Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Gastroenteritis
Robert J. Cybulski Jr.*1, Allen C. Bateman*#1, Lori Bourassa1, Andrew Bryan1, Barb Beail1,
Madison, USA
Corresponding author
Tel: 206-221-6770
Fax: 206-616-1575
email: fcfang@uw.edu
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
A multiplex PCR panel facilitated the more rapid institution of appropriate antimicrobial therapy
Short Title
Background. Molecular syndromic diagnostic panels can enhance pathogen identification in the
approximately 2-4 billion episodes of acute gastroenteritis that occur annually worldwide.
However, the clinical utility of these panels has not been established.
BioFire FilmArray Gastrointestinal PCR panel on clinical diagnosis and decision-making and
compared the clinical acuity of patients with positive results obtained exclusively with the
FilmArray with those detected by conventional stool culture. A total of 1,887 consecutive fecal
specimens were tested in parallel by FilmArray and stool culture. Laboratory and medical
records were reviewed to determine rates of detection, turnaround times, clinical features and the
Results. FilmArray detected pathogens in 35.3% of specimens, compared to 6.0% for culture.
Median time from collection to result was 18h for FilmArray and 47h for culture. Median time
from collection to initiation of antimicrobial therapy was 22h for FilmArray and 72h for
culture. Patients diagnosed by FilmArray were more likely to receive targeted rather than
empirical therapy, compared to those diagnosed by culture (p=0.0148). Positive STEC results
were reported 47h faster with FilmArray and facilitated discontinuation of empirical
identified cases with clinical acuity comparable to those identified by culture, and enabled
Accurate and timely diagnosis of acute gastroenteritis is an unmet clinical and public health need
[1, 2], as diarrhea remains a leading cause of morbidity and mortality worldwide [3, 4].
Approximately 80% of acute gastroenteritis cases are presently unattributed [4], partly due to
insensitive and pathogen-specific diagnostic tests [1, 5, 6]. Multiplex nucleic acid amplification
testing provides rapid turnaround time and allow clinicians to test on the basis of clinical
infections [10]. Many pathogens identified by multiplex panels respond to antimicrobial therapy
[11-20], offering potential benefit from timely results that enable targeted therapy and the
detection of Shiga-like toxin producing E. coli (STEC) for which antibiotics are contraindicated
[21, 22]. Multiplex testing improves laboratory workflow [23] and can enhance infection control
by increasing outbreak detection [24] and guiding contact precaution decisions [25].
Questions remain regarding the costs and benefits of multiplex panels. Increasing reliance upon
molecular assays may increase public health awareness of disease incidence, but fewer cultured
isolates may be available for outbreak investigations [26, 27]. Benefits realized from multiplex
syndromic testing may vary among patient populations [28-31]. It is also debated whether
treatment, and the clinical impact of multiplex panels is uncertain in the absence of coordinated
specimens by the BioFire FilmArray Gastrointestinal PCR panel and conventional methods.
The objectives were to determine whether the additional patients detected by multiplex PCR
have comparable clinical features to those diagnosed with conventional methods and to measure
METHODS
Parallel testing of stool specimens by FilmArray and conventional methods was performed
from Jan 1 to Sept 30, 2017. A historical control group comprised of patients with positive stool
cultures tested at the same laboratories from Jan 1 to Sept 30, 2016 was also analyzed. Eligible
subjects included newly-admitted (<3d) inpatients and outpatients from 17 outpatient clinics in
the greater Seattle, Washington metropolitan area served by the clinical laboratories of the
University of Washington and Harborview Medical Centers, ranging in age from 0 to 91 years.
Samples positive by FilmArray for C. difficile only were not included in the study due to the
Immediately prior to the study period, conventional stool culture was replaced as an orderable
test by the FilmArray panel. Clinicians were informed of the change in testing methodology by
Specimens were submitted in Cary-Blair transport medium or as fresh stool transferred into
11pm-7am were tested the following morning and results released as soon as available. For study
purposes, cultures continued to be performed in parallel. Stool was plated onto agar media
agars. As Aeromonas spp. are not detected by the FilmArray panel, Aeromonas isolated in
recovery of Vibrio spp. was added from Jun-Sep. Selenite broth enrichment for 24h prior to
plating onto Salmonella-Shigella Selective agar was performed at the University of Washington
but not Harborview Medical Center. Campylobacter Selective agar was incubated under
microaerophilic conditions at 42C for 3d, whereas other plates were incubated at 37C in
ambient air for 2d. Inoculation into Gram-negative broth (Hardy Diagnostics) for 16-24h
enrichment was conducted prior to performing the Immunocard STAT! EHEC Shiga toxin
immunoassay (Meridian Biosciences, Inc.). Additional conventional tests included ova and
ProSpecT stool antigen testing (Remel Inc), and a laboratory-developed viral gastroenteritis
multiplex PCR panel. Clinicians were not prevented from ordering these tests when FilmArray
was ordered. Results were reported in the laboratory information system with the exception of
Record numbers were obtained from the laboratory information system (LIS) for patients testing
positive by culture from Jan-Sept 2016 or by any method from Jan-Sept 2017 for chart review.
although their test results were included in the analysis of clinical sensitivity and time-to-
diagnosis.
Electronic chart review was performed by 4 doctoral-level clinical microbiologists and overseen
by the corresponding author, who is a physician and ID specialist. Ten charts were reviewed by
all 4 reviewers for initial training and standardization, with charts subsequently reviewed by
duration of symptoms, mucus, nature of stool, elevated WBC) and antimicrobial treatment. Time
of sample collection, arrival in the laboratory, and result reporting were obtained from the LIS.
Antibiotics were estimated to be prescribed at 5pm on the day on which they were ordered.
Empirical antimicrobial therapy was defined as therapy initiated prior to the release of results.
Targeted therapy was defined on the basis of documentation that the primary clinician received a
result and then prescribed an agent with predicted activity against the microbe detected.
Statistical Analysis
Clinical sensitivity was defined as the ability to detect a pathogen when the pathogen is present
conventional and molecular assays. To compare the clinical variables of distinct patient
populations, t-tests, Mann-Whitney tests, or Fisher's exact tests were performed, as appropriate.
Linear regression was performed to compare trends in targeted versus empirical initiation of
antimicrobial therapy. A p-value <0.05 was considered significant. Adjustments for multiple
Ethics Statement
Regulatory approval was provided by the University of Washington’s Institutional Review Board
(IRB #52540).
RESULTS
A total of 1,887 patient specimens were tested in parallel by FilmArray and conventional stool
culture between Jan 1 and Sept 30, 2017 (Figure 1, Supplemental Table 1). FilmArray
detected one or more pathogen in 669 (35.3%) specimens, compared to 113 (6.0%) detected by
culture. For conventionally cultured bacterial pathogens, 155 (8.2%) were positive by
detected by FilmArray in the absence of culture positivity were Campylobacter spp. (n=68, 18
additional). FilmArray cannot distinguish Shigella and EIEC, and EIEC is not cultivable by
standard clinical microbiology culture techniques. The most common FilmArray targets not
represented 5.5% of the total tested population with a positivity rate (33.7%) not significantly
different from the overall population and comparable pathogen-specific detection rates aside
from a higher (p=0.0001) rate of rotavirus detection (n=6, 5.31% of total tested). Comparison of
culture results from 2016 and 2017 indicated similar detection rates (Supplemental Table 2).
Fourteen specimens negative by FilmArray had positive cultures. Twelve of these were
organisms not on the FilmArray panel (8 Aeromonas spp., 3 Campylobacter hyointestinalis and
1 Helicobacter pullorum). Salmonella enterica (non-Typhi) and Campylobacter jejuni were each
recovered from a single culture when the FilmArray was negative. The Salmonella isolate was a
single colony, indicating a low organism burden. The Campylobacter isolate was part of a mixed
infection in which Giardia and Norovirus were detected by FilmArray, and 1+ Campylobacter
grew in culture. FilmArray reportedly fails to detect Campylobacter jejuni ssp. doylei [9] and
Clinicians’ simultaneous ordering of FilmArray and tests such as O&P examination, modified
acid-fast smear, Giardia antigen testing, and a laboratory-developed viral multiplex PCR panel
enabled a limited comparison (Figure 2). FilmArray led to increased detection of Entamoeba
histolytica and Giardia lamblia (n=23, 1.4% of specimens tested) when compared to O&P
examination of the same specimen (n=6, 0.3%). FilmArray also detected viral or parasitic
pathogens in 137 cases in which additional diagnostic tests were not ordered.
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targets were detected in 184 stool specimens (27.5% of all positive specimens, 9.8% overall).
culture. The remaining 115 coinfections included FilmArray targets unrecoverable by culture,
FilmArray testing in Jan-Sept 2017 had a median turnaround time (collection to first report) of
18h, which was significantly (p<0.0001) shorter than the 47h median turnaround time for culture
(Supplemental Table 3). The estimated median time from collection to antibiotic initiation was
26h in 2017 compared to 72h in 2016 (p < 0.0001). In 2017, 64 of 272 (23.5%) antimicrobial
prescriptions were initiated empirically at the time of encounter. This proportion is lower
(p=0.0148) than the 20 of 50 (40.0%) cases of empirical therapy in 2016 (Figure 3). The use of
FilmArray resulted in a significant (r2 = 0.65, p = 0.009 by linear regression) trend toward
targeted rather than empirical therapy over the course of the study period (Figure 4).
FilmArray identified 21 STEC infections, with 4 identified as E. coli O157:H7. Stool culture
turnaround-time for all FilmArray results was 18h, making the assay significantly faster than
stool culture and immunoassay for reporting positive (60.0h, p = 0.0006) and negative (75.0h,
p<0.0001) results. Nine of 21 patients with STEC-positive results were empirically prescribed
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Clinical features of 2017 patients detected by FilmArray or culture are presented in Table 2.
of symptoms at the time of presentation than those with concordant results (FilmArray-
FilmArray (Table 3). Patients with conventionally cultured pathogens presented more
frequently with chills and received antibiotics at a higher rate. The aggregate population of
patients infected with conventional pathogens Campylobacter, Salmonella and/or Shigella was
compared to those infected with the diarrheagenic E. coli species EPEC, EAEC and ETEC that
were not recoverable by culture (Supplemental Table 4). Patients with Campylobacter,
Salmonella and/or Shigella were more likely to report chills, have measurable fever and receive
antibiotic therapy. Patients with diarrheagenic E. coli infections reported a longer duration of
The clinical features of pediatric patients (ages 0-17y) were not significantly different from those
of adults (Supplemental Table 6). Patients with mixed infections had a higher rate of
international travel within 30d than those testing positive for a single pathogen (Supplemental
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of patients infected with Campylobacter spp., Salmonella spp. or Shigella/EIEC with concordant
or discordant results (Supplemental Table 8). For Campylobacter spp., concordant cases
followed general trends observed for the entire concordant population, with a slight non-
significant trend toward greater symptom severity. Shigella patients with concordant results were
more likely to be male and had a shorter duration of symptoms at presentation. No significant
DISCUSSION
Multiplex syndromic panels are more sensitive than conventional methods, although questions
remain regarding clinical utility and cost-effectiveness [7, 28-31]. To address these concerns, we
specimens by the BioFire FilmArray GI Panel and conventional diagnostics. Consistent with
previous reports [8, 9, 35-37], FilmArray demonstrated greater clinical sensitivity than stool
culture (Figure 1, Supplemental Table 1), identifying over three times as many pathogens as
conventional assays, including 41% more among targets common to both methods (Figure 2).
The majority of FilmArray targets not identifiable by conventional culture were diarrheagenic
E. coli (STEC, EPEC, EAEC and ETEC), long recognized as important causes of acute
FilmArray provided more rapid turnaround time compared to alternative conventional methods
(Table 1 and Supplemental Table 3). Patients with an infectious cause of acute gastroenteritis
detected by FilmArray were more likely (p=0.0148) to receive targeted rather than empirical
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turnaround time of FilmArray encouraged more targeted antimicrobial therapy. This effect on
prescribing decisions became more pronounced over the course of the study (Figure 4), further
suggesting that clinicians adjusted their practice as they became accustomed to the availability of
contrasts with earlier studies in which multiplex syndromic panels only impacted clinical
practice in the context of a coordinated stewardship effort [32, 33]. Reduced time-to-treatment
and an impact on antibiotic prescribing were also specifically observed in STEC infections.
Negative results allowed initiation of antimicrobial therapy without concern for the induction of
hemolytic-uremic syndrome [21, 22]. Positive STEC results led to the discontinuation of
antimicrobials in 8 of 9 cases when therapy had been initiated empirically, with a median time-
Patients infected with conventionally cultured pathogens identified by both FilmArray and stool
culture (concordant) tended to have greater symptom severity than those positive for those same
organisms by FilmArray only (discordant), although these trends were not significant with the
exception of a longer duration of symptoms among discordant patients (Table 2). These
observations are consistent with the higher organism burden required for culture positivity and
the relationship between organism burden and disease severity. However, neither antimicrobial
prescription rates nor duration of therapy differed significantly between these groups, suggesting
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discordant) (Table 3). More than 60% of these patients received antimicrobial therapy when
diagnosed with bacterial and/or parasite pathogens, suggesting that these diagnoses were viewed
by clinicians as clinically relevant. A specific subset comparison was performed between those
diarrheagenic E. coli species (EPEC, EAEC and/or ETEC) (Supplemental Table 4). The results
indicate that conventionally cultured pathogens may be more highly associated with certain signs
of inflammation, but the diarrheagenic E. coli pathogens should not be neglected due to their
potential to cause protracted illness. Together, these comparisons show that the additional cases
identified by FilmArray are clinically comparable to those identified by stool culture. Along
with the potential for rapid testing to encourage targeted rather than empirical therapy (Figure
4), these observations argue against the selective reporting of FilmArray results, which could
lead to both the overtreatment of patients lacking identifiable pathogens and the undertreatment
For Campylobacter spp., concordant patients were slightly but not significantly more
symptomatic than discordant patients (Supplemental Table 8). Concordant Shigella cases also
exhibited a non-significant trend toward increased severity, more recent symptom onset and an
association with male gender. An ongoing outbreak of Shigella infections among MSM in
several metropolitan areas including Seattle underscores the utility of highly sensitive molecular
assays for case detection and outbreak investigation [24]. For Salmonella infections, concordant
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coinfections has been noted previously [35], but there is uncertainty regarding the clinical
interpretation and relevance of these cases. Detection of multiple potential pathogens may
influence case management [39] and is not unusual in returning travelers who may have been
exposed to contaminated food or water [40]. Patients with coinfections were generally younger
and evenly gender-distributed, and more likely to have recent international travel (Supplemental
Table 7). We also observed mixed infection scenarios among MSM patients with Shigella. In
contrast to earlier studies in children [41], we did not observe greater severity of illness in
patients with coinfections. The detection of mixed bacterial and/or parasitic infections generally
A unique strength of the present study is the prospective parallel testing of a large patient cohort
their clinical characteristics. Limitations of the study include the insufficient size of certain
retrospective review of medical records is subject to confounding factors and biases. The study
was limited to two hospitals within a single healthcare system, although the academic medical
center, the county hospital and the 17 community clinics they support collectively represent a
broad and representative metropolitan demographic that includes both healthy immunocompetent
individuals and patients with various forms of immunocompromise and chronic illness.
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gastrointestinal panel markedly improves the sensitivity of laboratory diagnosis in patients with
acute diarrhea and allows clinicians to make more timely and targeted therapeutic decisions. The
additional cases detected by FilmArray are comparable in clinical presentation and acuity to
those diagnosed by conventional culture, indicating that the syndromic panel identifies clinically
diagnostics [1, 3], syndromic testing represents a significant advance in the laboratory diagnosis
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Acknowledgments. The authors thank Tom Smith, Sarah Jensen and Brett Norquist for their
Financial support. Test kits and instruments were provided by BioFire Diagnostics, a
bioMérieux Company.
Conflicts of Interest: Dr. Fang reports grants, personal fees and non-financial support from
BioFire, during the conduct of the study; grants, personal fees and non-financial support from
Cepheid, grants and non-financial support from ELITech, non-financial support from Luminex,
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Figure 4. Increase in targeted rather than empirical therapy over time after FilmArray
implementation. Results displayed indicate the total number (n) of cases where antimicrobials
were prescribed based upon test results (targeted) versus prescribed prior to having test results
(empirical), measured on a monthly basis following implementation of the FilmArray.
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on Clinical Decisions
Note. Categorical values analyzed for statistical significance by Chi squared test. Comparison of
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by FilmArray
Concordant Discordant
p
Results Results
Patients, n 98 68
Age, years
Mean (range) 40.3 (1-91) 39.6 (1-82) n.s.
Median (range) 34.0 (1-91) 36.0 (1-82) n.s.
Percent Female 35.60% 53.60% n.s.
Ordering location, n (%)
Outpatient 80 (79) 55 (80%) n.s.
ED 17 (17) 9 (13%)
Inpatient 4 (4) 5 (7%)
Mean # of symptoms per patient (range) 3.8 (0-8) 3.4 (0-8) n.s.
Patients with Headache, n (%) 9 (9) 5 (7) n.s.
Patients with Abdominal pain, n (%) 73 (75) 49 (72) n.s.
Patients with Tenesmus, n (%) 2 (2) 1 (2) n.s.
Patients with Nausea, n (%) 42 (43) 30 (44) n.s.
Patients with Vomiting, n (%) 19 (19) 14 (21) n.s.
Patients with Diarrhea, n (%) 96 (98) 62 (91) n.s.
Patients with Watery Diarrhea, n (%) 53 (54) 36 (53) n.s.
Patients with Blood in Stool, n (%) 22 (22) 8 (12) n.s.
Patients with Chills, n (%) 28 (29) 14 (21) n.s.
Patients with Fatigue, n (%) 27 (28) 13 (19) n.s.
Patients with Fever, n (%) 17/97 (18) 10/65 (15) n.s.
Patients with Leukocytosis, n (%) 20/48 (42) 5/30 (17) n.s.
Patients with Fecal Leukocytes, n (%) 5/12 (42) 1/9 (11) n.s.
Median duration of symptoms at presentation, days (range) 7 (1-90) 8.5 (1-240) <0.0001
Patients with international travel history, n (%) 33 (34) 31 (46) n.s.
Patients with bacteria/parasite receiving antibiotic, n (%) 79 (81) 47 (68) n.s.
Patients receiving empirical antibiotic therapy, n (%) 27 (34) 10 (21) n.s.
Median duration of antibiotics, days (range) 4.5 (1-10) 5 (1-28) n.s.
Patients hospitalized, n (%) 12 (12) 8 (12) n.s.
Cases with apparent resolution of symptoms, n (%) 88 (90) 62 (91) n.s.
Note. Categorical values analyzed for statistical significance by Chi squared test. Comparison of
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Conventionally FilmArray™
Cultured Exclusive p
Pathogens Pathogens
Patients, n 166 305
Age (years)
mean 40.0 (1-91) 40.7 (0-87) n.s.
median 36.0 (1-91) 39.5 (0-87) n.s.
Percent female 41.8% 44.6% n.s.
Ordering location, n (%)
Outpatient 135 (82) 263 (83) n.s.
ED 26 (16) 37 (12)
Inpatient 9 (2) 16 (5)
Mean number of symptoms per patient (range) 3.6 (0-8) 3.2 (0-8) n.s.
Patients with Headache, n (%) 14 (8) 16 (5) n.s.
Patients with Abdominal pain, n (%) 122 (73) 208 (68) n.s.
Patients with Tenesmus, n (%) 3 (2) 7 (2) n.s.
Patients with Nausea, n (%) 72 (43) 117 (38) n.s.
Patients with Vomiting, n (%) 33 (20) 63 (21) n.s.
Patients with Diarrhea, n (%) 158 (95) 282 (93) n.s.
Patients with Watery Diarrhea, n (%) 89 (54) 144 (47) n.s.
Patients with Blood in Stool, n (%) 30 (18) 35 (12) n.s.
Patients with Chills, n (%) 42 (25) 35 (12) 0.0001
Patients with Fatigue, n (%) 40 (24) 62 (20) n.s.
Patients with Fever, n (%) 27/162 (17) 25/292 (9) n.s.
Patients with Leukocytosis, n (%) 25/78 (32) 27/144 (19) n.s.
Patients with Fecal Leukocytes, n (%) 6/21 (29) 11/30 (37) n.s.
Median duration of symptoms at presentation, days (range) 7 (1-240) 7 (1-365) n.s.
Patients with international travel history, n (%) 64 (39) 119 (39) n.s.
Patients with bacteria/parasite receiving antibiotic, n (%) 126/166 (76) 145/240 (60) 0.0011
Patients receiving empirical antibiotic therapy, n (%) 37 (22) 38 (19) n.s.
Median duration of antibiotics, days (range) 5 (1-28) 5 (1-28) n.s.
Patients hospitalized, n (%) 20 (12) 47 (15) n.s.
Cases with apparent resolution of symptoms, n (%) 150 (90) 253 (83) n.s.
Note. Categorical values analyzed for statistical significance by Chi squared test. Comparison of
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