FILMARRAY® MENINGITIS/ENCEPHALITIS (ME) PANEL
Report
- Report Number
- 3002773840-2019-00006
- Event Type
- Death
- Date Received
- September 24, 2019
- Date of Event
- June 27, 2019
- Report Date
- October 18, 2019
- Manufacturer
- BIOFIRE DIAGNOSTICS, LLC
- Product Code
- PLO
- UDI-DI
- 00815381020123
- PMA / PMN Number
- K160462
- Adverse Event
- Yes
- Report Source
- Manufacturer report
- Reporter Location
- NY, US
- Reporter Occupation
- PHYSICIAN
Narratives
THE CUSTOMER PROVIDED BOTH FILMARRAY ME PANEL RUN FILES ON (B)(6) 2019. ANALYSIS OF THE FILMARRAY ME PANEL RUN FILES DID NOT SHOW ANY AMPLIFICATION OR MELT ACTIVITY FOR THE HSV-1, HSV2-1, AND HSV2-2 ASSAYS. THE CONTROLS FROM BOTH RUNS SHOWED NORMAL PERFORMANCE AND THERE IS NO INDICATION THAT A MALFUNCTION OCCURRED. THE SYSTEM WAS DETERMINED TO BE PERFORMING WITHIN SPECIFICATION. TO DATE, THE CUSTOMER HAS NOT SHARED WITH BIOFIRE ADDITIONAL INFORMATION ABOUT THIS ADVERSE EVENT. BIOFIRE HAS REQUESTED TO TEST THE CSF SAMPLE IN-HOUSE BUT THE CUSTOMER HAS NOT RESPONDED TO THIS QUERY.
ON SEPTEMBER 12, 2019, THE FDA CONTACTED BIOFIRE TO REPORT A CASE OF (B)(6) WITH THE FILMARRAY ME PANEL THAT MAY HAVE CONTRIBUTED TO THE DEATH OF A PATIENT. THIS ADVERSE EVENT OCCURRED IN (B)(6) 2019 AND WAS NOT REPORTED TO BIOFIRE AT THAT TIME. THE PATIENT PRESENTED WITH CLINICAL SUSPICION FOR (B)(6) ENCEPHALITIS AND WAS INITIALLY TREATED WITH (B)(6). THE PATIENT HAD A LUMBAR PUNCTURE PERFORMED ON (B)(6) 2019 THAT INCLUDED A FILMARRAY ME PANEL WHICH TESTED (B)(6) FOR BOTH (B)(6). IT WAS CLAIMED THAT (B)(6) TREATMENT WAS STOPPED DUE TO THIS (B)(6) RESULT. THE PATIENT CONTINUED TO WORSEN AND CLINICAL SUSPICION OF (B)(6) INFECTION REMAINED, SO A 2ND LUMBAR PUNCTURE WAS PERFORMED ON (B)(6) 2019 AND AGAIN WAS TESTED ON THE FILMARRAY ME PANEL. THIS RESULT WAS ALSO (B)(6). NO MENTION OF ANY OTHER COMPARATOR TESTS WAS PROVIDED. THE PATIENT ULTIMATELY DIED AND AN AUTOPSY REVEALED (B)(6) INFECTION (METHOD OF DETERMINATION UNKNOWN). NO RUN FILES HAVE BEEN PROVIDED. POUCH, POUCH QC, AND INSTRUMENT REVIEW COULD NOT BE CONDUCTED. NO OTHER INFORMATION HAS BEEN PROVIDED BY THE SITE; THEREFORE, NO INVESTIGATION HAS BEEN POSSIBLE REGARDING SAMPLE COLLECTION OR HANDLING OR OTHER ASPECTS OF THE TESTING PROCESS. CONCLUSION: BASED ON THE LIMITED INFORMATION PROVIDED, THE ROOT CAUSE OF THE DISCREPANCY COULD NOT BE DETERMINED CONCLUSIVELY. THE FOLLOWING ARE POSSIBLE CAUSES OF A FALSE NEGATIVE RESULT: LOW VIRAL TITER IN THE CEREBROSPINAL FLUID (CSF) SAMPLE. A LOW CONCENTRATION OF THE VIRUS BELOW THE HSV-1 AND HSV-2 ASSAYS LOD CAN CAUSE A FALSE NEGATIVE RESULT. LOW LEVELS OF HSV-1 MAY BE ENCOUNTERED IF THE CSF IS COLLECTED EARLY IN THE COURSE OF THE DISEASE-RESULTING IN LOW VIRAL COPIES, OR IF THE SAMPLE IS DILUTED PRIOR TO TESTING (1). IN ADDITION, THE MAJORITY OF HSV-1 REPLICATION OCCURS IN THE BRAIN, AND ONLY A FEW VIRAL PARTICLES ARE RELEASED INTO THE CSF WHERE THEY CAN BE DETECTED (2). THE LEVEL OF HSV-1 NUCLEIC ACIDS IN PATIENTS WITH ENCEPHALITIS CAN BE VERY LOW AT THE TIME OF DIAGNOSIS (IF DIAGNOSED EARLY), AS WELL AS FOR PATIENTS WITH MILD CLINICAL SYMPTOMS (3). ACCORDING TO TABLE 17 OF THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276, HTTPS://WWW.ONLINE-IFU.COM/ITI0035], THE CONFIRMED LOD FOR HSV-1 (TESTING STRAIN MACINTYRE, ISOLATE ZEPTOMETRIX 0810005CF) WAS DETERMINED TO BE 250 TCID50/ML (1.51×10^3 COPIES/ML). THE CONFIRMED LOD FOR HSV-2 (TESTING STRAIN MS, ISOLATE ZEPTOMETRIX 0810006CF) WAS DETERMINED TO BE 50 TCID50/ML (1.29×10^3 COPIES/ML). CONFIRMATION OF LOD WAS ACHIEVED BY TESTING 20 REPLICATES OF A CONTRIVED SAMPLE CONTAINING ANALYTES AT THEIR ESTIMATED LOD CONCENTRATION. LOD WAS CONFIRMED WHEN THE ORGANISM WAS DETECTED IN AT LEAST 19 OF THE 20 REPLICATES TESTED (19/20 = 95%). POTENTIAL HSV STRAIN VARIATION. A NEW SEQUENCE VARIANT COULD POSSIBLY CONTRIBUTE TO A FALSE NEGATIVE RESULT ON THE FILMARRAY ME PANEL. DEPENDING ON WHERE THE SEQUENCE MISMATCH IS LOCATED ON THE PRIMER BINDING SITE, THIS CAN CONTRIBUTE TO DRASTIC REDUCTION OF PCR SENSITIVITY AND THUS A MISSED DETECTION. IN THE PAST, AN EXTERNAL QUALITY ASSESSMENT CHALLENGE (QCMD 2017) IN-HOUSE INVESTIGATION DETERMINED FALSE NEGATIVE HSV-1 RESULTS WERE CAUSED BY A SEQUENCE MISMATCH TO THE HSV-1 PRIMERS LEADING TO FALSE NEGATIVE RESULTS DUE TO A PREVIOUSLY UNREPORTED STRAIN NOT AVAILABLE IN PUBLIC DATABASES AT THE TIME. THE CLINICAL SIGNIFICANCE OF THIS STRAIN VARIANT IS NOT CURRENTLY WELL KNOWN. ACCORDING TO TABLE 9 OF THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276, HTTPS://WWW.ONLINE-IFU.COM/ITI0035], THE CLINICAL PERFORMANCE OF HSV-1 AS COMPARED TO TWO PCR ASSAYS WITH BI-DIRECTIONAL SEQUENCING SHOWED A POSITIVE PERCENT AGREEMENT (PPA) OF 100% (95% CI 34.2-100) AND A NEGATIVE PERCENT AGREEMENT (NPA) OF 99.9% (95% CI 99.5-100). THE CLINICAL PERFORMANCE OF HSV-2 COMPARED TO TWO PCR ASSAYS WITH BI-DIRECTIONAL SEQUENCING SHOWED A PPA OF 100% (95% CI 72.2-100) AND AN NPA OF 99.9% (95% CI 99.5-100). POTENTIAL LABORATORY TECHNICAL ERROR. SAMPLE HANDLING ERROR OR HUMAN ERROR CAN CAUSE FALSE NEGATIVE RESULTS. EXAMPLES OF THIS TYPE OF ERROR INCLUDE CSF CENTRIFUGATION PRIOR TO TESTING, SAMPLE DILUTION, INSUFFICIENT VOLUME ADDED TO THE FILMARRAY INJECTION VIAL, AND SAMPLE LOADING ERROR. THE DETECTION OF ORGANISM NUCLEIC ACID IS DEPENDENT UPON PROPER SAMPLE COLLECTION, HANDLING, TRANSPORTATION, STORAGE, AND PREPARATION. FAILURE TO OBSERVE PROPER PROCEDURES IN ANY ONE OF THESE STEPS CAN LEAD TO INCORRECT RESULTS. THERE IS A RISK OF FALSE NEGATIVE RESULTS CAUSED BY IMPROPERLY COLLECTED, TRANSPORTED, OR HANDLED SPECIMENS. IMPORTANT NOTE: THE FILMARRAY ME PANEL INSTRUCTION BOOKLET [RFIT-PRT-0276, HTTPS://WWW.ONLINE-IFU.COM/ITI0035] INDICATES THAT 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. RESULTS FROM THE FILMARRAY ME PANEL MUST BE CORRELATED WITH THE CLINICAL HISTORY, EPIDEMIOLOGICAL DATA, AND OTHER DATA AVAILABLE TO THE CLINICIAN EVALUATING THE PATIENT. ANTIVIRAL THERAPY MAY BE INAPPROPRIATELY STOPPED IN CASES OF FALSE NEGATIVE HSV AND COULD RESULT IN DEATH OR PERMANENT NEUROLOGICAL DAMAGE AS NO OTHER TESTING MAY BE PERFORMED FOR THIS DIAGNOSIS. HOWEVER, GUIDELINES NOTE THAT FOR PATIENTS SUSPECTED OF HSV INFECTION THAT HAVE AN INITIAL PCR NEGATIVE SAMPLE, SHOULD REMAIN ON ANTIVIRAL THERAPY UNTIL AT A MINIMUM THERE IS A SECOND CSF COLLECTED AND REPEAT TESTING AT 48-72 HR (AFTER FIRST NEGATIVE PCR). REFERENCES: ROA, P. L., ALONSO, R., DE EGEA, V., USUBILLAGA, R., MUÑOZ, P., & BOUZA, E. (2013). PCR FOR DETECTION OF HERPES SIMPLEX VIRUS IN CEREBROSPINAL FLUID: ALTERNATIVE ACCEPTANCE CRITERIA FOR DIAGNOSTIC WORKUP. JOURNAL OF CLINICAL MICROBIOLOGY, 51(9), 2880-2883. DENES, E., LABACH, C., DUROX, H., ADOUKONOU, T., WEINBRECK, P., MAGY, L., & RANGER-ROGEZ, S. (2010). INTRATHECAL SYNTHESIS OF SPECIFIC ANTIBODIES AS A MARKER OF HERPES SIMPLEX ENCEPHALITIS IN PATIENTS WITH NEGATIVE PCR. SWISS MED WKLY, 140, W13107. ADLER, A. C., KADIMI, S., APALOO, C., & MARCU, C. (2011). HERPES SIMPLEX ENCEPHALITIS WITH TWO FALSE-NEGATIVE CEREBROSPINAL FLUID PCR TESTS AND REVIEW OF NEGATIVE PCR RESULTS IN THE CLINICAL SETTING. CASE REPORTS IN NEUROLOGY, 3(2), 172-178.
ON SEPTEMBER 12, 2019, BIOFIRE DIAGNOSTICS, LLC (BIOFIRE) RECEIVED THE FOLLOWING INFORMATION FROM THE FDA REGARDING AN INCIDENT MENTIONED ON THE (B)(6): A PATIENT PRESENTED WITH CLINICAL SUSPICION FOR (B)(6) ENCEPHALITIS AND WAS STARTED ON (B)(6)TREATMENT. PATIENT CSF COLLECTED ON (B)(6) 2019 TESTED (B)(6) FOR (B)(6) WITH THE FILMARRAY MENINGITIS/ENCEPHALITIS (ME) PANEL. BASED ON THESE TEST RESULTS, THE (B)(6) TREATMENT WAS DISCONTINUED AND THE PATIENT CONTINUED TO WORSEN. A FRESH CSF COLLECTED ON (B)(6) 2019 ALSO TESTED (B)(6) FOR (B)(6) ON THE FILMARRAY ME PANEL. THE PATIENT ULTIMATELY DIED AND THE AUTOPSY REVEALED (B)(6) INFECTION. UPON FOLLOW-UP FROM A SEPARATE SOURCE, BIOFIRE RECEIVED THE CONTACT INFORMATION FOR THE FACILITY IN WHICH THE EVENT HAD OCCURRED. BIOFIRE CONTACTED THE FACILITY ON SEPTEMBER 16, 2019 TO OBTAIN ADDITIONAL INFORMATION ABOUT THE EVENT. THE FACILITY INFORMED BIOFIRE THAT THIS EVENT WAS UNDER INTERNAL INVESTIGATION AND THEREFORE NO ADDITIONAL INFORMATION REGARDING THIS CASE COULD BE PROVIDED TO BIOFIRE. BASED ON THE LIMITED INFORMATION PROVIDED, THE ROOT CAUSE OF THE DISCREPANCY COULD NOT BE DETERMINED. THE FOLLOWING ARE POSSIBLE CAUSES OF A FALSE NEGATIVE RESULT ON THE FILMARRAY ME PANEL: LOW VIRAL TITER IN THE CEREBROSPINAL FLUID (CSF) BELOW THE LIMIT OF DETECTION (LOD) OF THE (B)(6) ASSAYS. POTENTIAL STRAIN VARIANT CAUSING REDUCTION IN PCR SENSITIVITY. POTENTIAL LABORATORY TECHNICAL ERROR.
Devices
| Seq | Brand | Generic | Product Code | Manufacturer | Model | Lot | UDI-DI |
|---|---|---|---|---|---|---|---|
| 904665 | FILMARRAY® MENINGITIS/ENCEPHALITIS (ME) PANEL | FILMARRAY ME PANEL | PLO | BIOFIRE DIAGNOSTICS, LLC | RFIT-ASY-0118 | 0454919 | 00815381020123 |
Patients
| Seq | Age | Sex | Outcome | Treatment |
|---|---|---|---|---|
| 1 | Death |