What pathogens cause mononucleosis?

Pathogens Causing Mononucleosis

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis, but cytomegalovirus (CMV), Toxoplasma gondii, and acute HIV infection can also produce mononucleosis syndromes. 1, 2, 3

Primary Pathogen

• EBV causes the vast majority of infectious mononucleosis cases, particularly in adolescents and young adults aged 15-35 years 2, 3
• EBV is transmitted primarily through saliva and infects B lymphocytes in the blood 2, 4
• The classic presentation includes the triad of fever, tonsillar pharyngitis, and cervical lymphadenopathy 2, 3

Alternative Pathogens

Cytomegalovirus (CMV)

• CMV produces a mononucleosis syndrome that is clinically similar to EBV infectious mononucleosis but with key distinguishing features 4, 5
• The heterophile antibody (Monospot) test is negative in CMV mononucleosis, whereas it is positive in EBV infectious mononucleosis 4, 5
• CMV is found in polymorphonuclear and mononuclear leukocytes, unlike EBV which is restricted to B lymphocytes 4
• CMV mononucleosis may cause hepatitis and pneumonitis due to direct viral cytopathic effects in target organs 4

Toxoplasma gondii

• Toxoplasma gondii is another cause of heterophile antibody-negative mononucleosis 4, 5
• Complications involve the heart, skeletal muscle, and central nervous system through direct parasitic invasion 4
• Although generally benign, toxoplasmosis can cause severe congenital infections 5

Acute HIV Infection

• Acute HIV infection can mimic infectious mononucleosis and must be considered in the differential diagnosis 5
• This is a critical diagnosis not to miss given the implications for treatment and transmission prevention 5

Diagnostic Approach

• The heterophile antibody (Monospot) test distinguishes EBV mononucleosis from other causes, as it is positive only in EBV infection 3, 4, 5
• When the Monospot test is negative in a patient with mononucleosis-like illness, serologic testing for EBV-specific antibodies (particularly IgM to viral capsid antigen) should be performed 2, 3
• If EBV is excluded, testing for CMV-specific antibodies, Toxoplasma antibodies, and HIV should be considered 5

Clinical Pitfalls

• Do not assume all mononucleosis is EBV—approximately 10% of mononucleosis syndromes are caused by non-EBV pathogens 5
• CMV and toxoplasmosis can cause severe congenital infections if acquired during pregnancy, making accurate diagnosis particularly important in women of childbearing age 4, 5
• Acute HIV infection presenting as mononucleosis represents a window of high infectivity and requires specific counseling and management 5