What is the likely diagnosis for a 20-year-old patient with a history of chest infection 3 weeks ago, now presenting with fatigue, normocytic anemia, and abnormal blood smear findings including hyperchromasia, microspherocytes, and anisocytosis?

Diagnosis: Infectious Mononucleosis with Hemolytic Anemia

The most likely diagnosis is infectious mononucleosis (option D), which can present with normocytic anemia secondary to autoimmune hemolytic anemia, explaining the microspherocytes and hyperchromasia on blood smear following a recent viral illness. 1, 2

Clinical Reasoning

Key Diagnostic Features Present

• Recent chest infection (3 weeks ago) suggests a preceding viral illness, which is consistent with the typical prodrome of infectious mononucleosis 1
• Fatigue as the predominant symptom is characteristic of infectious mononucleosis, where fatigue may be profound and typically resolves within three months 1
• Normocytic anemia occurs in infectious mononucleosis, particularly when complicated by hemolytic anemia 2, 3
• Blood smear findings of microspherocytes, hyperchromasia, and anisocytosis are pathognomonic for hemolytic anemia, which is a recognized complication of Epstein-Barr virus infection 2, 4

Why Other Options Are Incorrect

Hodgkin disease (option A) would typically present with persistent lymphadenopathy, B symptoms (fever, night sweats, weight loss), and would not explain the acute hemolytic picture with microspherocytes following a recent infection 1

Sickle cell disease (option B) is excluded because this patient is 20 years old with no prior history mentioned, and sickle cell disease would have manifested much earlier in life with recurrent vaso-occlusive crises 2

Biliary atresia (option C) is a neonatal/infant condition presenting in the first months of life with jaundice and cholestasis, making it completely irrelevant in a 20-year-old patient 5

Pathophysiology of Hemolytic Anemia in Infectious Mononucleosis

• Autoimmune hemolytic anemia occurs in infectious mononucleosis due to the formation of antibodies that cross-react against erythrocyte antigens, particularly of the I system 4
• Cold agglutinin syndrome is a specific type of hemolytic anemia mediated by IgM antibodies whose maximum activity occurs at 4°C, and can complicate infectious mononucleosis 4
• C3-positive hemolytic anemia has been documented in Epstein-Barr virus-induced cases, even when IgG direct antiglobulin test is negative 2

Essential Confirmatory Testing

• Monospot test (heterophile antibody test) is the most widely used method to detect serum heterophile antibodies of infectious mononucleosis 1
• Epstein-Barr virus serology for viral capsid antigen antibodies should be performed when confirmation is required in patients with mononucleosis-like illness and a negative monospot test 1
• Direct antiglobulin test (Coombs test) should be performed to confirm autoimmune hemolytic anemia, looking specifically for C3d monospecific positivity 4
• Peripheral blood smear review will show atypical lymphocytes constituting more than 10% of the total lymphocyte count, along with spherocytes and polychromasia 1, 4
• Complete blood count typically shows leukocytosis with lymphocytes making up at least 50% of the white blood cell differential count 1
• Lactate dehydrogenase and indirect bilirubin will be elevated, confirming hemolysis 2, 4

Management Approach

• Transfusion support may be required if hemoglobin drops to critical levels (as low as 3.7 g/dL has been documented) 4
• Conservative treatment with reduction of activity and bed rest as tolerated is recommended 1
• Avoid contact sports or strenuous exercise for 8 weeks or while splenomegaly is present, as spontaneous splenic rupture occurs in 0.1 to 0.5% of patients and is potentially life-threatening 1
• Monitor for splenic enlargement, which occurs in approximately 50% of cases 1
• Hemolysis typically resolves within 2 weeks after admission with supportive care alone 4

Critical Clinical Caveat

Cold agglutinin syndrome associated with infectious mononucleosis is a rare but potentially fatal complication that should be considered when findings suggestive of hemolysis are present, requiring timely initiation of support measures 4. The combination of recent viral illness, fatigue, normocytic anemia, and microspherocytes on blood smear creates a highly specific clinical picture for infectious mononucleosis complicated by autoimmune hemolytic anemia 2, 4.