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"

  • Rita Shaw
    06/16/2018 (4:28 pm)

    Hi everyone, it’s Rita Shaw again, I’m really confused. Like I said 3 not 2 Elisa came back high positive, 1.11, 1.25, 1.43
    But all western blot negative-Dr’s were shocked because I had all the symptom of Lyme, later test show high postive, ebna-Igg& vca-Igg 2006 , EBV, though clearly symptomatic, blood lab thought to be a passed on maternal infection?
    At 14, I was hospitalized for severely high fever, enlarged spleen, and liver?( And always had history since baby of tonsillitis (removed at 2)strep, bronchitis, pneumonia, laryngitis, swollen lymph nodes, etc, every years once or more.ever since) in 2006- I caught
    severe mrsa infection from work, also along with this, I didn’t know ..until this yr when asked for copies medical records, also 2006- 3 weeks after I had caught mrsa, and still fighting it, they protein in urine several times, went for sonogram of kidneys. Small white kidneys with unknown pathological lesion in right kidney? Cat scan recommended, not done) ( I knew I had something because dark bubbly, foamy urine alot over years) but drs never said nothing, also diagnosed same time
    Chronic glomerulonephritis kidney disease.? I was shocked because my egfr-=60. But I’ve been dehydrating since 2006, at least once a year, now my vision is horrible, I’m low on electrolytes and vitamins, Periherial neuropathy. Emg showed slowing of muscles, anterior pituitary disorder/ hypopituitism which I assumes was car accident tbi in 2005
    But on NibH Site” It says Periherial neuropathy, Ckd, hypopituitism, many more can all be connected.. kidneys are not able to fight off infections? Or my immune system. So this last year I started sweating exclusively, espiceally my face, head, embarrassing so…dehydrated urgent care again .
    Another bladder possible, kidney infection. I drink close to a 2 liter bottle of water a day because of thirst, but don’t urinate much? Constantly choke when swallowing fluid and food too at times.. Urgent care also, said ‘Anemic low iron, ferritin, very low transferritin?
    I’ve seen over 15 Dr’s since this started after car accident 2005, they gave up after Lyme was neg and called it fibromyalgia and fatigue, reiters disease, myalgia, myotis, migraines with aura, but with the other issues I dont think so.
    In 2007 tested postive for latent lyme, but turns out it was pneumonia, also had both feet operated on in 2007 cavus deformed foot structure ,and deformed upside down wine bottle look calves, surgeon said CMT inhertied, I told my dr and he said whats that?
    Now I’m looking for a new provider, n RI whose educated in the latest diseases, I’d like to go to Boston for free genetic testing and other tests but don’t drive, and no support system. I’m just curious, be honest…should I be right to keep searching as to whats happening in my body? Any resources if you agree?

    • Dr. Daniel Cameron
      06/17/2018 (11:08 pm)

      Keep searching for an answer. It is also possible that there is more than one answer that has been overlooked.

  • Beth
    05/24/2018 (10:39 pm)

    is it possible to have mono and Lyme disease? my daughter is 14 and was told by her dr. She has Lyme disease, mono, and her gallbladder isn’t working if anyone can give me info please let me know

    • Dr. Daniel Cameron
      05/27/2018 (1:08 pm)

      Some of my patients have had both. In some cases, Lyme disease was discovered when the symptoms of mono resolved.

  • Carl Tuttle
    02/26/2018 (8:06 pm)

    The Marques paper talks about false positive Epstein Barr serology but many believe outer surface protein A of the Borrelia spirochete causes immunosuppression for the following reasons…

    “Spirochetes disseminate to the lymph nodes, bone marrow, spleen and brain within a week of infection [1]. Lymph node germinal centers, where B cells are supposed to mature and be assigned an immune system function, are rendered incompetent [2] “B-cell AIDS”

    (1) https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002066

    (2) https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004976

    I truly believe that Lyme disease is immunosuppressive allowing latent viruses to rear their ugly heads and the positive EBV tests in the Marques case studies were reactivated infection as 90% of all Americans have been exposed to this virus but as you know, a healthy immune system keeps Epstein–Barr in check.

    It is well established that chronic Epstein–Barr virus can cause lymphoma and there is no disagreement within the medical community. I often tested positive for chronic EBV during the eight years treating chronic Lyme. Four years ago I had another tick bite (deer tick) in the right upper thigh area. Shortly thereafter the lymph node adjacent to that bite began to swell. All nodes swelled on the right side of the body followed by the left side and the swelling continued. A year later I was diagnosed with follicular lymphoma.

    Search Pubmed for: “Borrelia lymphoma”

    Carl Tuttle
    Lyme Endemic Hudson, NH

  • Carl Tuttle
    02/25/2018 (7:58 pm)

    The Marques paper talks about false positive Epstein Barr serology but many believe outer surface protein A of the Borrelia spirochete causes immunosuppression for the following reasons…

    “Spirochetes disseminate to the lymph nodes, bone marrow, spleen and brain within a week of infection [1]. Lymph node germinal centers, where B cells are supposed to mature and be assigned an immune system function, are rendered incompetent [2] “B-cell AIDS”


  • Colonyresidents
    02/25/2018 (5:17 am)

    How does this work, since we all know that the OspA that is released by the spirochetes damages the immune system and allows all kinds of other pathogens to reactivate?

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