Infectious Disease Compendium

Cryptococcus

Microbiology

A yeast. Cryptococcus neoformans, Cryptococcus gattii, Cryptococcus neoformans var grubii, Cryptococcus tetragattii (in Africa (Pubmed)) which must be 4 times worser than C. gattii.

Epidemiologic Risks

Pigeon droppings and Eucalyptus trees. Also found in a variety of decaying soils. Most disease is in the immunoincompetent.: transplant patients (although being on a calcineurin-inhibitor has a protective effect (PubMed)) and AIDS (CD4 < 200 as a rule); it can cause disease in people with no apparent immunologic deficiency.

3% of HIV patients with CD < 100 will be CRAG positive, a high enough rate to warrant screening (PubMed).

There is an ongoing problem with Cryptococcus neoformans var gattii on Vancouver Island (PubMed) and the Great Pacific NW, perhaps related to environmental changes from global warming (not that global warming exists, at least according to ex-President Bush. But he also said there were WMD in Iraq. Hmmmmm.) It is spreading across the US (PubMed).

The incubation period for C. gattii is 6 weeks to 13 months. C. gattii is being reported all over the US and in Europe, some acquired there and some reactivating long after leaving an endemic area (PubMed). And there was a cat that became ill >8 years after leaving an endemic era (PubMed). So this yeast can lurk a long time before rearing its ugly head.

C. gattii is harder to treat and may be recalcitrant to fluconazole, consider fungal susceptibility testing, and consider it strongly.

Cryptococcus neoformans var grubii is found in Vietnam/SE Asia and is harder to treat.

Autoantibodies to gamma interferon is a risk for disease (Pubmed); patients act like they have HIV. Also seen in patients with anti-GM-CSF autoantibodies (PubMed) (PubMed).

And there is the idiopathic low CD4 count syndrome, with or without other genetic defects (PubMed).

Syndromes

Pneumonia: usually asymptomatic, but in the transplant or HIV patient it can disseminate. In the normal host, smooth, multiple upper lobe nodules are the most common manifestation; lymphadenitis is unusual (PubMed). Check a serum cryptococcal antigen, and, if positive, do an LP. Maybe everyone should get an LP since the fungemia can be transient. I have seen two patients after they had a bit o' lung removed for a mass that turned out to be due to cryptococcus and not the expected tumor.

Meningitis: usually a granulomatous meningitis. "Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection are independently associated with increased mortality at 2 and 10 weeks (PubMed)."

As with most diseases, the sicker you are, the worse you do. For C. gattii, serum CRAG > 512 or CSF > 256 were bad prognostic findings (PubMed).

Skin lesions: can mimic molluscum contagiosum.

Treatment

C. gattii probably should be treated more aggressively (PubMed):

"Induction Amphotericin B, plus 5-flucytosine is indicated for C.gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks)" before moving to an azole.

From the 2009 IDSA Guidelines with mostly based on C. neoformans.

DO NOT give adjunctive dexamethasone. Patients do worse (PubMed)

Non HIV

Pulmonary:

In normal people with isolated pneumonia, it slooooooowly resolves with or without therapy and the serum antigen can be positive for years (Pubmed).

Mild-to-moderate symptoms or culture-positive specimen from this site

fluconazole, 200–400 mg/d for 6–12 months OR
itraconazole, 200–400 mg/d for 6–12 months OR
Amphotericin B, 0.5–1 mg/kg/d (total, 1000–2000 mg).
Severe symptoms and immunocompromised hosts
Treat like CNS disease

CNS:
Induction/consolidation: Amphotericin B, 0.7–1 mg/kg/d plus flucytosine, 100 mg/kg/d for 2 w, then fluconazole 400 mg/d for minimum 10 weeks OR
Amphotericin B, 0.7–1 mg/kg/d plus flucytosine, 100 mg/kg/d for 6–10 wks OR
Amphotericin B, 0.7–1 mg/kg/d for 6–10 wks OR
Lipid formulation of Amphotericin B, 3–6 mg/kg/d for 6–10 wks.

In solid organ transplant patients, lipid formulations are superior (PubMed) and are recommended in the guidelines.

Check the opening pressure and if > 25 or symptoms of increased intracranial pressure, patient my need frequent spinal taps or a shunt.

HIV

Pulmonary
Mild-to-moderate symptoms or culture-positive specimen from this site
fluconazole, 200–400 mg/d, lifelong OR
itraconazole, 200–400 mg/d, lifelong OR
fluconazole, 400 mg/d plus flucytosine 100–150 mg/kg/d for 10 wks.


CNS
Induction/consolidation: Amphotericin B, 0.7–1 mg/kg/d plus flucytosine, 100 mg/kg/d for 2 w, then fluconazole, 400 mg/d for a minimum of 10 wks OR
Amphotericin B, 0.7–1 mg/kg/d plus 5 flucytosine 100 mg/kg/d for 6–10 wks.

Since the guidelines were published, there is some data to suggest Amphotericin alone is sufficient in HIV (PubMed) and 5FC is expensive and toxic.

OR
Amphotericin B, 0.7–1 mg/kg/d for 6–10 wks OR
fluconazole, 400–800 mg/d for 10–12 wks OR
itraconazole, 400 mg/d for 10–12 wks OR
fluconazole, 400–800 mg/d plus flucytosine 100–150 mg/kg/d for 6 wks OR
Lipid formulation of Amphotericin B, 3–6 mg/kg/d for 6–10 wks.

AmB plus fluconazole (800–1200 mg/day) is as good as AmB plus 5 FC (PubMed).

Although not part of the guidelines, constant infusion Amphotericin B, which is a less toxic delivery mechanism and costs way less than lipid amphotericin, is equal to intermittent infusion (PubMed).

Maintenance:
fluconazole, 200–400 mg po q.d., lifelong OR
itraconazole, 200 mg po bid, lifelong OR
Amphotericin B, 1 mg/kg iv 1–3 times/w, lifelong.

In AIDS patients, wait 4 to 10 weeks after starting before HAART to avoid IRIS OR fluconazole +/- flucytosine. The fluconazole should be 400 mg/d at a minimum and continued for life at 200 mg qd in HIV. Less thrilling would be fluconazole alone. If you can't give flucytosine, then give more amphotericin, longer.

In resource poor areas (Malawi or the US thanks to our lack of health care) 14 days of fluconazole (1200 mg per day) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day) had reasonable outcomes in HIV patients (PubMed).

In recalcitrant disease, consider adding interferon gamma (PubMed). In one paper they succeeded with liposomal Amphotericin B (3 mg/kg), intravenous voriconazole, and subcutaneous recombinant interferon γ­1b (200 μg thrice weekly) (PubMed).

Notes

As is so often the case, patients with ID consultation, while sicker, have decreased mortality. (PubMed). What flabbers my gaster is there are docs at Washington School of Medicine who would manage the disease without ID consultation. Talk about a dumbass, suffering from the delusion that they know what they are doing. Dunning-Kruger. It kills. (PubMed).

Cryptococcus gattii is a worser disease: more cryptococcomas, less responsive to fluconazole, slower to respond to Amphotericin B. My bias (supported by the literature of course (PubMed)) is to treat with higher dose Amphotericin B at least 0.8 mg/kg d with flucytosine initially and the change to fluconazole. All the azole antifungals are probably the same (except itraconazole) (PubMed).

The mean duration of therapy for eradication with C. gattii is 18 months (PubMed), although some patients can take 2-3 years to eradicate the organism (PubMed).

All strains of C. gattii have heteroresistance, with MIC's that ranged between 4 μg/ml and 32 μg/ml. More C. gattii strains (86%) than Cryptococcus neoformans strains (46%) exhibited MIC's that were16 μg/ml (PubMed). This may be particularly true of strains from the great Pacific Northwest (PubMed) and the MIC to fluconazole is increasing in other parts of the world (PubMed).

Cryptococcus neoformans var grubii has higher MIC's to fluconazole, amphotericin and flucytosine and a worse prognosis (PubMed).

Higher MIC's to fluconazole (>=16) portend a bad outcome; either push the fluconazole or perhaps use voriconazole (Pubmed).

And don't use caspofungin; it does not work.

AIDS patients will have a positive serum cryptococcal antigen when the disease is in the CNS, transplant patients usually will not. So a negative serum antigen means that HIV patient does not have cryptococcus in the CNS; this is not true in the transplant patient. Usually.

The end point for treating the non AIDS patient is normal LP, not some arbitrary duration of therapy as in the two classic NEJM articles on the treatment of cryptococcal meningitis. They are crap and are a study in how to kill as many people as possible. They under treated both in dose and duration with the amphotericin. I repeat, the articles are crap. Read the IDSA guidelines for a more rational approach.

In Africa, "Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebral spinal fluid. (NEJM) (PubMed)."

Increased intracranial pressure with therapy is not uncommon and treat with LP and remove large volumes of CSF (do if opening pressure >25). May need to do daily.  On one HIV study, at least one theraputic LP decreased mortality (PubMed); " The association was observed regardless of opening pressure at baseline."

Normal pateints can get an arachnoiditis after therapy presenting with severe lower motor neuron involvement, cognitive changes, gait disturbances, asymmetric weakness and urinary retention. (PubMed).