Case Presentation Intern 8931150 Tutor VS 2007/01/26
About The Patient 38 years old worker ID: M120794700 Admission date: 2006/12/28 C.C.: Fever with headache for 2 days
Present Illness Smoker, alcoholism Liver cirrhosis 4-5 days ago: dry cough, rhinorrhea
Present Illness 2 days ago: fever, headache Poor appetite Insomnia Self-talking No seizure, visual disturbance, nausea / vomiting, diarrhea / constipation, gait abnormality, urine / stool incontinence No travel history
Social History
Past History & Family History Operation & hospitalization: due to right hip trauma in 8 years ago, s/p THR No hepatitis B or C, DM, HTN, cardiac disease Medications: His father has DM and HTN
Physical Examination T/P/R: 37.2/86/18, BP 126/80 mmhg Conscious: alert Mental status: clear but irritable Conjunctiva: pale. Sclera: icteric Chest: clear breath sounds Heart: RHB without murmur Abdomen: soft, normoactive bowel sounds Extremities: not edematous
Neurological Examination Cranial nerves: isocoric light reflex, full EOM, no nystagmus or ptosis, no facial numbness, symmetric facial expression, gag reflex(+) Muscle power: normal DTR: normal
Physical Examination Nuchal rigidity (+) Brudzinski sign (+) Kernig s sign (-)
Lab Data
Lab Data
Lab Data & Images 12/27 CXR 12/27 Brain CT EEG: normal Abdominal sonography: liver cirrhosis, fatty liver, splenomegaly
Impressions Suspect cryptococcal meningitis and encephalitis Suspect alcoholic liver cirhhosis Anemia, normocytic Thrombocytopenia Hyponatremia
Alcoholic liver cirrhosis Cryptococcal Meningitis Anemia Splenomegaly Thrombocytopenia Hyponatremia
The possibility of cryptococcal meningitis (O) in a 38 years old man (P) with isolated (C) positive CA (I) Data from Medline OVID, MD consult, UpToDate database emedicine and Google
UpToDate / emedicine Cryptococcal meningitis (yearly in USA) Non-HIV: 1-2 / 10 6 HIV: 6-7% Age: 20-40 years old Sensitivity and specificity of Ag assay: CSF: both 94-95% Serum: a little lower, 90-93% Compatible rate: 93.5%
Laboratory Corporation of America 2003 False positive CA tests are reported to occur in up to 15% of cases Usually at low titers, of 1:32 or below
Laboratory Corporation of America 2003 Causes: Rheumatoid factor Heterophil antibodies Anti-idiotypic antibodies Infection with organisms that share crossreacting antigen Trichosporon Capnocytophaga Stomatococcus Contaminants in culture media
Cryptococcosis Infect Dis Clin N Am 20 (2006) 507 544 Incidence : Non-AIDS: 0.2-0.8 / 10 6 AIDS:2-7 / 1000 in 2000 80% associated with AIDS
Cryptococcosis Direct examination Histopathology Serology Culture and identification
Cryptococcosis Direct examination: Direct microscopic exam India ink stain 30-50% sensitivity 10 3-10 4 colony forming units / ml False + : lysed lymphocyte, myelin globules, fat droplets, tissue cells, carbon particles
Cryptococcosis Histopathology stain: nonspecific Gram s Papanicolaous s Hematoxylin-eosin (HE) Diff-Quick May-Giemsa Riu s
Cryptococcosis Histopathology stain: specific Fungal chitin Gomori s methenamine silver stain Mayer s mucicarmine Periodic acid-schiff Alcain blue
Cryptococcosis Serology: Serum antibodies are not helpful in Dx Antigen assay: 10ng of polysaccharide / ml Correlated with the yeast burden Sensitivity & specificity : depends on the kit. Overall: 93-100% & 93-98%, false + 0-0.4%
Cryptococcosis Serology: Antigen assay: False + : initial tilter less or equal to 8 (except in patient with T. beigelii infection) False - : Prozone effect (if India ink + but CA -, try to dilute and retest), low fungal burden (ex: chronic cryptococcal meningitis)
Cryptococcosis Serology: Antigen assay: Diagnosis of cryptococcal meningoencephalitis at high tilter even when India ink exam or culture is negative
Cryptococcosis Serology: Antigen assay: Isolated cryptococccal polysaccharideidemia: high risk patients with Ag+, S/S and culture (Uganda: 38.1%) Patients who have isolated Ag+ and are in a high risk group would probably benefit from antifungal therapy for preventing or delaying development of overt cryptococcosis
Cryptococcosis Serology: Enzyme immunoassay: Detect GXM of polysaccharide capsule Sensitivity & specificity : 85.2-99% & 97% Compatible rate with LA : 84.6-97.8%
Cryptococcosis Culture : Negative may occur despite India ink + Negative might due to low fungal burden DNA probe for rrna for C. neoformans : Sensitivity & specificity : 100%
What is the significance of an isolated positive cryptococcal Ag in the CSF of cancer patients? 2003, Mycoses, 46, 161 163 12 patients with cancer In most of the cases, the test had a low titer, was frequently associated with an intracranial malignancy and was considered to represent a false-positive result
What is the significance of an isolated positive cryptococcal Ag in the CSF of cancer patients? Unless results of other tests prove to be diagnostic, continuation of therapy for cryptococcal meningitis, an infection having a low prevalence rate in this patient population, may not be needed
The significance of isolated positive CSF cryptococcal antigen in HIV-infected P ts Int Conf AIDS 1990 Jun 20-23; 6:236 1987/12-1989/04 Isolated positive tests: CA was + in the CSF but not in the serum, and cultures were negative Reviewed for other evidence of cryptococcal infection, HIV status and amphotericin B therapy
The significance of isolated positive CSF cryptococcal antigen in HIV-infected P ts 635 CSF sample: 597 CA -, 48 CA + 27 culture +, 21 culture - (mean tilter 1618) 10 HIV -, 11 HIV + (9 of 11, mean tilter 4.9) 9 HIV + with isolated CA + 2 treated with AmB, 7 untreated 4 no evidence of CI, 1 CI +, 2 lost of f/u
The significance of isolated positive CSF cryptococcal antigen in HIV-infected P ts Isolated + CSF CA tests were common in HIV+ pts Titers were substantially lower than in cases of CI + A significant proportion (66%?) appear to be false +
The significance of isolated positive CSF cryptococcal antigen in HIV-infected P ts Supporting evidence of CI should be sought in such cases prior to the institution of AmB if the clinical condition of the patient is stable
Cryptococcus: Antigen detection for diagnosis: false-positive reactions A 50 year old alcoholic male with diabetes presented with hyperosmolar coma but failed to improve after correction of metabolic abnormalities Brain MRI : normal
Cryptococcus: Antigen detection for diagnosis: false-positive reactions CSF : 195 cells (mostly neutrophils) with elevated protein CA 1:4 in the CSF and 1:256 in the serum CSF culture : negative CXR : a lower lobe infiltrate Repeat antigen tests and cultures were negative
Cryptococcus: Antigen detection for diagnosis: false-positive reactions Empiric treatment with amphotericin B and flucytosine He improved clinically in response to antifungal therapy
Cryptococcus: Antigen detection for diagnosis: false-positive reactions About false positive: Associated conditions : Cancer Collagen diseases Cirrhosis Sepsis Plasma cell dyscrasias Treatment with monoclonal antibodies
Cryptococcus: Antigen detection for diagnosis: false-positive reactions About false positive: Some studies suggest accepting isolated antigen positivity as presumptive evidence for disseminated disease and a basis for empiric therapy, at least in immunosuppressed patients, and in absence of conditions known to be associated with false-positivity
Cryptococcus: Antigen detection for diagnosis: false-positive reactions About false negative: Prozone effect Pronase : The LA test result in serum was negative in 11 of 57 (19.3%) patients suspected to have cryptococcal meningitis before treatment but positive after treatment with pronase Patients with very low fungal burden
Cryptococcus: Antigen detection for diagnosis: false-positive reactions Others for diagnosis: Enzyme immunoassay : no studies showing that EIA would identify false - LA specimens. EIA is not widely used because of the reliability & simplicity of LA. PCR : molecular diagnostics have not been fully evaluated to establish sensitivity, specificity, and role in clinical management of patients suspected to have cryptococcal meningitis
Cryptococcus: Antigen detection for diagnosis: false-positive reactions The patient appeared to improve in response to AmB and flucytosine. Thus continued treatment seems prudent. If those specimens were negative upon retesting in a referral laboratory, the diagnosis would be less certain
Cryptococcal meningitis in non-hiv-infected patients Q J Med 2000; 93:245 251 94 patients in NTU hospital 1977-1996 44.7% had underlying disease On multivariate analysis, lymphoma and initial high cryptococcal antigen titres were independent predictors of mortality
In Conclusion 38 years old man Liver cirrhosis CSF: Ag 1:256, culture(-), India ink(-) Serum: Ag(-), culture(-)
6-7% HIV(+) Treat as cryptococcal infection Isolated (+) Ag 15% False (+) Cross reaction Recheck HIV(-) 1-2/10 6 False (-) Low fungal burden Prozone effect
Diagnostic Plan Check HIV Ab Negative Recheck CSF routine/ag assay/india ink stain/culture Recheck serum Ag and blood culture The same outcome, false(+) rate: 2.25%
Therapeutic Plan Amphotericin B Spiking fever for 1 week Hypokalemia