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**

  1. 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 duration1, 5, 10; **or**
    * Persistent diarrhea of 14-30 days1, 5, 10; **or**
    * Acute diarrhea with signs or risk factors for severe disease to include any of the following: 
      1.         * fever,
        * bloody diarrhea,
        * dysentery,
        * dehydration,
        * severe abdominal pain,
        * hospitalization, or
        * an immunocompromised state 1, 5, 10  

  2. 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:

  1. Using a single NAAT or multiplex NAAT to test for clearance of the pathogen (i.e., "test of cure").1, 11
  2. Testing of asymptomatic patients.1,6,10,11,15
  3. 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
  4. 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 Microbiology1 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.  
  
Historically, it has been recommended that three specimens collected over a
seven-to-ten-day period be submitted for ova and parasite (O&P) examination.
Options today include O&P examination of a second or third specimen if the
previous was negative and the patient remains symptomatic. Targeted use of
immunoassay testing or NAAT for the most common parasites based on geographic
location, patient demographics, and physician request can be used as a screen,
only for negative patients with continued symptoms or for patients with
specific risk factors requiring full O&P examination. Immunoassays for Giardia
are sensitive enough that only one specimen may be needed. No data is
currently available on the number of specimens required to rule out infection
via NAAT. Pathogenic _Entamoeba histolytica_ can only be differentiated from
nonpathogenic _Entamoeba dispar_ using an immunoassay or NAAT.1  
  
Viral gastroenteritis is often of short duration and self-limited, and viral
shedding may persist after resolution of symptoms. Testing via multiplex NAATs
is not routinely performed except in immunocompromised patients, for infection
control purposes, or for outbreak investigations. Testing for cytomegalovirus
in immunocompromised patients should be performed using a quantitative NAAT
performed on plasma.1  
  
The Clinical Practice Guidelines for _Clostridium difficile_ Infection in
Adults and Children: 2017 Update by the Infectious Diseases Society of America
(IDSA) and Society for Healthcare Epidemiology of America (SHEA)11 states
their recommendations are intended to optimize patient care based on a
systematic review of the evidence and an assessment of the benefits and harms
of alternative care options. Per the guideline, repeat testing (within seven
days) during the same episode of diarrhea is not recommended. Also, stool
testing from asymptomatic patients is not recommended, except for the purpose
of epidemiological studies (strong recommendation, moderate quality of
evidence).11

  
The American College of Gastroenterology (ACG) Clinical Guideline: Diagnosis,
Treatment, and Prevention of Acute Diarrheal Infections in Adults5 focuses
primarily on immune-competent adult individuals and does not consider _C.
difficile_ associated infections. For epidemiology and public health
considerations, diagnostic evaluation using stool culture and culture-
independent methods, if available, should be used when the individual patient
is at high risk for spreading the disease and during known or suspected
outbreaks. The recommendations for diagnosis include use of stool diagnostic
studies, if available, in cases of dysentery, moderate-to-severe disease, and
symptoms lasting greater than seven days in order to clarify the etiology of
the illness and enable specific directed therapy. For the majority of cases of
acute diarrheal illness, traditional methods of diagnosis fail to identify the
etiology. If available, the use of Food and Drug Administration approved
culture-independent methods of diagnosis can be recommended at least as an
adjunct to traditional methods. Antibiotic sensitivity testing for management
of acute diarrheal infections is not recommended.  
  
While not considered in the ACG guidelines5, the work-up for chronic diarrhea
is briefly discussed and recommended to include the differential diagnoses
such as celiac disease, Crohn's disease, eosinophilic gastroenteritis, and
Whipple's disease. In the situation of chronic diarrhea occurring after
infectious diarrhea, a diagnosis of postinfectious IBS must be considered.10
The likely pathogens in cases of infectious chronic diarrhea are the parasites
_Cryptosporidium spp_ , _Giardia lamblia_ , _Cyclospora cayetanensis_ ,
_Cystoisospora belli_ , and _Entamoeba histolytica_.10  
  
The 2017 Infectious Diseases Society of America Clinical Practice Guidelines
for the Diagnosis and Management of Infectious Diarrhea10 recommend a detailed
clinical and exposure history be obtained from patients with diarrhea under
any circumstance with adherence to jurisdictional recommendations for outbreak
reporting and infection control. Patients with fever or bloody diarrhea should
be evaluated for enteropathogens for which antimicrobial agents may provide
clinical benefit. Enteric fever should be considered in a febrile patient with
exposure to _Salmonella enterica_ subspecies _Typhi_ or _Paratyphi_. When a
possible Shiga toxin-producing organism is suggested by clinical or epidemic
history, diagnostic approaches should be applied that detect Shiga toxin and
distinguish _Escherichia coli_ ( _E. coli_ ) O157:H7 from other Shiga toxin-
producing _E. coli_ (STEC) in stool. Diagnostic tests that can distinguish
between the more potent Shiga toxin 2 and less potent Shiga toxin 1 could be
used. _Shigella dysenteriae_ type 1, and rarely other pathogens, may produce
Shiga toxin and should be considered as a cause of hemolytic-uremic syndrome
(HUS), especially in patients with a recent history of international travel or
personal contact with a traveler. Clinicians should evaluate for
postinfectious and extraintestinal manifestations of enteric infections.  
  
Stool testing should be performed to detect _Salmonella, Shigella,
Campylobacter, Yersinia, C. difficile_ , and STEC in patients with diarrhea
who also have fever, bloody or mucoid stools, severe abdominal cramping or
tenderness, or signs of sepsis. Bloody stools are not expected with _C.
difficile_ infections. STEC O157 should be assessed by culture and non-O157
STEC should be detected by Shiga toxin or genomic assays. Specifically, test
for _Yersinia enterocolitica_ in patients with persistent abdominal pain and
fever at epidemiologic risk for yersiniosis. Stool specimens should be tested
for Vibrio species in patients with large volume rice water stools or exposure
to either salty or brackish waters, who have consumed raw or undercooked
shellfish, or who have traveled to cholera-endemic regions within three days
prior to onset of diarrhea. A broader set of bacterial, viral, and parasitic
agents should be considered in the context of a possible outbreak of diarrheal
illness. Selection of agents for testing should be based on a combination of
host and epidemiologic risk factors and ideally in coordination with public
health authorities.10  
  
For immunocompromised patients with diarrhea, a broad differential diagnosis
is recommended for evaluation of stool specimens by culture, viral studies and
examination for parasites. Patients with acquired immune deficiency syndrome
and persistent diarrhea should undergo testing for additional organisms
including, but not limited to, _Cryptosporidium, Cyclospora, Cystoisospora_ ,
microsporidia, _Mycobacterium avium_ complex, and CMV.10  
  
Clinical consideration should be included in the interpretation of multiplex
NAAT because these assays detect deoxyribonucleic acid (DNA) and not
necessarily viable organisms. All specimens that test positive for bacterial
pathogens by culture-independent diagnostic testing such as antigen-based
molecular assays (gastrointestinal tract panels), and where isolate submission
is requested or required under public health reporting rules, should also be
cultured in the clinical laboratory or at a public health laboratory to ensure
that outbreaks of similar organisms are detected and investigated. A culture
may also be required when antimicrobial susceptibility testing results would
affect care or public health responses. Specimens from patients involved in an
outbreak should be tested per public health department guidance.10  
  
In cases of outbreak when there is clinical suspicion of enteric fever or
diarrhea with bacteremia, it is recommended that culture independent testing,
including molecular diagnostics, should be performed on stool and blood
specimens.10  
  
Testing may be considered for _C. difficile_ in patients older than two years
of age, with a history of diarrhea following antimicrobial use, or in patients
with healthcare associated diarrhea. A single diarrheal stool specimen is
recommended for detection of toxin or a toxigenic _C. difficile_ strain.10  
  
A diarrheal stool specimen is optimal for laboratory diagnosis of infectious
diarrhea. A fresh stool sample is preferred for the identification of viral
agents, protozoal agents, and _C. difficile_ toxin. Molecular techniques
generally are more sensitive and less dependent on the quality of the specimen
than culture. Follow-up testing is not recommended in most patients following
resolution of diarrhea. Collection and analysis of serial stool specimens
using culture-dependent methods are recommended by local health authorities in
certain situations.10  
  
The Guidelines for the prevention and treatment of travelers' diarrhea: a
graded expert panel report14 indicates concerns regarding molecular testing
and the detection of colonization rather than infection as well as the use of
molecular diagnostic methods that do not allow for characterization of
microbial resistance to antibiotics. Thus, the clinician may be in a position
of ordering both culture-based and molecular tests to fully evaluate the
patient's illness and identify the best therapy. Further studies are needed to
evaluate the utility of these assays in a clinical setting of the returning
traveler with diarrhea.  
  
Per the article, New molecular diagnostic tools in traveler's diarrhea, the
increase in worldwide tourism has led to an increase in imported diseases in
patients returning to their home countries.13 Gastrointestinal problems remain
the first complaint among travelers with health problems. Although most
episodes of acute TD may resolve without the need for antimicrobial treatment
and without identification of the causative agent(s), antibiotic treatment
reduces the duration of diarrhea and related symptoms and also decreases time
spent incapacitated. Bloody diarrhea and persistent diarrhea always require
further investigation.13 Early diagnosis allows an appropriate antibiotic
prescription, if needed, and helps to decrease unnecessary prescriptions.
Antibiotic treatment can increase the risk of HUS in cases of STEC; therefore,
rapid detection can have a significant impact on patient outcome through
informing clinical decisions. An additional advantage of rapid diagnosis is
the potential to improve public health response during outbreaks.  
  
Molecular techniques for the routine diagnosis of diarrhea have been widely
introduced in microbiological laboratories worldwide. An important advantage
to multiplex testing is the automation of the laboratory workflow. Additional
advantages include speed, less need for highly specialized technical
personnel, minimal handling time, and reduced risk of contamination. Previous
studies have shown the sensitivity of molecular assays is higher than culture
and microscopy-based methods.5  Two of the main limitations of multiplex
testing are an inability to distinguish between infection and colonization and
the detection of an insignificant pathogen load that might not be involved
with a patient's clinical circumstances.6, 13 All microbiological results
should be interpreted within a clinical context.13 While multiplex testing can
detect lower levels of pathogenic organisms, false positive results can arise
from detection of nonviable microorganisms, free DNA or RNA, or nonspecific
amplifications.13 In addition, multiplex testing does not require culturing of
live organisms, which can limit downstream organism typing studies required
for outbreak assessments. Limitations in the detection of antibiotic
resistance can be another pitfall in utilizing multiplex tests.13 Finally, the
fixed composition of the majority of the molecular panels commercially
available can limit the utility of these tests in less common disease
presentations and contexts.13 There is a need for open multiplex molecular
platforms where the consumer can combine different pathogens to be detected
based on the local epidemiology, patient characteristics, and origin of the
diarrhea.13  
  

The health technology assessment of multiplex tests identifying
gastrointestinal bacteria, viruses and parasites in patients with suspected
infectious gastroenteritis16 concluded that in general, multiplex testing
correctly identifies pathogens that are also identified by conventional
testing. However, multiplex tests can also generate additional positive
results not seen in conventional testing, which have uncertain clinical
significance and potential to delay the patient's ability to return to their
job. Positive results could lead to unnecessary treatment when presenting
symptoms would spontaneously resolve with watchful waiting. Negative results
could lead to premature discharge from the hospital.  
  
Multiple studies3,4,15-21 evaluated the FilmArray GIP panel. In most of the
studies, the FilmArray specimens were submitted in Cary-Blair enteric
transport medium and a few studies used frozen specimens. The studies used
several different versions of the test, including a version for
investigational use only, version 1.7, and version 2.0. The FilmArray GIP
panel consists of automated nucleic acid extraction, reverse transcription,
amplification, and analysis with results available in approximately one hour.
The test detects 22 agents, including bacteria, viruses, and parasites. The
studies compared the results of the multiplex panel with conventional
laboratory techniques.  
  
In all of the studies,3,4,15-21  the FilmArray GIP panel was positive for more
pathogens than the conventional laboratory techniques and detected multiple
pathogens in a single specimen at a higher rate than the conventional
laboratory techniques. Limitations to the studies included a low number of
positive specimens for some of the test targets, a lack of differentiation
between live and dead organisms in FilmArray results, detection by FilmArray
of organisms at non-pathogenic levels, unclear significance to clinical
implications of detected coinfections, lack of clear distinction between
detection of symptom-associated organisms versus asymptomatic shedding of
organisms (colonization), and inability to untangle the influences and biases
inherent to differences in geographic locations, seasons of sampling, and
varied patient populations.  
  

In the Buss et al3 clinical trial, the FilmArray GIP panel had 100%
sensitivity/positive agreement (PPA) for 12 of the 22 targets and had greater
than or equal to 94.5% sensitivity/PPA for an additional seven of 22 targets.
It was not possible to assess the sensitivity/PPA for _Vibrio_ spp., _Vibrio
cholerae_ , and _Entamoeba histolytica_ , as the organisms were not detected
by comparator methods, or at all in the case of _Entamoeba histolytica_. The
specificity/negative percent agreement (NPA) was greater than or equal to
97.1% for all targets. In the Piralla et al17 trial, the PPA was 87.5% and the
NPA was 77.1%.  
  
In the Beal et al15 trial, researchers assessed the impact of the FilmArray
GIP panel. The study found patients who had multiplex panel testing had fewer
additional stool tests, fewer imaging studies, and fewer days on antibiotics.
The overall length of stay was decreased by 0.5 days. Limitations of the study
included absence of confirmatory testing when the results of multiplex panel
tests and the conventional tests did not agree and the use of a historical
cohort of patients for the control group as opposed to a contemporary group of
patients alongside the test group.

  
In the Cybulski et al19 trial, the clinical impact of the FilmArray GIP panel
was assessed. The investigators found patients with infections detected by the
multiplex panel test were more likely to receive targeted rather than
empirical therapy. Reduced time to treatment and an impact on antibiotic
prescribing were also observed in STEC infections. Patients infected with
pathogens identified both by culture and the multiplex panel test (concordant)
tended to have greater symptom severity than those patients with positive
multiplex panel tests and negative cultures (discordant). The investigators
stated these observations were consistent with a higher organism burden
required for positive cultures and the relationship of disease severity to the
level of organism burden. Patients with coinfections were generally younger
and were more likely to have recent international travel. Limitations to the
study included an insufficient size of certain subgroups to draw definitive
conclusions, a retrospective medical record review methodology that was
subject to confounding factors and biases, and restriction of the study to
only two hospitals within a single healthcare system.  
  
The Khare et al8 trial compared two commercial multiplex panels for detection
of gastrointestinal pathogens. Conventional laboratory techniques, testing on
the FilmArray platform, and testing on the MagPix platform (xTag
gastrointestinal pathogens panel) were performed on each specimen. The
investigators followed the manufacturer's instructions for the FilmArray
platform; however, they modified the manufacturer's FDA cleared protocol for
the xTag panel by using Cary-Blair stool instead of raw stool. The
investigators found that the majority of the targets represented on the panels
showed high sensitivity and specificity; however, there were analytes on both
panels that showed poorer performance. The FilmArray _Aeromonas_ assay had low
sensitivity and the xTag assay for _Yersinia enterocolitica_ had low
sensitivity. The xTag assay for norovirus had low specificity. This study also
found a high percentage of stool samples positive for two or more pathogens.
Limitations of the study included: different volumes of stool tested by the
FilmArray assay (200 microliters) and the xTag assay (100 microliters), more
dilute Cary-Blair specimens performed in the xTag sample rather than the FDA
cleared raw stool, a lack of available clinical information and treatment
decisions to compare with the test results, a relatively low number of
positive results for some targeted organisms and an absence of positive
results for other targets, and the lack of confirmation for some pathogens
identified in the multiplex assays due to inadequate specimen remaining for
confirmatory testing and/or unavailability of confirmatory testing.  
  
Multiple studies6,9,22 compared Verigene, FilmArray, and xTag assays. Huang et
al22 found that each of the assays demonstrated good clinical performance in
their patient population. The Verigene and FilmArray assays provided rapid,
on-demand testing for individual specimens in a moderate complexity
environment. The xTag assay was higher complexity but allowed greater
throughput in a single batch.  
  
The Ramanan et al6 study found that in addition to broad coverage and the
ability to identify a higher rate of coinfections, the multiplex panels
offered reduced turnaround time. The authors supported that clinical
laboratories need to be actively involved in the development of test
utilization strategies focusing on the use and interpretation of the results
of the tests as each of the panels had unique advantages and limitations.
Conventional methods are still needed to detect pathogens not covered by the
panels and provide antimicrobial susceptibility information.

The Binnicker9 study noted challenges associated with interpretation of the
results of the multiplex panels. First, the multiplex panels target microbial
nucleic acid and cannot distinguish between viable, replicating organisms
responsible for disease and nonviable pathogens or remnant nucleic acid. The
second challenge identified was the use of multiplex panels may increase the
detection of _C. difficile_ and potentially impact isolation and treatment
decisions. The third challenge relates to how health care providers will use
and interpret the large amount of data that will be made available with the
broad implementation of the multiplex panels. In the conclusions, the author
found each of the multiplex panels had unique advantages and limitations that
a clinical microbiology lab must consider. Although the panels increased both
the positivity rate and the number of coinfections detected, cultures will
continue to be needed for antibiotic susceptibility and epidemiologic
investigations. Future studies need to address clinically related issues,
including the impact of the panels on antibiotic use and the influence the
results have on management decisions and patient outcomes. In the author's
opinion, reserving the highly multiplexed panels to immunocompromised
patients, the critically ill, or patients with prolonged diarrhea may improve
test utilization and reduce inappropriate antibiotic use.  
  
 **Summary of Evidence (Post Comment Period)  
  
** In the Axelrad et al 23 retrospective study, resource utilization was
compared between patients receiving conventional stool testing (stool cultures
with or without an ova and parasites exam or enzyme immunoassay for viral
pathogens) and patients receiving GI panel testing (FilmArray GI pathogen
panel). Both populations were from the same site (New York Presbyterian-
Columbia University Medical Center), but were tested during two different time
frames: conventional testing between 2012-2015 and GI panel testing between
2015-2017. Both outpatient and inpatient populations were included. Outcome
metrics included the post-test likelihood to undergo endoscopy, to receive
abdominal radiology, to be prescribed an antibiotic, to require a longer
hospital stay, and to require a follow-up emergency department visit. Overall,
the absolute risk of receiving endoscopy, abdominal radiology, and antibiotics
was found to be lower in the GI panel testing population. This finding was
thought to be associated with a higher rate of positive test results in the GI
panel population. The researchers disclosed several limitations to their study
including incomplete information on patient presentation and outcome and lack
of thorough investigation into the cause and effect of positive findings and
the patient's signs and symptoms. Additionally, it should be noted that no
significant discussion differentiating results and outcomes between
outpatients and inpatients was identified while reviewing this publication.  
  
In the Chang et al 24 meta-analysis, two different Polymerase Chain Reaction
(PCR) multiplex-based tests (Luminex xTAG GPP and FilmArray GI panel) were
compared across 11 studies and conclusions were drawn regarding the accuracy
of both tests as compared to gold standards and regarding the performance of
these two tests as compared to each other. The researchers concluded that both
tests were "highly accurate" with FilmArray demonstrating overall "higher
sensitivity and post-test probability" than xTAG GPP. However, the researchers
stated that the meta-analysis did not clarify how these results would
"translate to a clinical setting."  
  
In the Machiels et al 25 study, patients at the Rodboud University Medical
Center were evaluated using "routinely performed" PCR panels. In parallel, the
same specimens were evaluated by the FilmArray GI panel, but these results
were not used to guide patient care. Then, the patients' clinical courses were
analyzed retrospectively, and the researchers theorized alternate clinical
outcomes for these patients had the FilmArray GI panel been used instead of
the PCR panels. The FilmArray GI panel was predicted to improve patient care.
This prediction was extrapolated through comparing the number of pathogens
detected by and the turn-around times of each test. Of note, the researchers
stated "In the outpatient population, we found no impact on either antibiotic
therapy or the number of prevented diagnostic procedures (data not shown)."25  
  
 **Contractor Advisory Committee (CAC) Evidentiary Summary**  
  
After review of literature, the CAC advisory panel, which met in April of
2019, discussed GIP panels utilizing NAATs. In general, the biggest difference
between the GIP multiplex NAAT testing panels is the number of targets.
Viruses can shed even in asymptomatic patients and an issue with the multiplex
NAATs testing panels is false positive results. The CAC panel emphasized
history and physical are important as well as severity and duration of the
patient's symptoms in determining which test should be performed. The CAC
panel mentioned overuse is always a concern with new tests and recommended
these tests not be done routinely or at first encounter in an emergency
department stating there should be criteria set such as fever, diarrhea, or
bloody stools. The CAC panel considered the guidelines and noted differences
between the current ACG and IDSA guideline recommendations. The CAC panel
discussed that the GIP multiplex NAAT testing panels are not to be ordered on
the otherwise healthy patient stating these tests are more appropriate for the
patient who is already ill, such as transplant patients or immunosuppressed
patients, when the provider needs specific information quickly.

In all of the studies evaluating sensitivity and specificity of the GIP panels
utilizing multiplex NAATs, stool specimens were tested. The use of GIP panels
utilizing multiplex NAATs on specimens other than stool has not been evaluated
for sensitivity and specificity. The literature reviewed supports the
appropriate approach to the evaluation 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.1 A detailed clinical and
exposure history should be obtained from all patients with diarrhea. For many
gastrointestinal infections, particularly noninflammatory diarrhea and acute
gastroenteritis of short duration, no laboratory testing is recommended.5 For
severe, bloody, febrile, dysenteric, nosocomial, or prolonged acute diarrhea,
fecal testing is indicated.1 The five most common bacterial gastrointestinal
pathogens causing bloody diarrhea are Salmonella, _Shigella, Campylobacter,
Yersinia_ , and STEC.  
  
Since publication of guidelines by the American Society for Microbiology on
utilization of optimal tests for detection of pathogens, several
gastrointestinal panels that detect more than 20 viral, bacterial, and
parasitic enteric organisms have become available.10 The guidelines focus on
clinical presentation of acute and persistent diarrhea, particularly in the
United States; therefore, this LCD provides limited coverage for outpatient
GIP testing with panels of 11 or fewer pathogens for beneficiaries with acute
diarrhea lasting at least seven days, for persistent diarrhea, and for
beneficiaries with acute diarrhea with signs or risk factors for severe
disease.1, 5, 10

For immunocompromised beneficiaries with acute or persistent diarrhea, a broad
differential diagnosis is recommended for evaluation of stool specimens by
culture, viral studies and examination for parasites (strong recommendation,
moderate quality of evidence);10 therefore, this LCD provides limited coverage
of outpatient GIP testing with panels of 12 or more pathogens.1, 9, 10  
  
GIP testing for likely pathogens for beneficiaries with chronic diarrhea,
defined as lasting longer than 30 days,5 is limited to rare instances. The
2017 Infectious Diseases Society of America Clinical Practice Guidelines for
the Diagnosis and Management of Infectious Diarrhea10 supports testing for the
likely pathogens _Cryptosporidium spp, Giardia lamblia, Cyclospora
cayetanensis, Cystoisospora belli_ , and _Entamoeba histolytica_ in patients
with persistent or chronic diarrhea (strong recommendation, moderate quality
of evidence). According to the ACG Clinical Guideline,5 performance of a
thorough and directed history is essential as the history may direct further
investigations when evaluating persisting symptoms.

Testing may be considered for _C. difficile_ in patients age two years old or
greater who have a history of diarrhea following antimicrobial use and in
patients with healthcare associated diarrhea.10 The use of multiplex panels
may increase the detection of _C. difficile_ and potentially impact isolation
and treatment decisions.9 Singleplex NAAT for _C. difficile_ toxin genes are
available.  
  
Unless treatment is indicated, diagnostic testing is not recommended in most
cases of uncomplicated TD.1 Travelers with diarrhea lasting 14 days or longer
should be evaluated for intestinal parasitic infections. Testing for _C.
difficile_ should be performed in travelers treated with antimicrobial
agent(s) within the preceding twelve weeks (strong recommendation, moderate
quality of evidence).10  
  
Selection of agents for testing should be based on a combination of host and
epidemiologic risk factors. Clinical consideration should be included in the
interpretation of multiplex NAATs because these assays detect DNA/RNA and not
necessarily viable organisms, or they may detect an insignificant pathogen
load that might not be the cause of the diarrhea. Since NAATs detect viable
and nonviable organisms, this LCD limits testing to symptomatic beneficiaries
(strong recommendation, low/moderate quality of evidence).1,6,10,11,16 Follow-
up testing is not recommended in most people following resolution of diarrhea
(strong recommendation, moderate quality of evidence);10 therefore, this LCD
does not provide coverage of testing for clearance of the pathogen ("test of
cure") and for repeat testing with GIP Panels utilizing NAATs within seven
days during the same episode of diarrhea.1,11  
  
 **Analysis of Evidence (Post Comment Period)  
  
** The literature submitted during the comment period reinforces the
usefulness of GIP panels. However, the articles do not clearly establish a
minimum or maximum number of targets best suited for evaluation of patients in
various clinical scenarios; instead, the studies utilized panels with
established sizes (e.g., a 22 pathogen panel) and either compared these panels
to standard of care (e.g., stool cultures) or other molecular tests, including
different panels. Additionally, please note that the LCD only addresses
testing in the outpatient setting. In the literature submitted, the impact of
GIP testing in the outpatient versus inpatient population was only briefly
examined. One study stated, "In the outpatient population, we found no impact
on either antibiotic therapy or the number of prevented diagnostic procedures
(data not shown)."25 Medicare only provides coverage for medically reasonable
and necessary testing; thus, testing should be tailored to specific clinical
circumstances and only ordered when it is expected to have an impact on
clinical management of the patient. While large GIP panels may be able to
encompass a broad differential diagnosis, often preliminary findings (e.g.,
history and physical) can rule out several potential etiologies, eliminating
the need for indiscriminate testing.