BEUDAMED
    FDA Adverse Event Death Summary report: N

    FILMARRAY MENINGITIS/ENCEPHALITIS (ME) PANEL

    MDR report key: 10535252 · Received September 15, 2020

    Report

    Report Number
    3002773840-2020-00003
    Event Type
    Death
    Date Received
    September 15, 2020
    Report Date
    September 15, 2020
    Manufacturer
    BIOFIRE DIAGNOSTICS, LLC
    Product Code
    PLO
    PMA / PMN Number
    K160462
    Adverse Event
    Yes
    Report Source
    Manufacturer report
    Reporter Location
    CO
    Reporter Occupation
    OTHER HEALTH CARE PROFESSIONAL

    Narratives

    Additional Manufacturer Narrative · 1

    INVESTIGATION: DURING A LITERATURE REVIEW, BIOFIRE FOUND A RETROSPECTIVE COHORT STUDY BY DIAZ ET AL1 WHICH ASSESSED THE FILMARRAY ME PANEL'S CLINICAL IMPACT AT HOSPITAL UNIVERSITARIO SAN JORGE DE PEREIRA IN COLOMBIA. IN THIS STUDY, THE PATIENT RECORDS OF 98 ADULTS WHO HAD A CLINICAL SUSPICION OF NEUROINFECTION AND SUBSEQUENT CEREBROSPINAL FLUID (CSF) ANALYSIS WERE REVIEWED, AND IT WAS NOTED THAT THERE WAS A FALSE NEGATIVE CRYPTOCOCCUS RESULT. BIOFIRE REACHED OUT TO THE PRIMARY STUDY AUTHOR FOR MORE INFORMATION ABOUT THIS FALSE-NEGATIVE CASE AND RECEIVED THE FOLLOWING INFORMATION: THE PATIENT WAS A (B)(6)-YEAR-OLD MALE WHO WAS DIAGNOSED WITH (B)(6) AND HAD BEEN EXPERIENCING NEUROLOGIC COMPROMISE IN RECENT MONTHS. THE PATIENT HAD A CSF SHUNT AND WAS BROUGHT TO THE EMERGENCY ROOM WITH SUSPICION OF SHUNT DYSFUNCTION. THE CSF SAMPLE WAS COLLECTED VIA LUMBAR PUNCTURE, AND WHEN THE SAMPLE WAS TESTED BY THE FILMARRAY ME PANEL THERE WERE NO REPORTED DETECTIONS FOR ANY ANALYTES. BASED ON THE FILMARRAY ME PANEL RESULTS AND THE CHARACTERISTICS OF THE CSF, THE PATIENT'S CARE PROVIDERS CONSIDERED A POSSIBLE DIAGNOSIS OF MENINGEAL TUBERCULOSIS AND INITIATED ANTI-TUBERCULOSIS TREATMENT WITH STEROID THERAPY. THE CUSTOMER PERFORMED A CULTURE (IT IS UNKNOWN IF THE CSF SAMPLE WAS THE SAME AS THE ONE USED FOR THE FILMARRAY ME PANEL TESTING) AND CRYTOCOCCUS LAURENTII WAS ISOLATED (IDENTIFIED BY VITEK [89%]). INDIA INK STAINING WAS NEGATIVE AND THE CUSTOMER DID NOT TEST FOR CRYPTOCOCCAL ANTIGEN. FURTHER STUDY OF THE ISOLATE WITH PANFUNGAL PCR (UNKNOWN ASSAY) AT A REFERENCE LABORATORY IN MEDILLIN, COLOMBIA IDENTIFIED CRYPTOCOCCUS NEOFORMANS. THE NATIONAL HEALTH INSTITUTE OF COLOMBIA ALSO IDENTIFIED C. NEOFORMANS, AND THEIR TEST RESULTS ARE SUMMARIZED BELOW: PHENOTYPIC TESTING: UREASE: POSITIVE, NITRATES: NEGATIVE, GROWTH IN CULTURE MEDIA GUIZOTTIA ABYSSINICA: POSITIVE. GLYCINE-L-CANAVANINA-BROMOTHYMOL BLUE AGAR: NEGATIVE. MOLECULAR TESTING: RESTRICTION FRAGMENT LENGTH POLYMORPHISM (RFLP) OF URA5 GENE. THE AMPLIFICATION OF THE URA5 GENE WAS OBTAINED, THE RESTRICTION WITH THE ENZYMES SAU96I AND HHAL IDENTIFIED THE ISOLATE IN THE MOLECULAR PATRON VNI CORRESPONDING TO C. NEOFORMANS VARIETY GRUBII. THE IDENTIFICATION OF THE ISOLATE WAS CONFIRMED THROUGH MALDI-TOF WITH A SCORE OF 2.138. THE FINAL IDENTIFICATION WAS C. NEOFORMANS. THE PATIENT WAS ON ANTI-TUBERCULOSIS TREATMENT AND STEROID THERAPY FOR 7 DAYS, AFTER WHICH THE TREATMENT WAS CHANGED TO AMPHOTERICIN B PLUS FLUCONAZOLE FOR 13 DAYS. ON DAY 10 OF THE AMPOTERICIN B PLUS FLUCONAZOLE TREATMENT, CEFEPIME WAS ADDED FOR BACTERIAL MENINGITIS. IN THE COURSE OF THE 20 DAYS OF TREATMENT, THE PATIENT'S CONDITION DETERIORATED AND THE CSF SHUNT WAS EXTRACTED VIA SURGERY. AFTER SURGERY THE PATIENT WAS IN THE INTENSIVE CARE UNIT AND PASSED AWAY DUE TO POST-SURGICAL BACTERIAL MENINGITIS. THE PATIENT EXPIRED ON THE THIRD DAY OF CEFEPIME TREATMENT. THE AUTHOR STATED THAT THE ANTI-TUBERCULOSIS TREATMENT WAS CONSIDERED INAPPROPRIATE AND THE DELAY IN RECEIVING APPROPRIATE TREATMENT CONTRIBUTED TO THE DEATH OF THE PATIENT. BIOFIRE REQUESTED ADDITIONAL INFORMATION FOR ANALYSIS SUCH AS THE FILMARRAY ME PANEL RUN FILE AND BATCH/LOT NUMBERS, BUT NO ADDITIONAL INFORMATION WAS PROVIDED. CONCLUSION: BASED ON THE INFORMATION AVAILABLE, THE DISCREPANT CRYPTOCOCCUS RESULT WAS MOST LIKELY DUE TO SENSITIVITY DIFFERENCES BETWEEN THE FILMARRAY ME PANEL AND CULTURE. THE FILMARRAY ME PANEL IS CAPABLE OF SIMULTANEOUS DETECTION AND IDENTIFICATION OF MULTIPLE BACTERIAL, VIRAL, AND YEAST NUCLEIC ACIDS DIRECTLY FROM CSF SPECIMENS OBTAINED VIA LUMBAR PUNCTURE FROM INDIVIDUALS WITH SIGNS AND/OR SYMPTOMS OF MENINGITIS AND/OR ENCEPHALITIS. BASED ON CURRENTLY AVAILABLE DATA, THE SENSITIVITY OF THE FILMARRAY ME PANEL CRYPTOCOCCAL ASSAY IS APPROXIMATELY 94% AS COMPARED TO CULTURE, AND THE SENSITIVITY IS IMPACTED BY FUNGAL BURDEN (PLEASE REFER TO CUSTOMER TECHNICAL NOTE "CRYPTOCOCCUS DETECTION BY THE BIOFIRE® FILMARRAY® MENINGITIS/ENCEPHALITIS (ME) PANEL" [FLM1-PRT-0278]). HOWEVER, THERE HAVE BEEN REPORTS OF NEGATIVE RESULTS BY THE FILMARRAY ME PANEL IN PATIENTS WITH NEWLY-DIAGNOSED CRYPTOCOCCAL MENINGITIS AND POSITIVE CRAG AND/OR CULTURE2,3. ONE ARTICLE REPORTED THREE FALSE-NEGATIVE CRYPTOCOCCUS RESULTS ON THE FILMARRAY ME PANEL COMPARED TO CULTURE, BUT LATER ON CRYPTOCOCCUS WAS OBSERVED ON THE CSF CULTURE (RANGE, 10 - 95 CFU/ML)4. THE MOST SENSITIVE TEST FOR THE DIAGNOSIS OF PRIMARY CRYPTOCOCCAL MENINGITIS IS THE DETECTION OF CRYPTOCOCCAL ANTIGEN (CRAG). BIOFIRE THEREFORE RECOMMENDS THAT PATIENTS WITH A SUSPICION OF CRYPTOCOCCAL MENINGITIS WHO RECEIVE A NEGATIVE CRYPTOCOCCAL RESULT WHEN USING A PCR TEST (SUCH AS A FILMARRAY ME PANEL), BE TESTED FOR CRAG [FLM-PRT-0278]. CRAG TESTING WAS NOT PERFORMED ON THE SAMPLE FOR THE PATIENT AT HOSPITAL UNIVERSITARIO SAN JORGE DE PEREIRA. IT IS POSSIBLE THAT THE ORGANISM WAS PRESENT WITHIN THE CLINICAL SAMPLE AT A LEVEL THAT WAS BELOW THE FILMARRAY ME PANEL'S LIMIT OF DETECTION (LOD). ACCORDING TO TABLE 17 OF THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276], THE LOD OF THE C. NEOFORMANS/GATTII ASSAY WAS DETERMINED TO BE 100 CFU/ML WHERE DETECTIONS WERE MADE >95% OF THE TIME AT THE LOWEST CONCENTRATION OF ORGANISM POSSIBLE BY USING QUANTIFIED STRAINS OF C. NEOFORMANS (VAR. GRUBII, ATCC 208821]) AND C. GATTII (ATCC MYA-4877). ADDITIONALLY, IT IS POSSIBLE THAT THE C. NEOFORMANS STRAIN DETECTED VIA CULTURE CONTAINS SEQUENCE MISMATCHES WITH THE FILMARRAY ME PANEL CRYPTOCOCCUS ASSAY. GENETIC MISMATCHES OF THE TARGET REGIONS OF THE ASSAY MAY LEAD TO REDUCED SENSITIVITY BY THE ME PANEL. THE CUSTOMER STATED THAT C. NEOFORMANS VAR. GRUBII WAS IDENTIFIED VIA MALDI-TOF WITH A SCORE >= 2.0 AS WELL AS RFLP. HOWEVER, ADDITIONAL STRAIN INFORMATION WAS NOT PROVIDED. THE FILMARRAY ME PANEL DOES NOT DETECT ALL SPECIES OF CRYPTOCOCCUS, INCLUDING C. NEOFORMANS. PLEASE REFER TO TABLE 21 OF THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276] FOR THE C. NEOFORMANS STRAINS DETECTED BY THE CRYPTOCOCCUS ASSAY DURING INCLUSIVITY TESTING FOR THE FILMARRAY ME PANEL. THE PERFORMANCE OF THE FILMARRAY ME PANEL HAS NOT BEEN SPECIFICALLY EVALUATED FOR CSF SPECIMENS FROM IMMUNOCOMPROMISED INDIVIDUALS (PLEASE REFER TO THE "LIMITATIONS" SECTION OF THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276]). ALTHOUGH RARE, DISCREPANCIES BETWEEN THE FILMARRAY ME PANEL AND OTHER TEST METHODS ARE PART OF THE NORMAL PERFORMANCE FOR THE SYSTEM. RESULTS FROM THE FILMARRAY ME PANEL ARE INTENDED TO BE INTERPRETED IN CONJUNCTION WITH A PATIENT'S SIGNS AND SYMPTOMS AND RESULTS FROM OTHER DIAGNOSTIC TESTS. A NEGATIVE FILMARRAY ME PANEL RESULT DOES NOT EXCLUDE THE POSSIBILITY OF CNS INFECTION AND SHOULD NOT BE USED AS THE SOLE BASIS FOR DIAGNOSIS, TREATMENT, OR OTHER MANAGEMENT DECISIONS. THERE IS A RISK OF FALSE NEGATIVE VALUES DUE TO THE PRESENCE OF SEQUENCE VARIANTS OR REARRANGEMENTS IN THE GENE TARGETS OF THE ASSAY, PROCEDURAL ERRORS, INHIBITORS IN SPECIMENS, TECHNICAL ERROR, SAMPLE MIX-UP, OR INFECTION CAUSED BY AN ORGANISM NOT DETECTED BY THE FILMARRAY ME PANEL. TEST RESULTS MAY ALSO BE AFFECTED BY CONCURRENT ANTIMICROBIAL THERAPY OR LEVELS OF ORGANISM IN THE SAMPLE THAT ARE BELOW THE LOD. THE FILMARRAY ME PANEL IS INDICATED AS AN AID IN THE DIAGNOSIS OF SPECIFIC AGENTS OF MENINGITIS AND/OR ENCEPHALITIS AND RESULTS ARE MEANT TO BE USED IN CONJUNCTION WITH OTHER CLINICAL, EPIDEMIOLOGICAL, AND LABORATORY DATA. ACCORDING TO THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276], CLINICAL PERFORMANCE FOR THE CRYPTOCOCCUS ASSAY COMPARED TO PCR WITH BI-DIRECTIONAL SEQUENCING SHOWED A POSITIVE PERCENT AGREEMENT (PPA) OF 100% (1/1) AND A NEGATIVE PERCENT AGREEMENT (NPA) OF 99.7% (95% CI 99.3-99.9) (TABLE 9). C. NEOFORMANS/GATTII WAS DETECTED IN 2/4 FP SPECIMENS USING A COMMERCIALLY AVAILABLE ANTIGEN TEST. ADDITIONALLY, FILMARRAY ME PANEL C. NEOFORMANS/GATTII ASSAY PERFORMANCE RELATIVE TO OTHER COMPARATOR METHODS (TABLE 11) SHOWED A PPA OF CRYPTOCOCCUS COMPARED TO CRAG OF 12.5% (95% CI 2.2-47.1) AND NPA OF 99.5% (95% CI 97.0-99.5). SEVEN SPECIMENS WERE POSITIVE BY CRAG TESTING PERFORMED AT THE CLINICAL SITE, BUT WERE NEGATIVE BY CULTURE, FILMARRAY ME PANEL, AND TWO COMPARATOR ASSAYS. ALL SEVEN SUBJECTS FROM WHOM THESE SPECIMENS WERE COLLECTED RECEIVED ANTIFUNGAL THERAPY PRIOR TO LP AND/OR HAD PRIOR HISTORY OF CRYPTOCOCCUS INFECTION. THE EIGHTH SPECIMEN WAS POSITIVE BY CRAG FILMARRAY ME PANEL, AND CULTURE. THE TECHNICAL NOTE TITLED "CRYPTOCOCCUS DETECTION BY THE BIOFIRE® FILMARRAY® MENINGITIS/ENCEPHALITIS (ME) PANEL" [FLM1-PRT-0278] PROVIDES MORE INFORMATION ON THE USE AND INTERPRETATION OF THE FILMARRAY ME PANEL AS AN AID TO THE DIAGNOSIS OF CRYPTOCOCCAL MENINGITIS. REFERENCES: DÍAZ KMO, PIEDRAHÍTA JAA, SUÁREZ BROCHERO OF, ET AL. IMPACT OF THE FILM ARRAY MENINGITIS/ENCEPHALITIS PANEL IN ADULTS WITH MENINGITIS AND ENCEPHALITIS IN COLOMBIA. EPIDEMIOLOGY AND INFECTION. 2020;148:E173. DOI:10.1017/S0950268820001648. CHEW KL, LEE CK, CROSS GB, LUM LHW, YAN B, JUREEN R. CULTURE-CONFIRMED CRYPTOCOCCAL MENINGITIS NOT DETECTED BY CRYPTOCOCCUS PCR ON THE BIOFIRE MENINGITIS/ENCEPHALITIS PANEL®. CLIN MICROBIOL INFECT. 2018;24(7):791-792. DOI:10.1016/J.CMI.2018.02.024. O'HALLORAN JA, FRANKLIN A, LAINHART W, BURNHAM CA, POWDERLY W, DUBBERKE E. PITFALLS ASSOCIATED WITH THE USE OF MOLECULAR DIAGNOSTIC PANELS IN THE DIAGNOSIS OF CRYPTOCOCCAL MENINGITIS. OPEN FORUM INFECT DIS. 2017;4(4):OFX242. PUBLISHED 2017 NOV 3. DOI:10.1093/OFID/OFX242. SSEBAMBULIDDE K, BANGDIWALA AS, KWIZERA R, ET AL. SYMPTOMATIC CRYPTOCOCCAL ANTIGENEMIA PRESENTING AS EARLY CRYPTOCOCCAL MENINGITIS WITH NEGATIVE CEREBRAL SPINAL FLUID ANALYSIS. CLIN INFECT DIS. 2019;68(12):2094-2098. DOI:10.1093/CID/CIY817.

    Description of Event or Problem · 1

    SUMMARY: DURING A LITERATURE REVIEW, BIOFIRE FOUND A RETROSPECTIVE COHORT STUDY BY DIAZ ET AL1 WHICH NOTED A FALSE NEGATIVE CRYPTOCOCCUS RESULT ON THE FILMARRAY MENINGITIS/ENCEPHALITIS (ME) PANEL DURING PATIENT TESTING. AFTER MAKING CONTACT WITH THE PRIMARY AUTHOR OF THE STUDY, BIOFIRE WAS INFORMED THAT DUE TO THE FILMARRAY ME PANEL RESULT, THE PATIENT RECEIVED INAPPROPRIATE TREATMENT FOR 7 DAYS. THIS INAPPROPRIATE TREATMENT LED TO DETERIORATION OF PATIENT HEALTH AND THE PATIENT ULTIMATELY PASSED AWAY FROM POST-SURGICAL BACTERIAL MENINGITIS. THE FILMARRAY ME PANEL RUN FILE AND SPECIFIC PRODUCT INFORMATION WAS UNAVAILABLE FOR REVIEW. BASED ON THE INFORMATION PROVIDED, THE INVESTIGATION CONCLUDED THAT THE MOST LIKELY CAUSE FOR THE DISCREPANT RESULT IS A SENSITIVITY DIFFERENCE BETWEEN THE FILMARRAY ME PANEL AND CULTURE. REFERENCES: . DÍAZ KMO, PIEDRAHÍTA JAA, SUÁREZ BROCHERO OF, ET AL. IMPACT OF THE FILM ARRAY MENINGITIS/ENCEPHALITIS PANEL IN ADULTS WITH MENINGITIS AND ENCEPHALITIS IN COLOMBIA. EPIDEMIOLOGY AND INFECTION. 2020;148:E173. DOI: 10.1017/S0950268820001648. CHEW KL, LEE CK, CROSS GB, LUM LHW, YAN B, JUREEN R. CULTURE-CONFIRMED CRYPTOCOCCAL MENINGITIS NOT DETECTED BY CRYPTOCOCCUS PCR ON THE BIOFIRE MENINGITIS/ENCEPHALITIS PANEL®. CLIN MICROBIOL INFECT. 2018;24(7):791-792. DOI:10.1016/J.CMI.2018.02.024. O'HALLORAN JA, FRANKLIN A, LAINHART W, BURNHAM CA, POWDERLY W, DUBBERKE E. PITFALLS ASSOCIATED WITH THE USE OF MOLECULAR DIAGNOSTIC PANELS IN THE DIAGNOSIS OF CRYPTOCOCCAL MENINGITIS. OPEN FORUM INFECT DIS. 2017;4(4):OFX242. PUBLISHED 2017 NOV 3. DOI:10.1093/OFID/OFX242. SSEBAMBULIDDE K, BANGDIWALA AS, KWIZERA R, ET AL. SYMPTOMATIC CRYPTOCOCCAL ANTIGENEMIA PRESENTING AS EARLY CRYPTOCOCCAL MENINGITIS WITH NEGATIVE CEREBRAL SPINAL FLUID ANALYSIS. CLIN INFECT DIS. 2019;68(12):2094-2098. DOI:10.1093/CID/CIY817.

    Devices

    Seq Brand Generic Product Code Manufacturer Model Lot UDI-DI
    997787 FILMARRAY MENINGITIS/ENCEPHALITIS (ME) PANEL FILMARRAY® MENINGITIS/ENCEPHALITIS (ME) PANEL PLO BIOFIRE DIAGNOSTICS, LLC RFIT-ASY-0118/RFIT-ASY-0119

    Patients

    Seq Age Sex Outcome Treatment
    1 40 YR Death