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.

25 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.

    • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

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