What are the next steps for a patient with a positive mononucleosis (mono) screen, mild thrombocytopenia, and lymphocytosis?

Management of Infectious Mononucleosis with Thrombocytopenia and Lymphocytosis

This patient with a positive mono screen, mild thrombocytopenia (platelets 110,000/µL), and marked lymphocytosis (absolute lymphocytes 9,000/µL) requires confirmatory testing with complete blood count with differential looking for >40% lymphocytes and >10% atypical lymphocytes, followed by supportive care with activity restriction for 3 weeks from symptom onset. 1

Immediate Diagnostic Confirmation

• Obtain CBC with differential to confirm >40% lymphocytes and >10% atypical lymphocytes, which are characteristic findings that support the diagnosis when combined with a positive heterophile antibody test 1
• Review peripheral blood smear to assess lymphocyte morphology and confirm the presence of atypical lymphocytes 1, 2
• Check liver enzymes (AST/ALT) as elevated transaminases increase clinical suspicion for infectious mononucleosis and are commonly present, particularly when thrombocytopenia occurs 1, 3
• Assess for hemolysis with reticulocyte count, haptoglobin, and direct Coombs test to evaluate for autoimmune hemolytic anemia, which can complicate EBV infection 4

Thrombocytopenia Assessment

The platelet count of 110,000/µL represents mild thrombocytopenia that typically does not require specific intervention beyond observation. 5, 3

• Monitor platelet trend as severe thrombocytopenia (<20,000/µL) occurs in less than 1% of infectious mononucleosis cases but can develop 5, 6
• Assess for bleeding symptoms including petechiae, purpura, mucosal bleeding, or other hemorrhagic manifestations 5, 3
• Do not initiate corticosteroids at this platelet level, as they are reserved for severe thrombocytopenia (<20,000/µL) with bleeding or platelet counts that continue to drop despite supportive care 5, 3

If Platelets Drop Below 20,000/µL:

• Initiate oral prednisone 1 mg/kg/day as first-line therapy for severe thrombocytopenia 5, 3
• Consider IVIG 400 mg/kg/day for 2-5 days if inadequate response to corticosteroids after 8-13 days or if bleeding symptoms worsen, as IVIG has shown rapid platelet recovery in 4 of 5 patients in case series 5
• Administer intravenous methylprednisolone for more severe cases, with monitoring for rebound thrombocytopenia after steroid discontinuation 3

Supportive Treatment Protocol

Treatment is entirely supportive, as routine use of antivirals and corticosteroids is not recommended for uncomplicated infectious mononucleosis. 1, 6, 2

• Ensure adequate hydration with oral or intravenous fluids as needed 6, 2
• Provide analgesics and antipyretics (acetaminophen or NSAIDs) for fever and pharyngitis, avoiding aspirin in younger patients 6, 2
• Allow patient-guided activity rather than enforcing strict bed rest, as energy level should determine activity tolerance 2
• Avoid corticosteroids unless respiratory compromise or severe pharyngeal edema develops 1, 2
• Do not prescribe acyclovir or other antivirals as they are not beneficial for routine infectious mononucleosis 2

Activity Restriction and Return to Sports

Patients must be withdrawn from contact or collision sports for at least 3 weeks from symptom onset due to risk of splenic rupture. 1, 2

• Implement mandatory 3-week restriction from all athletic activity, particularly contact and collision sports 1
• Extend restriction to 4 weeks for contact or collision sports specifically, as splenic injury risk persists 6, 2
• Use shared decision-making to determine exact timing of return to activity beyond the minimum 3-week period 1
• Counsel about splenic rupture risk which can occur even with minor trauma in the setting of splenomegaly 6

Monitoring and Follow-up

• Recheck CBC in 1 week to assess platelet trend and ensure thrombocytopenia is not worsening 5, 3
• Monitor for symptom resolution which typically occurs in 2-3 weeks, though fatigue may persist for months 6, 2
• Reassess if symptoms worsen or new findings develop, including severe pharyngeal edema, respiratory compromise, or neurologic symptoms 1, 2
• Consider repeat heterophile testing if initial test was negative but clinical suspicion remains high, as false-negative results are common in the first week of illness 1, 2

Critical Pitfalls to Avoid

• Do not prescribe antibiotics empirically without confirming streptococcal pharyngitis, and specifically avoid ampicillin/amoxicillin which cause a characteristic rash in 90% of patients with infectious mononucleosis 6
• Do not allow premature return to sports before 3 weeks, as splenic rupture can be fatal 1, 2
• Do not dismiss persistent or worsening thrombocytopenia as benign, since severe thrombocytopenia requires aggressive treatment 5, 3
• Do not overlook alternative diagnoses if heterophile antibody is negative, including cytomegalovirus, toxoplasmosis, HIV, or streptococcal infection 1, 2