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Cryptococcal Disease: 2019 Guideline
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Cryptococcal Disease: 2019 Guideline

Topics / Medical / Meningitis

Main Recommendations for 2019:Summary

Positive CrAg (Blood), Positive LP (CSF)

  1. If the patient’s CD4 count is < 200 cells/uL (used to be <100cells/uL): CrAg screening (in the blood) is recommended for all adults and adolescents (>10 years old). In some South African laboratories (such as the NHLS), this is done as a “reflex”, without a formal request.
  2. If there is a positive CrAg screening test, a lumbar puncture is needed to then diagnose Cryptococcal Meningitis (CM).
  3. Recommended Induction Regime for Treatment of CM:
    1. Amphotericin B deoxycholate IV (1mg/kg/day) for 1 week and flucytosine (100mg/kg/day in four divided doses), is followed by
    2. Fluconazole PO (1200mg daily) for 1 week in adults or 12mg/kg/day in children and adolescents up to a max of 800mg daily for 1 week.
    3. If the patient has Renal Dysfunction (Creatinine Clearance < 50ml/min), use liposomal amphotericin B-based options instead of the one above. Read the guideline for other options.
    4. NB: If there are any delays in initiating Amphotericin B, initiate the patient on Fluconazole 1200mg PO daily (while waiting for transfer, etc.)
    5. NB: If there is no Amphotericin B – Initiate the patient with Fluconazole 1200mg PO daily for 2 weeks and flucytosine 100mg/kg/day in 4 divided doses.
    6. NB: If there is no flucytosine – Initiate the patient with Amphotericin B 1mg/kg/day and fluconazole 1200mg/day for a period of 2 weeks.
  4. Recommended Consolidation Regime for Treatment of CM:
    1. Fluconazole PO (800mg daily for adults, 12mg/kg/day for children/adolescents max 800mg) for 8 weeks
  5. Recommended Maintenance Regime for Treatment of CM:
    1. Fluconazole PO (200mg daily) for > 12 months
    2. The regime should be continued for a period of at least 12 months until a single CD4 count is > 200 cells/uL and the HIV viral load is suppressed.
  6. CM and raised intracranial pressures:
    1. It is recommended to use a manometer.

Positive CrAg (Blood), Negative LP (CSF)

  1. Recommended Induction Regime:
    1. Fluconazole PO (1200mg) for 2 weeks alone (No Amphotericin)
  2. Recommended Consolidation Regime for Treatment of CM:
    1. Fluconazole PO (800mg daily for adults, 12mg/kg/day for children/adolescents max 800mg) for 8 weeks.
  3. Recommended Maintenance Regime for Treatment of CM:
    1. Fluconazole PO (200mg daily) for 12 months
    2. The regime should be continued for a period of at least 12 months until a single CD4 count is > 200 cells/uL and the HIV viral load is suppressed.
  4. * ARVs may be commenced immediately.

Initiating ARVs

  1. If Positive CrAg and Positive LP: Commence 4-6weeks after the introduction of antifungal therapy.
  2. If Positive CrAg and Negative LP: Commence 2 weeks after the introduction of antifungal therapy.
  3. NB: Follow the HIV National Guidelines for initiation of ARVs.

Monitoring Treatment Response

  • Monitor treatment response using the resolution of symptoms/signs. Unless indicated, LP should not be routinely performed after 7-14 days of antifungal treatment to document conversion.

Treatment of Raised ICP

  • Occurs in many of the patients with CM (75%). Results from obstruction of flow at the arachnoid villi/granulations. Treatment includes daily therapeutic LPs – remove around 10 – 30mls of CSF if the manometer reading is >25cm H2O. You should repeat the LP whenever the patient develops symptoms/signs of raised ICP (severe headaches, vomiting, confusion or depressed level of consciousness, ophthalmoplegia, Cushing’s triad).

Notes:

  1. The pathogen causing CM: Cryptococcus neoformans, an encapsulated yeast. Cryptococcus gattii (2% of all cases in South Africa) is managed in a similar manner.
  2. Common Symptoms/Signs of CM: Neck stiffness, raised intracranial pressure (including headache, confusion, altered level of consciousness, sixth cranial nerve palsies with diplopia and visual impairment and papilloedema), and encephalitis (including memory loss and new-onset psychiatric symptoms). Others: cutaneous lesions, pulmonary involvement.
  3. There is insufficient data to recommend “cryptococcal Antigenaemia (CrAg)” routine screening in children – incidence is much lower either way.
  4. Screening Strategies: Reflexive vs Clinician Initiated Screening.
  5. In the blood we test for CrAg, in the CSF we also test for CrAg. Other tests in the CSF include India Ink and fungal culture.
  6. Pregnancy: Fluconazole has been rarely associated with human teratogenicity when administered in the first trimester, especially at higher doses > 400mg/day. However, without it, there is a substantial risk of disease progression. You may try to lower the dose of fluconazole during the first trimester to 200mg daily until the second trimester. These women should be referred for the high-resolution US before 20 weeks of gestation to detect congenital abnormalities. Fluconazole is also transferred into breast milk as well. Please read further and consult.
  7. Subsequent or Repeated Episodes of CM: CSF should be submitted for prolonged fungal culture (minimum 14 days) (NB: India ink and CrAg tests are not useful for the diagnosis of subsequent episodes of cryptococcal meningitis as they can stay positive for a prolonged period despite successful treatment).
  8. If a patient has a positive blood culture, this is called Cryptococcal fungaemia and it is treated the same as CM.
  9. There is no indication for corticosteroids in the initial management of CM.
  10. There is no recommendation to increase fluconazole in patients taking Rifampicin.
  11. Amphotericin B should be reconstituted into 1L of 5% Dextrose water, given over 4 hours. Potassium (decreases), Magnesium(decreases), and Renal function(AKI) should be monitored. Some patients also get a decreased Hb. Read the guideline’s Table 7 for further information.
Download Guideline: Crypt Disease 2019
Published on 13 June 2022
Dr. RW Becerra Estevez
Dr. RW Becerra EstevezMBChB (WSU)

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