Case of the Month

B.A is a 12-year-old boy, living with HIV and virologically suppressed since 2020 after being changed to a Dolutegravir based antiretroviral therapy regimen. He was started on ART in 2012, with a long history of prior immunological and virological failure. He presented to the hospital with a 4-day history of vomiting, headache and blurred vision.

In Emergency Department: he was febrile, tachycardic and drowsy.  His Glasgow Coma Scale was 10/15. He had neck stiffness with positive Kernig’s sign.

Considering the clinical picture of fever associated with neurological deterioration and meningitic signs, a meningitis was high on the list of differentials.

• Cerebral CT scan: Unremarkable with no evidence of an intracranial lesion or hydrocephalus

Management

The management of cryptococcal meningitis is divided into 3 phases:

• Induction phase (2 weeks)
• Consolidation Phase (Further 8 weeks)
• Maintenance (Secondary prophylaxis)

Combination antifungal therapy has improved outcomes and antifungal monotherapy should be avoided. Flucytosine containing treatment regimens have higher survival rates. Cryptococcus species are intrinsically resistant to  Echinocandins (echinocandins).  

World Health Organization (WHO) guidelines:

https://www.who.int/publications/i/item/9789240052178

• At the first presentation: B.A received 2 weeks of Amphotericin B deoxycholate 1 mg/kg/day IV and fluconazole 12mg/kg/day followed by fluconazole 6mg/kg/day (consolidation phase).

• Second presentation: the problem list was as following:
  
  •  Symptoms of meningitis with positive CSF analysis and negative culture on repeated CSF.
    
  •    Initial CSF CX grew C. Gatii and C. Laurentii
  • The clinical deterioration presented at the same time of CD4 count improvement.
  • CrAg tests remain positive for weeks to months after cryptococcal meningitis has been treated. and cannot be relied on to diagnose a Cryptococcal meningitis relapse. The gold standard test is a CSF fungal culture which was negative on the second admission.
    

Does our patient need a change of his management in the second admission?

C. laurentii infections are rare and a standard treatment has not yet been established.

NIH Guideline for adults and adolescents with cryptococcal meningitis relapse recommend the following:

• Testing:
  • Cryptococcus isolates should undergo antifungal susceptibility testing.
• Review induction phase:
  • Patients who failed fluconazole monotherapy should be switched to amphotericin B, with or without flucytosine.
    
  • Those initially treated with amphotericin B formulation should remain on this agent until clinical response occurs.
    
  • Liposomal amphotericin B or amphotericin B lipid complex is better tolerated and has greater efficacy than the deoxycholate formulation and should be considered when initial treatment with other regimens fails.
• Confirm response to new regimen:
  • Verify CSF culture sterility at the completion of re-induction therapy.
• Recommendations for Consolidation therapy:
  • Fluconazole at a higher dose of 1,200 mg per day and optimization of ART.
    
  • Posaconazole, voriconazole, and isavuconazole—have activity against Cryptococcus spp. in vitro and may have a role in salvage therapy, but no specific advantages over fluconazole unless in vitro susceptibility testing indicates high-level fluconazole resistance.
    
  •  In case of decreased azole-susceptibility ( >16 µg/mL MIC for fluconazole):
    
    • Adjunctive weekly amphotericin B administration during consolidation therapy.
      
    • Higher doses of fluconazole (1,200 mg per day) in combination with flucytosine also may be considered.