Medical Policies - Medicine
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The use of gastrointestinal panels to detect and identify bacterial, viral and parasitic nucleic acid in stool samples from individuals with signs and symptoms of gastroenteritis or infectious colitis is considered experimental, investigational and/or unproven, including but not limited to xTAG® Gastrointestinal Pathogen Panel (GPP), ProGastro SSCS assay and FilmArray® Gastrointestinal (GI) Panels.
Gastroenteritis is an inflammation of the stomach and the intestines. Symptoms may cause nausea, vomiting and diarrhea. Numerous causes can be attributed to gastroenteritis including infectious organisms (e.g., viruses and bacteria).
According to a 2012 study by the Centers for Disease Control and Prevention (CDC) the number of people who died from gastroenteritis more than doubled from 1999 to 2007. The CDC used information from the National Center for Health Statistics to discover gastroenteritis-associated deaths from among all age groups in the United States. The study noted gastroenteritis associated deaths increased from nearly 7,000 to more than 17,000 per year. Eighty-three percent of deaths were noted in adults over 65 years of age. The most common infectious causes of gastroenteritis-associated deaths were clostridium difficile (C. difficile) and norovirus.
A detailed history of the patient’s illness along with diagnostic studies can help guide treatment decisions and determine if medication such as antibiotics may be necessary to deal with symptoms.
Several commercial gastrointestinal microorganism multiplex nucleic acid-based panels have become available and report decrease turnaround times in identification of pathogens that may be responsible for gastroenteritis.
Through the FDA (US Food and Drug Administration) 510(k) process xTAG® GPP (Luminex Molecular Diagnostics, Inc.) received clearance in March 2013. The following pathogen types, subtypes and toxin genes are identified using the xTAG GPP as listed on the indications for use:
• Campylobacter (C jejuni, C coli and C. lari only);
• Clostridium difficile (C. difficile) toxin A/B;
• Cryptosporidium (C. parvum and C. hominis only);
• Escherichia coli (E. coli) O157;
• Enterotoxigenic Escherichia coli (ETEC) LT/ST;
• Giardia (G. lamblia only also known as G. intestinalis and G. duodenalis);
• Norovirus GI/GII;
• Rotavirus A;
• Shiga-like Toxin producing E. coli (STEC) stxl/stx2;
• Shigella (S. boydii, S. sonnei, S. flexneri and S. dysenteriae).
Through the FDA 510(k) process ProGastro SSCS Assay (Gen-Probe Prodesse®, Inc.) received clearance in January 2013. ProGastro SSCS Assay indications for use include diagnostic test for qualitative detection and differentiation of the following:
• Campylobacter (C. Jejuni and Campylobacter coli only, undifferentiated) nucleic acids;
• Shiga Toxin 1 (stx1) and Shiga Toxin 2 (stx2) genes;
• Shiga toxin producing E coli (STEC) typically harbor one or both genes that encode for Shiga Toxins 1 and 2.
Through the FDA (US Food and Drug Administration) 510(k) process FilmArray® Gastrointestinal (GI) Panel for use with FilmArray Torch (Biofire Diagnostics) received clearance in April 2016. FilmArray Gastrointestinal (GI) Panel indications for use include simultaneous detection and identification of nucleic acids from multiple bacteria, parasites and viruses pathogen types to include the following:
• Campylobacter (C Jejuni/C. coli/C upsaliensis);
• Clostridium difficile (C. difficile) toxin A/B;
• Plesiomonas shigelloides;
• Vibrio (V parahaemolyticus/V. vulnificus/V. cholerae) including specific identification of Vibrio cholera;
• Yersinia enterocolitica;
• Enteroaggregative Escherichia coli (EAEC);
• Enteropathogenic Escherichia coli (EPEC);
• Enterotoxigenic Escherichia coli (ETEC) lt/st;
• Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2 (including specific identification of the E. coli O157 serogroup within STEC);
• Shigella/Enteroinvasive Escherichia coli (EIEC);
• Cyclospora cayetanensis;
• Entamoeba histolytica;
• Giardia lamblia (also known as G. intestinalis and G. duodenalis);
• Adenovirus F 40/41;
• Norovirus G1/Gil;
• Rotavirus A;
• Sapovirus (Genogroups 1, 11, IV, and V).
A search of peer reviewed literature through June 2017 was performed. The following is a summary of the key literature to date.
In a diagnostic study, Pankhurst et al. conducted a retrospective study of fixed numbers of samples positive for C. difficile, Campylobacter spp., Salmonella spp., norovirus and samples negative for all those pathogens. (3) MassCode assays were performed at Oxford University Hospitals NHS Trust. Additional, multiplex assays were performed using Luminex, were performed on the same set of samples at Leeds Teaching hospitals NHS Trust. Some of the authors results included: Using the MassCode assay, sensitivities for each organism compared with standard microbiological testing ranged from 43% to 94% and specificities from 95% to 98%, with particularly poor performance for S. enterica. Relatively large numbers of unexpected positives not confirmed with quantitative PCR were also observed, particularly for S. enterica, Giardia lamblia and Cryptosporidium spp. As the results indicated that S. enterica detection might provide generic challenges to other multiplex assays for gastrointestinal pathogens, the Luminex xTAG(®) gastrointestinal assay was also run blinded on the same extracts (937/948 remaining) and on re-extracted samples (839/948 with sufficient material). For Campylobacter spp., C. difficile and norovirus, high sensitivities (> 92%) and specificities (> 96%) were observed. For S. enterica, on the original MassCode/Oxford extracts, Luminex sensitivity compared with standard microbiological testing was 84% [95% confidence interval (CI) 73% to 93%], but this dropped to 46% on a fresh extract, very similar to MassCode, with a corresponding increase in specificity from 92% to 99%. The authors concluded the following: Overall, the Luminex xTag gastrointestinal panel showed similar or superior sensitivity and specificity to the MassCode assay. However, on fresh extracts, this test had low sensitivity to detect a key enteric pathogen, S. enterica; making it an unrealistic option for most microbiology laboratories. Extraction efficiency appears to be a major obstacle for nucleic acid-based tests for this organism, and possibly the whole Enterobacteriaceae family. To improve workflows in service microbiology laboratories, to reduce workload for infection control practitioners, and to improve outcomes for NHS patients, further research on deoxyribonucleic acid-based multiplex gastrointestinal diagnostics is urgently needed.
Beckmann et al. reported on the analysis of 312 consecutive stool samples from pediatric patients (n=127) with gastroenteritis and adult travelers returning from the tropics with suspected parasite infestation (n=185) using xTAG gastrointestinal pathogen panel, Luminex, a commercial multiplex nucleic acid amplification testing (NAT). (4) Positive samples and a portion of negative samples were compared to standard methods, including, bacterial culture and microscopy, direct antigen detection (DAD) and NAT. The following were the results reported: Of the 185 samples from adult travelers, 21 (11 %) were multiplexNAT-positive, with enterotoxigenic Escherichia coli (4 %) being the predominant pathogen. Microscopic examination revealed Blastocystis hominis in 23 % not covered by the panel. MultiplexNAT scored positive in 66 pediatric samples (52 %), with rotavirus (27 %) being the most prevalent. All adenovirus-, rotavirus-, Clostridium difficile- and Cryptosporidium-positive samples were confirmed in external laboratories, but only 40 % of norovirus- and 29 % of Giardia-positive samples. Analysis of frozen specimens by bacterial culture showed the highest discrepancies with the multiplexNAT. Conclusions reached by the authors included: broad detection of relevant gastroenteritis pathogens by multiplexNAT with a short turnaround time was demonstrated. This is important for diagnosis, infection control and empiric management of gastroenteritis patients, but may be selectively complemented by bacterial culture and resistance testing.
Wessels et al. compared the results obtained by testing 393 faecal samples collected during November and December 2011 using the xTAG® Gastrointestinal Pathogen Panel (GPP) assay with the results of the routine diagnostic procedure. (5) The authors reported the procedure included culture for bacteria and real-time PCR for viruses and parasites, but only if the test was requested by the clinician. If the clinician did not request the test for an xTAG(®) GPP-positive target, real-time PCR assays were used to confirm xTAG(®) GPP positivity. Discrepant results were also tested with real-time PCR assays. A total of 83 targets were detected in 76 samples using xTAG(®) GPP. The xTAG(®) GPP assay detected 43 additional positives compared with the routine diagnostic procedure, of which 11 targets could not be confirmed by real-time PCR. The non-confirmed targets were Campylobacter (one sample), Salmonella (four samples), Shigella (one sample) and E. histolytica (five samples). The xTAG(®) GPP was shown to be a convenient and sensitive assay for detection of 15 major gastrointestinal pathogens in a single molecular test, but for detection of E. histolytica and Salmonella, a confirmatory assay is indicate.
In an evaluation of two commercially available multiplex panels, FilmArray gastrointestinal (GI) panel and Luminex xTAG gastrointestinal pathogen panel (GPP) using Cary-Blair stool samples submitted to the laboratory for routine gastrointestinal testing (e.g. antigen testing, culture, microscopy, and individual real-time PCR) Khare et al. noted the following: “Among 230 prospectively collected samples, routine testing was positive for one or more GI pathogens in 19 (8.3%) samples, compared to 76 (33.0%) by the FilmArray and 69 (30.3%) by the Luminex assay. (6) Clostridium difficile (12.6 to 13.9% prevalence) and norovirus genogroup I (GI)/GII (5.7 to 13.9% prevalence) were two of the pathogens most commonly detected by both assays among prospective samples. Sapovirus was also commonly detected (5.7% positive rate) by the FilmArray assay. Among 270 additional previously characterized samples, both multiplex panels demonstrated high sensitivity (>90%) for the majority of targets, with the exception of several pathogens, notably Aeromonas sp. (23.8%) by FilmArray and Yersinia enterocolitica (48.1%) by the Luminex assay. Interestingly, the FilmArray and Luminex panels identified mixed infections in 21.1% and 13.0% of positive prospective samples, respectively, compared to only 8.3% by routine methods.”
Kahlau et al. performed a field test with 347 stool samples from adult hospitalized patients that were tested with the Luminex xTAG GPP assay; of the 157 samples positively tested for at least one pathogen by xTAG GPP, 30 samples were retested with the ProGastro SSCS assay. Comparisons of the assays were made to standard routine diagnostics. (7) The authors noted significantly reduced time to initial identification of a pathogen. Pathogens that were not requested by the physician were identified using the multiplexing tool and thus may be an important tool for avoiding nosocomial outbreaks. Conclusions noted by the author contained the following: “This first frontline approach with these assays approves their utility compared to conventional microbiological methods.” (7)
Although the importance of decreasing the turnaround time to identify a pathogen is acknowledged, some of the articles noted in the rationale, identify the need for confirmatory assay in certain instances or note that bacterial culture and resistance testing would complement the multiplex assays. Further investigation that demonstrates the clinical usefulness over conventional laboratory diagnostic methods is necessary. Therefore, the use of gastrointestinal panels to detect and identify bacterial, viral and parasitic nucleic acid in stool samples from individuals with signs and symptoms of gastroenteritis or infectious colitis is considered experimental, investigational and/or unproven.
Practice Guidelines and Position Statements
In 2016, the American College of Gastroenterology (ACG) provided recommendations in the Clinical Guidelines: Diagnosis, Treatment and Prevention in Acute Diarrheal Infections in Adults. (18) Under the Diagnosis section the following recommendations are made:
• “Stool diagnostic studies may be used if available in cases of dysentery, moderate-to-severe disease, and symptoms lasting >7 days to clarify the etiology of the patient’s illness and enable specific directed therapy. (Strong recommendation, very low level of evidence)”
• “Traditional methods of diagnosis (bacterial culture, microscopy with and without special stains and immunofluorescence, and antigen testing) fail to reveal the etiology of the majority of cases of acute diarrheal infection. If available, the use of FDA-approved culture-independent methods of diagnosis can be recommended at least as an adjunct to traditional methods. (Strong recommendation, low level of evidence)”
The ACG’s Guidelines note the following: “One potential drawback of molecular technologies is the need to predefine the particular microbes being sought. In addition the significance of an identified organism may not be clear as these molecular technologies, which involve nucleic acid amplification, are limited to our existing knowledge of a microbes’ genome and do not discriminate between viable and non-viable organisms. As a result they can detect microbes at nonpathogenic levels. Given the high rates of asymptomatic carriage of enteropathogens, this can be a considerable problem. To confound matters, further multiplex techniques are more commonly associated with increased detection of mixed infections and the relative importance of each pathogen may be unclear.”
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87505, 87506, 87507
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1. FDA –Summary xTAG® Gastrointestinal Pathogen Panel (GPP). Food and Drug Administration. Available at <https://www.accessdata.fda.gov> (accessed 2017 June 16).
2. xTAG® Gastrointestinal Pathogen Panel (xTAG GPP). Available at <https://www. Luminexcorp.com> (accessed 2017 June 16).
3. Pankhurst, L, Macfarlane-Smith, L, et al. Can rapid integrated polymerase chain reaction-based diagnostics for gastrointestinal pathogens improve routine hospital infection control practice? A diagnostic study. Health Technol Assess. 2014 Aug;18(53):1-167. PMID 25146932
4. Beckmann, C, Heininger, U, et al. Gastrointestinal pathogens detected by multiplex nucleic acid amplification testing in stools of pediatric patients and patients returning from the tropics. Infection. 2014 Dec; 42(6):961-70. PMID 25015433
5. Wessels, E, Rusman, Lg, et al. Added value of multiplex Luminex Gastrointestinal Pathogen panel (xTAG® GPP) testing in the diagnosis of infectious gastroenteritis. Clin Microbiol Infect. 2014 Mar; 20(3):0182-7. PMID 24131399
6. Khare R, Espy M, Cebelinski E, et al. Comparative evaluation of two commercial multiplex panels for detection of gastrointestinal pathogens by use of clinical stool specimens. J Clin Microbiol. 2014 Oct; 52(10):3667-73. PMID 25100818
7. Kahlau, P, et al. Utility of two novel multiplexing assays for the detection of gastrointestinal pathogens – a first experience. Springerplus, 2013 Dec; 2(1):106. PMID 23544178
8. FDA –Summary ProGastro SSCS Assay. Food and Drug Administration. Available at: <https://www.accessdata.fda.gov> (accessed 2017 June 16).
9. FDA –Summary FilmArray Gastointestinal (GI) Panel. Food and Drug Administration. Available at <https://www.accessdata.fda.gov> (accessed 2017 June 16).
10. Deaths from gastroenteritis double. Centers for Disease control and Prevention. Available at <https://www.cdc.gov> (accessed 2017 June 16).
11. Qin X, Klein E, Galanakis E, et al. Real-Time PCR Assay for Detection of Shiga Toxin-Producing Escherichia coli from Clinical Samples. J Clin Microbiol. 2015 Jul; 53(7):2148-53. PMID 25926491
12. Buss S, Leber A, Chapin K, et al. Multicenter Evaluation of the BioFire FilmArray Gastrointestinal Panel for Etiologic Diagnosis of Infectious Gastroenteritis. J Clin Microbiol. 2015 Mar; 53(3):915-25. PMID 25588652
13. Stockmann C, Rogatcheva M, Harrel B, et al. How Well Does Physician Selection of Microbiologic Tests Identify Clostridium difficile and other Pathogens in Paediatric Diarrhoea? Insights Using Multiplex PCR-Based Detection. Clin Microbiol infect. 2015 Feb; 21(2):179.e9-15. PMID 25599941
14. Spina A, Kerr K, Cormican M, et al. Spectrum of Enteropathogens detected by the FilmArray GI Panel in a multicenter study of community-acquired gastroenteritis. Clin Microbiol infect. 2015 Aug; 21(8):719-28. PMID 25908431
15. Farfan M, Piemonte P, Labra Y, et al. [Filmarray GI TM panel for detection of enteric pathogens in stool samples: preliminary experience]. Rev Chilena Infectol. 2016 Feb; 33(1):89-91. PMID 26965886
16. Rand K, Tremblay E, Hoidal M, et al. Multiplex gastrointestinal pathogen panels: implications for infection control. Diagn Microbiol Infect Dis. 2015 Jun; 82(2):154-7. PMID 25796558
17. Zhang H, Morrison S, Tang Y. Multiplex polymerase chain reaction tests for detection of pathogens associated with gastroenteritis. Clin Lab Med. 2015 Jun; 35(2):461-86. PMID 26004652
18. Riddle M, DuPont H, Connor B. ACG Clinical Guideline: Diagnosis, Treatment and Prevention of Acute Diarrheal Infections in Adults. Am J Gastroenterol. 2016 May; 111(5):602-22. Available at <http://www.gi.org> (accessed on 2017 June 8).
|10/1/2018||Reviewed. No changes.|
|7/15/2017||Document updated with literature review. Coverage unchanged.|
|10/1/2016||Reviewed. No changes.|
|1/1/2015||New medical document. The use of gastrointestinal panels to detect and identify bacterial, viral and parasitic nucleic acid in stool samples from individuals with signs and symptoms of gastroenteritis or infectious colitis is considered experimental, investigational and/or unproven, including but not limited to xTAG® Gastrointestinal Pathogen Panel (GPP), ProGastro SSCS assay and FilmArray® Gastrointestinal (GI) Panels.|