Cryptococcosis

Epidemiology

  • Incidence: decreasing in US (possibly due to increased use of azole drugs)
  • Exposure: bird droppings (although no clear exposure-disease relationship exists)
  • Transmission: no evidence of human-human or animal-animal transmission

Risk Factors


Physiology and Microbiology

  • Cryptococcus Gattii
  • Cryptococcus Neoformans

  • Inhalation of aerosol of Cryptococcus neoformans (budding, encapsulated yeast)

  • CNS involvement is convincing evidence that Crypto is disseminated
  • Crypto may be isolated from BM, blood, GI tract, GU tract (but clinical signs of involvement are uncommon)

Pathology

  • Organism: forms vary in size, ranging from 2 to 15 m with average diameters of 4 to 7 m
  • Yeast organisms have a thick mucinous capsule, which appears as a clear halo in Grocott-Gomori methenamine silver staining

Diagnosis

CXR/Chest CT Patterns

  • Diffuse Interstitial Infiltrates
    • Most common pattern in AIDS-related cases: may have unilateral or lobar interstitial involvement in some cases
  • Lobar Alveolar Infiltrates
    • May mimic bacterial pneumonia
    • May cavitate (cavitation is more common in those receiving steroids, as in HIV cases on PCP therapy)
  • Lung Nodule/Mass
    • Reported case of a single 10 cm mass in asymptomatic patient
  • Hilar Lymphadenopathy
    • May occur in association with parenchymal disease
  • Pleural Effusion
    • Usually occurs in association with parenchymal disease and in presence of AIDS or other immunocompromised state
    • 50% of cases with pleural effusion have disseminated Crypto

Blood Culture

  • May Be Positive

Sputum Fungal Stain and Culture

  • Demonstrate of encapsulated yeast forms is suggestive of the diagnosis
  • Growth of Cryptococcus is diagnostic: often positive in immunocompromised adult cases (presence in transplant patients indicates that this is a pathogen)

Bronchoscopy

  • Bronchoalveolar Lavage (BAL)
    • Demonstrate of encapsulated yeast forms is suggestive of the diagnosis
    • Growth of Cryptococcus is diagnostic

Fine Needle Aspirate (FNA) of Lung Nodule

  • FNA of an asymptomatic nodules may demonstrate yeast on histopathologic inspection, but the culture may be negative

Pleural Fluid

  • Exudate: usually
  • Cell Count and Differential: lymphocyte-predominant
  • Fungal Stain: yeast forms may be seen
  • Culture: usually positive
  • Pleural Cryptococcal Antigen (CRAG): may be positive

Serum Cryptococcal Antigen (CRAG)

  • Sensitivity
    • Immunocompetent Cases: insensitive for diagnosis of Cryptococcus Neoformans in immunocompetent patients
      • However, antigen testing may be more useful for diagnosis of cases due to Cryptococcus Gattii among immunocompetent hosts in regions where it is endemic (Australia) or in regions where it has caused outbreaks (United States Pacific Northwest and British Columbia)
    • Immunocompromised Cases: good screening test in suspected cases in immunocompromised hosts (however, negative CRAG does not exclude the diagnosis of cryptococcosis)
      • Positive at 1:2 to 1:2 million in AIDS cases with central nervous system involvement
      • Positive in virtually all patients with HIV infection and pulmonary cryptococcosis
      • Positive in 56-70% of patients with other underlying immunocompromising conditions and pulmonary cryptococcosis
      • Positive CRAG in solid organ transplants often indicates advanced pulmonary involvement and/or extra-pulmonary disease (fungemia, central nervous system infection)
  • Monitoring of CRAG: there is no role for monitoring serum CRAG titers to determine the duration of therapy in either immunosuppressed or immunocompetent hosts
  • False-Positives: rare
    • Infection with Stomatococcus
    • Infection with Capnocytophaga
    • Infection with Trichosporon Asahii (formerly Trichosporon Begelii)
    • Presence of Rheumatoid Factor: RF can be removed by pre-treatment with proteases or reducing agents

Urine Cryptococcal Antigen (CRAG)

  • May be positive

Head CT

  • xxx

Brain MRI

  • xxx

Lumbar Puncture (LP)

  • Indications
    • Immunocompromised State: even without neurologic symptoms
    • Neurologic Symptoms
    • Serum CRAG Titer >1:512
  • Opening Pressure: >20 cm H2O (increased pressure is due to large organism load)
  • WBC: usually 20-500 (usually with lymphocytic predominance)
    • Only 13-31% of AIDS patients with cryptococcal meningitis have WBC count >20
  • Glucose: <40
    • Only 33% of AIDS patients with cryptococcal meningitis have glucose >40
  • Protein: >45 mg/dL
  • India Ink: positive in >60% of cases
    • Positive in 72-88% of of AIDS patients with cryptococcal meningitis
  • Crypto Ag: positive in >85% of cases
    • Positive in 91-100% of of AIDS patients with cryptococcal meningitis
  • Cryptococcus Culture: positive in >95% of cases

Clinical Presentation-Immunocompetent Adult

Route of Infection

  • Inhalation: inhalation of Cryptococcus Neoformans (either in basidiospore form or as small poorly encapsulated yeasts)
    • Basidiospores are smaller than yeast forms and have much smaller polysaccharide capsules: the smaller size facilitates their deposition in alveoli and terminal bronchioles

Gastrointestinal Manifestations

  • Gastrointestinal Complaints: less common
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Neurologic Manifestations

  • Meningitis (see Meningitis, [[Meningitis]]): rarely occurs in immunocompetent hosts
    • While routine lumbar puncture in immunocompetent hosts is usually not necessary, it should be performed in patients with neurologic symptoms or serum CRAG titers >1:512 (suggesting higher organism load and higher risk of dissemination to the central nervous system)

Pulmonary Manifestations

Focal or Lobar Pneumonia (see Pneumonia, [[Pneumonia]])

  • Diagnosis
    • CXR/Chest CT
      • Cavitation: infiltrates may cavitate (cavitation is more common in patients receiving corticosteroids, as in HIV cases on PCP therapy)
  • Clinical
    • Degree of Clinical Symptoms: asymptomatic in as many as 32% of cases in immunocompetent hosts [MEDLINE]
      • Degree of symptoms may be related to the inoculum of fungi and virulence factors of the infecting strain
      • Immune status of host determines if the initial pulmonary infection resolves or disseminates
      • Foci of infection are usually smaller than those seen in tuberculosis and do not calcify as frequently as those seen in histoplasmosis
      • Infection can become latent: subsequently, if the host becomes immunocompromised, organisms may be liberated from the granulomatous complexes and cause active infection
    • Chest Pain (see Chest Pain, [[Chest Pain]])
    • Cough with Sputum(see Cough, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]])
    • Hemoptysis (see Hemoptysis, [[Hemoptysis]])
    • Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]]): may occur in association with parenchymal disease
    • Extension of Infiltrate from Lung to the Chest Wall: occurs rarely

Eosinophilic Pneumonia (see Pulmonary Infiltrates with Eosinophilia, [[Pulmonary Infiltrates with Eosinophilia]])

  • Epidemiology: less common presentation

Lung Nodule/Mass (see Lung Nodule or Mass, [[Lung Nodule or Mass]])

  • Diagnosis
    • CXR/Chest CT
      • Non-calcified
      • May be pleural-based
      • Large masses (up to 10 cm) have been reported in some cases
      • Cavitation: nodule/mass may cavitate (cavitation is more common in those receiving steroids, as in HIV cases on PCP therapy)
  • Clinical
    • Pancoast Syndrome: rare
      • Due to granulomatous inflammation associated with the host response to the organism

Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

  • Epidemiology
    • Usually occurs in association with parenchymal lung disease
    • Usually occurs in the presence of AIDS or other immunocompromised state
    • 50% of cases with pleural effusion have disseminated Cryptococcosis
  • Treatment: rarely require drainage

Superior Vena Cava (SVC) Syndrome (see Superior Vena Cava Syndrome, [[Superior Vena Cava Syndrome]])

  • Epidemiology: rare

Other Manifestations

  • Fever (see Fever, [[Fever]])
  • Malaise
  • Night Sweats (see Night Sweats, [[Night Sweats]])
  • Rash: less common

Clinical Presentation-Immunocompromised HIV-Negative Adult

Route of Infection

  • Reactivation of Latent infection: accounts for most cases in immunocompromised hosts
  • Direct Inoculation of Skin Site: has been reported in some transplant-related cases with cellulitis (in absence of dissemination)

General Comments

  • Degree of Symptoms: immunocompromised hosts with pulmonary cryptococcosis are usually more symptomatic than immunocompetent hosts
  • Presentation with Extra-Pulmonary Disease
    • Immunocompromised hosts with pulmonary cryptococcosis are more likely than immunocompetent hosts to present with extrapulmonary disease
  • Non-Meningeal, Non-Pulmonary Cryptococcosis: usually indicates disseminated infection
    • However, transplant patients may manifest cellulitis that results from direct inoculation (rather than dissemination)
  • Effect of Immune Reconstitution Inflammatory Syndrome (IRIS): (see Immune Reconstitution Inflammatory Syndrome, [[Immune Reconstitution Inflammatory Syndrome]]): immune reconstitution (after withdrawal of immunosuppression) may paradoxically worsen cryptococcal disease

Dermatologic Manifestations

  • General Comments: skin lesions are seen in 15% of disseminated cryptococcosis cases
  • Cellulitis (see Cellulitis, [[Cellulitis]])
    • Transplant patients may manifest cellulitis that results from direct inoculation (rather than dissemination)
  • Papules (see Papular-Nodular Skin Lesions, [[Papular-Nodular Skin Lesions]])
  • Plaques
  • Purpura (see Purpura, [[Purpura]])
  • Skin Abscesses/Sinus Tracts (see Skin Abscess, [[Skin Abscess]])
  • Ulcers (see Mucocutaneous Ulcers, [[Mucocutaneous Ulcers]])

Neurologic Manifestations

  • Meningitis (see Meningitis, [[Meningitis]]): lumbar puncture is indicated to rule out meningitis in immunocompromised cases (even in the absence of neurologic symptoms)

Pulmonary Manifestations

Focal or Lobar Pneumonia (see Pneumonia, [[Pneumonia]])

  • Epidemiology
    • Cryptococcal pneumonia and ARDS occur more frequently in organ transplant recipients than in other hosts: in this situation, ARDS is usually associated with disseminated infection and mortality rates are high
  • Diagnosis
    • CXR/Chest CT
      • Cavitation: infiltrates may cavitate (cavitation is more common in patients receiving corticosteroids, as in HIV cases on PCP therapy)
  • Clinical: ranges from asymptomatic pneumonia to acute respiratory failure
    • Chest Pain (see Chest Pain, [[Chest Pain]]): occurs in 44% of cases
    • Cough (see Cough, [[Cough]]): occurs in 17% of cases
    • Dyspnea (see Dyspnea, [[Dyspnea]]): occurs in 27% of cases
    • Hemoptysis(see Hemoptysis, [[Hemoptysis]]): occurs in 7% of cases

Lung Nodule/Mass (see Lung Nodule or Mass, [[Lung Nodule or Mass]])

  • Epidemiology: may occur

Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

  • Epidemiology: may occur

Rheumatologic Manifestations

  • Osteolytic Bone Lesions: occur in <10% of patients with disseminated cryptococcosis
    • Vertebrae are the most common site
    • Well circumscribed osteolytic lesion resemble that seen in malignancy
  • Septic Arthritis: rare

Other Manifestations

  • Fever (see Fever, [[Fever]]): occurs in 63% of cases
  • Other Sites of Dissemination
    • Adrenal Glands
    • Eyes: involvement of the eyes often reflects central nervous system infection
    • Liver
    • Lymph Nodes
    • Peritoneum
    • Prostate Gland: may serve as a reservoir of infection
    • Urogenital Tract

Clinical Presentation-Immunocompromised HIV-Positive Adult

Route of Infection

  • Reactivation of Latent infection: accounts for most cases in immunocompromised hosts

General Comments

  • Duration of Symptoms: symptoms may be present for 1 day-4 months (mean: 31 days) before diagnosis is made
  • Severity of Presentation
    • Immunocompromised hosts with pulmonary cryptococcosis are usually more symptomatic than immunocompetent hosts
    • Pulmonary cryptococcosis in HIV patients is more acute and severe than in other hosts
    • The severity of clinical symptoms and extent of dissemination are inversely proportional to the CD4 count: most symptomatic cases occur in patients with CD4 <100
  • Presentation with Extra-Pulmonary Disease
    • Immunocompromised hosts with pulmonary cryptococcosis are more likely than immunocompetent hosts to present with extrapulmonary disease
    • Pulmonary symptoms are less prominent in AIDS-related cases: only 27-31% of AIDS-related cases present with pulmonary symptoms
    • Dissemination from lungs to the central nervous system occurs in 65-94% of HIV-associated pulmonary cryptococcosis cases
  • Effect of Immune Reconstitution Inflammatory Syndrome (IRIS): (see Immune Reconstitution Inflammatory Syndrome, [[Immune Reconstitution Inflammatory Syndrome]]): immune reconstitution usually occurs within 6 mo after start of HAART therapy and may paradoxically worsen cryptococcal disease

Dermatologic Manifestations

  • General Comments: skin lesions are seen in 15% of disseminated cryptococcosis cases
  • Cellulitis (see Cellulitis, [[Cellulitis]])
  • Cutaneous Lesions Resmbling Molluscum Contagiosum or Kaposi Sarcoma
  • Papules (see Papular-Nodular Skin Lesions, [[Papular-Nodular Skin Lesions]])
  • Plaques
  • Purpura (see Purpura, [[Purpura]])
  • Skin Abscesses/Sinus Tracts (see Skin Abscess, [[Skin Abscess]])
  • Ulcers (see Mucocutaneous Ulcers, [[Mucocutaneous Ulcers]])

Gastrointestinal Manifestations

Neurologic Manifestations

  • Meningitis (see Meningitis, [[Meningitis]]): lumbar puncture is indicated to rule out meningitis in immunocompromised cases (even in the absence of neurologic symptoms)
    • Altered Mental Status/Delirium: 14-28% of cases
    • Focal Neurologic Deficits/Seizures: <10% of cases
    • Headache: occurs in 41% of cases
    • Increased Intracranial Pressure (ICP): often occurs in AIDS-related cases (due to high organism load)
    • Meningismus/Photophobia: <20-30% of cases

Otolaryngologic Manifestations

Pulmonary Manifestations

Focal or Lobar Pneumonia (see Pneumonia, [[Pneumonia]])

  • Diagnosis
    • CXR/Chest CT
      • Cavitation: infiltrates may cavitate (cavitation is more common in patients receiving corticosteroids, as in HIV cases on PCP therapy)
  • Clinical: ranges from asymptomatic pneumonia to acute respiratory failure
    • Cough (see Cough, [[Cough]]): occurs in 63-71% of cases
    • Dyspnea (see Dyspnea, [[Dyspnea]]): occurs in 5-50% of cases

Diffuse Interstitial Infiltrates (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])

  • Epidemiology: most common pattern in AIDS-related cases
    • May have unilateral or lobar interstitial involvement in some cases
    • May mimic the radiographic pattern of Pneumocystis jirovecii pneumonia

Lung Nodule/Mass (see Lung Nodule or Mass, [[Lung Nodule or Mass]])

  • Epidemiology: may occur

Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

  • Epidemiology: may occur

Rheumatologic Manifestations

  • Osteolytic Bone Lesions: occur in <10% of patients with disseminated cryptococcosis
    • Vertebrae are the most common site
    • Well circumscribed osteolytic lesion resemble that seen in malignancy
  • Septic Arthritis (see Septic Arthritis, [[Septic Arthritis]]): rare

Other Manifestations

  • Fever (see Fever, [[Fever]]): occurs in 81-94% of cases
  • Malaise
  • Night Sweats (see Night Sweats, [[Night Sweats]])
  • Other Sites of Dissemination
    • Adrenal Glands
    • Eyes: involvement of the eyes often reflects central nervous system infection
    • Liver
    • Lymph Nodes
    • Peritoneum
    • Prostate Gland: may serve as a reservoir of infection
    • Urogenital Tract

Treatment

Mild-Moderate Pulmonary Cryptococcosis (Immunocompetent or Immunocompromised)

Definition

  • Absence of Cryptococcemia
  • Absence of Dissemination (Disease in at Least 2 Non-Contiguous Sites)
  • Absence of Severe Pulmonary Cryptococcosis (Diffuse Infiltrates)
  • Serum CRAG Titer <1:512

Observation without Treatment

  • Immunocompetent Host
    • Patients who are asymptomatic and have cryptococcosis diagnosed indicentally during lung nodule resection to rule out malignancy (and who have negative cultures and negative CRAG) may not require treatment
    • There are case reports of asymptomatic, immunocompetent patients with positive cultures, serology and/or histopathology who have improved radiographically without anti-fungal therapy
  • Pregnancy
    • Pregnant patients with stable pulmonary cryptococcosis may be followed closely, with initiation of fluconazole following delivery
    • Immune reconstitution inflammatory syndrome can occur in the post-partum period (see Immune Reconstitution Inflammatory Syndrome, [[Immune Reconstitution Inflammatory Syndrome]]): nearly 50% of cryptococcosis cases reported in pregnancy presented with symptomatic disease in the third trimester or post-partum period

Anti-Fungal Therapy

  • Fluconazole (Flucon) (see Fluconazole, [[Fluconazole]])
    • First-line agent
    • Studies
      • Treatment of Solid Organ Transplants with Non-Central Nervous System Cryptococcosis (1996) [MEDLINE]: comparable mortality (10-11%), comparing fluconazole with amphotericin therapy
      • Treatment of HIV-Negative Immunocompromised Patients with Pulmonary Cryptococcosis (2001) [MEDLINE]: fluconazole treatment had a 1-year survival rate of 95%
    • PO Dose: 400 mg (6 mg/kg) per day x 6-12 mo
  • Itraconazole (see Itraconazole, [[Itraconazole]])
    • Alternative agent
    • PO Dose: 200 mg BID
  • Voriconazole (see Voriconazole, [[Voriconazole]])
    • Alternative agent
    • PO Dose: 200 mg BID
  • Posaconazole (see Posaconazole, [[Posaconazole]])
    • Alternative agent
    • PO Dose: 400 mg BID
  • Amphotericin B (see Amphotericin, [[Amphotericin]])
    • Alternative agent

Chronic Suppressive Anti-Fungal Therapy

  • HIV-Positive Patients
    • Fluconazole (Flucon) (see Fluconazole, [[Fluconazole]]): after initial treatment, lifelong 200 mg PO qday
      • May be discontinued after 1 year if patient is receiving HAART (with CD4 >100), has suppressed viral load, and has CRAG <1:512 that is not increasing
  • Patients Who Responded to Pulmonary Cryptococcosis Therapy and Subsequently Require Chemotherapy/Intensive Therapy for Graft Rejection Within 2 years of the Cryptococcosis Diagnosis
    • Fluconazole (Flucon) (see Fluconazole, [[Fluconazole]]): 200 mg PO qday during the immunosuppression

Surgery

  • Indications for Resection of Infected Tissue
    • Mass impingement on adjacent structures
    • Localized pulmonary infection not responding to medical therapy

Isolated Non-Pulmonary, Non-Meningeal Cryptococcosis (Immunocompetent)

  • Same as above for “Mild-Moderate Pulmonary Cryptococcosis (Immunocompetent or Immunocompromised)”

Severe Pulmonary Cryptococcosis (Diffuse Infiltrates), Dissemination (Disease in at Least 2 Non-Contiguous Sites), or CRAG Titer >1:512

Definition

  • Cryptococcemia
  • Dissemination (Disease in at Least 2 Non-Contiguous Sites)
  • Severe Pulmonary Cryptococcosis (Diffuse Infiltrates)
  • Serum CRAG Titer >1:512

Non-HIV, Non-Transplant Patients

  • Induction
  • Consolidation/Maintenance

Organ Transplant Patients

  • Induction

    • Liposomal Amphotericin B (3-4 mg/kg IV per day) (see Amphotericin, [[Amphotericin]]) + Flucytosine (100 mg/kg per day PO in four divided doses, adjusted for renal function) (see Flucytosine, [[Flucytosine]]) for at least 2 wks

    • Amphotericin B Lipid Complex (5 mg/kg IV per day) (see Amphotericin, [[Amphotericin]]) + Flucytosine (100 mg/kg per day PO in four divided doses, adjusted for renal function) (see Flucytosine, [[Flucytosine]]) for at least 2 wks

    • Amphotericin B Deoxycholate: due to the frequency of reduced renal function in transplant recipients (approximately 25% have Cr >2.0 mg/dL) and the risk of nephrotoxicity associated with concurrent use of amphotericin B deoxycholate and calcineurin inhibitors, amphotericin B deoxycholate is not recommended as first-line therapy in this population

      • If used, 0.7 mg/kg per day with frequent renal function monitoring may be used
  • Consolidation/Maintenance

    • Fluconazole (400 to 800 mg [6 to 12 mg/kg] orally daily) (see Fluconazole, [[Fluconazole]]) for 8 wks

Positive Sputum Culture with Normal CXR/LP: no treatment

Mild-moderate isolated pulmonary Crypto: flucon 400 mg/day x 6-12 mo or itra 400 mg/day x 6-12 mo or ampho 0.5-1 mg/kg/day (to total of 1-2 g)

Severe pulmonary Crypto or disseminated disease with CNS (or other organ) involvement:
1) Induction: ampho 0.7-1 mg/kg/day + 5-flucytosine 100 mg/kg/day x 2 wks (or until improved by clearance of CSF Crypto cultures), then change to flucon 400 mg/day consolidation x 10 wks

-Alternative: ampho 0.7-1 mg/kg/day + 5-flucytosine 100 mg/kg/day x 10 wks or ampho 0.7-1 mg/kg/day x 10 wks
–Follow 5-flucytosine levels (especially with renal failure)
–5-flucytosine SE: dose-related BM suppression, hepatotoxicity

2) Maintenance (for AIDS only): flucon 200 mg/day for life (or ampho 1 mg/kg 1-3x/wk)
—Flucon has good CSF penetration (ampho, keto, and itra have relatively poor CSF penetration), long serum half-life, and decreases risk of recurrence at all sites (3% risk vs. 37% risk in placebo group)

Management of increased ICP: may require daily LP or ventric or VP shunt to decrease the ICP/steroids are controversial, but are generally contraindicated

Isolated pleural Crypto: systemic treatment required for cases with positive serum or CSF CrAg, AIDS, and other immunocompromised state
-Other cases should be treated only if effusion enlarges, pleural cell counts or LDH increase, CrAg becomes positive, etc.

Residual GU Crypto culture positivity: has been reported after treatment of Crypto meningitis (suggests possible source for relapse)


References

  • Primary pulmonary cryptococcosis. Am Rev Respir Dis. 1966 Aug;94(2):236-43 [MEDLINE]
  • Epidemiology of cryptococcosis in France: a 9-year survey (1985-1993). French Cryptococcosis Study Group. Clin Infect Dis. 1996 Jul;23(1):82-90 [MEDLINE]
  • Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001 Sep 1;33(5):690-9. Epub 2001 Jul 26 [MEDLINE]
  • Analysis of 23 cases of pulmonary cryptococcosis. Chin Med J (Engl). 2004 Sep;117(9):1425-7 [MEDLINE]
  • Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest. 2006 Feb;129(2):333-40 [MEDLINE]
  • Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194 [MEDLINE]
  • Cryptococcal lung disease. Curr Opin Pulm Med. 2009 May;15(3):254-60. doi: 10.1097/MCP.0b013e328329268d [MEDLINE]
  • Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:291 [MEDLINE]