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Cryptococcal Antigen

Cryptococcal meningitis is an opportunistic infection caused by Cryptococcus neoformans (serotypes A and D) and Cryptococcus gattii (serotypes B and C), which are encapsulated yeast. Cryptococcus neoformans is acquired by inhalation of aerosolized particles from bird droppings, soil and decaying wood.  Cryptococcosis can occur as a primary disease or secondary to immunosuppression. 

Cryptococcus most commonly infects the lungs, central nervous system (CNS), skin, and bones. CNS involvement by C. neoformans can cause headaches, lethargy, fever, meningismus, vision defects, sensory deficits, and cranial nerve palsies. Formation of yeast aggregates can obstruct the outflow of CSF, resulting in increased intracranial pressure. Cryptococcal meningitis can cause small-vessel vasculitis that results in lacunar infarcts.

Guideline-based treatment for cryptococcal meningitis consists of three phases: induction, consolidation, and maintenance therapy. Standard induction treatment includes a combination of intravenous liposomal amphotericin B and flucytosine for 2 to 4 weeks. This treatment is followed by consolidation therapy with fluconazole for 8 weeks. After completion of induction and consolidation therapy, maintenance therapy with lower-dose fluconazole is continued for up to 1 year to prevent recurrence.

Previously, cryptococcal meningitis was diagnosed by staining CSF with India Ink.  A more sensitive cryptococcal antigen test based on latex agglutination replaced the India ink test and was able to detect fungus in both serum and CSF. 

The cryptococcal antigen lateral flow assay (LFA) (IMMY, Norman, OK, USA) detects capsular polysaccharide antigens of the four major cryptococcal serotypes (A and D for C. neoformans and B and C for C. gattii). LFA is a sandwich immunochromatographic assay that uses specimen wicking to capture gold-conjugated, anti-cryptococcal antigen (anti-CrAg) monoclonal antibodies and gold conjugated control antibodies on the test membrane.

The test provides both qualitative and semi-quantitative results in ten minutes with no specimen pretreatment. Quantitative titers may be ascertained by mixing the specimen with diluent solution; the highest sample dilution that produces a positive result is considered the LFA titer.

Falsely negative results can occur in patient with high organism loads due to the high dose hook effect, which is also referred to as prozone. This occurs when excess analyte, such as high concentrations of the cryptococcal antigen, result in decreased visual intensity of the test lines and negative test results. Exceedingly high concentrations of unbound CrAg may out-compete the gold-labeled antibody-antigen complex that normally wicks up the membrane to interact with the test line which has the immobilized anti-CrAg monoclonal antibodies. The latter reaction will result in a visible test line, but unbound CrAg interacting avidly with the monoclonal antibodies will result in no line. A 1 to 2 dilution could be routinely performed for all undiluted samples from patients with a high suspicion of disease that tested negative to prevent the high dose hook effect.

Detection of cryptococcal antigen in serum or cerebrospinal fluid indicates cryptococcosis. Titers should not be used to monitor treatment or determine cure. Low level titers may persist following resolution of infection.

Specimen requirement is one SST tube of blood  or 0.5 mL of spinal fluid. 

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