Cryptococcosis differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Overview

Cryptococcosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial and viral infections. Cryptococcal meningitis can be indistinguishable from bacterial or viral meningitis. Cryptococcosis must be differentiated from diseases that cause symptoms of lower respiratory tract infection (fever, dyspnea, cough) and meningitis (fever, headache, neck stiffness, focal neurological deficits) such as coccidioidomycosis, histoplasmosis, tuberculosis, and community/hospital-acquired pneumonia. Cutaneous cryptococcosis in HIV/AIDS patients must be differentiated from molluscum contagiosum and Kaposi's sarcoma.

Differentiating Cryptococcosis from other Diseases

Cryptococcosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases which all may cause neurological dysfuntion in an immunocompromised patient:

Disease	Differentiating signs and symptoms	Differentiating tests
CNS lymphoma	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli Chest X-ray shows cavitations
Aspergillosis	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl's eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.

Cutaneous Cryptococcosis must be differentiated from the following diseases:

• Molluscum contagiosum
  • Is very similar in appearance to disseminated cryptococcosis manifesting on the skin (umbilicated lesions).
  • Patients are usually less sick, as molluscum is restricted to the skin.
• Kaposi's Sarcoma
  • Cutaneous cryptococcosis may also present with violaceous papules.
  • It can only be differentiated by biopsy.
• Blastomycosis
  • CNS involvement is much less common with blastomyces.
  • Cutaneous manifestations may resemble cutaneous cryptococcosis.
  • Not ubiquitous, more common in endemic areas in North America.

Differentiating cryptococcal meningitis from other causes of meningitis

Cryptococcal meningitis may be differentiated from other causes of meningitis by cerebrospinal fluid examination as shown below:

Cerebrospinal fluid level	Normal level	Bacterial meningitis	Viral meningitis	Cryptococcal meningitis	Tuberculous meningitis	Malignant meningitis
Cells/ul	< 5	>300	10-1000	10-500	50-500	>4
Cells	Lymphocyte:Monocyte 7:3	Granulocyte > Lymphocyte	Lymphocyte > Granulocyte	Lympho.>Granulocyte	Lymphocytes	Lymphocytes
Total protein (mg/dl)	45-60	Typically 100-500	Normal or slightly high	High	Typically 100-200	>50
Glucose ratio (CSF/plasma)	> 0.5	< 0.3	> 0.6	<0.3	< 0.5	<0.5
Lactate (mmols/l)	< 2.1	> 2.1	< 2.1	>3.2	> 2.1	>2.1
Others	ICP:6-12 (cm H2O)	CSF gram stain, CSF culture, CSF bacterial antigen	PCR of HSV-DNA, VZV	CSF gram stain, CSF india ink	PCR of TBC-DNA	CSF tumor markers such as alpha fetoproteins, CEA