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Cryptococcal Disease - 2/22/2013

posted Feb 22, 2013, 8:07 AM by Rohit Das   [ updated Feb 22, 2013, 11:22 AM by Purnema Madahar ]

At CRS today, we proceeded through a case of a young man with advanced AIDS who presented with a couple of weeks of respiratory symptoms, fevers, and new papular skin lesions. Workup ultimately revealed disseminated cryptococcemia – interesting case. So, I’d thought I’d take this opportunity to talk about this fantastically fun fungus:

·         What’s the deal with Cryptococcus – where does it live? Why is it pathogenic? Who does it effect?

·         How can it present clinically, and how is it diagnosed?

·         What are the treatment options? What’s the prognosis?

What’s the deal with Cryptococcus – where does it live? Why is it pathogenic? Who does it effect?

·         First, a nice history lesson. The first case of Cryptococcus EVER was in 1895, in a poor young woman with a leg ulcer over her right tibia. On autopsy, yeast forms were detected on the ulcer, and those same yeasts were detected in several other organs in her body. A couple of decades later, the first case of Cryptococcus meningitis was documented. It wasn’t until around the 1950s that the two predominantly pathogenic Cryptococcal species got their names – Cryptococus neoformans and Cryptococcus gattii.

·         C. neoformans has been isolated from soil samples worldwide, with a particular predilection towards areas frequented by birds (especially pigeons (DAMN pigeons) and chickens) and their excrement…it also seems to have developed a niche in rotting wood and vegetation. It’s thought that birds harbor Cryptococcus in their GI tract and act as a vector from vegetation to the soil/dust that humans are exposed to. Cryptococcus gattii is interesting in that it has a particular geographic distribution (tropic and subtropic areas), has never been cultured from bird poop, and has developed a niche within Eucalyptus trees (exported from Australia to various parts of the world)…

·         There are three main reasons why Cryptococcus is pathogenic:

o   Firstly, it can grow well at mammalian body temperatures, obviously a prerequisite for all pathogenic fungi.

o   Secondly, its polysaccharide capsule is central to its pathogenesis. Mutant variants that are hypocapsular or acapsular are rendered markedly less virulent or non-virulent. The capsule serves a number of beneficial functions for the pathogen, but most importantly impairs antibody binding and phagocytosis.

o   Thirdly, most pathogenic strains of Cryptococcosis have the ability to synthesis melanin, which coats its cell wall and serves as an antioxidant that protects against the oxidative guns of immune cells. Similar to the scenario with the capsule, mutant strains without the enzyme needed to make melanin are avirulent in animal models.

·         As I’m sure we all know, C. neoformans is one of the characteristic opportunistic infections seen in immunocompromised patients. Though most commonly seen in AIDS patients with CD4 counts below 100, it is also seen after prolonged treatment with glucocorticoids, advanced hematologic malignancies, organ transplantation, cirrhosis and DM. Importantly, up to 10-15% of cryptococcal infections occur in normal hosts without any identifiable risk factor.

·         Prior to the AIDS era, cryptococcal disease was rare – 0.8 cases/million persons/year. In 1992, the peak of the AIDS epidemic, it became much more common – 5 cases per 100,000 persons/year. With ARVs, the incidence has stabilized and decreased to around 1 case per 100,000 persons/year.

o   Importantly, cryptococcal disease is extremely prevalent in sub-Saharan Africa and a big killer. In this region, some reports have cited that 15 to 45% of patients with advanced AIDS succumb to cryptococcal infection, with incidence rates in ARV-naïve cohorts as high as 14 cases/1000 persons/year. Though the data is not as precise as it is here, still pretty unbelievable.


How can it present clinically, and how is it diagnosed?

·         The large majority of cases of Cryptococcus manifest in either the CNS (around 50%) or the lungs (around 30%), which is where the fungus initially sets up shop before it proliferates and disseminates. I’m going to focus on these two sites, BUT other common sites of infection:

o   Skin - papular lesions with ulcerated centers, usually a sentinel finding for disseminated cryptococcemia, i.e., fungus in the blood

o   Prostate - usually asymptomatic, but remarkably difficult to eradicate, serving as a sanctuary from antifungal therapy for these critters

o   Eye - can be catastrophic and lead to blindess, either due to endopthalmitis (severe inflammation of the vitreous cavity) or compression of the ophthalmic artery due to increased intracranial pressure.

o   Other – bone lesions, peritoneum (mainly in patients undergoing peritoneal dialysis or patients with advanced chronic liver disese)…basically ANY site in the body has some case report associated with it…

·         CNS cryptococcosis is the most prevalent manifestation of infection, especially in HIV patients, and is the main contributor to Cryptococcus related mortality. Most patients present over 2-4 weeks with fever, malaise and headaches…nuchal rigidity, photophobia and vomiting actually occur in a minority (20-30%). It can also present acutely over days, but such a presentation is less common.

o   Diagnosis is made via examination of the CSF, looking for high ICP (usually marked elevated on initial LP), positive India Ink exam (50-75% of the time), moderately elevated cell count with mononuclear predominance (usually 0-50 in HIV patients, but 20-200 in non HIV-patients), and low glucose/elevated protein levels.

o   CSF cryptococcal antigen is an extremely accurate test, with sensitivity ranging from 95-100%, and specificity around 94-98%.

·         Pulmonary disease has a variable presentation, from asymptomatic to ARDS – the presence and severity of symptoms correlates well with the degree of immunosuppression. Radiologic findings are also variable. In normal hosts, the most common finding are solitary or multiple nodules, but all types of imaging findngs are possible…importantly, in immunocompromised patients, alveolar/interstitial infiltrates are particularly common and often mimic PCP. Occasionally, the radiograph may show nothing – in one series of 20 AIDS patients with symptomatic cryptococcal PNA, 4 had normal chest films.

o   Diagnosis of Cryptococcus infection outside the CNS depends on imaging findings, positive serum cryptococcal antigen titers, and positive respiratory cultures. Even if no CNS symptoms are present, for patients who are at high risk for disseminated disease CSF exam should be part of the workup, as it alters management…

 

What are some general treatment principles? What’s the prognosis?

·         For patients with good prognostic factors (lack of diffuse infiltrates, non-CNS/disseminated infection, titers < 1:512), oral fluconazole is pretty efficacious. Regardless of immune status, patients with limited cryptococcal pulmonary disease are treated with fluconazole, 400 mg/day for 6-12 months. In studies of immunocompromised patients not due to HIV, outcomes were similar when compared to amphotericin B, and overall 1 year survival was 95%.

o   HIV patients should generally be treated with suppressive therapy after completing the initial course, at 200mg/day. If the CD4 gets above 100 and the cryptcoccal titer is low and not increasing, stopping suppressive therapy can be considered.

·         CNS or dissemintated disease is a different ballgame. The importance of “fungicidal” therapy takes precedence, and randomized trials have shown that initial induction therapy with fluconazole (“fungistatic”) leads to higher mortality and slower CSF sterilization. Furthermore, combination fungicidal therapy in randomized trials leads to faster sterilization rates and lower relapse rates, without a significant increase in toxicity. The specific guidelines differ based on etiology/presence of immunocompromise, renal function and other parameters…but here are some generalized recommendations:

o   Induction therapy should be given with amphotericin B (0.7-1 mg/kg/day) plus flucocystine (100 mg/kg/day) for a 2-4 week duration. During this timeframe, if CNS infection has been documented, it is imperative to reduce CSF pressure (by at least 50% or to a normal pressure - ≤20mm H2O) and document sterilization of the CSF before moving on to consolidation and maintenance therapy…

o   Amphoterrible has a host of adverse effects – infusion reactions can be minimized by concurrent Tylenol/antihistamines, and renal complications can be minimized with pre/post saline administration.

o   After induction therapy, consolidation therapy is given with fluconazole at 400 mg/day for around 8 weeks, followed by maintenance therapy at 200 mg/day for 6-12 months.

·         An important caveat to cryptococcal treatment is IRIS. Studies have described an incidence as high as 20% in AIDS patients, and 5-10% in HIV negative patients. Generally, this occurs during the induction phase of treatment, and manifests clinically as symptoms related to increasing intracranial pressure. Diagnosis of HIV-related IRIS is very much dependent on the time course of ARV initiation and symptom onset, documenting response to ARV therapy (drop in viral load more important than CD4 increase), and negative CSF cultures…I believe I wrote a daily on IRIS…take a look!

·         As mentioned, the bad-end of the prognosis spectrum is mainly attributable to CNS disease. Unsurprisingly, patients with concurrent malignancy have the worst survival (median of 2 months), though HIV-related disease isn’t too great either – 10-week mortality of 10-25%. Poor prognostic factors include a high antigen titer (>1:32), positive India ink exam, and low inflammatory count (<20 cells) at initial LP – overall representative of a common theme – if you can’t fight the infection, and have a high burden of the organism, you’re probably not going to do so well…

 

Attached are relatively recent review papers on CNS and pulmonary cryptococcal disease, as well as the most recent IDSA guidelines on management. Have a good weekend!


HIV-Associated Cryptococcal Meningitis
Jarvis et. al., AIDS 2007, Volume 21: 2119-2129

Shirley et. al., Curr Opin Pulm Med 2009, Volume 15: 254-250

Perfect et. al., Clin Inf Dis 2010, Volume 50: 291-322

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