Cryptococcosis

Cryptococcosis, also known as

cryptococcal disease, is a potentially
fatal fungal disease. It is caused by one
of two species; Cryptococcus
neoformans and Cryptococcus gattii.
These were all previously thought to be
subspecies of C. neoformans but have
now been identified as distinct species.
 Cryptococcosis

Micrograph of cryptococcosis showing the

characteristically thick capsule of cryptococcus.
Field stain.

Pronunciation /ˌkrɪptəkəˈkoʊsɪs, -toʊ-,

-kɒ-/[1][2]

Specialty Infectious disease,

Pulmonology

Cryptococcosis is believed to be
acquired by inhalation of the infectious
propagule from the environment.
Although the exact nature of the
infectious propagule is unknown, the
leading hypothesis is the basidiospore
created through sexual or asexual
reproduction.

Cause
Cryptococcosis is a defining
opportunistic infection for AIDS, and is
the second-most-common AIDS-defining
illness in Africa. Other conditions that
pose an increased risk include certain
lymphomas (e.g., Hodgkin's lymphoma),
sarcoidosis, liver cirrhosis, and patients
on long-term corticosteroid therapy.
Distribution is worldwide in soil.[3] The
prevalence of cryptococcosis has been
increasing over the past 20 years for
many reasons, including the increase in
incidence of AIDS and the expanded use
of immunosuppressive drugs.

In humans, C. neoformans causes three

types of infections:

Wound or cutaneous cryptococcosis

Pulmonary cryptococcosis
Cryptococcal meningitis.

Cryptococcal meningitis (infection of the

meninges, the tissue covering the brain)
is believed to result from dissemination
of the fungus from either an observed or
unappreciated pulmonary infection.
Often there is also silent dissemination
throughout the brain when meningitis is
present. Cryptococcus gattii causes
infections in immunocompetent people
(fully functioning immune system), but C.
neoformans v. grubii, and v. neoformans
usually only cause clinically evident
infections in persons with some form of
defect in their immune systems
(immunocompromised persons). People
with defects in their cell-mediated
immunity, for example, people with AIDS,
are especially susceptible to
disseminated cryptococcosis.
Cryptococcosis is often fatal, even if
treated. It is estimated that the three-
month case-fatality rate is 9% in high-
income regions, 55% in low/middle-
income regions, and 70% in sub-Saharan
Africa. As of 2009 there were globally
approximately 958,000 annual cases and
625,000 deaths within three months after
infection.[4]

Although the most common presentation

of cryptococcosis is of C. neoformans
infection in an immunocompromised
person (such as persons living with
AIDS), the C. gattii is being increasingly
recognised as a pathogen in what is
presumed to be immunocompetent
hosts,[5] especially in Canada and
Australia. This may be due to rare
exposure and high pathogenicity, or to
unrecognised isolated defects in
immunity, specific for this organism.

Diagnosis
Dependent on the infectious syndrome,
symptoms include fever, fatigue, dry
cough, headache, blurred vision, and
confusion.[6] Symptom onset is often
subacute, progressively worsened over
several weeks. The two most common
presentations are meningitis (an
infection in and around the brain) and
pulmonary (lung) infection.

Any person who is found to have

cryptococcosis at a site outside of the
central nervous system (e.g., pulmonary
cryptococcosis), a lumbar puncture is
indicated to evaluate the cerebrospinal
fluid (CSF) for evidence of cryptococcal
meningitis, even if they do not have signs
or symptoms of CNS disease. Detection
of cryptococcal antigen (capsular
material) by culture of CSF, sputum and
urine provides definitive diagnosis.[7]
Blood cultures may be positive in heavy
infections. India ink of the CSF is a
traditional microscopic method of
diagnosis,[8] although the sensitivity is
poor in early infection, and may miss 15-
20% of patients with culture-positive
cryptococcal meningitis.[9] Unusual
morphological forms are rarely seen.[10]
Cryptococcal antigen from cerebrospinal
fluid is the best test for diagnosis of
cryptococcal meningitis in terms of
sensitivity.[11] Apart from conventional
methods of detection like direct
microscopy and culture, rapid diagnostic
methods to detect cryptococcal antigen
by latex agglutination test, lateral flow
immunochromatographic assay (LFA), or
enzyme immunoassay (EIA). A new
cryptococcal antigen LFA was FDA
approved in July 2011.[9][12] Polymerase
chain reaction (PCR) has been used on
tissue specimens.

Cryptococcosis can rarely occur in the

non-immunosuppressed people,
particularly with Cryptococcus gattii.
Prevention
Cryptococcosis is a very subacute
infection with a prolonged subclinical
phase lasting weeks to months in
persons with HIV/AIDS before the onset
of symptomatic meningitis. In Sub-
Saharan Africa, the prevalence rates of
detectable cryptococcal antigen in
peripheral blood is often 4–12% in
persons with CD4 counts lower than 100
cells/mcL.[13][14] Cryptococcal antigen
screen and preemptive treatment with
fluconazole is cost saving to the
healthcare system by avoiding
cryptococcal meningitis.[15] The World
Health Organization recommends
cryptococcal antigen screening in HIV-
infected persons entering care with
CD4<100 cells/μL.[16] This undetected
subclinical cryptococcal (if not
preemptively treated with anti-fungal
therapy) will often go on to develop
cryptococcal meningitis, despite
receiving HIV therapy.[14][17]
Cryptococcosis accounts for 20-25% of
the mortality after initiating HIV therapy
in Africa. What is effective preemptive
treatment is unknown, with the current
recommendations on dose and duration
based on expert opinion. Screening in the
United States is controversial, with
official guidelines not recommending
screening, despite cost-effectiveness
and a 3% U.S. cryptococcal antigen
prevalence in CD4<100 cells/μL.[18][19]
Treatment
Treatment options in persons without
HIV-infection have not been well studied.
Intravenous Amphotericin B combined
with flucytosine by mouth is
recommended for initial treatment
(induction therapy).[20]

Persons living with AIDS often have a

greater burden of disease and higher
mortality (30-70% at 10-weeks), but
recommended therapy is with
amphotericin B and flucytosine. Where
flucytosine is not available (many low
and middle income countries),
fluconazole should be used with
amphotericin.[16] Amphotericin-based
induction therapy has much greater
microbiologic activity than fluconazole
monotherapy with 30% better survival at
10-weeks.[7][21] Based on a systematic
review of existing data, the most cost-
effective induction treatment in resource-
limited settings appears to be one week
of amphotericin B coupled with high-
dose fluconazole.[21] After initial
induction treatment as above, typical
consolidation therapy is with oral
fluconazole for at least 8 weeks used
with secondary prophylaxis with
fluconazole thereafter.[16]
The decision on when to start treatment
for HIV appears to be very different than
other opportunistic infections. A large
multi-site trial supports deferring ART for
4–6 weeks was overall preferable with
15% better 1-year survival than earlier
ART initiation at 1–2 weeks after
diagnosis.[22] A Cochrane review also
supports the delayed starting of
treatment until cryptococcosis starts
improving with antifungal treatment.[23]

IRIS in those with normal

immune function

The immune reconstitution inflammatory

syndrome (IRIS) has been described in
those with normal immune function with
meningitis caused by C. gattii and C.
grubii. Several weeks or even months into
appropriate treatment, there can be
deterioration with worsening meningitis
symptoms and progression or
development of new neurological
symptoms. IRIS is however much more
common in those with poor immune
function (≈25% vs. ≈8%).

Magnetic resonance imaging shows

increase in the size of brain lesions, and
CSF abnormalities (white cell count,
protein, glucose) increase. Radiographic
appearance of cryptococcal IRIS brain
lesions can mimic that of toxoplasmosis
with ring enhancing lesions on head
computed tomography (CT). CSF culture
is sterile, and there is no increase in CSF
cryptococcal antigen titre.

The increasing inflammation can cause

brain injury or be fatal.[24][25][26]

The mechanism behind IRIS in

cryptococcal meningitis is primarily
immunologic. With reversal of
immunosuppression, there is paradoxical
increased inflammation as the recovering
immune system recognises the fungus.
In severe IRIS cases, treatment with
systemic corticosteroids has been
utilized - although evidence-based data
are lacking.
Other animals
Cryptococcosis is also seen in cats and
occasionally dogs. It is the most
common deep fungal disease in cats,
usually leading to chronic infection of the
nose and sinuses, and skin ulcers. Cats
may develop a bump over the bridge of
the nose from local tissue inflammation.
It can be associated with FeLV infection
in cats. Cryptococcosis is most common
in dogs and cats but cattle, sheep, goats,
horses, wild animals, and birds can also
be infected. Soil, fowl manure, and
pigeon droppings are among the sources
of infection.[27][28]
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External links
Classification ICD-10: B45 • D

ICD-9-CM: 117.5 •
MeSH: D003453 •
DiseasesDB: 3213

External resources MedlinePlus:

001328 •
eMedicine: med/482 •
Patient UK:
Cryptococcosis

Medscape entry on cryptococcosis

Retrieved from
"https://en.wikipedia.org/w/index.php?
title=Cryptococcosis&oldid=858960358"

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