid levels. Upon receiving the news that I was having a severe EBV reactivation episode, I asked to be tested for CMV and for Lyme. CMV was negative, but I was confirmed to have Lyme (this was on 7/5/2017). I had been so ill that I had to resign from my job in mid-June and have not been able to work. I was referred to a LLMD and had to wait several weeks to get in to see him. Within the week, I began IV treatments to start my fight to regain my strength and health. This is an exhausting journey – physically, spiritually, emotionally and financially. Just in the last 3 days, I have begun to see little improvements in how I feel. This gives me hope. Hope that I will get my joy, my energy and my life back from my complexities of conditions.

  • Mary K Hull
    08/18/2017 (3:37 pm)

    Two weeks ago my arm, chest, and hands started to hurt and I noticed clusters of puss pimple like rashes on the same right arm and palm. In a few days the pain was so awful I ended up in the then emergency room. I am a 54-year-old mother of 4 and I have never known such pain. My right knee started to hurt. I used a cane most days. I have been tested for everything including STDs and parvo. I have also developed vertigo. The only thing that has come back positive is mono. What do I do? This is no way to live considering I was hiking up to 14 miles a day just 1 year ago. I had tick tests and they were also neg. Please help

    • Dr. Daniel Cameron
      08/19/2017 (9:01 am)

      I am sorry to hear you are ill. It sounds as if the doctors have been working on finding an answer. The All Things Lyme Blog reminds based on a review of the literature reminds us as doctors that sometimes a tick borne illness may end up a factor.

    • K Murray Leisure MD
      09/27/2018 (1:09 am)

      Consider also right-sided body shingles, VZV. Interesting that some cases of Lyme have been followed by Varicella zoster virus (shingles, reactivated chicken pox virus) blocks of rash within the same nerve distribution, the same dermatome, as the tick bite. Perhaps the arachnid / tick bite activated VZV usually latent in the spinal column to erupt in the limbs peripherally?

      • Dr. Daniel Cameron
        09/27/2018 (3:32 pm)

        Good question. We have a lot to learn.

      • Jackie
        10/12/2018 (9:34 pm)

        I got lyme from a spider bite and so did the NP who’s treating me. (She came from a rheumatology practice and left because she didn’t agree with their diagnosis and treatment protocols.)

  • Helen
    07/06/2017 (8:29 pm)

    38 years ago while working as a RN I became so totally exhausted to the point that I could barely get out of bed and had to sleep. I was a very healthy active woman at 26 years old. The lab called me and first told me I had mono then, that I was pregnant. I was very happy since we were planning to have a baby, our first of two daughters 13 months apart. I was also happy that there were two “reasons” why I was completely exhausted yet I still felt I was TOO exhausted. Not until 11 years later after I had a huge bulls eye rash summer of 1987 at age 37 did I begin to feel even more anxious and irritable and depressed. I remembered I began having anxiety out of the blue when I had “mono”. Unfortunately back then I didn’t know about Lyme disease etc. Same year our younger daughter at 9 years old began to get very ill. Nightmare time truly began. We took her to countless Dr’s. Despite her constant painful pressure headaches, knees being so painful it made it almost impossible for her to walk and only wanting to sleep we were told there was nothing wrong physically with our bright happy daughter who loved school. Finally we found the life saving neurologist who diagnosed our daughter with Lyme disease. A few days before we had our first appointment with this angel Dr our daughter complained that her vision was getting “fuzzy”. She was hospitalized immediately, IV antibiotics began and our local pediatrician agreed that our daughter have a lumbar puncture and that she’d work with our LLMD/neurologist who saved our daughter’s life. Our daughter had pseudo-tumor cerebri and papilledema. She was treated aggressively for a year, IV then orals. Our daughter got better. Fast forward, I began to have more symptoms and 7 years after my bulls eye rash and deathly ill I was diagnosed with Lyme disease. Our other daughter got very sick at 17, Lyme again and another Picc line etc. My husband also got sick in his early 40’s. Picc line #3 and long term treatment as well.
    My family seemed to feel much better and were able to resume their lives. I was so grateful. But I didn’t. After initially feeling much better with treatment I totally crashed when treatment ended. I got my first Picc line. Not until another several years was I diagnosed with WA-1 babesiosis, erlichiosis, mycoplasma HHV 6/8 by a well known LLMD. I’ve been extremely sick (intractable cranial nerve pain, had vegetations aortic valve, SPECT severe hypoperfusion both cortical hemispheres, severe monoparesis left side and have been treatment resistant but am doing better. Our grandson now 6 got sick when he was 2. Lyme disease again. I’ve heard about having a positive mono test but it’s Lyme disease. Thinking back to my positive mono lab when also told I was pregnant 38 years ago and the anxiety depression and irritability that came out of the blue then makes me wonder if I had Lyme then before my bulls eye rash 11 years later.

    • Stacey
      08/06/2017 (6:52 am)

      Thanks for sharing everyone. I gave birth 17 months ago and kept thinking I felt so tired from the new house, new baby and work. Never once did i think I was sick. Just always tired. Then I got dizzy spells but I had suffered with migraines for three-four years before my daughter so I assumed this was my body reacting to migraines (even though I got those in check now). I went back to my naturopathic doctor who helped with the Migraines and she did a full work up. Same as she had done in 2015 before I got pregnant and when I went off the migraine drugs. Somewhere between then and now I had mono and I have Lyme disease. I’ve been seeing a cardiologist because my body feels like it will explode at times (literal heart palpitations) and so far everything is looking good. Yet now I have an irregular heartbeat that I didn’t have before. Do to the mono? Because the Lyme was just diagnosed and I’m told I’m in the early stage (thankfully) and have been put on meds for it. Dizzy spells? If not from the Lyme than what? This is all so crazy to me. I was a perfectly healthy 35 year old before I got pregnant. Yes I had migraines but nothing else bothered me. I worked full time and ran a side business. I had so much energy. And I’ve been chalking this up to motherhood prior but I don’t think that’s it. What scares me most is now I fall asleep randomly. I don’t even realize im falling asleep until I wake up scared because I do not know when it occurred. Between the dizzy spells, the heartbeat and the crazy sleeping I’ve been so scared. I just want to know how to fix it all so I can be around for my daughter. I waited to have her until I was ready and now that I am I feel like my health is controlling my life.

      • Dr. Daniel Cameron
        08/06/2017 (10:49 pm)

        Thanks for sharing your story. It is worth looking past mono.

      • Joyce Dahlberg
        02/26/2018 (10:16 pm)

        So many of the stories could be mine. I got sick in 1977 or 1978 but did not understand what the 1st symptoms meant. SO 37 years later I am able to recall as my mind has returned due to being treated for Lyme starting in 2016. 2015 was a hell of a year with heart palpitations, pains, pins and needles and so much more. As getting better (at times feeling worse) symptoms emerged. The saying is that the first symptom you had is the last one to go away. Well I started to have shortness of breath, sneezing and others. Asked to get tested for mycoplasma and I tested pos for chlamydophila C pneumonia. Although identified as Lyme this one is NOT A TICK based disease but spread from person to person. My mind returned for a 25 year absence. 1977 or 78 I had an ear infection (only have had one in my entire life/felt like a funnel, then a sore lung that eventually went away. SO decades of cysts, skin issues (job syndrome) and mental health issues I was able to identify that staph aureus from water contamination is the root. Husband (prior to marriage), all his family members with lots of issues/deaths. Area the same lots of lyme/cancers/pneumonia (including many family members). A dr in that Midwest are (MN) even stated to another family member you do not need a tick bite to get Lyme. That is true because all insects can pass it and also people are infecting each others. The chlamydophila C pneumonia that I have is caused by staph aureus bacteria (#31 which is opsA). #34 is the deeper infection (opsB) that favors the lung and brain. Believe me I had my share of that in the past. # 41 is the spirochete (not necessarily Lyme). Now you know all these brain diseases origin. Yes MS is #2 on this too and so is Alzheimer, lupus, and so many others. SO I have a systemic infection (even validated by Garth Nicholson) and totally no tick involved. I do not think I knew tick existed in 1977. The USA 300 strain is the staph aureus #31. Mine is possibly USA 252 and goes with #34. Yes methicillin resistant bacteria and yes # 31 has biofilm.

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