What is the most likely etiology of a 16-year-old boy with leukemia, on corticosteroids (corticosteroid therapy), presenting with a 2-week history of nocturnal cough, chest pain, and fever, with cerebrospinal fluid (CSF) analysis showing elevated opening pressure, slightly decreased glucose, and significantly elevated leukocyte count?

Most Likely Etiology: Cryptococcal Meningitis

In this immunocompromised 16-year-old on corticosteroids with subacute symptoms and CSF showing elevated opening pressure (250 mmH₂O), low glucose (40 mg/dL), and elevated leukocytes (250 cells/μL), cryptococcal meningitis is the most likely diagnosis. 1

Clinical Reasoning

Why Cryptococcus is Most Likely

• Immunosuppression profile: Corticosteroid therapy for leukemia creates profound immunosuppression, making opportunistic infections like cryptococcosis highly probable 1

• CSF pattern matches cryptococcal infection: The combination of elevated opening pressure (>250 mmH₂O is typical), low glucose, and moderate pleocytosis is classic for cryptococcal meningitis 1

• Subacute presentation: The 2-week history of nocturnal cough, chest pain, and low-grade fever (38°C) suggests pulmonary cryptococcosis with CNS dissemination—a common pattern where pulmonary infection precedes meningitis 1

• Age and risk factors: While cryptococcosis occurs in only 1% of HIV-infected children, it typically affects those aged 6-12 years with severe immunosuppression, matching this patient's profile 1

Key Diagnostic Features

CSF findings in cryptococcal meningitis 1:

• Opening pressure is usually elevated (as seen here at 250 mmH₂O)
• CSF cell count, glucose, and protein might be virtually normal OR show the pattern seen here
• India ink staining and cryptococcal antigen testing are diagnostic

Pulmonary involvement 1:

• The nocturnal cough and chest pain suggest pulmonary cryptococcosis
• Can present with unexplained recurrent fever, cough with scant sputum, and focal or diffuse pulmonary infiltrates
• Pulmonary disease without dissemination is unusual but occurs

Immediate Diagnostic Workup

Essential CSF studies 1:

• India ink-stained wet mount examination
• Cryptococcal antigen detection by latex agglutination (CSF and serum)
• Fungal cultures using lysis-centrifugation method for blood specimens
• Note: CSF antigen might be negative despite positive culture due to prozone effect, low antigen levels, or nonencapsulated strains

Additional testing 1:

• Chest imaging to evaluate pulmonary involvement
• Blood cultures with lysis-centrifugation method
• Serum cryptococcal antigen

Critical Management Principles

Without treatment, cryptococcosis is fatal 1. Combination therapy is recommended for severe cryptococcosis and cryptococcal meningitis based on adult literature 1.

Common Pitfalls to Avoid

• Don't assume CNS leukemia first: While this patient has leukemia, the subacute presentation with pulmonary symptoms and specific CSF pattern points away from leukemic CNS infiltration 1, 2

• Don't delay antifungal therapy: Start empiric treatment while awaiting culture results if clinical suspicion is high 1

• Monitor for elevated intracranial pressure: The elevated opening pressure requires close monitoring and may need therapeutic lumbar punctures 1

• Check for treatment failure indicators: A CSF cryptococcal antigen titer >1:8 after completion of therapy indicates treatment failure or pending relapse 1

Alternative Considerations (Less Likely)

CNS leukemia 1, 2:

• Would typically present more acutely
• Less likely to have prominent pulmonary symptoms
• CSF would show lymphoblasts on cytology
• Opening pressure elevation less characteristic

Bacterial meningitis 3:

• Would present more acutely in immunocompromised patients
• Higher CSF leukocyte count typically expected
• Lower glucose values usually seen

Treatment-related neurotoxicity 3, 4:

• More common during induction phase (first 2 months)
• Usually presents with seizures, hemiparesis, or headache rather than this subacute pattern
• Would not explain pulmonary symptoms