Cryptococcus spp. are fungi that prefer to grow in areas of high nitrogen so they tend to be associated with bird and bat droppings. Patients who live in urban environments are then more prone to acquiring this infection. Transmission typically occurs when the patient inhales aerosolized yeast cells from the environment. Cryptococcus neoformans is the most common species and is found worldwide in pigeon droppings. Cryptococcus gattii is mostly found in the tropics, and is weirdly associated with Eucalyptus spp. trees.
This fungus has a very large polysaccharide capsule, so much so that it’s often used to demonstrate how India Ink staining works. It has the ability to change the antigens in the capsule to assume a more virulent form once inside the human. Speaking of changing forms, this fungi seems to be monomorphic, and we have only been able to find it’s yeast form. There are some instance in the lab, where they were able to force the organism into a semi-reproductive state, but we’ve never found this form in nature. Therefore, the only reproduction that Cryptococcus spp. undergo is through narrow-budding in the yeast form.
One really interesting virulence factor is phenol oxidase, which is part of the pathway to create melanin, and break down dopamine, and epinephrine. Melanin is an antioxidant which means that it will negate the effects of the reactive oxygen burst from immune cells. If the organism is in the CSF, the catecholamines might be able to destroy the cell, however the phenol oxidase that is produced would destroy the catecholamines allowing the organism a bit more protection.
Cryptococcus spp. also produce urease which is a really weird thing to have for an organism that causes mainly pulmonary and CSF infections. We think the urease helps the fungi avoid destruction in the phagolysosome of macrophages. The urease will neutralize the pH in the phagolysosome and actually triggers the macrophage to spit the fungi back out without harming it.
Patients who most often acquire Cryptococcus spp. infections are patients who are immunocompromised, especially patients with AIDS. One fascinating fact is that prior to the pandemic explosion in the 1980s, the most common Cryptococcus spp. was a different organism. After the 1980s, it changed to be Cryptococcus neoformans affecting AIDS patients.
After transmission this will typically cause pulmonary cryptococcus and cause a spectrum of disease from asymptomatic to bilateral, fulminate pneumonia. This can cause lung nodule formation and mimic tuberculosis, or form cavitary lesions. It is highly like to be fatal if the patient has symptoms and they are inappropriately treated.
This can spread from the lungs into the blood stream and filter into any bone causing osteomyelitis.
It can also spread from the blood into the cerebrospinal fluid and filter into the brain causing the formation of gelatinous pseudocysts which cause the appearance of the “soap bubble” brain on imaging. This is when it appears like several circular densities in the middle cerebral artery. This will cause the patient to present with the symptoms of meningoencephalitis, and analysis of the CSF will have the typical findings of a fungal infection: high lymphocyte percentage, low glucose, high protein, high pressure.
Diagnosis can occur via a rapid test that uses latex agglutination to detect a Cryptococcus spp. capsular protein. Latex agglutination uses latex beads that are coated with antibodies specifically against the target antigen. The beads will bind up the antigen if it’s presence causing the latex beads to clump together (or agglutinate). This can be performed on the CSF or serum.
As I mentioned earlier you could take a sample and stain with India Ink to easily visualize that gigantic capsule. If you take a tissue sample, it will often show many cysts in the lung and you can visualize the fungal cells within these cysts with silver staining, or you can use mucicarmine staining to see the capsules. Positive mucicarmine fungal cells is specific for Cryptococcus spp. You can also culture any sample on Sabouraud’s agar but it will take a few weeks to produce growth.
The majority of cases of symptomatic patients are from a reactivation of a latent, lung nodule infection. Therefore, if you are aware of your patient’s immunocompromized status, it is important to know if they have a lung nodule or not. If they do have a Cryptococcal lung nodule, then you can give them fluconazole prophylactically to try to prevent reactivation.
A 56-year-old female presents in Utah for a surgery to fix multiple broken leg bones acquired during a mechanical fall. While being admitted, she develops a temperature of 101.6F. Physical examination and lung auscultation were normal. Serum white blood cell counts revealed a 8.4 x 109 / L. Chest radiography revealing a peripheral pulmonary solitary nodule. Transthoracic biopsy revealed encapsulated yeast forms. Repeated CD4+ T-cell counts are consistently under 200 cells/mm3. Additional biochemical testing revealed that the fungal cells produce melanin. What is the virulence factor responsible for the production of melanin?
A. Urease
B. Catalase
C. Ketone reductase
D. Phenol oxidase
First, diagnose the patient.
This patient is presenting with very mild symptoms, and a lung nodule. Biopsy reveals an encapsulated yeast form. CD4+ T-cell numbers reveal a consistently immunocompromised state.
Patients who are immunocompromised, presenting with mild symptoms and lung nodules could have: histoplasmosis, blastomycosis, coccidiomycosis, paracoccidiomycosis, aspergillosis, or pulmonary cryptococcus. The location of Utah eliminates histoplasmosis, blastomycosis, coccidiomycosis, and paracoccidiomycosis. Leaving aspergillosis and pulmonary cryptococcus. It’s amazing what knowing that geography will help you with in microbiology.
So to distinguish between aspergillosis and pulmonary cryptococcus, we have to think about the histological findings. Both would have a patient presenting with mild pulmonary symptoms and could form lung nodules. However, there is no known yeast form for Aspergillus spp. they would present as acute-angle branching hyphae, even within the human tissue. Cryptococcus spp. only present in the yeast form, there is no hyphael form, so the most likely diagnosis is: pulmonary cryptococcus.
- A spectrum of pulmonary symptoms from asymptomatic to bilateral fulminate failure
- Most often associated with patients with AIDS
- Associated with pigeon droppings or urban environments
- Can disseminate and cause osteomyelitis or meningoencephalitis
- Meningoencephalitis will present with pseudocyst formation in the brain causing the appearance of soap-bubble brain.
A. Urease is an enzyme that Cryptococcus spp. produce. However, it cleaves urea causing a reduction in acidity. Cryptococcus spp. use this enzyme to escape from the phagolysosome.
B. Catalase is an enzyme that many bacteria and some fungi have that reduce the potency of reactive oxygen species.
C. Ketone reductase is an enzyme that species within the Mucorales genera have. This helps them thrive in the acidic bloodstreams of people with ketoacidosis. They most often cause rhinocerebral mucormycosis causing a severe necrosis of the nasal cavity.
D. Phenol oxidase is the virulence factor that allows Cryptococcus spp. to produce melanin. It is the only fungi that can create melanin, and it uses it as an antioxidant reduce the potency of reactive oxygen species.
Therefore,
References:
https://pubmed.ncbi.nlm.nih.gov/29906292/
https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-4453-x
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