How Mononucleosis Is Diagnosed

The diagnosis of infectious mononucleosis (mono) is usually made based on the symptoms, findings in a physical examination, and blood tests. Mono is usually caused by the Epstein-Barr virus (EBV) or similar viruses, but strep throat and some other conditions can cause similar signs and symptoms. While the Centers for Disease Control (CDC) no longer recommends the ​monospot test, many guidelines still encourage using this test to help identify the cause of mono.

Self-Checks

You or your child might not recognize the onset of mono right away. The early symptoms resemble a cold, the flu, or strep throat. Avoid self-diagnosing mono because similar illnesses require different treatments.

Symptoms that may prompt you to visit your healthcare provider include swollen neck lymph nodes, extreme fatigue, a sore throat, fever, and body aches lasting longer than 10 days.

Symptoms in babies and young children may be mild.

Record the timeline of symptoms, noting when they started, which symptoms developed, and their duration. This information can aid your healthcare provider in diagnosing the illness during an evaluation.

Seek immediate medical care if you experience serious symptoms of mono such as:

• High fever
• Severe or persistent abdominal pain
• Severely swollen throat or tonsils
• Difficulty breathing or swallowing
• Limb weakness
• Severe headache

These symptoms could be related to mono or other conditions and complications.

Labs and Tests

During your evaluation, your healthcare provider will assess your symptoms and age, as EBV-related mono is more common in teens and young adults. Your provider will check your throat for red spots (petechiae), feel for swollen lymph nodes in your neck and other areas, and listen to your lungs.

Typically, your provider will order a complete blood count (CBC) and an antibody test. If you have a sore throat, a rapid strep test is likely. Pregnant individuals may undergo further antibody testing to rule out issues affecting pregnancy.

CBC

If you have mono, your CBC will typically show an elevated white blood count (WBC) with more lymphocytes than usual, which is known as lymphocytosis. Lymphocytes are a part of your body’s immune system and it is natural for them to be elevated during certain types of infections. These lymphocytes will have an atypical appearance when examined with a microscope.

You will also have fewer of the other predominant type of white cells, neutrophils, and you may have a lower than usual platelet count.

Antibody Testing

Your blood may be analyzed in a laboratory for antibodies, although this test isn’t required for a diagnosis of infectious mononucleosis. Antibodies are produced by your immune system to fight infections.

The monospot (heterophile antibody test) is an older test that is commonly used to make the mono diagnosis. A positive monospot test accompanied by the symptoms of mono helps in the diagnosis of infectious mononucleosis. However, the CDC says the monospot test is no longer recommended because it produces too many inaccurate results.

False results include:

• Monospot tests can be false-negative about 10% to 30% of the time, particularly in the early stages of the illness. 
• You stand an approximately 25% chance of getting a false-negative test result if you are tested within the first week of symptom onset. 
• You can have a false negative test if you waited too long to see a healthcare provider because the antibodies rapidly decrease after you’ve been infected for more than four weeks.
• If you have mono from a different virus than EBV, such as cytomegalovirus (CMV), the monospot won’t detect it.
• A monospot test can be falsely positive with hepatitis, leukemia, lymphoma, rubella, systemic lupus erythematosus, and toxoplasmosis.

More extensive antibody tests may be done if the illness symptoms aren’t typical for mononucleosis or you have been ill for more than four weeks. You may be tested for cytomegalovirus or Toxoplasma antibodies. 

More specific tests for EBV include:

• Viral capsid antigen (VCA)
• Early antigen (EA)
• EBV nuclear antigen (EBNA) tests

Mononucleosis Doctor Discussion Guide

Get our printable guide for your next doctor’s appointment to help you ask the right questions.

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Differential Diagnosis

Your healthcare provider will consider your symptoms and other tests to distinguish between EBV mono and other conditions. Illness with CMV and Toxoplasma gondii may be designated as infectious mononucleosis or called a mono-like illness. As with EBV mono, only supportive treatment is recommended. However, these illnesses can complicate pregnancy, so further tests to identify the cause of the illness are recommended for moms-to-be.

Similar conditions your doctor may consider include:

• A sore throat, fever, and swollen glands seen in mono can appear like the symptoms of strep throat. A rapid strep test or throat culture can help distinguish these. Strep throat usually improves quickly to antibiotics, which have no effect on mono.
• Influenza can also mimic some of the symptoms of mono but usually doesn’t produce swollen neck glands. Influenza will usually get better in less than two weeks.
• Mono-like symptoms can be seen in infections other than Epstein-Barr virus. Other pathogens (infectious organisms) that can produce these symptoms include CMV, adenovirus, human immunodeficiency virus (HIV), rubella, hepatitis A, human herpesvirus-6, and the parasite Toxoplasma gondii.