LCD L39226: Multiplex Gastrointestinal Pathogen Panel (GPP) Tests for Acute Gastroenteritis (AGE)

Indications and Limitations of Coverage*

One † multiplex GPP^ is covered when at least ONE of the following applies:

• Community-acquired acute diarrhea (≥3 loose or watery stools/day for ≤14 days) with at least ONE of the following (1-3):

• >1 week duration

• Severe illness (e.g., profuse watery diarrhea, signs of hypovolemia, passage of ≥6 unformed stools per 24 hours, severe abdominal pain, need for hospitalization)

• Inflammatory diarrhea (bloody diarrhea, small volume mucous stools, fever)

• High-risk host (e.g., age ≥70 years, cardiac disease, immunocompromising condition, inflammatory bowel disease, pregnancy)

• Public health concerns (e.g., food handler, health care or day care worker)

• Pre-transplant evaluation (4)

Contraindications to Coverage (ANY)

• As a test of cure (3,5)

• More than 72 hr. after hospitalization while still an inpatient (1,6-8)

• Laxatives in the prior 48 hours (7, 32), excluding those with signs of severe disease

*See associated Billing & Coding article for specific diagnosis codes, POS, and credentialing requirements.

† A second panel test for the same clinical indication is covered if the first panel yielded a negative result AND there is a high index of suspicion for a pathogen as the cause of symptoms, AND the patient’s clinical condition is not improving or is deteriorating, AND as long as the test fulfills the criteria for coverage set forth in the LCD.

^Tests must be FDA approved/cleared, or if a laboratory developed test (LDT), have a published, peer-reviewed study supporting analytic validity, or certification by a third-party consistent with the New York State Department of Health’s Clinical Laboratory Evaluation Program (CLEP) review standards.

The CDC estimates nearly 48 million AGE US cases annually, costing approximately $150M (3). A wide spectrum of responsible enteric pathogens include bacteria (e.g., campylobacter, clostridium difficile, salmonella, shigella, vibrio, yersinia); viruses (e.g., norovirus, rotavirus, astrovirus, adenovirus); and parasites (e.g., giardia, entamoeba histolytica and cryptosporidium) (3,9). AGE cases are usually self-limited with no laboratory testing recommended (10) except for certain populations such as immunocompromised hosts, the critically ill, and those with prolonged disease refractory to treatment. Sequelae can include Guillain-Barré syndrome, reactive arthritis, irritable bowel syndrome, malabsorption syndrome, or hemolytic uremic syndrome (11). Therefore, in select cases, expeditious pathogen identification is important to facilitate appropriate therapy, local infection control, and epidemiologic measures.

Traditionally, diarrheal pathogens have been identified using cultures for bacteria, monoplex (one-target) polymerase chain reaction (PCR) assays for viruses, and microscopy or enzyme immunoassays (EIA) for parasites. However, such methods are time-consuming, labor-intensive, operator-dependent, and often involve test selection based on clinically indistinguishable illness (12). Turn-around times of several days is typical, during which a patient is isolated with empiric or no therapy (13). Recently, multiplex GPPs, which exploit multiplex nucleic acid amplification methodology, have gained traction due to reduced sample volume requirements, broad coverage without the need to select specific tests, enhanced ability to detect coinfections, increased sensitivity, higher throughput, and faster turnaround time to ≤ 1 day (9,12).

Three longstanding FDA-approved/cleared multiplex GPP assays that detect >5 stool pathogens are the Luminex xTAG gastrointestinal pathogen panel (Luminex GPP; Luminex Corporation, FDA approval/clearance 2013, 14 targets), the BioFire FilmArray gastrointestinal panel (BioFire GIP; BioFire Diagnostics, FDA approval/clearance 2014, 22 targets), and the Verigene Enteric Pathogens panel (Verigene EP, Luminex Corporation, FDA approval/clearance 2014, 9 targets) (14). A substantial body of research evaluating the BioFire GIP and Luminex GPP is available and demonstrates that both assays yield more positive results (22-74%) than conventional testing (8-18%) methods (15-17), likely due to a combination of greater sensitivity and target number. The most commonly detected organisms are C. difficile, enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), salmonella, norovirus, rotavirus, sapovirus, and cryptosporidium (15-19). One study comparing GPPs to conventional testing in 152 stool from patients with ACE found the range of sensitivity/specificity to different pathogens common to each was BioFire (94.7-100%/98.6-100%), Luminex (79.2-100%/100%), Verigene (71.4-95.4%/99.1-100%) (20). All three GPPs detected the majority of gastrointestinal pathogens when compared to conventional methods.

Multiplex GPPs consistently detect multiple targets more frequently than conventional testing. One study of 709 samples found multiple pathogens in 16.4% of samples using the BioFire GIP versus 1% after conventional testing (17). Among samples with multiple pathogens, 84% were positive for EAEC or EPEC. Impact studies have found that GPP testing is associated with a significant decrease in endoscopic procedures, abdominal imaging, antibiotic use, and reduced hospital length of stay (7,11,21). A prospective multi-center study evaluating 1887 fecal specimens from patients with AGE found that use of a GI panel enhanced organism detection and improved clinical sensitivity, and enabled clinicians to provide more timely and targeted antimicrobial therapy (22). Positive Shiga-like toxin producing E. coli (STEC) results led to appropriate discontinuation of empiric antibiotics sooner. A study in patients with inflammatory bowel disease (IBD) found that GPP testing led to lower rate of IBD treatment modification (23). In outpatients with IBD relapse, testing was associated with significantly lower rates of IBD therapy escalation and endoscopy compared to patients who underwent conventional testing (24). A study evaluating GI infections prior to hematopoietic cell transplantation (HCT) in 112 asymptomatic patients found more than one-third were colonized with a wide range of GI pathogens, with colonization predicting the infectious etiology of post-transplantation diarrhea in nearly 75% of cases (4). The authors suggest that pre-transplant GPP testing may be warranted in asymptomatic patients.