Cryptococcosis differential diagnosis

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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^[1]	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis^[2]	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^[3]	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^[4]	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^[5]	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^[6]	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^[7]	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^[8]^[9]	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^[10]	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^[11]
- 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^[12]^[13]
- Cutaneous cryptococcosis may also present with violaceous papules.
- It can only be differentiated by biopsy.
Blastomycosis^[14]
- 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:^[15]^[16]^[17]^[18]^[19]


Cerebrospinal fluid level	Normal level	Bacterial meningitis^[18]	Viral meningitis^[18]	Cryptococcal meningitis	Tuberculous meningitis^[20]	Malignant meningitis^[15]
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)^[16]	> 0.5	< 0.3	> 0.6	<0.3	< 0.5	<0.5
Lactate (mmols/l)^[17]	< 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

References

↑ Gerstner ER, Batchelor TT (2010). "Primary central nervous system lymphoma". Arch. Neurol. 67 (3): 291–7. doi:10.1001/archneurol.2010.3. PMID 20212226.
↑ von Reyn CF, Kimambo S, Mtei L, Arbeit RD, Maro I, Bakari M, Matee M, Lahey T, Adams LV, Black W, Mackenzie T, Lyimo J, Tvaroha S, Waddell R, Kreiswirth B, Horsburgh CR, Pallangyo K (2011). "Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality". Int. J. Tuberc. Lung Dis. 15 (8): 1087–92. doi:10.5588/ijtld.10.0517. PMID 21740673.
↑ Latgé JP (1999). "Aspergillus fumigatus and aspergillosis". Clin. Microbiol. Rev. 12 (2): 310–50. PMC 88920. PMID 10194462.
↑ Rassi A, Rassi A, Marin-Neto JA (2010). "Chagas disease". Lancet. 375 (9723): 1388–402. doi:10.1016/S0140-6736(10)60061-X. PMID 20399979.
↑ Emery VC (2001). "Investigation of CMV disease in immunocompromised patients". J. Clin. Pathol. 54 (2): 84–8. PMC 1731357. PMID 11215290.
↑ Bustamante CI, Wade JC (1991). "Herpes simplex virus infection in the immunocompromised cancer patient". J. Clin. Oncol. 9 (10): 1903–15. doi:10.1200/JCO.1991.9.10.1903. PMID 1919640.
↑ Hambleton S (2005). "Chickenpox". Curr. Opin. Infect. Dis. 18 (3): 235–40. PMID 15864101.
↑ Alvis Miranda H, Castellar-Leones SM, Elzain MA, Moscote-Salazar LR (2013). "Brain abscess: Current management". J Neurosci Rural Pract. 4 (Suppl 1): S67–81. doi:10.4103/0976-3147.116472. PMC 3808066. PMID 24174804.
↑ Patel K, Clifford DB (2014). "Bacterial brain abscess". Neurohospitalist. 4 (4): 196–204. doi:10.1177/1941874414540684. PMC 4212419. PMID 25360205.
↑ Tan CS, Koralnik IJ (2010). "Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis". Lancet Neurol. 9 (4): 425–37. doi:10.1016/S1474-4422(10)70040-5. PMC 2880524. PMID 20298966.
↑ Penneys NS, Hicks B (1985). "Unusual cutaneous lesions associated with acquired immunodeficiency syndrome". J Am Acad Dermatol. 13 (5 Pt 1): 845–52. PMID 3001157.
↑ Jones C, Orengo I, Rosen T, Ellner K (1990). "Cutaneous cryptococcosis simulating Kaposi's sarcoma in the acquired immunodeficiency syndrome". Cutis. 45 (3): 163–7. PMID 2311432.
↑ Blauvelt A, Kerdel FA (1992). "Cutaneous cryptococcosis mimicking Kaposi's sarcoma as the initial manifestation of disseminated disease". Int J Dermatol. 31 (4): 279–80. PMID 1634295.
↑ Boyars MC, Zwischenberger JB, Cox Jr CS. Clinical manifestations of pulmonary fungal infections. Journal of thoracic imaging. 1992 Sep 1;7(4):12-22.
↑ ^15.0 ^15.1 Le Rhun E, Taillibert S, Chamberlain MC (2013). "Carcinomatous meningitis: Leptomeningeal metastases in solid tumors". Surg Neurol Int. 4 (Suppl 4): S265–88. doi:10.4103/2152-7806.111304. PMC 3656567. PMID 23717798.
↑ ^16.0 ^16.1 Chow E, Troy SB (2014). "The differential diagnosis of hypoglycorrhachia in adult patients". Am J Med Sci. 348 (3): 186–90. doi:10.1097/MAJ.0000000000000217. PMC 4065645. PMID 24326618.
↑ ^17.0 ^17.1 Leen WG, Willemsen MA, Wevers RA, Verbeek MM (2012). "Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice". PLoS One. 7 (8): e42745. doi:10.1371/journal.pone.0042745. PMC 3412827. PMID 22880096.
↑ ^18.0 ^18.1 ^18.2 Negrini B, Kelleher KJ, Wald ER (2000). "Cerebrospinal fluid findings in aseptic versus bacterial meningitis". Pediatrics. 105 (2): 316–9. PMID 10654948.
↑ Brouwer MC, Tunkel AR, van de Beek D (2010). "Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis". Clin Microbiol Rev. 23 (3): 467–92. doi:10.1128/CMR.00070-09. PMC 2901656. PMID 20610819.
↑ Caudie C, Tholance Y, Quadrio I, Peysson S (2010). "[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]". Ann Biol Clin (Paris). 68 (1): 107–11. doi:10.1684/abc.2010.0407. PMID 20146981.

[pmid20212226-1] Gerstner ER, Batchelor TT (2010). "Primary central nervous system lymphoma". Arch. Neurol. 67 (3): 291–7. doi:10.1001/archneurol.2010.3. PMID 20212226.

[pmid21740673-2] von Reyn CF, Kimambo S, Mtei L, Arbeit RD, Maro I, Bakari M, Matee M, Lahey T, Adams LV, Black W, Mackenzie T, Lyimo J, Tvaroha S, Waddell R, Kreiswirth B, Horsburgh CR, Pallangyo K (2011). "Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality". Int. J. Tuberc. Lung Dis. 15 (8): 1087–92. doi:10.5588/ijtld.10.0517. PMID 21740673.

[pmid10194462-3] Latgé JP (1999). "Aspergillus fumigatus and aspergillosis". Clin. Microbiol. Rev. 12 (2): 310–50. PMC 88920. PMID 10194462.

[pmid20399979-4] Rassi A, Rassi A, Marin-Neto JA (2010). "Chagas disease". Lancet. 375 (9723): 1388–402. doi:10.1016/S0140-6736(10)60061-X. PMID 20399979.

[pmid11215290-5] Emery VC (2001). "Investigation of CMV disease in immunocompromised patients". J. Clin. Pathol. 54 (2): 84–8. PMC 1731357. PMID 11215290.

[pmid1919640-6] Bustamante CI, Wade JC (1991). "Herpes simplex virus infection in the immunocompromised cancer patient". J. Clin. Oncol. 9 (10): 1903–15. doi:10.1200/JCO.1991.9.10.1903. PMID 1919640.

[pmid15864101-7] Hambleton S (2005). "Chickenpox". Curr. Opin. Infect. Dis. 18 (3): 235–40. PMID 15864101.

[pmid24174804-8] Alvis Miranda H, Castellar-Leones SM, Elzain MA, Moscote-Salazar LR (2013). "Brain abscess: Current management". J Neurosci Rural Pract. 4 (Suppl 1): S67–81. doi:10.4103/0976-3147.116472. PMC 3808066. PMID 24174804.

[pmid25360205-9] Patel K, Clifford DB (2014). "Bacterial brain abscess". Neurohospitalist. 4 (4): 196–204. doi:10.1177/1941874414540684. PMC 4212419. PMID 25360205.

[pmid20298966-10] Tan CS, Koralnik IJ (2010). "Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis". Lancet Neurol. 9 (4): 425–37. doi:10.1016/S1474-4422(10)70040-5. PMC 2880524. PMID 20298966.

[pmid3001157-11] Penneys NS, Hicks B (1985). "Unusual cutaneous lesions associated with acquired immunodeficiency syndrome". J Am Acad Dermatol. 13 (5 Pt 1): 845–52. PMID 3001157.

[pmid2311432-12] Jones C, Orengo I, Rosen T, Ellner K (1990). "Cutaneous cryptococcosis simulating Kaposi's sarcoma in the acquired immunodeficiency syndrome". Cutis. 45 (3): 163–7. PMID 2311432.

[pmid1634295-13] Blauvelt A, Kerdel FA (1992). "Cutaneous cryptococcosis mimicking Kaposi's sarcoma as the initial manifestation of disseminated disease". Int J Dermatol. 31 (4): 279–80. PMID 1634295.

[pmid1404541-14] Boyars MC, Zwischenberger JB, Cox Jr CS. Clinical manifestations of pulmonary fungal infections. Journal of thoracic imaging. 1992 Sep 1;7(4):12-22.

[pmid23717798-15] 15.0 ^15.1 Le Rhun E, Taillibert S, Chamberlain MC (2013). "Carcinomatous meningitis: Leptomeningeal metastases in solid tumors". Surg Neurol Int. 4 (Suppl 4): S265–88. doi:10.4103/2152-7806.111304. PMC 3656567. PMID 23717798.

[pmid24326618-16] 16.0 ^16.1 Chow E, Troy SB (2014). "The differential diagnosis of hypoglycorrhachia in adult patients". Am J Med Sci. 348 (3): 186–90. doi:10.1097/MAJ.0000000000000217. PMC 4065645. PMID 24326618.

[pmid22880096-17] 17.0 ^17.1 Leen WG, Willemsen MA, Wevers RA, Verbeek MM (2012). "Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice". PLoS One. 7 (8): e42745. doi:10.1371/journal.pone.0042745. PMC 3412827. PMID 22880096.

[pmid10654948-18] 18.0 ^18.1 ^18.2 Negrini B, Kelleher KJ, Wald ER (2000). "Cerebrospinal fluid findings in aseptic versus bacterial meningitis". Pediatrics. 105 (2): 316–9. PMID 10654948.

[pmid20610819-19] Brouwer MC, Tunkel AR, van de Beek D (2010). "Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis". Clin Microbiol Rev. 23 (3): 467–92. doi:10.1128/CMR.00070-09. PMC 2901656. PMID 20610819.

[pmid20146981-20] Caudie C, Tholance Y, Quadrio I, Peysson S (2010). "[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]". Ann Biol Clin (Paris). 68 (1): 107–11. doi:10.1684/abc.2010.0407. PMID 20146981.

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Cryptococcosis differential diagnosis

Overview

Differentiating Cryptococcosis from other Diseases

Differentiating cryptococcal meningitis from other causes of meningitis

References

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