Confusable diagnoses · PANCE / PANRE

Infectious Mononucleosis vs Toxoplasmosis

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

Infectious Mononucleosis and Toxoplasmosis are easy to mix up on the boards. Here's a side-by-side comparison — presentation, workup, imaging, and first-line treatment — drawn from our full outlines.

Infectious Mononucleosis vs Toxoplasmosis at a glance

  • Infectious Mononucleosis: Acute viral syndrome caused by Epstein-Barr virus — fever, pharyngitis, posterior cervical lymphadenopathy, fatigue, and atypical lymphocytosis.
  • Toxoplasmosis: Obligate intracellular protozoan infection (Toxoplasma gondii) — usually asymptomatic, but causes severe congenital disease and CNS lesions in immunocompromised hosts.

Try two board-style questions on Infectious Mononucleosis vs Toxoplasmosis

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Question 1Infectious DiseaseEasy
A 22-year-old college student has fever, severe sore throat, posterior cervical lymphadenopathy, fatigue, tonsillar exudate, splenomegaly, and periorbital edema. Monospot test is positive. WBC 12K with 65% atypical lymphocytes. Which of the following is the most appropriate management?
  • AOral amoxicillin
  • BIntravenous acyclovir
  • COral prednisone taper
  • DSupportive care and rest
Reveal answer & full explanation
Correct answer: D — Supportive care and rest
  • AOral amoxicillin
  • BIntravenous acyclovir
  • COral prednisone taper
  • DSupportive care and rest✓

Why Supportive care and rest is correct

  • Infectious mononucleosis (Epstein-Barr virus, EBV) is managed supportively: rest, antipyretics, and fluids
  • Positive Monospot with atypical lymphocytosis, posterior cervical adenopathy, and splenomegaly confirms the diagnosis
  • Contact-sports restriction for at least 3-4 weeks is required due to splenic rupture risk

Why the others are wrong

  • Oral amoxicillin — must be avoided; it causes a diffuse maculopapular rash in a substantial minority (about 30%) of EBV patients and does not treat a viral illness (confused-with strep pharyngitis)
  • Intravenous acyclovir — reduces oropharyngeal EBV shedding but does not improve clinical symptoms and is not indicated (right-concept-wrong-target)
  • Oral prednisone taper — is reserved only for severe complications such as airway compromise, severe thrombocytopenia, or hemolytic anemia, not routine cases (overtreatment)

Additional high-yield points

  • Monospot (heterophile antibody) is positive in 85-90% of adults after 1 week; less sensitive in the first week and in young children
  • Atypical lymphocytes are reactive cytotoxic T-cells responding to EBV-infected B-cells
  • Group A Strep would show a positive rapid strep/culture and lacks splenomegaly or atypical lymphocytosis
Question 2Infectious DiseaseMedium
A 38-year-old man with untreated HIV (CD4 count 42 cells/µL) presents with a 10-day history of worsening headache, low-grade fever, and new right-arm weakness. On exam he is afebrile, somnolent but arousable, with right-sided hemiparesis. MRI of the brain with contrast shows multiple ring-enhancing lesions with surrounding edema in the basal ganglia and at the gray-white junction. Serum Toxoplasma IgG is positive. Which of the following is the most appropriate initial management?
  • AVancomycin, ceftriaxone, and IV ampicillin
  • BLiposomal amphotericin B and oral flucytosine
  • CPyrimethamine, sulfadiazine, and leucovorin
  • DIsoniazid, rifampin, pyrazinamide, ethambutol
Reveal answer & full explanation
Correct answer: C — Pyrimethamine, sulfadiazine, and leucovorin
  • AVancomycin, ceftriaxone, and IV ampicillin
  • BLiposomal amphotericin B and oral flucytosine
  • CPyrimethamine, sulfadiazine, and leucovorin✓
  • DIsoniazid, rifampin, pyrazinamide, ethambutol

Why Pyrimethamine, sulfadiazine, and leucovorin is correct

  • The clinical picture — advanced HIV with CD4 below 100, subacute focal neurologic deficits, multiple ring-enhancing lesions favoring the basal ganglia/gray-white junction, and positive Toxoplasma IgG — is CNS toxoplasmosis until proven otherwise.
  • IDSA/NIH OI guidelines name pyrimethamine + sulfadiazine + leucovorin as preferred first-line induction therapy (6 weeks), with leucovorin to prevent pyrimethamine-induced myelosuppression; clinical and radiographic improvement within ~2 weeks supports the empiric diagnosis. TMP-SMX is an accepted alternative.

Why the others are wrong

  • Liposomal amphotericin B and oral flucytosine treat cryptococcal CNS disease; cryptococcomas are typically smaller and accompanied by a positive cryptococcal antigen, not the multifocal basal-ganglia ring lesions seen here.
  • Isoniazid, rifampin, pyrazinamide, ethambutol treat CNS tuberculosis/tuberculoma, which classically shows an indolent course with basal meningeal enhancement, not multiple gray-white-junction ring lesions in this CD4 range.
  • Vancomycin, ceftriaxone, and IV ampicillin provide empiric coverage for acute bacterial meningitis (including Listeria in an immunocompromised host), which presents more acutely with meningismus and does not match this subacute, multifocal, IgG-positive presentation.
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Side-by-side comparison

FeatureInfectious MononucleosisToxoplasmosis
At a glanceAcute viral syndrome caused by Epstein-Barr virus — fever, pharyngitis, posterior cervical lymphadenopathy, fatigue, and atypical lymphocytosis.Obligate intracellular protozoan infection (Toxoplasma gondii) — usually asymptomatic, but causes severe congenital disease and CNS lesions in immunocompromised hosts.
Classic presentationAn adolescent with sore throat, fatigue, posterior cervical adenopathy, and a diffuse maculopapular rash after a course of amoxicillin given for presumed strep is EBV until proven otherwise.; Prodrome (1-2 weeks): malaise, low-grade fever, headache, anorexia; Classic triad: fever, exudative pharyngitis (often with palatal petechiae),…AIDS patient with CD4 <100, headache, focal neuro deficit, and multiple ring-enhancing brain lesions on MRI in the basal ganglia or gray-white junction — toxoplasmosis until proven otherwise. Congenital infection: diffuse intracranial calcifications (vs. periventricular in CMV).; Immunocompetent: usually asymptomatic; minority develop…
Workup / key labsClinical syndrome + positive heterophile antibody OR positive EBV VCA IgM with negative EBNA-1 IgG.; CBC with differential: lymphocytic predominance with ≥10% atypical lymphocytes (Downey cells); Heterophile antibody (Monospot) — positive in ~85% of adolescents/adults; may be falsely negative in the first week and in young children (<4…Clinical syndrome + serology/PCR + imaging. CNS toxoplasmosis in HIV often diagnosed empirically with response to therapy (2-week trial); biopsy if no improvement.; Toxoplasma IgG (lifelong) and IgM (acute; IgM can persist >1 year); IgG avidity (high avidity excludes recent infection — useful in pregnancy); PCR — amniotic fluid…
ImagingAbdominal ultrasound only if splenic enlargement clinically suspected and would change activity counseling (most evidence does not support routine imaging)MRI brain with contrast: multiple ring-enhancing lesions with surrounding edema, predilection for basal ganglia and gray-white junction; CT (if MRI unavailable): hypodense lesions with ring enhancement; Fetal ultrasound: hydrocephalus, intracranial calcifications, IUGR, hepatosplenomegaly; Funduscopic exam for chorioretinitis
First-line treatmentSupportive care: hydration, NSAIDs/acetaminophen, rest, throat lozenges/saltwater gargles; Avoid contact sports/heavy exertion for at least 3 weeks (and until splenomegaly resolves) due to splenic rupture risk; Avoid amoxicillin/ampicillin — high rate of maculopapular rash (immune-mediated, not true allergy)Acute acquired in immunocompetent host: typically no treatment unless severe or visceral disease; Ocular toxoplasmosis: pyrimethamine + sulfadiazine + leucovorin × 4-6 weeks; corticosteroids if vision-threatening; CNS toxoplasmosis (HIV/immunocompromised):; • Pyrimethamine 200 mg load then 50-75 mg PO daily + sulfadiazine 1-1.5 g PO QID…

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Full outlines

Infectious Mononucleosis (EBV) Toxoplasmosis All 514 diagnoses

Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.