Differential Diagnosis for Mononucleosis with Mild Spleenomegaly

Single Most Likely Diagnosis

• Infectious Mononucleosis (caused by Epstein-Barr Virus): This is the most common cause of mononucleosis and often presents with mild spleenomegaly, fever, sore throat, and lymphadenopathy. The diagnosis is typically confirmed by the presence of atypical lymphocytes on a blood smear and positive serologic tests for EBV.

Other Likely Diagnoses

• Cytomegalovirus (CMV) Infection: Similar to EBV, CMV can cause a mononucleosis-like syndrome with spleenomegaly. It's more common in immunocompromised individuals but can occur in anyone.
• Toxoplasmosis: Although more commonly associated with lymphadenopathy, toxoplasmosis can cause a mononucleosis-like illness, especially in immunocompromised patients.
• Acute HIV Infection: The acute retroviral syndrome can mimic mononucleosis, with symptoms including fever, rash, lymphadenopathy, and sometimes spleenomegaly.

Do Not Miss Diagnoses

• Lymphoma: Both Hodgkin and non-Hodgkin lymphoma can present with lymphadenopathy, fever, and spleenomegaly, mimicking infectious mononucleosis. Missing this diagnosis could be fatal if not treated promptly.
• Leukemia: Acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) can present with symptoms similar to mononucleosis, including spleenomegaly. Prompt diagnosis is crucial for effective treatment.
• Tuberculosis: Although less common, TB can cause a mononucleosis-like presentation, especially in endemic areas or in immunocompromised individuals. It's critical not to miss this diagnosis due to its public health implications and the need for specific treatment.

Rare Diagnoses

• Brucellosis: A zoonotic infection that can cause fever, lymphadenopathy, and spleenomegaly, among other symptoms. It's rare but should be considered in individuals with exposure to animals or contaminated animal products.
• Cat-Scratch Disease (Bartonellosis): Typically causes lymphadenopathy but can rarely present with systemic symptoms including mild spleenomegaly.
• Malaria: In areas where malaria is endemic, it can cause spleenomegaly and a systemic illness that might be confused with mononucleosis, especially if the patient has recently traveled to such an area.