LCD L38227: Gastrointestinal Pathogen (GIP) Panels Utilizing Multiplex Nucleic Acid Amplification Techniques (NAATs)

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

For many gastrointestinal infections, particularly noninflammatory diarrhea and acute gastroenteritis of short duration, no laboratory testing is recommended. 1 In the past, diagnostic testing for these pathogens was accomplished by techniques such as stool culture or examination for ova and parasites. Multiplex nucleic acid-based assays are now available to detect a number of these pathogens in a single stool sample, with results available in a much shorter timeframe. Diagnostic tests may be medically reasonable and necessary according to Medicare when they affect patient management to improve health outcomes.

This LCD provides limited coverage for outpatient testing of GIP panels utilizing multiplex nucleic acid amplification techniques (NAATs) for specific conditions. This LCD does not address coverage in the inpatient setting.

History/Background and/or General Information

The Centers for Disease Control estimates that illness potentially transmitted through food causes roughly one in six Americans (or 48 million people) to become sick, 128,000 people to be hospitalized, and 3,000 deaths each year. 2 Infectious diarrhea may be due to a variety of pathogens including bacteria, parasites, and viruses. 2-5 Conventional diagnostic testing for these pathogens includes techniques such as stool culture or examination for ova and parasites. Historically, treatment decisions were based on symptoms or conventional diagnostic test results. More recently, multiplex nucleic acid-based assays have been introduced to detect a number of pathogens in a single sample, and most require less time than conventional testing methods. 1,6-8

Recent development of commercial, panel-based, molecular diagnostics for the rapid detection of certain pathogens has resulted in a shift in clinical microbiology and clinical practice. 6 These panel-based assays offer less time for sample preparation, rapid turnaround time, and detection of a large number of microorganisms. The tests present challenges including definition of ideal test utilization strategies (e.g., optimal ordering) and test interpretation. Clinicians may not be familiar with all organisms and/or resistant genes that are detected, which may lead to inappropriate treatment and unnecessary subsequent laboratory testing. The design of the multiplex platforms, including those marketed as closed systems, carries a risk of contamination which may be difficult to recognize. 6 Studies demonstrate that, compared to conventional methods, the use of multiplex panels increase the positivity rates of GI pathogens by two to four fold. 9 Thus, another challenge is with the broad use of multiplex GIP panels, how will healthcare providers use and interpret the large amount of data made available. 9

The literature supports that the use of GIP panels for the detection of specific pathogens associated with gastrointestinal disease may be important in certain patient populations, such as immunocompromised hosts, the critically ill, or individuals with prolonged disease that is refractory to treatment. 1,8,10

Diarrhea:

One of the most commonly reported illnesses in the United States is acute diarrhea. For the purposes of this LCD, acute diarrhea is defined as lasting less than 14 days, persistent diarrhea is defined as lasting between 14 and 30 days, and chronic diarrhea is defined as lasting longer than 30 days. 5 Severe illness is defined as total disability due to diarrhea, moderate illness is defined as the ability to function but with forced change in activities, and mild illness is defined as no change in activities. The best specimen is a diarrheal stool sample which is characterized as a sample that will take the shape of the container. 1,10

Clostridium difficile (C. difficile):

The diagnosis of C. difficile infection is based on a combination of laboratory and clinical findings including: (a) the presence of diarrhea or evidence of megacolon or severe ileus, and (b) either a positive laboratory test result or evidence of pseudomembranes on endoscopy or histopathology. C. difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings. Advanced age and duration of hospitalization are two of the most important risk factors for C. difficile infections. The most important modifiable risk factor is exposure to antibiotics. 11

C. difficile is a spore-forming, anaerobic, gram-positive bacillus that is picked up from the environment or via the fecal-oral route. The presence of C. difficile Toxins A and B are responsible for gastrointestinal disease. 12 Toxin or nucleic acid amplification testing for C. difficile should only be done on diarrheal stool, not formed stools, unless the physician notes that the patient has an ileus. 1

Travelers’ diarrhea (TD):

Gastrointestinal problems remain the first complaint among travelers with health problems. 13 TD is defined as a gastrointestinal infection resulting in loose, watery stools that occur during travel or within ten days of returning from travel to resource-limited countries or regions. TD can be classified as functional impact: mild, moderate or severe based on the number of loose stools that are passed in 24 hours. The overall impact of TD is substantial although declining due to awareness and improvements of global health, sanitation and hygiene. 14

Unless treatment is indicated, diagnostic testing is not recommended in most cases of uncomplicated TD. 10 Travelers with diarrhea lasting 14 days or longer should be evaluated for intestinal parasitic infections (strength of recommendation: strong, quality of evidence: moderate). 10 In addition, the guidelines from the Infectious Disease Society of America recommend that gastrointestinal tract disease including inflammatory bowel disease and postinfectious irritable bowel syndrome (IBS) should be considered during evaluation. 10 Testing for C. difficile should be performed in travelers treated with antimicrobial agent(s) within the preceding eight to 12 weeks. 10

The Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report, 14 also support microbiologic testing in returning travelers with severe or persistent symptoms (diarrhea lasting two weeks or longer) or in those who fail empiric therapy. The authors also state that molecular testing, aimed at a broad range of clinically relevant pathogens, is preferred when rapid results are necessary for a direct medical treatment decision, or when non-molecular tests available have failed to establish a diagnosis (ungraded). 14 The authors noted no studies have been published which show that using molecular testing improves patient outcomes. 14

Covered Indications

• GIP panels utilizing NAATs, 11 or fewer targets, are medically reasonable and necessary for the evaluation of Medicare beneficiaries with the following:

• Acute diarrhea present for at least seven days duration 1, 5, 10 ; or

• Persistent diarrhea of 14-30 days 1, 5, 10 ; or

• Acute diarrhea with signs or risk factors for severe disease to include any of the following:

• fever,

• bloody diarrhea,

• dysentery,

• dehydration,

• severe abdominal pain,

• hospitalization, or

• an immunocompromised state 1, 5, 10

• GIP panels utilizing NAATs, 12 or more targets, are medically reasonable and necessary for the evaluation of Medicare beneficiaries with the following:

• An immunocompromising medical condition with acute or persistent diarrhea. 1,9,10

Limitations

GIP panels utilizing multiplex NAATs are considered not medically reasonable and necessary for any of the following:

• Using a single NAAT or multiplex NAAT to test for clearance of the pathogen (i.e., “test of cure”). 1, 11

• Testing of asymptomatic patients. 1,6,10,11,15

• Repeat testing utilizing the same or a different GIP panel within seven days during the same episode of diarrhea by the same or different provider. 1,11

• Performance of more than one GIP panel on the same date of service by the same or different provider.

It is expected that GIP panels utilizing multiplex NAATs for the evaluation of chronic diarrhea (e.g., infectious) would be rare, 5, 10 and may be considered for coverage on redetermination.

Provider Qualifications

Laboratory services must meet all applicable requirements of the Clinical Laboratory Improvement Amendments of 1988 (CLIA), as set forth at 42 CFR part 493. Please see CMS IOM, Publication 100-02, Medicare Benefit Policy Manual , Chapter 15, Section 80.1 – Laboratory services, for provider applicable requirements.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Disease Society of America and the American Society of Microbiology 1 includes guidance for infections of the gastrointestinal tract. The guide states for many gastrointestinal infections, particularly noninflammatory diarrhea and acute gastroenteritis of short duration, no laboratory testing is recommended. The specimen of choice to diagnose diarrheal illness is diarrheal stool, not a formed stool or a swab, except in pediatrics where a swab is acceptable when feces are noted on the swab. Multiple stool specimens are rarely indicated for the detection of stool pathogens. Toxin or nucleic acid amplification testing for C. difficile should only be performed on diarrheal stool unless the patient has a confirmed diagnosis of ileus. 1

The guide states the appropriate approach to the diagnosis of diarrheal illness is determined by the patient’s age and status, severity of the disease, duration and type of illness, time of year, and geographic location. For severe, bloody, febrile, dysenteric, nosocomial, or persistent diarrhea, fecal testing using culture or culture-independent methods is indicated. To determine what organisms, methods, and screening parameters are included as part of the routine culture or culture-independent method, communication with the laboratory is required. Stool cultures often fail to detect the causative agent; therefore when necessary, culture-independent methods are recommended as adjunct methods. 1

Culture-independent methods can detect pathogens in one to five hours compared to 24 to 96 hours required for cultures. The assays are reported to be more sensitive than culture and have much higher detection rates. Highly multiplexed assays allow for the detection of mixed infections. The importance of detection of each pathogen is unclear. The clinical significance of a greater number of pathogens detected by the more sensitive assay is uncertain, and could confound treatment. Culture-independent methods should not be used as a test of cure, because they will detect both viable and nonviable organisms. 1,11

C. difficile toxin detection by either enzyme immunoassay (EIA) or immunochromatographic methods are widely used in clinical practice. These tests have a reported sensitivity of 70%-85% with faster result time than the toxigenic culture and the cytotoxin assay. Glutamine dehydrogenase antigen assays are sensitive but not specific. NAATs for the detection of C. difficile have a reported sensitivity of 93%-100%. 1 NAATs detect viable and nonviable organisms; therefore, to reduce the identification of colonized patients, some laboratories are performing both NAATs and toxin production tests. When testing is limited to patients with unexplained and new-onset diarrhea who are not receiving laxatives, NAAT alone or toxin EIA as part of a multistep algorithm are recommended.