Utility of (1–3)-β-d-Glucan Testing for Diagnostics and Monitoring Response to Treatment During the Multistate Outbreak of Fungal Meningitis and Other Infections

Litvintseva, Anastasia P.; Lindsley, Mark D.; Gade, Lalitha; Smith, Rachel M.; Chiller, Tom; Lyons, Jennifer L.; Thakur, Kiran T.; Zhang, Sean X.; Grgurich, Dale; Kerkering, Thomas M.; Brandt, Mary E.; Park, Benjamin J.

doi:10.1093/cid/cit808

Cited by 87 publications

(64 citation statements)

References 20 publications

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“…Using this assay and a stratified sample of CSF specimens, we demonstrated that approximately 45% of the CSF specimens from case patients with negative PCR assay results had elevated levels of BDG. Our results, as well as others, also demonstrated that consistently elevated levels of BDG in CSF may indicate a relapse or persistent infection (6,7). However, because the BDG assay is not species specific, can cross-react with certain bacteria and drugs, and is prone to contamination, this test cannot be used to provide a definitive confirmation of fungal infection (6,8).…”

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confidence: 56%

“…Our results, as well as others, also demonstrated that consistently elevated levels of BDG in CSF may indicate a relapse or persistent infection (6, 7). However, because the BDG assay is not species specific, can cross-react with certain bacteria and drugs, and is prone to contamination, this test cannot be used to provide a definitive confirmation of fungal infection (6,8). A real-time molecular beacon PCR assay for detection of Exserohilum has also been reported (9) and used to test blood from patients with a possible association with the outbreak (10).…”

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confidence: 99%

“…Although the sensitivity of the PCR assay was considerably better than that of culture, which was able to confirm only 10% of the cases, a large percentage of the case patients remained without laboratory confirmation of infection. We also investigated the utility of the Fungitell assay for the detection of beta-D-glucan (BDG) in CSF for diagnosis and monitoring of the response to treatment (6). Using this assay and a stratified sample of CSF specimens, we demonstrated that approximately 45% of the CSF specimens from case patients with negative PCR assay results had elevated levels of BDG.…”

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Utility of Real-Time PCR for Detection of Exserohilum rostratum in Body and Tissue Fluids during the Multistate Outbreak of Fungal Meningitis and Other Infections

et al. 2015

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bExserohilum rostratum was the major cause of the multistate outbreak of fungal meningitis linked to contaminated injections of methylprednisolone acetate produced by the New England Compounding Center. Previously, we developed a fungal DNA extraction procedure and broad-range and E. rostratum-specific PCR assays and confirmed the presence of fungal DNA in 28% of the case patients. Here, we report the development and validation of a TaqMan real-time PCR assay for the detection of E. rostratum in body fluids, which we used to confirm infections in 57 additional case patients, bringing the total number of case patients with PCR results positive for E. rostratum to 171 (37% of the 461 case patients with available specimens). Compared to fungal culture and the previous PCR assays, this real-time PCR assay was more sensitive. Of the 139 identical specimens from case patients tested by all three methods, 19 (14%) were positive by culture, 41 (29%) were positive by the conventional PCR assay, and 65 (47%) were positive by the real-time PCR assay. We also compared the utility of the real-time PCR assay with that of the previously described beta-D-glucan (BDG) detection assay for monitoring response to treatment in case patients with serially collected CSF. Only the incident CSF specimens from most of the case patients were positive by real-time PCR, while most of the subsequently collected specimens were negative, confirming our previous observations that the BDG assay was more appropriate than the real-time PCR assay for monitoring the response to treatment. Our results also demonstrate that the real-time PCR assay is extremely susceptible to contamination and its results should be used only in conjunction with clinical and epidemiological data. Since September 2012, U.S. state and local health departments, the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration have been investigating the largest documented health care-associated outbreak in the United States of fungal meningitis and other infections developed after epidural, paraspinal, or joint injections with contaminated methylprednisolone acetate (MPA) from a single compounding pharmacy (1-3). The major cause of this outbreak was Exserohilum rostratum, a plant pathogen that rarely causes disease in humans (4). By using culture, PCR, and histopathology, this fungus was identified in cerebrospinal fluid (CSF), synovial fluid, abscess aspirate, fresh tissue, and formalin-fixed, paraffin-embedded tissue samples from 153 case patients, as well as in unopened vials of two implicated lots of MPA (3). Previously, we developed a method for extracting free circulating fungal DNA from different types of body fluids and tissues from patients in this outbreak and used two PCR tests, followed by DNA sequencing, to detect fungal DNA in patient specimens (5). Using this approach, we were able to detect fungal DNA in 28% of the case patients (3). Although the sensitivity of the PCR assay was considerably better than that of culture, which was ab...

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Utility of Real-Time PCR for Detection of Exserohilum rostratum in Body and Tissue Fluids during the Multistate Outbreak of Fungal Meningitis and Other Infections

et al. 2015

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“…In the setting of CNS mycosis due to Exserohilum rostratum secondary to iatrogenic organism introduction, CSF ␤-glucan sensitivity and specificity were found for proven meningitis to be 96 and 95%, respectively (24). There was also some correlation of CSF ␤-glucan with a clinical response in those cases (24,25), although not a good correlation with CSF leukocyte counts, glucose, or protein. A study of cryptococcal meningitis (16) found a correlation of CSF ␤-glucan with CSF fungal burden, CSF cryptococcal antigen, and clinical outcome.…”

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Cerebrospinal Fluid (1,3)-Beta- d -Glucan Testing Is Useful in Diagnosis of Coccidioidal Meningitis

et al. 2016

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c Diagnosing coccidioidal meningitis (CM) can be problematic owing to its infrequency and/or a delay in the positivity of a cerebrospinal fluid (CSF) culture or CSF antibody, particularly if the primary coccidioidal infection is unrecognized. We tested 37 CSF specimens, 26 from patients with confirmed CM and 11 from patients with suspected microbial meningitis without fungal diagnosis, for (1,3)-beta-glucan (BG). BG in CM CSF specimens ranged from 18 to 3,300 pg/ml and in controls ranged from <3.9 to 103 pg/ml. Diagnostic performance was determined using a 31-pg/ml cutoff (the bottom of the serum range according to the directions for the commercial kit, although further serial dilutions of the standard indicated linearity to 3.9). Sensitivity was 96%, specificity was 82%, positive and negative predictive values were 93% and 90%, and the area under the receiver operating characteristic curve was 0.937. Fifteen of 15 samples of >103 pg/ml were CM. The one false-negative specimen was from a patient with a pseudosyrinx, without inflammatory evidence of meningitis activity. Serial samples from some patients were positive at <8 years, indicating no loss of positivity with chronicity. Samples stored frozen since 2000 included those with 2 of the 3 highest values, indicating that fresh samples not required. A previous study indicated serum sensitivities of 53% in acute, 50% in resolved, and 83% in disseminated and meningeal coccidioidomycosis. Three studies of other fungal meningitides ranged from 86 to 1,524 pg/ml CSF, with 37 controls of <4 to 115 pg/ml CSF. CSF BG analysis had good diagnostic performance in CM. CSF BG testing can be useful in CM, and a commercial kit is available. It will be of interest to correlate this with course, treatment, outcome, inflammation, and antigen. The only mycoses with common central nervous system (CNS) involvement are cryptococcal and coccidioidal, so CSF BG screening can be useful in meningitis diagnosis. C occidiodal meningitis, the most feared complication of coccidioidomycosis, has a documented mortality if untreated of 90% in 1 year and 100% in 2 years. It is estimated that there are 200 to 500 new cases per year. It is a granulomatous meningitis, usually involving the basilar meninges. The spinal cord is often involved. It may have an acute, a subacute, or a chronic type of presentation. It may be accompanied by parenchymal abscesses. Complications include hydrocephalus, cerebral infarction, vasculitis, arachnoiditis, cranial nerve palsy, syringomyelia, transverse myelitis, cord compression, seizures, and hyponatremia owing to inappropriate antidiuretic hormone secretion (1).Definitive diagnosis rests on isolating Coccidioides from cerebrospinal fluid (CSF) or other central nervous system (CNS) specimens, although results are only positive in about one-third of patients. A presumptive diagnosis has classically been made by identifying anticoccidioidal antibodies in the CSF; however, antibody results may be negative early in the disease, and false-positive results can occur wit...

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“…39 Additional CSF tests to consider include β-D-glucan for Candida meningitis, mycobacterial cultures with acid-fast bacilli smear, and other tests based on the differential diagnosis (eg, polymerase chain reaction), fungal and parasitic assays (eg, Cryptococcus, Toxoplasma, Taenia), and serology and virus-detection assays. 40,41 Biochemistry of the CSF can also be helpful. CSF lactate concentration may differentiate bacterial from viral meningitis better than white blood cell count, glucose level, and protein concentration, although CSF lactate may be elevated in patients with other CNS diseases.…”

Section: Laboratory Testsmentioning

confidence: 99%

Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis

Rigakos¹,

Liakou²,

Felipe

et al. 2017

Cancer Control

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Utility of (1–3)-β-d-Glucan Testing for Diagnostics and Monitoring Response to Treatment During the Multistate Outbreak of Fungal Meningitis and Other Infections

Cited by 87 publications

References 20 publications

Utility of Real-Time PCR for Detection of Exserohilum rostratum in Body and Tissue Fluids during the Multistate Outbreak of Fungal Meningitis and Other Infections

Utility of Real-Time PCR for Detection of Exserohilum rostratum in Body and Tissue Fluids during the Multistate Outbreak of Fungal Meningitis and Other Infections

Cerebrospinal Fluid (1,3)-Beta- d -Glucan Testing Is Useful in Diagnosis of Coccidioidal Meningitis

Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis

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