This contractor will provide limited coverage for Gastrointestinal Pathogen
(GIP) molecular assays identified by multiplex nucleic acid amplification
tests (NAATs), and will limit GIP coverage in immune competent beneficiaries
up to 5 bacterial targets which represent the top 90-95% of foodborne
infections ([incidence of infection per 100,000 population] in decreasing
incidence): Salmonella [15.89]; Campylobacter [12.97]; Shigella [5.53];
Cryptosporidium [3.31]; Shiga toxin producing E. coli (STEC) non-O157 [1.64]
and STEC O157 [.95].

In addition, when there is a clinical concern for Clostridium difficile
colitis, this contractor will cover up to 11 targets if Clostridium difficile
is one of the organisms tested for.

Testing for 12 or more organisms will only be covered in critically ill or
immunosuppressed patients.

In immune competent individuals, most people with Cryptosporidium, a parasitic
disease, will recover without treatment. The pathogens in some of the GIP
panels are determined by the manufacturers that make them, and do not
represent specific pathogens that cause a common age-based syndrome, or
represent organisms that commonly are found in a specific sample type, patient
population or reflect community acquired foodborne infections. Because of the
unique clinical circumstances of immune compromised patients, ICU patients,
and HIV positive patients with diarrhea, GIP testing for bacteria, virus and
parasite testing may be indicated, and thus a Medicare benefit.

Traditionally, stool testing algorithms required physicians to consider which
specific pathogens that might be associated with individual cases of
gastroenteritis, and choose a testing scheme that ensured that all the
appropriate pathogens were targeted. In the setting of community-acquired
diarrheal illness, large foodborne GIP testing panels for parasites and viral
etiologies is not reasonable and necessary because these GI diseases are:

  * Generally self-limited,
  * Virus specific therapies are not available, and
  * Patients are managed by supportive care and hydration.

Travelers with >2weeks of symptoms, after bacterial pathogens have been ruled
out, may require traditional ova and parasite stool examination and/or
specific protozoa antigen or molecular testing. Medicare specifies that
testing must be reasonable and necessary for the specific needs of a given
patient. Large panels that represent a "one size fits all" approach to testing
without regard for a patient's medical history, time of year, clinical
setting, and patient symptoms are not reasonable and necessary, and thus not a
Medicare benefit. A "one size fits all" panel approach is not restricted to
specific population subgroups, such as neonates, pediatrics, or adults, is not
differential between community-acquired vs traveler source of infection, and
does not differentiate the needs of select patient populations, such as the
ICU patient or immunocompromised patients. In addition, while identification
of specific viruses may be of interest in an outbreak or epidemiologically,
clinical management is not predicated on viral test results, and are thus not
reasonable and necessary.

This contractor recognizes that GIP assays are closed systems, without random
access for physician directed, patient-specific testing. However, some
laboratories elect to use GIP panel tests but report only the specific tests
ordered by the physician. In other words, and the laboratory "blinds"
unnecessary test results or utilize disclaimers in their reporting and bill
only for the medically necessary test results. Other laboratories report
results of all tests in the panel, which adds unnecessary cost to the
healthcare system when reimbursement is directly related to the number of
organisms in the panel. The Food and Drug Administration (FDA)
approved/cleared assays discussed below are comparable with coverage limited
to bacterial organisms for acute diarrhea, with justification of medical
necessity recorded in the patient's medical record.

**Nucleic Acid Amplified Probe Technique (NAAT) for Identification of
Microorganisms:**

Tests performed by NAAT uses a microorganism's deoxyribonucleic acid (DNA) or
ribonucleic acid (RNA) to directly identify specific bacteria, viruses, and/or
protozoa rather than standard microorganism detection techniques such as
bacterial culture, microscopy with and without stains, direct fluorescent
antibody testing, rapid antigen testing, qualitative and quantitative
immunoassay for identification of antigens or toxins from stool and single-
plex polymerase chain reaction (PCR) assays. Multiplex NAAT tests are included
in the larger grouping of culture-independent diagnostic tests (CIDT). CIDT
includes but is not limited to simplex direct probe and amplified probe
techniques. This technology offers same day results in a matter of hours
rather than 2-3 days of time-consuming and labor intensive bacterial cultures
and immunoassays for processing stool specimens. CIDT are touted as providing
a more comprehensive assessment of disease etiology by increasing the
diagnostic yield compared with conventional diagnostic tests permitting
earlier initiation of appropriate therapeutic agents targeted to the detected
pathogen(s), if any, rather than empirical therapy until culture results are
available.

CIDT testing is not without its challenges; latent infections or colonization
cannot be distinguished from active, clinically significant infections.
Additionally, fragments of nucleic acids from dead microorganisms may cloud
organism identification, complicating clinical interpretation, and
potentially, clinical management. In a CIDT comparative study, mixed
infections were identified in 13-21% of positive prospective stool samples
compared to only 8.3% by routine (culture/immunoassay/microscopy) methods.1 In
another recent study, 32.9% of the FilmArray gastrointestinal (GI) Panel
positive specimens were found to contain more than 1 potential pathogen.2 The
significance of detecting coinfections may be difficult to understand, as the
clinical implications of specific pathogen combinations are not well
documented or understood. Many GI pathogens can be shed asymptomatically or
for prolonged periods of time after symptoms subside, further complicating the
interpretation of positive results. For example, Salmonella spp. and norovirus
can be shed for weeks to months after symptoms subside. Asymptomatic infection
with Cryptosporidium spp. or G. lamblia is common in children.2 High rates of
asymptomatic carriage of enteropathogens, often identified as a co-infection
in large microbial panels, create diagnostic confusion by the interpreting
clinician.3

From a public health and epidemiologic point of view, CIDT testing does not
provide the culture isolates that are needed for antimicrobial susceptibility
testing, serotyping, subtyping and whole genome sequencing that are critical
for monitoring trends, detecting clusters of illness and investigating
outbreaks. For Salmonella, the inability to distinguish serotypes will prevent
tracking of important changes in incidence by serotype, and markedly limit
detection and investigation of outbreaks (not a Medicare benefit). For Shiga
toxin producing E. coli (STEC), because identification of serogroups requires
culture, it is not known which STEC-positive CIDT result represents 0157 vs
non-01574.

**FDA-approved GIP Assays:**

Five FDA approved GIP assays are currently on the market, and all are closed
system tests that do not allow random access for physicians to select likely
etiologic agents of diarrhea. These include:

  * **Hologic/Gen-Probe 's ProGastro SSCS:**
    * Targets identified: 
      * Salmonella
      * Shigella
      * Campylobacter (C. jejuni and C. coli only, undifferentiated) nucleic acids
      * Shiga toxin 1 (stx1) /Shiga toxin 2 (stx2) genes (STEC typically harbor 1 or both genes that encode for Shiga toxins 1 and 2)
    * TAT (turn-around time) - 4 hr.

  * **BD Diagnostics ' BD MAX Enteric Bacterial Panel (EBP):**
    * Targets identified: 
      * Campylobacter spp. (jejuni and coli)
      * Salmonella spp.
      * Shigella spp.
      * Enterohemorragic E.coli (EHEC)
      * Shiga toxin 1 (stx1)/Shiga toxin 2 (stx2) genes (found in STEC, as well, as Shigella dysenteriae)
    * TAT - 3-4 hr.

  * **Nanosphere 's Verigene Enteric Pathogens(EP):**
    * Targets identified: 
      * Campylobacter Group (comprised of C. coli, C. jejuni, and C. lari)
      * Salmonella species
      * Shigella species (including S. dysenteriac, S. boydii, S. sonnei and S. flexneri)
      * Vibrio Group (comprised of V. cholera and V. parahoemolyticus)
      * Yersinia enterocolitica
      * Shiga toxin I gene and Shiga toxin 2 gene virulence markers, Shiga toxin-producing E coli (STEC)
      * Norovirus
      * Rotavirus
    * TAT - 2 hr.

  * **Luminex 's xTAG Gastroenterology Pathogen Panel (GPP):**
    * Targets identified: 
      * 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 E. coli (ETEC) LT/ST
      * Giardia (G. lamblia only) (aka G. intestinalis and G. duodenalis)
      * Norovirus GI/GII
      * Rotavirus A
      * Salmonella
      * Shiga-like Toxin producing E. coli (STEC) stx 1/stx 2
      * Shigella (S. boydii, S. sonnei, S. flexneri and S. dysenteriae)
      * E. histolytica
      * Adenovirus 40/41
      * Vibrio cholera
    * TAT - <5 hr.

  * **Biofire Diagnostic 's FilmArray GI Panel:**
    * Targets identified 
      * Campylobacter (C. jejuni/C. coli/C.upsaliensis)
      * Clostridium difficile (C. difficile) toxin A/B
      * Plesiomonas shigelloides
      * Salmonella
      * 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)
      * Cryptosporidium
      * Cyclospora cayetanensis
      * Entamoeba histolytica
      * Giardia lamblia (also known as G. intestinalis and G. duodenalis)
      * Adenovirus F 40/41
      * Astrovirus
      * Norovirus GI/GII
      * Rotavirus A
      * Sapovirus (Genogroups I, II, IV, and V)
    * TAT -1-2 hr.

All targeted viruses included in GIPs are more prevalent in young children
than in adults. In 1 study, Sapovirus was detected in 10% of all specimens
from children >1 year old and 7.4% of specimens from children between 1 to 5
years of age.2 Enteropathogenic E. coli (EPEC), historically associated with
developing countries, are known to cause both acute and persistent diarrhea in
2 young children in the US and were identified in 1 study in 24.8% of all
samples collected from children <1 year of age, and 37% of all samples from
children between age of 1 and 5 years. EPEC strains can also be found in
healthy children and adults, thus confounding its significance when identified
in symptomatic children and adults.

Similarly, the interpretation of C. difficile toxin A/B detection is also
complicated, especially in children <1 year old. The American Academy of
Pediatrics does not recommend routine testing for C. difficile in children <1
year of age and suggests that positive C. difficile results be interpreted
with suspicion in children <3 years old.5

Most recently a publication looking at Syndromic Panel-Based Testing,
specifically the multiplex detection of GI pathogens, states that it makes the
interpretation of positive results difficult in asymptomatic individuals
colonized with C. difficile. Patients experiencing diarrhea associated with
antecedent of antibiotic or hospitalization are at risk for C. difficile
infection; in such cases, specific testing for C. difficile is most cost-
effective. GIP's detection of multiple targets has created confusion for
healthcare providers that now faced with results that were not previously
reported and for which current guidelines provide no direction as to
management (treatment, clinical significance or the need for additional or
repeat testing).12

A meta-analysis (of 10 studies) by National Health Service (NHS) in UK found
that GIP testing produces a greater number of pathogen-positive findings than
conventional testing. It is unclear whether or not these additional
"positives" are clinically important. The review identified no robust evidence
to inform consequent clinical management of patients. There is considerable
uncertainty about cost-effectiveness of GIP panels used to test for suspected
infectious gastroenteritis in hospital and community settings. The systemic
review and cost-effectiveness model identify uncertainties about the adoption
of GIP tests. GIP testing will generally identify pathogens identified by
conventional testing; however, these tests also generate considerable
additional positive results of uncertain clinical importance.13

**Indications for Foodborne GI Testing**

Acute diarrhea, often called gastroenteritis, can be defined as the passage of
a greater number of stools of decreased form from the normal lasting < 14
days. Acute diarrhea is generally associated with clinical features of nausea,
vomiting, abdominal pain and cramps, bloating, flatulence, fever, passage of
bloody stools, tenesmus and fecal urgency. It is the leading cause of
outpatient visits, hospitalizations, and lost quality of life occurring
domestically and those traveling abroad. The Centers for Disease Control and
Prevention (CDC) has estimated 47.8M cases occurring annually in the US with
an estimated healthcare cost upwards of US$150M.6 Detection of microbial
pathogens associated with GI disease may be important in certain populations,
such as immunocompromised hosts, the critically ill and individuals with
prolonged disease that is refractory to treatment.

Over a 20 year period, some foods that have been linked to foodborne outbreaks
include milk (Campylobacter), shellfish (Noroviruses), unpasteurized apple
cider (Escherichia coli O157:H7), raw and undercooked eggs (Salmonella), fish
(ciguatera poisoning), raspberries (Cyclospora); strawberries (Hepatitis A
virus); and ready-to-eat meats (Listeria).7

Although the etiologic agents responsible for about 80% of GI illnesses are
unidentified or otherwise unspecified, Norovirus and Salmonella spp (non-
typhoidal) are currently the most commonly identified pathogens associated
with foodborne disease in the US and account for 5.5 and 1.0 million cases
each year, respectively.8 Clostridium perfringens, Campylobacter and
Staphylococcus aureus follow Norovirus and Salmonella spp. in decreasing
frequency in domestically acquired foodborne illnesses. Healthcare- and
antibiotic-associated diarrhea is also problematic, with the major causative
pathogen being toxin-producing Clostridium difficile.9 In the US, >300,000
cases of C. difficile are diagnosed annually, with associated costs of >$1
billion.

In 2015, the number and incidence of confirmed infections per 100,000
population were reported for Salmonella (15.89), Campylobacter (12.97),
Shigella (5.53), Cryptosporidium (3.31), Shigatoxin producing Escherichia coli
(STEC) non-O157 (1.64), STEC O157 (0.95), Vibrio (0.39), Yersinia (0.29),
Listeria (0.24) and Cyclospora (0.13).4 Among confirmed infections, the vast
majority were diagnosed only by culture. Compared with incidence in 2012-2014,
the incidence of confirmed infections was significantly higher for STEC
non-O157 (40% increase) and Cryptosporidium (57% increase). No significant
changes were observed in 2015 for other pathogens compared with the previous
3-year averages. In addition to the 20,107 confirmed cases of infection, there
were 3,112 positive CIDT case reports. In general, the incidence of most
foodborne bacterial pathogens and for Cryptosporidium is highest among
children aged <5, except for Listeria and Vibrio for which the highest
incidence is among persons aged  65 years.10

Many episodes of acute diarrhea are self-limited and require fluid replacement
and supportive care. Oral rehydration is indicated for patients who are mildly
to moderately dehydrated, IV fluids may be required for more severe
dehydration. Routine use of antidiarrheal agents is not recommended because
many of these agents have potentially serious adverse effects, particularly in
infants and young children. Antimicrobial therapy is warranted only for
patients with severe disease, or for individuals with severely weakened immune
systems or are severely weakened from medications and other illnesses.11

Laboratory testing algorithms for infectious causes of diarrhea generally
agree that testing is NOT warranted for community-acquired diarrhea of <7 days
duration without signs or symptoms of severe (fever, bloody diarrhea,
dysentery, severe abdominal pain, dehydration, hospitalization and
immunocompromised state) disease. In general, when community-acquired diarrhea
persists for 7 days, or the diarrhea is travel-related, or there are
signs/symptoms of severe disease, GIP testing may be warranted. Additional
directed testing may be indicated if the GIP results are negative and diarrhea
persists. No additional testing is indicated for GIP-positive result, unless
the clinical pictures changes. Clostridium difficile molecular testing is
warranted on health-care associated diarrhea with onset after the 3rd
inpatient day or after recent antibiotic use.

_Level of Evidence_

Quality of Evidence: Moderate  
Strength of Evidence: Moderate  
Weight of Evidence: Moderate

**Summary Medicare Coverage Decision:**

GIP testing is limited to no more than 5 bacterial pathogen targets when not
testing for Clostridium difficile. Testing for 6-11 pathogens is covered when
there is a clinical concern for Clostridium difficile colitis, and Clostridium
difficile is one of the pathogens being tested. Testing for viral etiologies
is not reasonable and necessary, because these GI diseases are generally self-
limited, virus specific therapies are not available, and patients are managed
by supportive care and hydration. Travelers with >2weeks of symptoms, after
bacterial pathogens have been ruled out, may require traditional ova and
parasite stool examination and/or specific protozoa antigen or molecular
testing. Large panels inclusive of 11 viruses and protozoa are not reasonable
and necessary for community-acquired diarrheal illness. There is no Medicare
benefit for GIP testing for national, state or local agency tracking of
diarrheal outbreaks, for epidemiologic purposes, or to confirm another
etiologic test result. Once the target etiology of an outbreak is identified,
subsequent patient testing is generally not indicated and patients are managed
empirically. However, if the clinical presentation varies from the outbreak
prototype, a specific test for the causative organism may be indicated. The
Medicare benefit is specifically for the clinical identification and
management of disease for a given beneficiary. The Medicare benefit does not
extend for purposes of the family or community tracking or surveillance.

**Limitations**

A GIP test **panel** is a single service with a single unit of service (UOS
=1). A panel cannot be unbundled and billed as individual components,
regardless of the fact that the GIP test reports multiple individual pathogens
and/or targets. The panel is a closed system performed on a single platform,
and as such, is a single test panel with multiple components (UOS=1). If C.
difficile is not included in a GIP panel, testing for C. difficile may be
reasonable and necessary when ordered in addition to a GIP bacterial pathogen
panel and supported by documentation in the medical record.