Response to Comments: MolDX: Food-Based Gastrointestinal Panels Identified by Nucleic Acid Multiplex Amplifications (NAAT) (A56207) (2023)

Multiplex DNA extraction PCR technology is one of the most important advances in clinical medicine in recent decades. In syndromic diseases such as diarrhea, whether acute or chronic, the ability to make an accurate and rapid microbiological diagnosis is crucial in terms of clinical management.

As you know, I specialize in gastroenterology, internal medicine, tropical medicine and travel. I have extensive research and clinical experience in the field of travelers' diarrhea over the last 25 years. One of the problems in diagnosis has been the fact that diarrhea is often proteinaceous and bacterial, parasitic and viral etiologies are often clinically indistinguishable but are approached very differently in terms of treatment. Before the availability of DNA extraction PCR, diagnosis relied on stool cultures, which often required special selective media and typically took 48 to 72 hours. In our hospital, one of the largest teaching hospitals in the country, only 5 bacterial pathogens were studied before this technology, so the vast majority of pathogens went undiagnosed. Likewise, in the case of parasitic causes, the microscopic examination of oocytes and parasites (O&P) with or without special stains is fraught with inaccuracy, since this procedure relies on a technician prone to over- or underestimate. Viral pathogens have been difficult to diagnose due to a lack of adequate commercial testing capacity.

Efforts to limit diagnostic options to the 4-5 most likely pathogens are not only bad practice, they are counterintuitive. In doing so, we will reinforce the bad practices of the last few decades and continue to overlook the vast majority of specific microbial pathogens. This is particularly important for travelers' diarrhea as there are etiological causes such as Giardia, Cyclospora and diarrhea-causing E.coli that are often missed by conventional testing.

Even in community-acquired diarrhea, although most cases are viral, it is useful to demonstrate a viral origin and withhold antibiotics in the interests of antimicrobial management and prevention of antibiotic resistance.

In a recent study of the BioFire GI panel versus traditional testing methods, it was found that the cohort of patients tested on the GI panel had more targeted than empiric therapy. In cases where antibiotics were not indicated, e.g. in patients with Shiga toxin-producing E. coli, the study showed that empiric antimicrobial withdrawal was 47 hours faster than traditional methods (Cybulski, 2018). In another recent study, patients being tested as part of the BioFire GI panel were asked to reduce downstream testing methods such as CT scans, X-rays, and ultrasound compared to traditional methods, likely because the doctor was able to Identify infectious cause and stop looking for possible causes of diarrhea (Beal, 2018). Without the use of a comprehensive, rapid, and accurate test, many of the benefits found in these studies are unlikely to materialize.

Another point the project emphasizes is the need to identify only five known common causes of infectious diarrhea, mostly bacterial. Identifying viral and parasitic causes of acute diarrhea is also important and can inform not only treat/not treat decisions, but also infection control decisions, recommendations for a return to work, school, or other activities affecting the patient's health can affect affect .public. Health. In addition, studies have shown that treating parasitic infections can effectively shorten the disease (Rossignol, 2001) and in other cases, without treatment, prolong it by several months (Beal, 2018. MacKenzie, 1994) without the right course of therapy. Because potential viral and parasitic causes may not be routinely tested or have low sensitivity but represent a significant portion of the diarrheal burden in the US, their presence in a multiplex NAAT is appropriate.

In addition, current practice guidelines (ACG 2016 and ISTM 2017) recommend the use of culture-independent multiplex molecular tests to identify potential causes of acute diarrhea as they may influence patients' treatment decisions. The guidelines provide a framework for physicians to consider when considering which patients should undergo testing, treatment, and other patient management recommendations. The guidelines reviewed the existing literature and drew on expert opinion to make recommendations that include the use of culture-independent multiplex molecular tests and how they can be used to better inform clinicians about what might be affecting their patients.

We also know that diarrheal disease is not the benign, self-limiting disease we once thought it was. There is a non-negligible incidence of post-infectious sequelae such as chronic gastrointestinal symptoms after acute diarrhea such as post-infectious irritable bowel syndrome (PI-IBS), post-infectious functional gastrointestinal disorders (PI-FGD) and hemolytic-uremic diseases. Syndrome, Reactive Arthritis and Gillian-Barre Syndrome There is evidence that prompt diagnosis and treatment can reduce or eliminate these post-infectious sequelae and reduce potential morbidity and mortality.

Multiplex PCR technology also has the potential benefit of reducing healthcare resource consumption and reducing overall healthcare costs by providing complete and accurate infectious disease results in a clinically actionable timeframe. As a gastroenterologist, the use of this diagnostic technique has reduced the need for endoscopic interventions in my practice. I have had patients with chronic diarrhea scheduled for various endoscopic procedures where a stool sample has been found to have pathogens such as Giardia, sparing them the expense and inconvenience of these invasive procedures.

In summary, the latest LCD design involving molecular GI multiplex panels should be reconsidered and should include favorable reimbursement for such testing. Multiplex molecular GI testing has been shown to provide faster, more comprehensive, and more accurate results that can lead to more specific patient therapy/management decisions, leading to better outcomes and more likely patient satisfaction. This technology changed clinical practice and revolutionized the field of diarrheal diseases. I would strongly advise against limiting the number of goals and encouraging more dialogue. I am available for a conversation at any time.

Based on the feedback received, we are expanding the procedures covered to include test coverage for up to 11 pathogens. Although it is possible that several additional pathogens could be identified using molecular methods, we generally believe that this is unnecessary, either because the number of pathogens to be tested can be reduced based on patient history or because there is no clear clinical benefit . for positive identification. The ACG guidelines cited by the previous commenter provide an evaluation and treatment algorithm that in many cases does not rely on microbiological evaluation. In addition, this guideline highlights a number of shortcomings of culture-independent diagnostic modalities, including the ability to identify the presence of pathogenic nucleic acids that are non-viable in a given patient and not necessarily clinically significant. In summary, although molecular diagnostic techniques can identify many pathogens, their clinical utility is not established.

Thank you for this opportunity to respond to your draft local coverage determination for MolDX: Foodborne Gastrointestinal Panels Identified by Multiplex Nucleic Acid Amplification Test (NAAT) (DL37709). American Gastroenterological Association (AGA), American Society for Microbiology (ASM), Molecular Pathology Association (AMP), Association of Public Health Laboratories (APHL); The College of American Pathologists (CAP), the Infectious Diseases Society of America (IDSA), and the Pan American Society of Clinical Virology (PASCV), representing diverse practice areas, collaborated to provide the most comprehensive analysis for their preliminary designation. coverage place. The members of the six organizations writing these comments are subject matter experts in the diagnosis and treatment of gastrointestinal disorders covered by this policy, and their possible implementation will directly impact their practices. We are submitting joint comments because our organizations share the same concerns about this Local Coverage Determination (LCD) project. To help Palmetto, this letter also provides specific recommendations for LCD language changes if medically necessary, followed by supporting comments and literature reviews. In addition, there is a recommended configuration of ICD-10 codes that support medical demand language.

We recommend amending the section titled “Indications, Limitations and/or Medical Necessity for Coverage” as follows:

(Note: Strikethrough font indicates recommended removal from original LCD language draft; blue bold font indicates recommended additions)

This contractor will provide limited coverage for molecular assays of Gastrointestinal Pathogens (GIP) identified by Multiplex Nucleic Acid Amplification Testing (NAAT) and will limit coverage of GIP orp to 5 bacterial targets representing Athe top 90-95% of foodborne infections([frequency of infection per 100,000 inhabitants] with decreasing incidence): salmonella [15,89]; Campylobacter [12.97]; Shigela [5.53]; Cryptosporidium [3.31]; Shiga toxin-producing E. coli (STEC) non-O157 [1,64] and STEC O157 [0,95]. In immunocompetent individuals, most people with cryptosporidium, a parasitic disease, 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-related syndrome, nor do they represent organisms commonly found in a specific sample type, patient population, or population specific patient population are found to reflect the community. Acquired infections transmitted through food.considered clinically necessary for therapeutic decision-making. These infectious agents includesalmonella,Campylobacter,ShigellaShiga-Toxin-Produzent E coli(STEC) non-O157 and STEC O157 as well as enterotoxigenicE coli, enteropathogenE coli, enteroaggregativeE coli,Clostridium difficile,Yersinia enterocolitica,vibriogroup(composed by Vibrio parahaemolyticusÖharmful vibrationsor Vibrio Cholera, of whichVibrio parahaemolyticusis more common),Giardien,KryptosporidiumB. norovirus, rotavirus and enteric adenovirus. Diarrheal diseases pose a significant diagnostic challenge because the history, signs and symptoms, and other features are often nonspecific, yet effective therapy requires accurate microbial identification. This clinical need has led to a new generation of diagnostic panels covering this broad spectrum of probable infectious etiologies. In addition, a vulnerable subset of patients, including the immunocompromised and elderly, are particularly susceptible to complications. Although immunocompetent people can recover from some infections without treatment, older people have reduced immune function and an increased risk of mortality from gastrointestinal infections. This contractor recognizes that patients can benefit from rapid diagnosis and early intervention (e.g., antibiotic therapy). Due to the significant overlap in clinical signs and symptoms in patients with acute gastrointestinal infections, the diagnostic approach and rapid analysis offers large molecular GIP assays instead of the sequential and stepwise approach of one-step assays. medically necessary.

In rare, if not infrequent, situations where the clinical features of the patient's picture suggest a specific etiology and/or microbial therapy, traditional culture methods or single-target molecular assays should be used instead of a broad GIP.Because of the unique clinical circumstances of immunocompromised patients, patients in intensive care units, and HIV-positive patients with diarrhea, GIP testing to detect bacteria, viruses, and parasites may be indicated and therefore a Medicare benefit.

We recommend changing the paragraph titled "Summary of Medicare Coverage Decision" as follows

read below:

(Note: scratchedFont indicates recommended removal of original LCD language draft; blue font indicates recommended additions)

The GIP test is limited to no more than 5 bacterial pathogen targets. Testing for viral etiologies is neither useful nor necessary because these gastrointestinal disorders are usually self-limiting, virus-specific therapies are unavailable, and patients are managed with supportive care and fluids.GIP testing is limited to the minimum number of targets required for therapeutic decision making. The following clinical indications and contraindications characterize the role of the GIP test:

SPECIFIED:

1. Individuals with moderate to severe symptoms associated with acute diarrhea
2. people with dysentery
3. Individuals with acute diarrhea lasting > 7 days
4. Immunocompromised people with acute diarrhea

NOT DISPLAYED:

• Immunocompetent individuals with mild diarrhea, particularly those lasting ≤ 7 days
• Individuals in whom the clinical presentation of acute diarrhea suggests a specific microbial etiology (eg, patient on antibiotics or history of hospitalization)

Physicians should follow current clinical guidelines from the American College of Gastroenterology (ACG) unless the specific clinical situation requires otherwise. A broad GIP molecular panel (with 6-22 targets) is indicated when a patient presents with an overlapping clinical picture and symptoms consistent with multiple possible microbiological etiologies. If the patient's history and clinical presentation suggest a specific microbial etiology and/or therapy, a broad GIP with more than 5 infectious targets is not indicated.

Although viral infections can be self-limiting, this contractor believes that molecular assays for GIP, including GI viruses (such as norovirus), are clinically necessary to guide initial patient management through better supportive care, including hydration and avoidance of overuse of associated antibiotics with secondary infections.Clostridium difficileInfection.

For patients in long-term care facilities, virus-containing GIP molecular panels (norovirus, rotavirus, and enteric adenovirus) are useful and necessary, as the results inform individual treatment decisions of the patient, e.gof the patient (which may increase the risk of unrecognized delirium) and decisions about the appropriate use of antibiotic therapy.

Travelers with > 2 weeks of symptoms may require conventional testing of parasite eggs and faeces and/or specific protozoal antigen or molecular testing after bacterial pathogen exclusion. large plates inclVirusProtozoa are neither useful nor necessary for the common community-acquired diarrheal disease.

There is no Medicare benefit for the use of GIP testing by federal, state, or local agencies to monitor diarrheal outbreaks, for epidemiological purposes, or to confirm the result of any other etiological test. Once the etiology of a flare is identified, further evaluation of patients is generally not indicated and patients are treated empirically. However, if the clinical presentation of an individual patient deviates from the outbreak prototype, specific testing for the etiological organism may be indicated. The Medicare benefit is specifically for clinical identification and disease management for a specific beneficiary. Medicare benefit will not be renewed for family purposes or for community monitoring or monitoring.

Justification for the above language

We support Palmetto's proposal to cover molecular assays for gastrointestinal pathogens (GIPs) identified by multiplex nucleic acid amplification assays. While we agree that the Codes apply to up to five bacterial targets, we also believe that additional targets should be included and that there are clinical scenarios where more than five targets are clinically needed. The LCD draft lists five bacterial targets eligible for GIP coverage:salmonella;Campylobacter;Shigella;Kryptosporidium; and Shiga toxin producersEscherichia coli(STEC) O157 and not O157. Several clinical studies have shown that these targets are insufficient to identify 90-95% of the major pathogens that can cause diarrhea in patients (Buss,and other,2015).

Testing for more than five infectious targets is required to achieve a 90-95% pathogen diagnosis rate.. Restricting testing to five priority bacterial targets would likely miss most of the pathogens responsible for gastrointestinal infections in the elderly. In a prospective study published by the Infectious Diseases Society of America (IDSA),salmonella,Campylobacter,Shigella, and STEC (O157 and not O157) accounted for less than half of the gastrointestinal pathogens detected in adults 98 years and younger with diarrhea. The other pathogens detected were enterotoxigenicE coli, enteropathogenE coli, enteroaggregativeE coli,Clostridium difficile,Yersinia enterocolitica,vibriogroup(composed by Vibrio parahaemolyticusÖharmful vibrationsÖVibrio-Cholera,of whichVibrio parahaemolyticusit is more common), Aeromonassp.,Entamoeba histolytica, Giárdia,KryptosporidiumB. adenovirus, astrovirus, calicivirus and rotavirus(Svenungsson, et al., 2000). In addition, in a separate study published by the American Society for Microbiology,salmonella,Campylobacter,Shigella, and STEC (O157 and not O157) accounted for only 24% of the GI pathogens detected in patients 65 years of age and older. At least three other pathogens were commonly detected in these patients (Buss, et al., 2015)

Command:We recommend adding coverage for Group 2 CPT code 87506 (Targets 6-11) as detailed in the ICD10 Coding section.

The American College of Gastroenterology (ACG) guidelines recommend using wide GIP panels.Because of the significant overlap in clinical signs and symptoms in patients with acute gastrointestinal infections, a comprehensive diagnostic approach may be required. The ACG guidelines recognize that "because the symptoms of acute diarrhea vary, attempts to diagnose etiological agents or classes based on symptoms are subjective at best and fraught with inaccuracy due to overlap" in the symptoms. While clinical features can be helpful in distinguishing bacterial from protozoal causes, they are often unreliable indicators of the likely pathogen responsible.” Consequently, infectious diarrhea is the second most important syndrome in need of better diagnosis (Blaschke et al., 2015) . This is the precise rationale necessitating the use of broad GI multiplex panels in clinical practice (Riddle et al., 2016). We recommend adding coverage for Group 2 CPT code 87506 (Objectives 6-11). , as described in the ICD10 coding section

The ACG guidelines also recognize the specific advantages that a more comprehensive NAAT analysis offers over other diagnostic approaches for making therapeutic decisions.. The ACG guidelines state that "it is now possible to use culture-independent molecular techniques to identify a wide variety of bacterial, protozoal, and viral pathogens that cause diarrhea, including some not commonly identified in clinical laboratories." Diarrheal diseases by definition have a broad spectrum of potential pathogens that are particularly amenable to multiplex molecular testing.” Molecular diagnostic testing can provide a more comprehensive assessment of disease etiology and increase diagnostic yield compared to traditional diagnostic testing (Riddle et al., 2016). This benefit is important for therapeutic decision-making, as older adults are at greater risk of serious illness and complications from infectious diarrhea and benefit from therapeutic intervention, similar to how patients with congenital or acquired immunosuppression are defined (Guerrant et al., 2001) Chen et al., 2015, Jagai et al., 2014, Hall et al., 2012. Another recent study confirms the benefits of these interventions.

A recent study comparing the FilmArray GI panel to culture-based methods showed that the panel promoted targeted therapy over empiric therapy and reduced the time to initiation of appropriate therapy. The study also found that patients detected by multiplex PCR are just as symptomatic and just as likely to receive antimicrobial therapy as patients detected by more traditional methods. It is clear from these results that the additional positive results demonstrated by the panel are clinically important. (Cybulski et al., in press). Although GIPs can identify multiple targets in asymptomatic and symptomatic individuals, providers and laboratory professionals routinely consider all aspects of the patient's condition (e.g., duration and severity of symptoms and prior antimicrobial treatment) when interpreting results from multiplexed GI panels and act accordingly (Ramanan et al., 2018). In the hospital setting, medical professionals want to know the cause of gastroenteritis in order to determine the appropriate level of isolation measures, even when targeted therapy (e.g. for norovirus) is unavailable (Beal et al, 2018).

It is necessary to additionally test more than five bacterial targets as alternative diagnosesPrioritized "5 Goals" (i.e.. Salmonella, Campylobacter, Shigella,KryptosporidiumShiga-Toxin-ProduzentE coli), have been shown to benefit from specific therapy (see specific examples below). We recommend adding coverage for Group 2 CPT code 87506 (Targets 6-11) as detailed in the ICD10 Coding section

1. smaller Cryptosporidium: Prolonged symptoms may also occur in immunocompetent hosts. A randomized clinical trial of nitazoxanide demonstrated the effectiveness of an antiparasitic treatment in reducing the duration of symptoms and eliminating oocysts (Rossignol et al., 2001, Dupont 2016).
2. Clostridium difficile: Delays in diagnosis are common and associated with poor patient outcomes. Oral vancomycin may shorten the duration of symptoms (Guerrero et al., 2011).
3. Enteropathogen/EnteroaggregativcoliInfections in older adults respond to specific antimicrobial treatment (Nataro et al., 2006; Thorén et al., 1980; Wanke et al., 1998; Glandt et al., 1999).
4. enterotoxigencoli: Fluoroquinolone therapy may shorten the duration of symptoms in patients with enterotoxigenic disordersE colifrom an average of 3 days to 1 day (Mattila et al., 1993).
5. Yersinia enterocolitica:Symptoms, including chronic diarrhea in patients up to 94 years of age, can be easily managed (Saebø et al. 1992, Gayraud et al., 1993).
6. Vibration:Fluoroquinolone therapy confers clinical and microbiological response in patients withvibrio(Butler et al., 1993)
7. Giardien- Albendazole and metronidazole improve symptoms and shorten the time it takes to eliminate the parasite. (Grandados and Others, 2012)
8. Amoebic dysentery: Effective treatment options include metronidazole, tinidazole, and secnidazole. (Marie and Petri. 2013)
9. Cyclospora:Treatment reduces the duration of symptoms and shedding of parasites in persistent diarrhea in immunocompetent and immunocompromised hosts (Hoge et al., 1995).

A comprehensive review of persistent diarrhea by the Journal of the American Medical Association (JAMA) emphasizes the challenges of broad differential diagnosis, including enteropathogenic diseases.E coli,enteroaggregativeE coli,Clostridium difficile, Aeromonas, Campylobacter, Salmonella, Shigella,Norovirus,Entamoeba histolytica, Giardia, CryptosporidiumjCyclospora(Du Pont 2016). This review states: “Culture-independent diagnostic sequencing methods are now available and incorporate a multiplex approach that allows for the simultaneous detection of multiple bacterial, viral and parasitic enteropathogens in a single assay. These methods arefaster and has higher sensitivity than culture-based methodsThis facilitates identification of the many pathogens to consider when looking for the cause of persistent diarrhea." There are an estimated 226,000 foodborne illnesses in adults ≥ 65 years of age in the US, resulting in approximately 9,700 hospitalizations and 500 deaths, underscoring the burden of foodborne illness in older adults and the need for rapid diagnosis and treatment in this age group.

There is evidence that using GIP assays with more than five targets would benefit patients because of the incidental findings that result.. Convincing data indicate that it is an accidental findIt's toughhowever, it is beneficialIt's toughis one of the bacterial targets omitted from the LCD project. infections byIt's toughThey are a major problem for patients in long-term care facilities. A study at a long-term care facility operated by the Department of Veterans Affairs found delays in diagnosisIt's toughthey are common and associated with worse outcomes (Guerrero et al., 2011). IDSA found this outIt's toughis the leading cause of gastroenteritis-related deaths, largely explaining the increasing trend, with norovirus being the second most common pathogen, usually as co-infection withIt's tough(Halle et al., 2012). A lack of clinical suspicion can lead to underdiagnosisIt's toughCommunity infection (Reigadas et al., 2015). Increasing evidence suggests that a significant burden ofIt's toughthe infection is community-acquired and some of these patients lack traditional risk factors such as antibiotic exposure or recent hospitalization (Khanna et al., 2012). In the population-based study by Khanna et al. were 41% ofIt's toughCases of infection were community-acquired, and nearly a quarter of these cases had no prior history of antibiotic use.We recommend adding coverage for GIP tests with more than five targets (group 2 CPT code 87506).It's toughEvidence to reflect current practice and improve patient care.

Additional evidence that patients benefit from the adventitious detection of unexpected pathogens comes from a study that found that routine use of a multiplexed molecular panel (BioFire Diagnostics, Salt Lake City, UT) for diagnosis resulted in faster detection of an outbreak of cyclosporiasis had. . In the clinical microbiology laboratoryCyclosporaThe test is usually performed using a specially ordered, modified, acid-fast stained fecal swab. Prior to detection and during the early stages of the cyclosporiasis outbreak, unidentified specimens tested positiveCyclosporausing the FilmArray GI panel in the research study were not detected by the clinical laboratory because the clinicians did not order the modified acid-fast dye. When the medical community became aware of the outbreak, direct stool analysis was performedCyclosporabecame common practice, and stool samples collected from the clinical study later in the outbreak period were more likelyCyclosporaordered exam. Since then, the routine use of NAAT testing with more than five targets as a diagnostic tool would have resulted in faster detection of the cyclosporiasis outbreakCyclosporawould have been discovered before anyone specifically searched for this parasite (Buss et al., 2013).

Testing for more than five bacterial targets is a significant benefit for immunocompromised patients, including the elderly.Immunocompromised people are more susceptible to infection from enteric pathogens and are more likely to develop more serious illnesses and complications. The spectrum of etiologies in normal and immunocompromised hosts is similar (Guerrant et al., 2001), and gastrointestinal pathogens can cause persistent diarrhea in immunocompetent and immunocompromised hosts (Hoge et al., 1995, Rossignol et al., 2001). One study found that the effects of aging on the immune system manifest itself at multiple levels, including reduced production of B and T cells in the bone marrow and thymus and decreased functionof mature lymphocytes in secondary lymphoidsAs a result, older people do not respond as well to immunological challenges as young people, which qualifies them as immunocompromised (Montecino-Rodriguez et al., 2013). Failure to expand infectious targets beyond those prioritized in this LCD draft can lead to missed infections in susceptible patients and delay effective treatment. Timely identification and treatment of these patients would greatly benefit Medicare beneficiaries and, in turn, the Medicare program as a whole. Application of this testing strategy results in actionable diagnoses for Medicare beneficiaries.

Testing for more than five bacterial targets is a significant benefit for cancer patients with diarrhea.A recent study confirms the benefits of these interventions in cancer patients. In a study of 311 cancer patients with diarrhea tested with the FilmArray GI Panel multiplex PCR assay, diarrhea was a very common occurrence.E coli, especially EPEC and EAEC. Patients' clinical symptoms were similar at presentation and 92% received antibiotic treatment and 87% of treated symptoms resolved, although some of the patients had been symptomatic for weeks at presentation. (Chao et al, 2017)

Testing more than five bacterial targets is cost effective.Additionally, a recent study showed that using these panels not only increases the detection of key pathogens, but also has the potential to reduce overall healthcare costs. When the impact of the FilmArray GI Panel on usage was assessed in 241 patients admitted or admitted to the ED, there was a significant reduction in antibiotic use and abdominal or pelvic imaging compared to control patients diagnosed using conventional methods . (Beal et al., 2018).

Another study of hospitalized patients (n=800) compared the costs associated with laboratory testing and patient isolation when using conventional enteric pathogen testing with the Luminex GIP assay (Goldenberg et al., 2014). Goldenberg et al. report that while the GIP study increased laboratory costs (an additional £22,283), this approach reduced the overall cost of patient care by reducing the number of days patients remained under isolation protocols (£66,765 saving). When physicians order multiple single tests for faecal pathogens, which is likely in hospitals, the overall cost can be comparable to or more expensive than performing a single multiple test, making multiple tests less expensive (Ramanan et al, 2018).

Command:We recommend adding coverage for Group 2 CPT code 87506 (Targets 6-11) as detailed in the ICD10 Coding section

Command:In immunocompromised patients, e.g. Cancer patients receiving chemotherapy, transplant patients (e.g. kidney, liver or bone marrow transplant), intensive care patients and HIV-positive patients with diarrhea, we recommend coverage of group 2 CPT code 87507 (targets 12-25), as described in the ICD10 coding section. These patients are susceptible to mixed infections, including the viruses targeted by FDA-approved GIP assays.

We recommend that this LCD draft be updated to recognize that >5 targets need to be tested to achieve the LCD's stated target of covering 90-95% of foodborne infections. The LCD should reflect ACG guidelines supporting the use of broad GIP panels with >5 targets and recognizing that many of the pathogens detected by multiplex assays have specific treatments that may benefit patients. Clinical scenarios require molecular GIP assays consisting of >5 targets that are clinically necessary for the treatment of immunocompromised Medicare patients (including the elderly). Patients evaluated with GIP assays with more than five targets also benefit from incidental findings such asIt's tough. Coverage of actionable diagnostics beyond the 5 goals listed in this LCD draft will greatly benefit Medicare patients and improve their health outcomes.

Experts from our organizations who have reviewed this guideline believe that Palmetto's view of actionable gastrointestinal pathogens is too narrow. There are other common pathogens in the Medicare population that affect providers' correct diagnosis and treatment decisions. Acute gastroenteritis is an important cause of morbidity and mortality in the elderly.

Diagnosis of viruses that cause gastroenteritis is clinically necessary because they are associated with higher morbidity/mortality rates in the elderly and medical intervention is available.Norovirus is the leading cause of acute gastroenteritis in the United States and a common cause of outbreaks in long-term care facilities (Wikswo et al., 2015, White et al., 2016). Norovirus accounts for 10-20% of gastroenteritis hospitalizations and 10-15% of deaths from all causes gastroenteritis in older adults. People aged 65 and older are at higher risk of serious complications, longer stays and higher costs with 200% higher attributable mortality rates than other patient groups (Lindsay et al., 2015, Belliot et al., 2014). Although norovirus is the most common cause of gastroenteritis outbreaks in long-term care facilities, a significant percentage of outbreaks can also be attributed to rotavirus and enteric adenovirus (Gaspard et al., 2015, Gerber et al. 2011). Older people living in nursing homes are disproportionately affected by complications from norovirus infection. Norovirus is commonly included in GIP panels, but is not included in the LCD Project's limited list of covered targets. Pathogens such as norovirus have specific implications for the treatment and control of infections that can benefit patients and public health. Because norovirus needs to be included in the list of infectious agents for which identification is clinically required, we recommend coverage of Group 2 CPT code 87506 (Objectives 6-11) as described in the ICD10 Coding section.

Correct norovirus diagnosis influences therapeutic decision-making (think.Is intervention or prescription of antibiotics necessary?)For example, NAATs enabled faster detection of noroviruses andIt's toughInfections in elderly patients, in whom diarrhea is often initially mistaken for laxative use (Salmona et al., 2016). In this situation, a diagnosis is required before patients receive supportive care and hydration. Diagnosing a viral infection can also prevent the unnecessary use of antibiotics. This approach, in turn, can reduce the rate ofIt's toughinfections associated with antibiotic therapy and is expected to result in cost savings for the Medicare program. A study published by ASM showed that exposure to antibiotics andIt's toughInfection are closely related (Wenisch et al., 2014). The policy does not address the potential benefits to beneficiaries of NAATs that exclude or include a diagnosis with specific infection control implications (e.g., norovirus,It's tough).The CDC recommends isolating norovirus patients, using EPA-approved disinfection procedures, and using personal protective equipment, including masks with eye protection, for at least 2 weeks after clinical resolution. This is important because contact precautions can increase the incidence of delirium and other adverse events for the Medicare beneficiary (Day et al. 2012; Croft et al. 2015). The use of sensitive diagnostic assays can allow for accurate case identification, prevent secondary transmission to other Medicare beneficiaries, and benefit patients by avoiding unnecessary contact isolation in uninfected individuals (Mattner et al., 2015).Based on this evidence, we recommend that palmetto provide coverage for norovirus testing.This change would benefit Medicare beneficiaries and, in turn, the Medicare program as a whole.

As published evidence has shown, older people are at higher risk for gastroenteritis, but Medicare beneficiaries also include a smaller population of patients under the age of 65 (e.g., people with disabilities, patients with amyotrophic lateral sclerosis [ALS], or end-stage kidney disease) . . It is important that any policy related to GIP coverage adequately meets the requirementsthe entire Medicare populationand to ensure that everyone is given due consideration in all policy decisions. We recommend that the LCD draft be revised to recognize that viral pathogens can cause GI infections in patients of any age and that the Medicare population is at increased risk of complications, hospitalizations, and death from these infections.

codification

We support the recommendations of the ACG Clinical Guideline: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults (Riddle et al, 2016). Recommendation 3 specifies “Traditional diagnostic methods (bacterial culture, microscopy with and without special stains, etc.) Immunofluorescence and antigen tests) cannot reveal the etiology of most cases of acute diarrheal infection. Where available, the use of culture-independent diagnostic methods approved by the Food and Drug Administration (FDA) may be recommended as an adjunct to conventional methods.” We see that various FDA-approved laboratory tests detect anywhere from 4 to 22 different pathogens.

Experts in our organizations can describe very few situations where the clinical indicators are sufficiently robust to allow an accurate bedside diagnosis that would only require testing for a specific pathogen. A rare example of this type may be when hemolytic uremic syndrome (HUS) develops, indicative of infection with Shiga toxin-producing E. coli (STEC). Other potential scenarios where multi-target testing may not be required include outbreak investigations with a known pathogen (i.e. Norwalk virus) or antibiotic exposure suggestive of Clostridium difficile infection (CDI) but in the outpatient setting even this is not a very meaningful parameter. . Furthermore, there are few clinical scenarios where a study with 3-5 smaller endpoints (CPT 87505) compared to a larger panel would be appropriate. Such a rare scenario would be in a lab that has replaced culturing of stool bacteria with only molecular methods and wants to detect these culturable bacteria with a limited panel of 3-5 targets (e.g. BD Max, Prodesse). This laboratory would need to offer other tests using non-molecular methods (e.g. parasites) and perhaps also a separate molecular test for norovirus.

ICD10 codes supporting medical need for group 1 CPT code 87505.

The proposed policy lists codes ICD-10, A01.00-A05.3 as the only codes used in support of medical necessity. Based on available evidence, we propose that ICD-10 codes A01.00-A05.3 plus over 80 additional ICD-10 codes listed in the table below are the medical necessity for Group 1 CPT code 87505 support. 10 provides a detailed classification of disorders related to gastrointestinal infections, many of which codes are relevant to the proposed draft guideline. We request that additional ICD-10 codes be added to this policy including but not limited to the following list:

ICD10 codes apply to Group 1 CPT code 87505 for LCD DL37709

ICD10 codes supporting medical need for group 2 CPT code 87506.

Based on the evidence presented in the body of the letter, we propose that ICD10 codes that are appropriate for Group 1 CPT code 87505 are also appropriate for Group 2 CPT code 87506. We request that additional ICD-10 codes be added to this policy including but not limited to the following list:

ICD10 codes apply to Group 2 CPT code 87506 for LCD DL37709

ICD10 codes supporting medical need for group 2 CPT code 87507.

In the table below, we also advocate additional ICD-10 codes to support the medical necessity of Group 2 CPT code 87507 in immunocompromised patients, such as transplant patients and cancer patients receiving chemotherapy. Large syndromic panels have not been adopted by all labs, and there are still small FDA-approved panels that would meet ACG guidelines. Therefore, we are also requesting coverage for Group 1 CPT code 87505 and Group 2 CPT code 87506 when an ICD-10 code for immunocompromised patients is used in conjunction with these CPT codes.

We respectfully ask that you consider these comments, which were prepared by panels of experts, including members of the AGA, ASM, AMP, APHL, CAP, IDSA, and PASCV, who provide services to Palmetto-covered Medicare beneficiaries. Without hesitation we are ready to help you by providing you with additional clinical information, references, contacts or whatever is needed to help you with this LCD design.

We appreciate the detailed feedback from the reviewers. Based on these comments and reassessment of the evidence and guidelines, we are amending the LCD to allow testing for the presence of 6-11 pathogens to allow testing for additional organisms, specifically Clostridium difficile. It is unclear whether testing for more than 11 pathogens is necessary after proper history and screening, nor is it necessarily able to provide actionable clinical information regardless of the immune status of the patient being tested. Therefore, testing for more than 11 pathogens will continue to be an uncovered service.

From my point of view, multiplex GI panels were a revolutionary advance for my diarrhea patients. More sensitive assays allow laboratories to make a specific microbiological diagnosis five times faster than before, provide targeted treatment that is more likely to work, and withhold empiric treatment when the cause is a virus. antibiotics. Specific and effective treatments are available for many of the targets included in the new multiplex panels, including not only Salmonella, Shigella, Campylobacter and C. difficile, but also less valued pathogens such as ETEC, EPEC, EAEC, Yersinia enterocolitica , Vibrio spp. B. Giardia duodenalis, Entamoeba histolytica, Cryptosporidium parvum and Cyclospora cayetanensis.

Because the clinical signs and symptoms of the various causes of acute gastroenteritis overlap so much, I think it makes much more sense to commission a "syndrome panel" than to expect doctors to list all possible infectious causes of diarrhea, since they will surely be overlooked by some . I do not believe that using a culture-agnostic diagnostic test interferes with public health efforts because the lab performs targeted cultures each time a molecular test detects a culturable pathogen, allowing the public health lab to continue receiving its isolates. Instead, the lab is now detecting more foodborne pathogens that would have been missed with less sensitive culture-based approaches, boosting public health efforts. It was also a pleasant surprise that the higher cost of assay reagents is largely offset by a reduced lab workload and faster turnaround time, so the net financial impact on the lab was not significant.

When these tests first became available, my primary concern was whether the additional diagnoses made possible by the multiplex panels were clinically relevant. Therefore, I decided to conduct a prospective multicenter study to compare the clinical features of patients detected by conventional methods with those detected only by the most sensitive PCR-based tests. After analyzing 1887 consecutive samples and their clinical correlations, the results were unequivocal: the patients identified by culture or PCR were comparable in almost all aspects and were judged by their physicians to be equally likely to justify antimicrobial therapy. The difference is that the faster test allowed doctors to provide specific rather than empirical treatment, and the faster treatment may result in shorter duration of symptoms as well as shorter clearance from the body, which should limit community transmission . We also found that clinicians were willing to discontinue antibiotic treatment if only virus was detected, and some of these patients would likely have received empiric antibiotics had PCR testing not been available. Our article has been accepted for publication in the journal Clinical Infectious Diseases and I am including an advance copy if you find it helpful.

As promised, here is a sub-analysis of patients ≥65 years from our study, which I did with the help of Dr. Rob Cybulski. At the end it contains a recommendation on the indication of tests in these patients. I hope the additional information is helpful to you. Please let me know if anything needs clarification.

Clinical impact ofFilmArray GI panel in patients ≥65 years

Patients ≥ 65 years of age represented 20.2% (382 out of 1887) of the total patient population studied during the period of our study (January to September 2017). A total of 52 elderly patients (13.6%) were diagnosed with an infectious cause for their gastroenteritis, including 22 cases in which patients were infected with two or more pathogens at the same time. The range of pathogens detected by FilmArray? was only comparable for patients aged ≥ 65 years and the general populationClostridioides difficileDetection rates vary significantly (p<0.0001) between these groups (Figure). These observations are consistent with the fact that our study population consisted predominantly of outpatients (82%) and patients with community-acquired diseases.It's toughInfections tend to be younger than those with nosocomial infections (Khanna et al., 2012).

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The distribution of pathogens detected in patients ≥65 years and the overall population showed some differences (Table 1), which was consistent with previous studies.Campylobacter, Salmonella, Shigella/EIEC and STEC (including O157:H7) accounted for only 18.7% of the total pathogens detected. Viral pathogens (particularly sapovirus and norovirus) accounted for a greater proportion of the total detections in patients ≥ 65 years of age (24%) than in the general population (15%). diarrheaE colienteropathogenic speciesE coli(EPEC) and enteragregativeE coli(EAEC) were also more common in the elderly population (37% vs. 30%). This is notable as pathogens such as norovirus, sapovirus, EPEC and EAEC are considered pediatric pathogens and may be underestimated and underestimated as pathogens in older adults (Nataro et al., 2006; Gaspard et al., 2015; White et al., 2006 ; White et al..al., 2016).It's toughand parasitic pathogens were found less frequently in patients ≥65 years.

The use of FilmArray has nearly doubled the sensitivity of laboratory detection of common bacterial pathogens for both FilmArray and conventional stool cultures in patients ≥ 65 years of age (Table 2). Two-thirds of patients ≥ 65 years of age in whom treatable targets were identified were receiving antimicrobial therapy, which was comparable to the treatment rate in the general study population. The median time from sample collection to the start of antimicrobial therapy was 21 hours. FilmArray detected an additional 35 cases of bacterial infection caused by E. coli or C. difficile diarrhea, none of which were curable by conventional culture. FilmArray has detected a parasitic infection (Giardia lamblia)UMBRELLAif the ordering physician did not order a stool and Giardia egg antigen test and would likely have been missed had no panel been ordered. The patient received targeted antiparasitic treatment. Eighteen cases of viral gastroenteritis were diagnosed using FilmArray, and the University of Washington Laboratory's Viral Gastrointestinal Pathogens (PCR) panel developed the same pathogen in one of the two cases ordered. In the other 16 cases, no specific viral test was ordered and diagnoses were likely missed. Although viral gastroenteritis is not treated with antimicrobial therapy, detection of a viral agent allows one to avoid empiric antibiotics, which put C. difficile at risk, and also triggers infection control precautions in hospitals and long-term care facilities to prevent other residents infect (Mattner et al., 2015). With regard to clinical visual acuity, patients ≥ 65 years with confirmed pathogens were very similar to the overall patient population in terms of clinical characteristics (Table 3). When patient records were reviewed for the presence or absence of symptoms characteristic of acute gastroenteritis, patients ≥ 65 years of age had a mean number of characteristics similar to the overall population (3.1 vs. 3.3 ), which indicates a comparable degree of disease severity. Elderly patients were hospitalized more frequently compared to the general population, although the difference did not reach statistical significance. This supports previous observations that older people are at higher risk for serious illness and acute complications of gastroenteritis such as immunosuppression (Belliot et al., 2014; Chen et al., 2015; Lindsay et al., 2015).

In conclusion, we found that the FilmArray GI Panel improved as in the general population in acute diarrhea (≥ 65 years), identified patients with clinical characteristics comparable to younger patients, and enabled physicians to take more therapeutic actions. timely and specific. decisions

According to recent guidelines from the American College of Gastroenterology (Riddle et al., 2016), specific indications for multiple diagnostic tests in elderly patients with acute diarrhea are the presence of dysentery, moderate to severe illness, or symptoms lasting more than 7 days. In addition, the guidelines indicate that the test may be indicated in vulnerable populations at risk of serious illness, including many elderly patients, as well as in patients with proven immunodeficiency or recent international travel.

Table 1. Comparison of positive evidence in ≥65 years and overall patient populations.

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NutsP-values ​​refer to comparison of percent positive between total samples analyzed by stool culture and FilmArray.

abbreviations. POS, positive sum; %TOT, positive percentage of total tested; %POS, percentage of positives over total positives; n / D; not applicable; n.s., not significant

1. FilmArray cannot differentiate between Shigella and enteroinvasive E. coli (EIEC).
2. FilmArray cannot distinguish between pathogenic and non-pathogenic strains of Yersinia enterocolitica
3. Detection by culture/immunoassay using the O157:H7 specific FilmArray GI objective
4. Total STEC, including O157:H7
5. Non-O157:H7 STEC isolates are not recoverable using standard culture techniques

Table 2. FilmArray comparisonUMBRELLAversus stool culture in the population of patients ≥65 years

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NutsP-values ​​refer to comparison of percent positive between total samples analyzed by stool culture and FilmArray.

abbreviations. POS, positive sum; %TOT, positive percentage of total tested; %POS, percentage of positives over total positives; at; not applicable; n.s., not significant

1. FilmArray cannot differentiate between Shigella and enteroinvasive E. coli (EIEC).
2. FilmArray cannot distinguish between pathogenic and non-pathogenic strains of Yersinia enterocolitica
3. Detection by culture/immunoassay using the O157:H7 specific FilmArray GI objective
4. Total STEC, including O157:H7
5. Non-O157:H7 STEC isolates are not recoverable using standard culture techniques

Tisch 3.Clinical characteristics of patients ≥65 years compared to the entire patient population

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Thanks for the detailed and thoughtful answer. We proofread the manuscript copy. It is important to note that this manuscript does not discuss medium or long-term outcomes and focuses primarily on short-term outcomes of the care process such as antibiotic prescription.

Therefore, we believe the scope of the study does not include the information necessary to change our coverage decision. It is worth noting that the Infectious Disease Society of America, in their 2017 guidelines, generally does not recommend the use of empiric antibiotics for gastrointestinal infectious diseases except in very specific circumstances. Even when an organism is identified, guidelines do not necessarily recommend specific antibiotic treatment for all organisms. While these guidelines may not be universal for all patients, we believe these guidelines reflect the broadly applicable and evidence-based use of antibiotics in the management of infectious diarrhea. Thus, in order for the results of this study to inform our coverage decision (although they do not necessarily change the decision themselves), we need at least data detailing the indications for the use of empirical and targeted antibiotic treatment in this study. . . .

Shane, AL, Mody, RK, Crump, JA et al., 2017. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for Diagnostic and Treatment of Infectious Diarrhea. Doenças Infecciosas Clínicas, 65(12), S.e45-e80.

While it is clear that high-order multiplex testing is not indicated for all patients with diarrhea, the availability of multiplex enteric infection panels has enhanced my ability to manage patients with diarrhea in many ways.

The American College of Gastroenterology recommends diagnostic testing for patients with diarrhea who have a) dysentery; b) moderate to severe illness; or c) symptoms lasting > 7 days. These recommendations are clear and clinically appropriate, and patients who fall into these categories can become infected with a variety of pathogens, including viruses, bacteria, and parasites.

While ideally a physician would be able to assess a patient's history, symptoms, and duration of illness and prioritize testing for enteric pathogens that would lead to a diagnosis in the fewest steps, several studies have shown that this is not clinical is. Reality. Symptoms of GI disease are not pathogen specific; Even statistical learning tools to assess criteria that can be used to predict viral, bacterial, and protozoal etiologies of infection are inadequate, suggesting that it is not possible to know with sufficient certainty what disease is present. And while the manifestations of the disease may be similar, the treatments are not. Even among the bacterial causes of diarrhea, antibiotics are suitable for some, but dangerous for others. And the use of antibiotics in viral or protozoal diseases is always inappropriate.

In addition to the therapeutic implications of diagnosing a specific bacterial or protozoal cause of diarrhea, diagnosing a viral cause of diarrhea also affects treatment in a number of ways. This includes reducing the use of antibiotics, which can have unwanted side effects such as dysbiosis and C. difficile, prolong symptoms and lead to new interventions. examination and treatment. Diagnosis of viral gastroenteritis allows for supportive measures to be initiated, as well as appropriate infection control measures at home, in the community, or in the hospital. Routine testing for viral gastroenteritis is not routinely available outside of multiplex panels.

In patients with severe or persistent symptoms, traditional enteric pathogen testing can be time-consuming and expensive. Before the introduction of multiplex panels, standard tests first involved a culture with a turnaround time of several days; Sometimes protozoal testing was included early, but often a negative bacterial result followed, leading to follow-up appointments and ongoing illness. In addition, many traditional tests are less sensitive than PCR and can therefore miss pathogens. The "diagnostic odyssey" of persistent gastroenteritis has been frustrating for both patients and physicians, often resulting in over- or under-treatment of the disease.

Patients with conditions that suppress the immune system are at risk of prolonged illness from a variety of gastrointestinal pathogens, which has implications for both the management of bowel disease and the subsequent management of their underlying disease. They are at high risk of contracting bacterial diseases, including C. difficile, but also serious and persistent viral infections.

Multiplex testing for gastrointestinal pathogens does not solve all of our problems, and there is a clear need for such testing by physicians and laboratory personnel. Repeat tests and re-tests for curing are generally not necessary when using a multiplex board. Interpreting the results can be complex, but we're learning more every day. Despite some issues, the availability of multiplex panels containing a variety of pathogens has improved care for our patients, both in terms of cost and patient and provider satisfaction. I hope that this type of testing will continue to be a covered benefit for the patients that I see.

Thanks for the comment. The ACG guideline for treating diarrhea does not provide clear guidance on which pathogens a patient should be screened for. For the purposes of antibiotic therapy targeting, the draft LCD will allow testing for those organisms for which the ACG guidelines contain specific recommendations for antibiotic therapy targeting. With regard to viral gastrointestinal diseases, we are not aware of any evidence that shows that better results can be achieved with large panel tests.

I am sure you have gleaned valuable information and data from sources far more qualified than me as you approach these logs. The purpose of this email is to emphasize our desire and willingness to continue working together and working towards the most appropriate reimbursement model for the Multiplex Syndrome Test. One that truly benefits Medicare beneficiaries while positively impacting the quality and cost of care. Please let us know if we can provide you with additional information and data to assist in this effort. We appreciate this opportunity to have these types of discussions and your openness to participate in them.

Thank you for this arrangement. We remain open to covering tests with proven analytical validity, clinical validity, and clinical utility.

Mercy Health Systems includes more than 40 hospitals throughout Missouri and neighboring states. Our hospital laboratories work together under the direction of our Board of Pathology Specialties (composed of highly experienced pathologists) and subject matter expert groups (composed of experienced clinical laboratory scientists) to determine which laboratory tests best meet the needs of our patients. . We chose to offer the BioFire FilmArray GI Pathogen Panel in our laboratories because we believe this assay benefits individual patient health, the health of our communities, and the fiscal health of our system.

Again and again we have seen the benefits of these rapid tests for individual patients. The coverage guide implies that the symptoms and signs of the infections analyzed in the gastrointestinal pathogen panels are completely different. If so, GI pathogens could be diagnosed by history and physical exam alone, which is definitely not the case. We have used the gastrointestinal pathogen panel to diagnose gastrointestinal diseases with great success. A middle-aged woman with 3-day diffuse abdominal pain and bloodless diarrhea associated with complex diseases, including lupus, was diagnosed with Cyclospora by a panel of gastrointestinal pathogens. A parasite was not expected and the diagnosis spared the patient further costly investigations and initiated appropriate treatment. A panel of gastrointestinal pathogens found that a young child with a few days of bloody diarrhea had salmonella, which was diagnosed days before results were obtained by traditional bacterial cultures. Appropriate antibiotic treatment can be started immediately. Knowing that antibiotics are contraindicated in some forms of bloody diarrhea, such as B. Shiga toxin-producing E. coli, in this case enabled the doctor to safely proceed with the appropriate treatment with a quick diagnosis. Since the launch of the GI Pathogen Panel in 2016, we have had many such stories. Once the diagnosis is made, we can stop looking for another cause of the patient's illness, even if it is a viral disease with no treatment other than supportive care. illness and the continued support of the patient during his illness.

The Gastrointestinal Pathogens Panel benefits the health of all our patients and communities. By quickly identifying GI pathogens, we are able to provide our physicians and public health officials with timely information to properly remove patients from high-exposure facilities such as daycares and initiate contact tracing. Early diagnosis makes it possible to quickly identify and treat other sufferers and prevent further infection. Considering all patients who underwent GI pathogen panel testing or traditional GI pathogen testing, we found that patients who underwent GI pathogen panel testing had a shorter median stay ( 2.3 days vs. 3.8 days in patients with a traditional diagnosis, n=7,008 in 2016 and 2017).

Perhaps our most prominent example of the public health impact of the GI Pathogen Panel was demonstrated this summer when we used the GI Pathogen Panel to detect an outbreak of Cyclospora. Other hospitals in the area that tested conventional bacterial cultures did not find a higher incidence of Cyclospora simply because they did not test.

Cyclospora, a parasitic infection, is not detected by bacterial cultures in stool and requires separate analysis of eggs and parasites using traditional methods. Through testing with the GI Pathogen Panel, we have identified over twenty State Laboratory Confirmed Cyclospora cases. On July 12, 2018, the St. County Department of Public Health announced. Louis released an announcement about the increased occurrence of Cyclospora in the region. Although the epidemiological investigation is still ongoing, this news prompted McDonald's to withdraw its salads from the Missouri market. Detection of this outbreak would have been late or missed if the GI pathogen panel had not been used.

Although critics of multiplex panels for gastrointestinal pathogens are quick to argue that the panel is more expensive than traditional culture, in our experience this is not the case. Taken together, the cost of bacterial stool culture, microscopic examination of oocytes and parasites, and viral testing exceed the cost of a number of gastrointestinal pathogens. In addition, we found that the panel of gastrointestinal pathogens leads to better utilization of our healthcare resources. Looking at the fixed and variable direct costs (including labor, medical supplies, medications, medical costs and capital) and indirect costs (indirect medical costs) for the 7,008 patients who underwent a gastrointestinal diagnostic test in 2016 and 2017 , we found that patients who had a BioFire FilmArray GI Pathogen Panel had an average cost per patient of $2743.64 less than patients who were evaluated using traditional methods.

As a healthcare system, we recognize that both a rapid multiplex pathogen panel and traditional approaches are expensive and have established guidelines to reduce unnecessary testing. Gastrointestinal pathogen panel tests are only allowed in patients hospitalized less than 24 hours. If the gastrointestinal pathogen panel is ordered in a hospitalized patient, the ordering physician should consult a pathologist regarding the indication for the test. This policy has proven effective in preventing inappropriate testing, and most tests ordered for hospitalized patients are canceled after consultation with a pathologist.

We all have to be stewards of limited healthcare resources, and we appreciate your commitment to seriously evaluating the utility of rapid diagnostic tests for gastrointestinal pathogens. Failure to reimburse this important and effective diagnostic tool harms our patients and our communities.

Our decision to limit coverage for multiplex GI panels applies only to Medicare coverage, not the entire network of care. Our coverage decision is based on our evaluation of evidence that large multiplex panels are not appropriate or necessary for Medicare benefit. As revised in the LCD draft, the Medicare benefit does not cover epidemiological and infection control testing. Therefore, the ability of these panels to be useful in such scenarios makes them not covered by Medicare benefit.

I am now writing about the latest LCD designs for Palmetto and other MolDx molecular GI testing program subscribers. As you know, the latest draft does not advocate reimbursement for multiplex nucleic acid amplification GI testing (NAATs), and as a clinician using tests such as the BioFire GI panel, I would like to explain why multiplex testing for infectious gastroenteritis Test methods are an advance and have a significant impact on patient care and potential patient satisfaction.

Multiplex DNA extraction PCR technology is one of the most important advances in clinical medicine in recent decades. In syndromic diseases such as diarrhea, whether acute or chronic, the ability to make an accurate and rapid microbiological diagnosis is crucial in terms of clinical management.

As you know, I specialize in gastroenterology, internal medicine, tropical medicine and travel. I have extensive research and clinical experience in the field of travelers' diarrhea over the last 25 years. One of the problems in diagnosis has been the fact that diarrhea is often proteinaceous and bacterial, parasitic and viral etiologies are often clinically indistinguishable but are approached very differently in terms of treatment. Before the availability of DNA extraction PCR, diagnosis relied on stool cultures, which often required special selective media and typically took 48 to 72 hours. In our hospital, one of the largest teaching hospitals in the country, only 5 bacterial pathogens were studied before this technology, so the vast majority of pathogens went undiagnosed. Likewise, in the case of parasitic causes, the microscopic examination of oocytes and parasites (O&P) with or without special stains is fraught with inaccuracy, since this procedure relies on a technician prone to over- or underestimate. Viral pathogens have been difficult to diagnose due to a lack of adequate commercial testing capacity.

Efforts to limit diagnostic options to the 4-5 most likely pathogens are not only bad practice, they are counterintuitive. In doing so, we will reinforce the bad practices of the last few decades and continue to overlook the vast majority of specific microbial pathogens. This is particularly important for travelers' diarrhea as there are etiological causes such as Giardia, Cyclospora and diarrhea-causing E.coli that are often missed by conventional testing. Even in community-acquired diarrhea, although most cases are viral, it is useful to demonstrate a viral origin and withhold antibiotics in the interests of antimicrobial management and prevention of antibiotic resistance.

In a recent study of the BioFire GI panel versus traditional testing methods, it was found that the cohort of patients tested on the GI panel had more targeted than empiric therapy. In cases where antibiotics were not indicated, e.g. in patients with Shiga toxin-producing E. coli, the study showed that empiric antimicrobial withdrawal was 47 hours faster than traditional methods (Cybulski, 2018). In another recent study, patients being tested as part of the BioFire GI panel were asked to reduce downstream testing methods such as CT scans, X-rays, and ultrasound compared to traditional methods, likely because the doctor was able to Identify infectious cause and stop looking for possible causes of diarrhea (Beal, 2018). Without the use of a comprehensive, rapid, and accurate test, many of the benefits found in these studies are unlikely to materialize.

Another point the project emphasizes is the need to identify only five known common causes of infectious diarrhea, mostly bacterial. Identifying viral and parasitic causes of acute diarrhea is also important and can inform not only treat/not treat decisions, but also infection control decisions, recommendations for a return to work, school, or other activities affecting the patient's health can affect affect .public. Health. In addition, studies have shown that treating parasitic infections can effectively shorten the disease (Rossignol, 2001) and in other cases, without treatment, prolong it by several months (Beal, 2018. MacKenzie, 1994) without the right course of therapy. Because potential viral and parasitic causes may not be routinely tested or have low sensitivity but represent a significant portion of the diarrheal burden in the US, their presence in a multiplex NAAT is appropriate.

In addition, current practice guidelines (ACG 2016 and ISTM 2017) recommend the use of culture-independent multiplex molecular tests to identify potential causes of acute diarrhea as they may influence patients' treatment decisions. The guidelines provide a framework for physicians to consider when considering which patients should undergo testing, treatment, and other patient management recommendations. The guidelines reviewed the existing literature and drew on expert opinion to make recommendations that include the use of culture-independent multiplex molecular tests and how they can be used to better inform clinicians about what might be affecting their patients.

We also know that diarrheal disease is not the benign, self-limiting disease we once thought it was. There is a non-negligible incidence of post-infectious sequelae such as chronic gastrointestinal symptoms after acute diarrhea such as post-infectious irritable bowel syndrome (PI-IBS), post-infectious functional gastrointestinal disorders (PI-FGD) and hemolytic-uremic diseases. Syndrome, Reactive Arthritis and Guillain-Barré Syndrome There is evidence that prompt diagnosis and treatment can reduce or eliminate these post-infectious sequelae and reduce potential morbidity and mortality.

Multiplex PCR technology also has the potential benefit of reducing healthcare resource consumption and reducing overall healthcare costs by providing complete and accurate infectious disease results in a clinically actionable timeframe. As a gastroenterologist, the use of this diagnostic technique has reduced the need for endoscopic interventions in my practice. I have had patients with chronic diarrhea scheduled for various endoscopic procedures where a stool sample has been found to have pathogens such as Giardia, sparing them the expense and inconvenience of these invasive procedures.

In summary, the latest LCD design involving molecular GI multiplex panels should be reconsidered and should include favorable reimbursement for such testing. Multiplex molecular GI testing has been shown to provide faster, more comprehensive, and more accurate results that can lead to more specific patient therapy/management decisions, leading to better outcomes and more likely patient satisfaction..This technology changed clinical practice and revolutionized the field of diarrheal diseases. I would strongly advise against limiting the number of goals and encouraging more dialogue. I am available for a conversation at any time.

Thanks for the comment. A notable limitation of GI pathogen testing is the inability to use the information to change patient care in ways that necessarily result in a better outcome. The comment raises the issue that nucleic acid amplification testing allows for targeted rather than empiric therapy. That is probably true, but it is unclear whether such a targeted therapy makes sense and is necessary for many patients or infections. Our coverage policy is designed to allow providers to test a wide range of organisms to identify those organisms that are clinically likely and whose identification will result in actionable clinical information. The LCD design reflects our understanding of what information is currently clinically useful. We will revisit this LCD when we learn of relevant new evidence.

Diatherix Eurofins is pleased to provide feedback to the Palmetto GBA on the decision to limit detection of gastrointestinal pathogens by molecular assays to 5 bacterial targets associated with foodborne illness.

Gastroenteritis

There are many causes of gastroenteritis, but the symptoms are similar. These common symptoms include vomiting, diarrhea, and abdominal discomfort. However, differences in cause (whether viral, bacterial, or both) make a significant difference in the magnitude of the severity and duration of symptoms. Not only does the clinician face the challenge of associating the patient's symptoms with a specific etiology, but non-infectious causes are common and include poor nutrition, malabsorption syndromes, various enteropathies, and inflammatory bowel disease.¹

When the etiology of bacterial gastroenteritis is examined, it becomes clear that each pathogen has specific pathogenic mechanisms that can provoke a spectrum from mild to severe disease. Some (like pathogensEscherichia coli) use different mechanisms that can start with mucosal ulcers and abscesses. The initial infection can progress through an inflammatory cascade and lead to enteric fever syndrome. With the above spectrum of diseases that can be caused by the pathogenE coligroup, the differentiation of the specific etiology in the group is very significant. Furthermore, a diagnostic test that can accurately predict the specific organism is not only necessary but essential.²When invasive infections occur, antimicrobial therapy can limit the adjacent and systemic spread of bacteria and also reduce the production of toxins that control enteric and extraenteric cellular processes. Appropriate interventional steps can control significant fluid loss and progression of infection.¹It is important to note that the culture technique cannot reliably and quickly distinguish between pathogens.E coli.³In addition, culture cannot readily distinguish non-culturable causes of infectious diarrhea, such as viruses and protozoa, which may also be present as co-infections. Delays in intervention and specific treatment not only worsen the patient's symptoms, but can also prolong recovery and encourage the spread of the disease.¹

As indicated by the proposed Local Coverage Determination (LCD) project looking at the use of multiplex NAATs, most of these gastroenteritis syndromes are "generally self-limiting".The fact is, they often aren't.Gastroenteritis syndromes caused by pathogenic species

E. coli, Salmonella, Shigella, Campylobacter, Aeromonas, Clostridium, Vibrio and Yersiniathey produce a considerable spectrum of diseases and their prevalence has doubled in recent years (see Table 1).⁴5 It should be of particular interest to CMS that the more than 17,000 gastroenteritis-related deaths tabulated by the CDCIt's tough83% of this was in adults over 65 years of age. Highly sensitive and specific molecular assays for the detection of pathogenic strains ofIt's toughare included in current American Gastroenterological Association guidelines of practice and the clinical impact of these sensitive and specific assays has been significant.⁴

It is important to note that the importance of co-screening in the assessment of gastroenteritis is absent from the draft LCD dialog. Viruses in combination with other viruses or bacteria can be an important factor in gastroenteritis; resulting in worsening of symptoms, prolonged clinical course and an increase in hospital admissions. Patients with co-infection represent a subset of patients with acute gastroenteritis who may require extensive management. Double infections raise the question of whether a single pathogen is responsible for the disease or whether several pathogens act synergistically.^{5 7}; The combinations of organisms commonly observed in gastroenteritis are shown in Table II.

In children, the influence of co-infections on the severity and duration of gastroenteritis has received increasing attention. For example, mixed infections with rotaviruses are common and include other viruses, bacteria, and protozoa. Several clinical studies have shown that children infected with rotavirus and a bacterial pathogen have more severe diarrhea and/or dehydration and a longer course of the disease. It is important to note that rotavirus infections (alone or in combination with another pathogen) cause approximately 611,000 child deaths per year worldwide. Better access to more comprehensive diagnostics, such as B. multiplex molecular testing, would lead to a better understanding of the need for more comprehensive treatment regimens to reduce the morbidity and mortality of these often dual infections.⁸

Additionally, the LCD draft proposes that the multiplex tests currently available as FDA-approved platforms or as LDTs ​​are a "one-size-fits-all" panel approach that is not limited to specific populations. In both FDA-approved platforms and LDT approaches to developing multiplex platforms for diagnosing gastroenteritis, the pathogens included in the test panels are those that cause disease in a variety of patient populations. Because patients seeking medical treatment are often symptomatic, these highly sensitive and specific assays have high positive and negative predictive value as a diagnostic tool, providing the physician with actionable data on which to base treatment. In addition, rapid diagnostics and aggressive treatment regimens have a positive effect on pathogen-oriented therapy and epidemiological control mechanisms that limit the spread of highly virulent bacterial and viral strains. It is true that many of these diseases are self-limiting, but others are invasive and create a spectrum of treatable diseases. Relevant and timely diagnoses often provide life-saving results.

Finally, neither culture-independent nor culture-independent diagnostic tests can reliably distinguish active infection from colonization; especially in infections with heavily colonized mucosal surfaces. Because there are no established thresholds for bacterial or viral load associated with true infection of mucosal surfaces, diagnosis is based on disease symptoms. Molecular assays are very sensitive, and this sensitivity can detect DNA or RNA fragments for weeks after a few infections. The most important diagnostic element for the doctor is whether the patient is symptomatic or not. Specific bacterial or viral loads indicative of infection have not been identified and are unlikely to be subject to the observed fluctuations in a patient's immune status. Relying on a single laboratory test (either culture or molecular) to determine if a patient is infected is currently beyond the capabilities of the laboratory.

Diploma

We call on the Palmetto GBA to reconsider its decision to provide limited coverage for multiple molecular gastrointestinal pathogen assays for up to 5 bacterial targets implicated in foodborne illness. The advent of molecular diagnosis has made it possible to anticipate the importance of mixed infections and will provide a better understanding of the epidemiology of diarrheal diseases and the contribution of mucosal immunology to the development and management of gastroenteritis in children and adults. These new technologies provide a more detailed and accurate picture of the pathogenesis of infectious diarrhea.

Table I. Pathogens Causing Common Gastroenteritis Syndromes*

*Rapid diagnostic tools inform the doctor in advance of a complication that may be developing.

Table II. Association of different microorganisms and their frequency⁶*

Total infections 27

*Routine detection of co-infections is possible with the multiplex PCR test.

References:

1. http://emedicina.Such asArtikel/176400-oveAnalyse.
2. Kaper et al. Pathogens Escherichia coli. Nature Reviews in Microbiology.vol. two; February,
3. 3.http://DX.makeÖRg/10.1016/8978-0-12-800886-7.00012-1.
4. Surawicz et al. Guidelines for the diagnosis, treatment and prevention ofClostridium difficile infections. Bitter. Day. gastronomy Flight 108: 478-498.
5. httDP://CDC.gov/mmwr/vorschau/mmwrTHml/ss6412a1.htm.
6. Valentinie et al. Co-infection in acute gastroenteritis predicts a more severe clinical course in children. EUR. J.Clin. microbial. Infect. Dis. (2013) 32:909-915.
7. Feghally et al. Viral co-infections are common and with an increased bacterial burden in children with C.difficultDecember 2013; 57(6):813-816.
8. Grimpell and others. Rotavirus disease: impact of co-infections. Ped Infect Dis Volume 27 (No. 1). January

Thanks for the comment. A notable limitation of GI pathogen testing is the inability to use the information to change patient care in ways that necessarily result in a better outcome. This comment specifically raises the issue that co-infection contributes to more severe disease progression and increased intensity of treatment required. However, according to current treatment guidelines, the nature and intensity of care for patients with gastrointestinal disease is generally based on symptomatic and physiological measures of disease severity rather than identification of the underlying causative organism. The LCD is designed to allow limited testing so that organism identification can be performed to identify organisms whose identification management should change.

Luminex Corporation is pleased to have the opportunity to comment on Noridian Healthcare Solutions' ("Noridian") LCD project referred to above, which relates to molecular assays for gastrointestinal pathogens (GIPs) identified by multiplex nucleic acid amplification assays (NAATs). become. Luminex manufactures two IVD Gastrointestinal Pathogen Panels, the xTAG® Gastrointestinal Pathogen Panel (GPP) and the VERIGENE® Enteric Pathogen Test (EP). These commercial panels have been cleared by the FDA for the detection of gastrointestinal pathogens in stool samples. Both Luminex In Vitro Diagnostic (IVD) tests, xTAG® GPP and VERIGENE® EP, are relevant to Noridian's LCD project.

Our interest in the LCD project relates to how it limits the scope of molecular GIP assays. We strive to ensure that the appropriate testing service is performed and is in accordance with the guidelines of the Nationally Recognized Specialty Medical Society.

1. Clinical guidelines of the Society for Medical Specialties

The LCD proposed by Noridian contradicts the expert panel's recommendations, which are based on a review of the scientific literature used to develop specific clinical guidelines. In April 2016, the American College of Gastroenterology (ACG) published the revised clinical guideline,Diagnosis, treatment and prevention of acute diarrheal infections in adults. In the revised clinical guideline, the ACG made a strong recommendation for the use of FDA-approved culture-independent diagnostic methods, at least as a supplement to traditional methods.1

The ACG clinical guideline endorses testing indications such as "Laboratory testing for an infectious etiology of diarrhea may be indicated for community-acquired diarrhea lasting > 7 days or travel-related diarrhea or diarrhea with signs or risk factors for serious illness." xTAG® GPP and VERIGENE® EP panels are serious disease factors.” The xTAG® GPP and VERIGENE® EP panels are discussed in the ACG clinical guidelines as FDA-approved laboratory tests for enteric pathogens.

The limited coverage in the LCD design is contrary to ACG clinical guidelines. Luminex is submitting this request to Noridian to expand GIP coverage to include testing for viral and parasitic pathogens when the clinical circumstances meet the indications for testing in the ACG guidelines.

2. ICD-10 codes supporting medical needs

Group 1:

The proposed policy only considers ICD-10 codes for gastroenteritis related to bacterial pathogens to support the medical need for Group 1 code 87505 (Goals 3-5). Luminex is asking Noridian to revise the ICD-10 codes supporting medical necessity to include the following viral and parasitic codes in Group 1:

A07.1 Giardiasis (Lambliasis)

A07.2 Criptosporidiose

A07.8 Other specified protozoal enteric diseases

A08.0 Rotavirus-Enteritis

AOS.11 Acute gastroenteropathy due to Norwalk agent

AOS.2 Adenoviral Enteritis

AOS.8 Other specified intestinal infections

Group 2:

The proposed policy only considers gastroenteritis codes associated with ICD-10 Group 1 bacterial and immunocompromised pathogens to address the medical need for Group 2 codes 87506 and 87507. Recipients using multiplex PCR assays because the specific treatment (combination of cyclosporine and mycophenolate mofetil) increases the risk factor for developing norovirus infection.2 The authors concluded that molecular tools can improve the detection of single enteric infections and several compared to conventional techniques and potentially significantly improved may be the key element in the treatment of severe acute diarrhea in transplant recipients.

Luminex is asking Noridian to revise the ICD-10 codes supporting medical necessity to include the following transplant recipient status codes in addition to the previously proposed group 1 bacterial, viral and parasitic codes:

Z94.0 Status do transplante renal

Z94.1 Cardiac transplant status

Z94.2 Lung transplant status

Z94.3 Heart and lung transplant status

Z94.4 Lebertransplantationsstatus

Z94.5 skin graft status

Z94.6 Bone graft status

Z94.7 Corneal transplant status

Z94.81 Bone marrow transplant status

Z94.82 Intestinal transplant status

Z94.83 Pancreas transplant status

Z94.84 stem cell transplant status

Z94.89 Status of other transplanted organs and tissues

3. Aetna Clinical Policy Bulletin (CPB): Polymerase Chain Reaction Test - Selected Indications

In April 2017, Aetna revised the above CPB and considered polymerase chain reaction (PCR) testing clinically necessary for the panel of gastrointestinal pathogens for certain indications. 3

Aetna covers gastrointestinal pathogen panels for the following indications: I) community-acquired diarrhea lasting ≥:7 days; 2) travel-related diarrhea; and 3) diarrhea with signs or risk factors for serious illness (fever, bloody diarrhea, dysentery, dehydration, severe abdominal pain, hospitalization and/or immunocompromised condition).

Aetna Medical Policy cites ACG Policy as a reference for this coverage benefit.

4. Clarification of pathogens listed in xTAG GPP and Verigene EP assays

We have revised the list of pathogens in the proposed policy and provided the following clarifications for the pathogens listed in the studies.

xTAG® Gastrointestinal Pathogen Panel (GPP):

The following pathogens are not listed in the Noridian LCD project: Vibrio cholera, Adenovirus 40/41 and Entamoeba histolytica. These pathogens are contained in the FDA-cleared device. FDA document K140377 lists the pathogens Vibrio cholera, Adenovirus 40/41, and Entamoeba histolytica contained in this FDA-cleared device.4 This document supersedes all other FDA documents and confirms that these pathogens are included in the GPP assay are included.

Verigene® Enteric Pathogens Nucleic Acid (EP) Test:

The following viruses are not listed in Noridian's LCD draft: Norovirus GI/GU and Rotavirus A. FDA document K142033 confirms that Norovirus GI/GU and Rotavirus A are contained in this FDA-cleared device.5 This document supersedes all other documents and confirms that these pathogens are included in the EP assay.

Luminex is asking Noridian to revise the draft policy to include the above pathogens.

5. Application for review for the EP test

Luminex Corporation manufactures FDA approved Verigene^®enteric pathogens

nucleic acid test. Noridian's LCD design names Nanosphere as the manufacturer. Luminex is asking Noridian to revise the policy to reflect Luminex as the manufacturer of the EP Assay.

references:

4. Riddle MS, DuPont HL, Connor BA. ACG Clinical Guidelines: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults. I'm J Gastroenterol. 2016;111(5):602-622.
5. Costa JF and colleagues. J.Clin. microbiological June 2013 Vol. 51 No. 61841-1849.
6. Aetna Clinical Policy Bulletin (CPB): Polymerase chain reaction test: selected indications (0650). Available at http://www.aetna.com/
7. xTAG® Gastrointestinal Pathogen Panel (OPP) 51O(k) SUMMARY OF THE ESSENTIAL EQUIVALENCE DECISION. FDA document K140377
8. Verigene® Enteric Pathogens Nucleic Acid Test (EP) 510(k) SUMMARY OF DECISION DETERMINING ESSENTIAL EQUIVALENCE. FDA document K142033.

Thanks for the comment. The explanation in the LCD text underlying the coverage decision agrees that the appropriate range of organisms for which immunocompromised individuals should be tested may be broader than the appropriate organisms for which immunocompetent individuals should be tested .

Some of the diagnoses that the Commentary proposes to include in Group I would be particularly indicated in immunocompromised recipients. Because the current LCD design allows for testing of a large number of organisms in an immunocompromised patient but not testing of a smaller number of organisms in an immunocompromised patient, we added ICD-10 codes that would indicate an immunocompromised individual. Group 1 code list status.

The Commentary also recommends adding a number of ICD-10 codes to the list of diagnoses covered in Group 2. We agree that transplantation can often be associated with immunosuppression. For this reason, we have included transplant diagnoses, which would typically accompany a state of immunosuppression.

BioFire agrees that the FilmArray GI panel should only be used when appropriate and clinically necessary.BioFire supports the appropriate use of diagnostic testing and believes that rapid, comprehensive diagnostic testing leads to better patient care and lowers overall healthcare costs. It is reasonable to assume that better patient care will be achieved when healthcare professionals can quickly get to the patient's diagnosis and treatment plan. The ideal diagnostic test would support this goal by providing a rapid, accurate, and comprehensive test result in a clinically feasible time frame.

Although molecular panel assays have higher reagent costs, overall healthcare cost savings can be realized by reducing the additional medical tests and procedures performed while the physician is trying to determine the cause of the disease, thereby reducing the number of physician visits . high. Improving triage, reducing length of stay (including time in the ED), reducing the number of secondary cases, and preventing adverse events associated with incorrect diagnosis and treatment. In addition, proper application of infection control practices can reduce the risk of nosocomial infections (by using appropriate contact precautions for patients who test positive), reduce costs, and improve patient care by preventing unnecessary isolation of patients (e.g., patients who test negative). or by identifying a pathogen that does not need to be isolated).

In fact, a poster presented at the recent AACC meeting (Beal, August 2017) found that implementing the FilmArray GI panel for inpatient pediatric and adult patients increased the diagnostic yield from 6.9% to 32.8% and improved the average time result of 54.75 hours. to 8.94 hours compared to traditional doctor-ordered tests. Next, implementation of the FilmArray GI panel resulted in a reduction in the number of additional stool tests compared to a matched historical control group (3.02 vs. 0.58, p=0.001), a trend toward shorter duration, longer, shorter Duration of antibiotics (2.12 days vs. 1.54 days, p=0.06), significantly fewer imaging studies (0.39 vs. 0.18, p=0.0002), and shorter length of stay after sample collection (3rd .9 days vs. 3.4 days, p=0.04). The reduction in length of stay was more pronounced in the adult population (4.3 days vs. 3.6 days, p=0.01).

The LCD draft outlines limited coverage for gastrointestinal pathogen (GIP) molecular assays to detect 5 bacterial targets, suggests that testing for viral etiologies is neither useful nor necessary, and restricts testing for parasites to travelers who are older than 2 weeks with symptoms and have a negative bacterial test for pathogens. BioFire disagrees with these recommendations and believes that they are not supported by the current medical literature or medical necessity.

Current tests for infectious gastroenteritis are suboptimal and require physicians to be intimately familiar with the composition and methods of laboratory tests. Several studies have shown that clinical testing practices for gastroenteritis are problematic, in part due to the complexity of which pathogens are covered by each test (Hennessy 2004; van den Brandhof, 2006; McNulty, 2014; Polage, 2011). In addition, stool testing suffers from low diagnostic yield, technical complexity, and long time to get results. As a result, doctors often order multiple tests for the same stool sample, or perform sequential testing until a causative pathogen is identified. For example, a study at a children's hospital (Stockmann, 2015) found that an average of 3 tests (range 1 to 10) were ordered per stool sample.

The FilmArray GI Panel was specifically designed to address the unmet medical need of providing a rapid, accurate, and comprehensive diagnostic test to identify pathogens that cause gastroenteritis. The composition of the FilmArray GI Panel was determined through careful review of the medical literature and in consultation with medical and laboratory experts. BioFire researchers compiled lists of possible pathogens that were carefully reviewed by medical experts. Pathogen-specific assays have been included in the FilmArray GI panelonlywhether the pathogen was known to cause gastroenteritis and whether they were considered clinically indicated by the panel of medical experts for the diagnosis of infectious gastroenteritis. In contrast, the menu for traditional microbiological tests (e.g. bacterial culture, O&P tests) is often based on laboratory test methods and not on medical needs or patient needs. For example, the LCD design suggests that theKryptosporidiumIt's a common cause of foodborne gastroenteritis, but the LCD only includes testing for 5 bacterial pathogens and says "most people with cryptosporidium...will recover without treatment." As a matter of fact,Kryptosporidiumcan cause very long-lasting diarrhea even in immunocompetent individuals, and a prospective, randomized, double-blind, placebo-controlled clinical trial demonstrated that nitazoxanide is effective in the treatment of cryptosporidiosis (Rossignol, 2001). Reason for exclusionKryptosporidiumof LCD appears to have more to do with pathogens found through cultured stool than with medical necessity and good patient care.

It is also well recognized that there are many causative agents of gastroenteritis and that they cannot be reliably identified from the clinical presentation. In fact, the American College of Gastroenterology (ACG) recently published guidelines for the diagnosis, treatment, and prevention of acute diarrheal infections in adults (Riddle, 2016). This guide includes the following quote,

“Because the symptoms of acute diarrhea are varied, attempts to diagnose the etiological agents or classes are subjective at best and imprecise due to overlapping symptoms. Although clinical features can be helpful in distinguishing between bacterial and protozoal causes, they are generally an unreliable indicator of the pathogen likely responsible. As with any syndromic disorder, symptoms caused by different agents can overlap significantly.

Instead of using the composition or number of pathogens from a multiplex panel as a guide to determining medical need, the American College of Gastroenterology (ACG) and the Mayo Clinic publishedClinical guidelines for the diagnosis of diarrheal diseases(Riddle, 2016; http://www.mayomedicallaboratories.com/it-mmfiles/Laboratory_Testing_For_Infectious_Causes_of_Diarrhea.pdf). These guidelines recognize that most cases of gastroenteritis are self-limiting and that patients should be treated with rehydration and supportive care when not requiredanymicrobiological tests. The guidelines provide clinical criteria for determining when a microbiological evaluation should be performed. These are limited to;

- Patients at high risk of spreading disease (ACG)

- For known or suspected outbreaks (ACG)

- Patients with bloody diarrhea, moderate to severe disease (defined as disruption of normal function) and those with symptoms lasting > 7 days (ACG and Mayo Clinic).

In addition, Recommendation 3 of the ACG Guide states:

„Conventional diagnostic methods (bacterial culture, microscopy with and without special stains, immunofluorescence and antigen tests) cannot reveal the etiology of most cases of acute diarrheal infection. When available, the use of Food and Drug Administration-approved culture-independent diagnostic methods may be recommended, at least as a supplement to conventional methods.

This statement underscores the well-known complexity of stool testing (consisting of many different and technically complex test methods) and the low diagnostic value. As already indicated, even after conducting several different tests, it is often not possible to identify the causative agent of the disease. In fact, the current IDSA practice guidelines for the management of infectious diarrhea (Guerrant, 2001) report that stool culture yields range from 1.5 to 2.9%, with a cost per positive result of US$952 to US$1,200. In addition, a properly performed O&P assay requires the collection and analysis of three different stool samples. This is known to be a technically difficult method with low sensitivity, low utility and low diagnostic yield (1.4%, Polage, 2011). In fact, the reason for the increasing use of multiplex molecular assays is that they address an unmet clinical need. Multiplex molecular tests were developed with a broader menu precisely because current test methods have low sensitivity and diagnostic power.

In addition to appropriate antimicrobial therapy, implementation ofappropriate infection control measuresis extremely important for the correct treatment of patients with infectious gastroenteritis. In a recent retrospective study (Rand, 2015), the FilmArray GI Panel was used to test frozen stool samples that had previously been tested for rotavirus andIt's toughfor infection control purposes. The study showed that 22% of the samples contained pathogens that should require infection control measures, including norovirus, rotavirus andIt's tough. Of these patients, 60% took no or no contact precautions, a total of 109 patient days. In contrast, 24.5% of patients with negative FilmArray GI Panel results were required to be unnecessarily contact protective measures for a total of 181 patient days. This study shows that contact precautions are not used judiciously without a prompt and complete test result, leading to an increased risk of nosocomial infections and the unnecessary costs and morbidity associated with improperly used contact precautions. These are important factors when it comes to caring for patients in hospitals and long-term care facilities. A separate study (Goldenberg, 2014) found that using a CIDT multiplex panel for inpatient care was cost-effective, as the increased cost of laboratory testing was more than offset by the cost savings from eliminating unnecessary contact arrangements.

According to current IDSA guidelines (Guerrant, 2001)Identifying the causative agent of gastroenteritis is important to make appropriate treatment decisions. For example, antibiotics are contraindicated when Shiga toxin is produced.E coli(STEC, increased HUS risk) andIt's tough(worsening of the infection) are the pathogens. Instead, antibiotics are indicated for severe or persistent gastrointestinal diseaseCampylobacter, vibrio,Plesiomonasjsalmonellain infants Antibiotics have also been shown to shorten the duration of gastroenteritis caused by , although not usually indicatedShigella, EnterotoxischE coli(ETEC), EnteroaggregativE coli(EAEC) und EnteropathogeneE coli (EPEC). This is an important consideration, particularly when treating elderly patients who are at highest risk of poor patient outcomes. The recommended antibiotic therapy (medication and dose) depends in each case on the pathogen and the clinical picture of the patient. The use of antibiotics is inappropriate when the gastroenteritis is caused by a viral pathogen and pathogen-specific therapies (antibiotics or antiparasitics) may be indicated to treat a parasitic infection.It's tough(oral metronidazole or vancomycin). Because pathogen identification in infectious gastroenteritis is important to patient management, it is clinically necessary and should be a covered service.

The use of culture-independent multiplex panels hassignificantly increased diagnostic yieldfor stool tests due to increased test sensitivity and extended test menu. Studies using the FilmArray GI Panel have identified a pathogen in ~40-50% of stool samples (Spina, 2015; Buss, 2015; Stockmann, 2016). The FilmArray GI panel is unique in that it also offers the benefit of results being available approximately an hour after the test begins, is technically simple to perform and requires very little intervention time by a technician.

Prior to this LCD DRAFT, BioFire had established a specific billing code (Z-Code) that had a lower reimbursement rate compared to CPT codes for multiple pathogens. The rationale for the specialized code was that the evaluation of the original test was based on the evaluation of a traditional molecular testing method (Luminex XTag) which requires much more laboratory resources including additional laboratory equipment (nucleic acid extraction device, PCR thermocycler and the specific Luminex instrument). ), more hands-on time for technologists, and more peripherals. The FilmArray GI panel is an easy-to-use system that requires only about 2 minutes of technician time, requires no additional lab equipment (just the FilmArray instrument), and virtually everything needed to perform the test is included in the package. kit.

Using the FilmArray GI panel to test patients who meet clinical criteria described by medical experts (ACG, Mayo Clinic) in conjunction with specific reimbursement for the test would be eligibleoffer the advantage of rapid and accurate pathogen identification at a reasonable cost.

In the past, clinicians did not have to select specific tests for individual pathogens. Samples were sent to the microbiology lab to be "cultured," and the lab was tasked with identifying any pathogens. The use of immunoassays and molecular methods rely on organism-specific antibodies or primers and have therefore required clinicians to select pathogen-specific tests. New molecular technologies have made it possible to return to the simultaneous evaluation of each sample for a comprehensive range of pathogens associated with the specific clinical syndrome. However, reimbursement for IVD PCR assays is currently based on outdated and no longer economically viable per-target models. BioFire recommends setting a rebate level based on an economic assessment of the specific technology. In this way, patient care can be improved by providing comprehensive diagnostic information for patients with gastroenteritis in a clinically actionable timeframe, without negatively impacting the cost of care.

In this section, BioFire provides answers to the specific information presented in Determining Local Coverage.

[MolDX has been reformatted below with a combination of italics and plain text to avoid using red text that was part of the commenter's original comment.]

Coverage indications, limitations and/or medical necessity

This contractor will provide limited coverage for molecular assays for gastrointestinal pathogens (GIP) identified by multiplex nucleic acid amplification assays (NAAT) and will limit GIP coverage to up to 5 bacterial targets covering the upper 90-95 % of food-borne viral infections ( [frequency of infection per 100,000 inhabitants] with decreasing incidence): Salmonella [15,89]; Campylobacter [12.97]; Shigela [5.53]; Cryptosporidium [3.31]; Shiga toxin-producing E. coli (STEC) non-O157 [1,64] and STEC O157 [0,95]. In immunocompetent individuals, most people with cryptosporidium, a parasitic disease, 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-related syndrome, nor do they represent organisms commonly found in a specific sample type, patient population, or population specific patient population are found to reflect the community. Acquired infections transmitted through food. Because of the unique clinical circumstances of immunocompromised patients, patients in intensive care units, and HIV-positive patients with diarrhea, GIP testing to detect bacteria, viruses, and parasites may be indicated and therefore a Medicare benefit.

BioFire Answer -Gastroenteritis has both infectious and non-infectious causes. Infectious causes include bacteria, viruses, and parasites, and while many infections are transmitted through food, they can also result from contaminated water sources and human-to-human transmission. The intended use of the FilmArray GI Panel is "for individuals with signs and symptoms of gastrointestinal infection." Test coverage should not be limited to foodborne pathogens. However, although limitedAccording to the CDC, the leading causes of death, hospitalization, and foodborne illness (www.cdc.gov/foodborneburden/questions-and-answers.html)

• not typhussalmonella,Toxoplasma,Listeriaand norovirus caused the most deaths.
• not typhussalmonella, Norovirus,Campylobacter, OfToxoplasmacaused most hospital admissions.
• Norovirus causes most diseases. Although norovirus usually causes mild illness, norovirus is a leading cause of foodborne deaths because it affects so many people and can cause serious illness in the elderly.

In the UK, the most common causes of community-acquired gastroenteritis are norovirus (16.5%), sapovirus (9.2%),Campylobacter(4.6%) and rotavirus (4.1%) (Tam, 2012). There are also non-infectious causes, such as irritable bowel disease or drug side effects, and it is often desirable to rule out infectious causes of gastroenteritis when non-infectious causes are being evaluated.

The rationale for limiting diagnostic testing to the 5 bacteria listed does not provide sufficient information to diagnose gastroenteritis. It ignores viral agents such as norovirus, which are the most common etiologic agents. In most of these cases, bacterial tests are negative and additional tests are ordered (eg, individual viral PCR test, EIA viral tests, O&P investigations), resulting in suboptimal quality of patient care, delaying proper patient treatment. and increase the risk of transmission.

bottom

Traditionally, stool testing algorithms have required physicians to consider which specific pathogens might be associated with individual cases of gastroenteritis and choose a testing regimen that ensures that all appropriate pathogens are targeted. In the context of community-acquired diarrheal diseases, large foodborne GIP panel tests for parasites and viral etiologies are neither useful nor necessary because these gastrointestinal diseases are:

• Usually self-limiting
• Virus-specific therapies are not available and
• Patients are managed with supportive care and hydration.

Travelers with symptoms for more than 2 weeks may request traditional testing of eggs and faeces for parasites and/or specific protozoal antigens or molecular testing after bacterial pathogen exclusion.

Response to Biofire- ACG and Mayo Clinic guidelines also state that most cases of gastroenteritis are self-limiting and suggest that no microbiological study should be performed unless the patient meets certain clinical criteria or risk factors. BioFire agrees that clinicians should select a testing regimen that ensures all appropriate pathogens are targeted. In any case, if clinical evidence points to a specific pathogen, a specific test should be ordered. In many cases, however, the clinical presentation is not indicative of a specific pathogen, and a complete, accurate, and immediate result increases the chance of identifying the pathogen at the time when the patient is most likely to benefit. The notion that screening for viral pathogens should not be a covered service just because there is no specific therapy is short-sighted. Medicare covers many tests to detect viral pathogens for which there is no specific treatment (ie, individual norovirus PCR test, rotavirus EIA test). Because patient management is more than just prescribing a drug. Identification of a viral pathogen confirms that antibiotics are not necessary and directs physicians to focus on hydration and supportive care. Excluding a full list of GI pathogens can aid in the proper diagnosis and treatment of non-infectious gastroenteritis such as irritable bowel syndrome, or deter patients from taking unnecessary and costly contact precautions. Furthermore, in immunocompromised individuals, particularly those undergoing transplantation, rapid identification of a pathogen can save lives and prevent nosocomial transmission.

Background (continued)

Medicare states that testing must be appropriate and necessary for the specific needs of a particular patient. Large panels that represent a consistent testing approach without considering the patient's medical history, time of year, clinical setting, and patient's symptoms are inappropriate or necessary and therefore not a Medicare benefit. A one-size-fits-all panel approach is not limited to specific population subgroups such as neonates, pediatricians, or adults, does not differentiate between the community-acquired source of infection and the source of travel, and does not differentiate according to the needs of selected patient populations, such as the ICU patient or immunocompromised patients. Furthermore, while identification of specific viruses may be of interest in an outbreak or from an epidemiological perspective, clinical management is not based on viral test results and is therefore neither useful nor necessary.

Response to Biofire- The composition of the FilmArray GI Panel was determined through careful literature review and consultation with medical experts. The panel was designed to take into account the low diagnostic throughput, the long time to obtain results and the reality that most stool samples have to be analyzed with many different tests, often without identifying the causative pathogen. This delays outcomes, wastes resources and leads to suboptimal patient care as the treatment plan must be determined without important diagnostic information. The FilmArray GI Panel is similar to a culture test, asking the lab to screen for a full set of pathogens that can cause a specific clinical syndrome (in this case, gastroenteritis). Traditional tests have such low throughput and slow turnaround times that the value of the tests is often questioned (Guerrant, 2001) and the cost per positive result is very high. BioFire encourages clinicians to carefully evaluate any given situationPatient medical history, time of year, clinical setting, and patient symptoms prior to ordering the FilmArray GI Panel and when interpreting the FilmArray GI Panel results.

Background (continued)

This contractor acknowledges that GIP studies are closed systems with no random access for physician-led, patient-specific studies. However, some labs choose to use GIP panel testing but only report the specific tests ordered by the physician. In other words, the lab “hides” unnecessary test results or uses disclaimers in its reports and only considers clinically necessary test results. Other laboratories report the results of all panel tests and add unnecessary costs to the healthcare system when reimbursement is directly related to the number of organisms on the panel. The FDA approved/cleared studies discussed below are similar to the limited sampling of bacterial organisms in acute diarrhea with the justification of medical necessity being noted on the patient's medical record.

Response to Biofire– As mentioned above, BioFire does not believe that reimbursement should be directly related to the number of organisms in a panel. Instead, the profitability of the individual test system in combination with the medical added value of clinically usable diagnostic results should be used to determine an appropriate level of reimbursement. Current compensation for the FilmArray System is based on technology evaluation for traditional PCR-based assays. These current models do not apply to easy-to-use sample-to-response systems. The reimbursement structure needs to change to make these valuable tests available for appropriate patient care. BioFire has already started assigning a specific Z-Code with a reduced refund rate to address this issue. We would appreciate the opportunity to discuss a reasonable refund rate for the FilmArray GI panel.

Nucleic Acid Amplified Probe Technique (NAAT) to identify microorganisms:

Tests performed by NAAT use a microorganism's DNA or RNA to directly identify specific bacteria, viruses and/or protozoa, rather than standard microorganism detection techniques such as bacterial culture, stained and unstained microscopy, direct fluorescent antibody tests, antigen Rapid tests, qualitative tests and quantitative immunoassays to identify antigens or toxins from stool and single complex PCR assays. Multiplex NAAT tests belong to the larger group of culture-independent diagnostic tests (CIDTs). CIDT includes, but is not limited to, simple direct probing and amplified probing techniques. This technology provides same-day results in hours instead of 2-3 days of time-consuming bacterial cultures and labor-intensive immunoassay processing of stool samples. CIDTs are presented to provide a more comprehensive assessment of disease etiology, increase diagnostic yield compared to traditional diagnostic tests, and allow early initiation of appropriate therapeutic agents targeted to the detected pathogens, if present, in lieu of empiric therapy until Culture results are available. .

CIDT testing has its challenges; Latent infection or colonization cannot be distinguished from clinically significant active infection. In addition, nucleic acid fragments from dead organisms can obscure organism identification, complicating clinical interpretation and potentially clinical management. In a comparative CIDT study, mixed infections were identified in 13-21% of positive prospective stool samples compared to only 8.3% by routine methods (culture/immunoassay/microscopy).

From an epidemiological and public health perspective, CIDT testing does not provide the culture isolates required for antimicrobial susceptibility testing, serotyping, subtyping, and whole genome sequencing, which are essential for monitoring trends, detecting disease clusters, and investigating outbreaks. For Salmonella, the inability to distinguish serotypes will prevent tracking large changes in incidence by serotype and severely limit outbreak detection and investigation (no Medicare benefit). For Shiga toxin-producing E. coli (STEC), it is not known which STEC-positive CIDT result represents 0157 versus non-0157 because culture is required to identify the serogroup.⁴

Response to Biofire– According to the rationale described in this MDC, the public health impacts should not be considered a medical necessity as they do not present a medical benefit to the specific patient. However, fast burst detection is one of the main benefits of the increased sensitivity and menu of CIDT molecular panels. In fact, during the 8-month clinical study for the FilmArray GI Panel, two distinct outbreaks of gastroenteritis (Cyclospora in Nebraska (Buss, 2013) and Shigellosis in Rhode Island (Prakash, 2015)) were identified and reported by health authorities in a recent publication on the impact of CIDT on foodborne disease surveillance (Shea, 2017).

Culture-Independent Diagnostic Tests (CIDTs) improve diagnoses in ways that significantly benefit patient care. CIDTs can test for a wide range of clinically important infections, including respiratory, blood, and intestinal infections, faster and more effectively than other methods. Many of the benefits and challenges of implementing CIDT were discussed at a CIDT forum organized by APHL and CDC in April 2012 (1). The APHL praises the benefits of CIDT technology and suggests actions all players can take to avoid unintended negative consequences (2).'

Health authorities recognize that new technologies need to be developed to replace older methods that rely on obtaining cultured isolates (e.g. sequencing). However, the CDC, APHL, clinical laboratories and IVD manufacturers also recognize that it is critical that the public and private sectors work together to find ways to obtain isolates when a CIDT is positive. BioFire's Vice President of Medical and Scientific Affairs (Dr. Christine Ginocchio) is actively working with the CDC on this issue, and BioFire fully supports "potential short-term solutions," including efforts to:

1. Encourage clinical laboratories to work with public health laboratories to continue culturing and isolating harmful bacteria from sick CIDT-positive individuals. Samples from patients with positive CIDT forsalmonellaShiga-Toxin-ProduzentColi,jShigellamust be cultured to isolate the bacterial strain. Selected laboratories should also do thisCampylobacter.
2. The CDC is considering ways to make subsequent cultures easier and less expensive for clinical laboratories.
3. CDC works closely with APHL, public health authorities, regulatory agencies, diagnostic laboratories, CIDT kit manufacturers and physicians to ensure that cultures are obtained in clinical laboratories when CIDTs are positive or the patient sample is positive. health labs so they can grow it.
4. Live DCs so they can be cultured if they test positive. BioFire meets this requirement because our samples are tested in a Cary-Blair transport medium that helps maintain viable organisms.
5. The CDC adapts surveillance systems such as the Foodborne Disease Active Surveillance Network orFoodNet(https://www.cdc.gov/foodnet/index.html) to include only infections diagnosed by CIDT.

In some cases, clinical laboratories perform the culture and in other cases, the sample is sent to the public health laboratory for culture recovery. In either case, culture can be limited to the recovery of a specific organism and does not require a full examination of the stool culture. This method has been quite successful in providing cultured isolates for public health needs and has improved the ability to detect foodborne outbreaks.

As a possible long-term solution, the CDC is working with partners to develop advanced testing methods (next-generation sequencing) that do not require bacterial isolates to provide the information health authorities need. These tests can also provide healthcare professionals with additional information about the pathogen's potential for antibiotic resistance or the likelihood of causing serious disease.

FDA Approved GIP Assays:

There are currently five FDA-approved GIP studies on the market, all of which are closed-system studies that do not allow random access for clinicians to screen for potential etiologic agents of diarrhea. These include:

• Hologic/Gen-Sonde ProGastro SSCS:
  • Identified targets:
    • salmonella,
    • Shigella,
    • Nucleic acids from Campylobacter (only C. jejuni and C. coli, undifferentiated) and
    • Shiga toxin 1 (stx1)/Shiga toxin 2 (stx2) genes (STEC usually contains one or both of the genes encoding Shiga toxin 1 and 2)
  • TAT (Response Time) - 4 hrs.
• Enteric Bacteria Panel (EBP) BD MAX von BD Diagnostics:
  • Identified targets:
    • Campylobacter spp. (fasting from the colon),
    • Salmonella spp.,
    • Shigella spp.,
    • enteroinvasive E. coli (EIEC),
    • Shiga toxin 1 (stx1)/Shiga toxin 2 (stx2) genes (found in STEC as well as Shigella dysenteriae
  • ACT - 3-4 hours.
• Nanosphere (EP) Verigen enteric pathogens:
  • Identified targets:
    • Group Campylobacter (composed of C. coli, C. jejuni and C. lari),
    • types of salmonella,
    • Shigella species (such as S. dysenteriae, S. boydii, S. sonnei and S. flexneri),
    • Group Vibrio (composed of V. cholerae and V. parahaemolyticus),
    • Yersinia enterocolitica,
    • Shiga toxin gene I and Shiga toxin gene 2 virulence markers, Shiga toxin-producing E. coli (STEC)
  • TTA - 2 hours.
• Luminex xTAG Gastroenterologie-Pathogen-Panel (GPP):
  • Identified targets:
    • Campylobacter (C. jejuni, C. coli and C. lari only)
    • Clostridium difficile (C. difficile) toxina A/B
    • Cryptosporidium (only C. minor von C. hominis)
    • Escherichia coli (E. coli) O157
    • Enterotoxigene E. coli (ETEC) LT/ST
    • Giardia (G. lamblia only) (also known as G. intestinalis and G. duodenalis)
    • Norovirus GI/GII
    • Rotavirus A
    • salmonella
    • Shiga-like toxin-producing E. coli (STEC) stx 1/stx 2
    • Shigels (S. boydii, S. sonnei, S. flexneri and S. dysenteriae)
  • TAT - <5 Std.
• Biofire Diagnostic GI FilmArray-Panel:
  • Identified Targets
    • Campylobacter (C. jejuni/C. coli/C. upsaliensis),
    • Clostridium difficile (C. difficile) toxina A/B,
    • Plesiomonas shigelloides,
    • salmonella,
    • Vibrio (V. parahaemolyticus/V. vulnificus/ V. cholerae), including specific identification of Vibrio cholerae,
    • Yersinia enterocolitica,
    • Escherichia coli enteroagregativa (EAEC),
    • Escherichia coli enteropatógena (EPEC),
    • Escherichia coli enterotoxigenica (ETEC) lt/st,
    • Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2 (including specific identification of E. coli serogroup O157 within STEC),
    • Shigella/Escherichia coli enteroinvasiva (EIEC),
    • Kryptosporidium,
    • 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 (Genogrupos I, II, IV and V)
  • TAT -1-2 hours.

All of the specific viruses contained in the GIPs are more common in young children than in adults. In one study, sapovirus was detected in 10% of all samples from children over 1 year of age and in 7.4% of samples from children 1 to 5 years of age.²Enteropathogenic E. coli (EPEC), historically associated with developing countries, is known to cause acute and persistent diarrhea in young children in the United States and was found in 24.8% of all samples from children < 1 year and 37% of which identified all samples from children between 1 and 5 years. EPEC strains can also be found in healthy children and adults, confusing their importance when identified in symptomatic children and adults.

Response from BioFire:Although high rates of viral infection are found in children, a recent systematic review of 225 articles on the burden of gastroenteritis in China identified high rates (∼29%) of norovirus infection in adults and the elderly, and in children aged 6 to 12 35 months of age (∼ 22%) (Zhou, 2017). An additional study conducted in Alberta, Canada, identified viruses in the diarrheal stool of 17.0% of the people tested, with norovirus GII being the most common (8.0%), followed by sapovirus (4.3%), rotavirus (2.0%), Astrovirus (1.8%). , Norovirus GI (0.9%) and Norovirus GIV (0.1%) (Leblanc, 2017). The prevalence of mixed viral infections in patients with diarrhea was 2.8% (n=11). Children aged 1 to 5 years had a higher prevalence of positive stools, followed by the elderly (≥70 years). Severe viral gastroenteritis in the elderly can lead to rapid dehydration, and failure to identify an outbreak early in long-term care can result in increased transmission, hospitalizations, morbidity, and mortality (Rajagopalan, 2016). A review of the literature showed that older adults are at greater risk of serious health problems associated with norovirus, hospitalization rates are higher, length of stay is longer, disease is more severe, and patients incur higher costs than younger patients (Lindsay, 2015) . Mortality rates in people 65 and older with norovirus were about 200% higher than in children under 5, underscoring the need for rapid screening for older adults and to prevent institutional spread.

FDA Approved GIP Assays: (Continued)

Likewise, the interpretation of the detection of C. difficile toxin A/B is challenging, especially in children < 1 year. 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 in children < 3 years of age should be interpreted with suspicion.⁵

BioFire's answer- Recent studies have documented significant exposureIt's toughCommunity infections (Chitnis, 2013). Many of these patients lack common risk factors, such as B. a recent hospitalization or use of antibiotics (Khanna, 2012). The use of GI panels increased the detection of non-suspectsIt's toughInfections when doctors sought a different diagnosis (Stockmann, 2014).

Indications for foodborne gastrointestinal testing

Acute diarrhea, often referred to as gastroenteritis, can be defined as passing a larger number of smaller-than-normal stools that last < 14 days. Acute diarrhea is usually associated with clinical symptoms such as nausea, vomiting, abdominal pain and cramps, bloating, gas, fever, bloody stools, tenesmus and urgency to defecate. It is the leading cause of outpatient consultations, hospitalizations and loss of quality of life experienced by both domestic and international travelers. The Centers for Disease Control and Prevention (CDC) estimates that the United States has 47.8 million cases annually, with an estimated health care cost of over $150 million.⁶Detection of microbial pathogens associated with gastrointestinal disease may be important in certain populations, such as:

Over a 20-year period, some foods that have been linked to foodborne outbreaks, such as milk (Campylobacter), seafood (Norovirus), unpasteurized cider (Escherichia coli O157:H7), raw or undercooked eggs (Salmonella), Fish (Ciguatera ) poisoning), raspberries (Cyclospora); strawberries (hepatitis A virus); and ready-to-eat meat (listeria).⁷

Although the etiological agents responsible for approximately 80% of GI diseases have not been identified or specified, norovirus and Salmonella spp. (non-typhoid) are currently the most commonly identified pathogens associated with foodborne illness in the US, representing 5.5 and 1.0 million cases each year and⁸Clostridium perfringens, Campylobacter and Staphylococcus aureus follow Norovirus and Salmonella spp. in reducing the incidence of foodborne illnesses acquired in the country. Diarrhea associated with medical care and antibiotics is also problematic, with the main pathogen being the toxin-producing Clostridium difficile.⁹More than 300,000 cases of C. difficile are diagnosed annually in the United States, resulting in a cost of more than $1 billion.

In 2015, the number and incidence of confirmed infections per 100,000 population for Salmonella (15.89), Campylobacter (12.97), Shigella (5.53), Cryptosporidium (3.31), toxin-producing Escherichia coli Shiga (STEC) No. O157 (1.64) reported. , STEC O157 (0.95), Vibrio (0.39), Yersinia (0.29), Listeria (0.24) and Cyclospora (0.13).⁴Among the confirmed infections, the vast majority were diagnosed by culture alone. Compared to the incidence in 2012-2014, the incidence of confirmed infections for non-O157 STEC (40% increase) and Cryptosporidium (57% increase) was significantly higher. For other pathogens, no significant changes were observed in 2015 compared to the previous 3-year means.⁴In addition to the 20,107 confirmed cases of infection, 3,112 reports of positive CIDT cases were added. In general, the incidence of most foodborne bacterial pathogens and cryptosporidia is highest in children younger than 5 years of age, with the exception of Listeria and Vibrio, for which the highest incidence occurs in individuals ≥ 65 years of age.¹⁰

BioFire's answer– The prevalences reported in the previous paragraph are inconsistent with the previous paragraph and reflect the limited number of pathogens considered. Norovirus is the leading cause of gastroenteritis and the leading cause of hospitalizations and death from gastroenteritis. Discrepancies in reported rates are directly related to the wide variety of testing methods, the varying sensitivity of testing methods, which pathogens need to be reported, and the lack of comprehensive standardized testing. Low rates of some pathogens are the direct result of a simple lack of routine diagnostic testing.

Indications for foodborne gastrointestinal testing(Continuation)

Many episodes of acute diarrhea are self-limiting and require fluid replacement and supportive measures. Oral rehydration is indicated for patients with mild to moderate dehydration. If dehydration is more severe, intravenous fluids may be needed. The routine use of antidiarrheal drugs is not recommended because many of these drugs have potentially serious side effects, particularly in infants and young children. Antimicrobial therapy is justified only in patients with severe disease or in people with severely compromised immune systems from drugs and other diseases.¹¹

Laboratory testing algorithms for infectious causes of diarrhea generally agree that tests for community-acquired diarrhea lasting less than 7 days without serious signs or symptoms (fever, bloody diarrhea, dysentery, severe abdominal pain, dehydration, hospitalization, and immunocompromised disease). . In general, GIP testing may be warranted when community-acquired diarrhea lasts ≥ 7 days, or the diarrhea is travel-related, or there are signs/symptoms of serious illness. Additional targeted testing may be indicated if GIP results are negative and diarrhea persists. Additional testing is not indicated for a positive GIP result unless clinical conditions change. Molecular testing for Clostridium difficile is warranted for treatment-emergent diarrhea onset after the third day of hospitalization or after recent antibiotic use.

Response to Biofire- This information is consistent with the use of the patient's signs and symptoms, rather than the testing menu, to determine when testing is clinically necessary. If testing for this patient population is limited to the listed bacterial pathogens, a pathogen would be identified less than 3% of the time (Guerrant, 2001).

Summary of Medicare Coverage Decision:

The GIP test is limited to no more than 5 bacterial pathogen targets. Testing for viral etiologies is neither useful nor necessary because these gastrointestinal disorders are usually self-limiting, virus-specific therapies are unavailable, and patients are managed with supportive care and fluids. Travelers with symptoms for more than 2 weeks may request traditional testing of eggs and faeces for parasites and/or specific protozoal antigens or molecular testing after bacterial pathogen exclusion. Large panels with viruses and protozoa are neither useful nor necessary in the case of community-acquired diarrheal diseases.

There is no Medicare benefit for the GIP test to be used by national, state, or local agencies to monitor diarrheal outbreaks, for epidemiological purposes, or to confirm the outcome of other etiological tests. Once the objective etiology of relapse has been identified, further evaluation of patients is generally not indicated and patients are treated empirically. However, if the clinical appearance deviates from the outbreak prototype, a targeted examination for the pathogen may be indicated. The Medicare benefit is specifically for clinical identification and disease management for a specific beneficiary. Medicare benefit is not extended for family or community monitoring or surveillance purposes.

restrictions

A GIP testTableit is a single service with a single service unit (UOS=1). A panel cannot be disaggregated and billed as individual components, regardless of whether the GIP test reports multiple pathogens and/or single targets. The panel is a closed system built 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 useful and necessary if ordered in addition to a GIP bacterial-pathogen panel and supported by documentation in the medical record.

references

Buss SN, Alter R, Iwen PC, Fey PD. Impact of independent panel-based culture detection of Cyclospora cayetanensis.November 2013; 51(11):3909.

Buss SN, Leber A, Chapin K, Fey PD, Bankowski MJ, Jones MK, et al. Multicentric evaluation of the BioFire FilmArray gastrointestinal panel for the etiological diagnosis of infectious gastroenteritis. Journal of Clinical Microbiology. 2015;53(3):915-25.

Chitnis AS, Holzbauer SM, Belflower RM, Winston LG, Bamberg WM, Lyons C, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 to 2011. JAMA Intern Med. 22 July 2013; 173 (14): 1359-67. doi: 10.1001/jamainternmed.2013.7056.

Goldenberg SD, Bacelar M, Brazier P, Bisnauthsing K, Edgeworth JD. A cost-effectiveness analysis of the Luminex xTAG gastrointestinal pathogen panel for the detection of infectious gastroenteritis in hospitalized patients. J Infect. 2015 May;70(5):504-11.

GuerreroRL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV,and otherPractical guidelines for treating infectious diarrhea.Clin Infect Dis. 1. Februar 2001; 32(3):331-51.

HennessyTW, Marcus R, Deneen V, Reddy S, Vugia D, Townes J, et al. Survey of medical diagnostic practices for patients with acute diarrhea: clinical and public health implications. Clin Infect Dis. 2004 Apr 15;38 Addendum 3:S203-11.

ChannaS, Pardi DS, Aronson SL, Kammer PP, Orenstein R, St Sauver JL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. I'm J Gastroenterol. January 2012; 107(1): 89-95.

leblanc d,English,Boras VF,Brasard J.,stop. The prevalence of enteric RNA virus in the stool of people with and without diarrhea in southwestern Alberta, Canada.Arch Virol.January 2017; 162(1): 117-128.

Lindsay eu, Wolter J., De Coster I., Van Damme P., Verstraeten T.A decade of norovirus disease risk among older adults in upper- and middle-income countries: a systematic review.BMC-Infection dis. 14 October 2015; 15:425.

McNulty CA, Lasseter G, Verlander NQ, Yoxall H, Moore P, O'Brien SJ, et al.METROManagementof suspected infectious diarrhea by UK GPs: are they right?Hno. J Gen Pract. 2014 ene;64(618):e24-30.

MurphyCN, Fowler RC, Iwen PC, Fey PD.Evaluation of the BioFire FilmArray® Gastrointestinal Panel at a Midwest University Hospital.Eur J Clin Microbiol Infect Dis. April 2017; 36 (4): 747-754.

Polage CR,Stoddard G.J.,RT Rolf,Petti CA. Medical uses of parasite testing in the United States from 1997 to 2006 and in a Cryptosporidium outbreak in Utah in 2007.J. Clin Microbiol.February 2011; 49(2):591-6.

Prakash VP, Leblanc L, Alexander-Scott NE, Skidmore J, Simmons D, Quilliam D, et al. Use of a culture-independent gastrointestinal multiplex PCR panel during a shigellosis outbreak: clinical laboratory and public health considerations. Journal of Clinical Microbiology. July 2015; 53(3):1048-9.

Rajagopalan S.,Yoshikawa TT. Norovirus infections in long-term care facilities.J Am Geriatr Soc.May 2016;64(5):1097-103.

Rand KH, Tremblay EE, Hoidal M, Fisher LB, Gray KR, Karst SM. Multiplex panels of gastrointestinal pathogens: implications for infection control. Diagnostic microbiology and infectious diseases. 2015;82(2):154-7.

Rätsel MS, DuPont HL, Connor BA.ACGClinical guidelines: Diagnosis, treatment and prevention of acute diarrheal infections in adults.I am J Gastroenterol. May 2016;111(5):602-22.

RossignolJF, Ayoub A, Ayers MS.Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide.J Dys infections. Aug 1, 2001; 184(3):381-4.

Shea S, Kubota KA, Maguire H, Gladbach S, Woron A, Atkinson-Dunn R, et al.The introduction of culture-independent diagnostic testing by clinical microbiology laboratories is a threat to foodborne disease surveillance in the United States.J. Clin Microbiol. December 28, 2016; 55(1):10-19.

Spina A, Kerr K, Cormican M, Barbut F, Eigentler A, Zerva L, et al. Spectrum of enteropathogens detected by the FilmArray GI Panel in a multicenter study of community-acquired gastroenteritis. Clinical Microbiology and Infection. 2015;21(8):719-28.

Stockmann C, Rogatcheva M, Harrel B, Vaughn M, Crisp R, Poritz M, et al. How well does medical screening microbiological testing detect Clostridium difficile and other pathogens in pediatric diarrhea? Insights with multiplex PCR-based detection. Clinical Microbiology and Infection. 2015;21(2).

Stockmann C, Pavia AT, Graham B, Vaughn M, Crisp R, Poritz MA, et al. Detection of 23 gastrointestinal pathogens in children with diarrhea. Journal of the Society for Pediatric Infectious Diseases. April 2016

Tam CC, O'Brien SJ, Tompkins DS, Bolton FJ, Berry L, Dodds J, et al.Changes in the causes of acute gastroenteritis in the UK over 15 years: microbiological findings from 2 prospective population-based studies of infectious bowel disease.Clin Infect Dis 2012 54 (9): 1275-1286.

van den Brandhof WE, Bartelds AI, Koopmans MP, van Duynhoven YT.general practitionerPractice in ordering laboratory tests for patients with gastroenteritis in the Netherlands, 2001-2002.BMC family practice. Oct 2, 2006; 7:56.

Zhou HL,Zhen-SS,Wang JX,Zhang C.J.,qiu c,Wang SM, and other. Burden of acute norovirus gastroenteritis in China: a systematic review.J Infect.17 June 2017. pii: S0163-4453(17)30208-6.

We appreciate the detailed feedback and the LCD test. We are expanding the readouts on our LCD screen to allow up to 11 pathogens to be tested if Clostridium difficile is one of them.

The above comment highlights that many pathogens implicated in diarrheal and foodborne illnesses are associated with adverse events. However, for many pathogens, we are not aware of evidence to show that identification of the pathogen will necessarily reliably predict outcomes in an individual patient, and as treatment is in many cases similar supportive care, addressing an individual's signs and symptoms oriented, regardless of the underlying pathogen, a positive identification of the pathogen does not necessarily provide actionable clinical information. The LCD design includes tests to enable identification of pathogens where this might be clinically feasible. The specific pathogens for which testing is recommended in the IDSA guidelines for treatment decisions (mentioned in the comment above) are covered by this LCD.

I am the founder of OmniPathology, a physician-run pathology laboratory specializing in gastrointestinal pathology. I am a gastrointestinal pathologist by training and work with many gastroenterologists reviewing their patients' biopsies. I receive requests from other pathologists asking for my expert opinion on difficult GI cases. I am also involved in training pathologists and fellows at UCLA and Harbor UCLA Medical Centers.

I am writing about the proposed LCD DL37350 title of the proposed LCD MolDX: Gastrointestinal Foodborne Panels Identified by Multiplexed Nucleic Acid Amplification Tests (NAAT).

Edel:Coverage indications, limitations and/or medical necessity

“This contractor will provide limited coverage for molecular assays of gastrointestinal pathogens (GIP) identified by multiplex nucleic acid amplification assays (NAAT) and will limit GIP coverage to up to 5 bacterial targets covering the top 90- represent 95% of infections. ([incidence of infection per 100,000 population] decreasing

incidence): salmonella [15,89]; Campylobacter [12.97]; Shigela [5.53]; Cryptosporidium [3.31]; Shiga toxin-producing E. coli (STEC) non-O157 [1.64] and STEC O157 [0.95]”.

FilmArray GI panel background

The FilmArray GI panel tests for 22 gastrointestinal pathogens: 13 bacteria, 4 parasites, and 5 viruses. The test setup requires 2 minutes of practice and provides results in about an hour. Upon completion, a report is generated detailing the result of each objective. Identifying the etiological agents of my patient's GI infection with the FilmArray GI Panel enables my clients (gastroenterologists and general practitioners) as referring physicians to make an informed therapeutic decision and assign specific treatment based on the pathogen(s). prescribe. who suffer from diarrheal disease. Patients are treated much faster for infections than if traditional stool culture had been ordered instead of the FilmArray GI Panel.

In addition, the early detection of infections not only helps to determine the appropriate therapy, but also counteracts the unnecessary prescription of antibiotics for viral diseases.

Despite the high incidence of GI infection, there are limited clinical guidelines for diagnosing and treating patients with suspected GI infection. In addition, traditional testing methods present a number of challenges in diagnosing the causative infectious agent. Challenges with traditional testing methods include:

• waste of time
• low profit
• insensitive/nonspecific
• complex to execute
• Collecting, storing and transporting multiple samples over several days is cumbersome and highly inconvenient for patients/family members, resulting in increasing delay and failure to perform recommended testing)

Rationale for clinical use

Because of the current diagnostic and treatment paradigm when GI infection is suspected, many physicians choose empiric broad spectrum antibiotic therapy as a first resort, or may prescribe an antibiotic that is ineffective against the specific pathogen and therefore may lead to drug resistance. . and a prolonged illness. In addition, many gastrointestinal infections can lead to post-illness complications, such as: B. Guillain-Barré syndrome, irritable bowel syndrome and reactive arthritis.

Unlike traditional stool analysis methods, the FilmArray GI Panel is fast, accurate, and complete.

As an example, we recently had a patient, a medical student, who had just returned from a volunteer trip to Africa. Suffering from severe diarrhea, he was in town over the weekend to visit family before returning to school. His family took him to a client of mine who requested the test on a Friday. We performed the test, which was positive for enteroaggregative and enteropathogenic E. coli. My client was able to prescribe the right antibiotic treatment and the patient was already on the mend before he went back to school on Sunday evening. Without the ability to deliver results quickly, this patient could not have been treated in such a short amount of time. Furthermore, accurate knowledge of the infecting organisms enabled targeted antibiotic coverage and avoided the empirical approach to antibiotic treatment.

During the microscopic examination of biopsies taken from patients with chronic diarrhea, the pathologist finds morphological changes that can sometimes be nonspecific. Previously, he reported the findings descriptively and provided the endoscopist with a differential diagnosis involving a long-standing infectious process and inflammatory bowel disease. In many cases, the primary presentation of IBD may not have the characteristics of a chronic lesion, and the exclusion of an infectious process helps the clinician narrow down the diagnosis. As you can see, with the help of such a comprehensive dashboard, the clinician gets better quality information.

Therefore, limiting the remuneration to 5 positions would not only be arbitrary, but also disadvantageous for the patients. Additionally, there is no option to test fewer organisms on these panels, and if the option is available, it would be impossible to predict which to choose. We live in a diverse society where people travel to and from different parts of the world and to rely on what is 'common' and 'unusual' in this case would lead to an unscientific guesswork process.

We agree that many organisms can cause symptoms in a given patient. However, for many organisms a positive identification does not necessarily provide clinically useful information and the LCD is intended to cover clinically useful information. The case example above does not appear to be representative of the Medicare population. When research becomes available showing the use of extensive testing in a population representative of the Medicare population, we are prepared to reconsider this coverage decision.

As a CAC representative for the California Medical Association, and also as a representative for the California GI Societies, I have comments that I hope Noridian will consider in various LCD designs.

DL37350 MolDX LCD Suggested Title: Gastrointestinal Foodborne Panels Identified by

Nucleic Acid Amplification Multiplex Assays (NAAT)

This is what you propose as indications of coverage, limitations and/or medical necessity

“This contractor will provide limited coverage for molecular assays for gastrointestinal pathogens (GIPs) identified by multiplex nucleic acid amplification assays (NAAT) andwill limit GIP coverage to 5 bacterial targetsrepresent the top 90–95% of foodborne infections ([infection incidence per 100,000 population] decreasing incidence): Salmonella [15,89]; Campylobacter [12.97]; Shigela [5.53]; Cryptosporidium [3.31]; Shiga toxin-producing E. coli (STEC) non-O157 [1.64] and STEC O157 [0.95]”.

While your comments on the evidence and cited references seem reasonable, limiting coverage to 5 pathogens is highly short-sighted and clinically burdensome and will discourage adequate and comprehensive assessments of the range of pathogens causing significant gastroenteritis. Normally healthy people with severe symptoms deserve a quick and accurate diagnosis, which antibiotic treatment, and if so, with which antibiotic, can be an urgent decision that cannot wait for weeks of symptom control, informed guessing if there is a better way. , or broad-spectrum shotgun antibiotics. Already, C. difficile testing is recommended for acute diarrhea in the community because of the increasing prevalence and the often incomplete pathogen exposure and antibiotic history in our patients.

The high-risk person may have a much greater potential for infectious agents and will sometimes need antibiotics, even if antibiotics are not used in immunocompetent patients. Additionally, if a more limited choice of antibiotics can be made, or if a pathogen is confirmed not to benefit from antibiotic treatment, we save not only cost and patient inconvenience, but also risks, of which C difficile is aware. . , Now. a great scourge.

Compared to paying multiple separate CPT codes for standard bacterial cultures for the range of bacterial targets, ordering C difficile toxin or other tests (PCR, GH or combined), and sometimes multiple O&P scans and Giardia antigen ( I understand All of this is often requested by GPs and ER doctors), here is a single test with a sample that can be easily shipped to a lab via UPS/FEDEX and can have a one-off turnaround time (e.g. Biofire), a big one Step forward.

Our own group discovered examples of Entamoeba, Vibrio, E. coli variant, co-occurrence of E. coli and C. difficile and other pathogens in the last 2 weeks, knowledge of which compromised treatment options.

I hope that this test will be used by hospital emergency departments once it is adopted by hospital laboratories and used to screen patients with acute gastroenteritis who have a positive diagnosis of viral syndrome versus C. difficile versus one of the “ 5 bacterial targets” possible difference, important difference. Even patients with symptoms that last 4 to 6 weeks and who have a chronic inflammatory bowel disease can now be examined much better for an infectious cause in many cases, which in some cases makes a colonoscopy superfluous. mesalamine or corticosteroids. .

Arbitrarily limiting payment, I stress arbitrarily, to the lowest MolDx payment tier and not recognizing the actual amount of testing performed is inappropriate or punitive for labs trying to meet the actual needs of physicians for their Medicare beneficiaries.

I would further question this policy considering the ordering doctor is NOT asking for 5 targets but for the full panel. The lab only does what the doctor ordered. This differs from the situation where a pathologist receives a pathological specimen (88013) and makes a decision on the extent of special staining or immunohistochemistry that can be performed; here it is the judgment and choice of the pathologist.

Therefore, we ask that the coverage limitation for this technology is NOT implemented.

We agree with the commenter that identifying some organisms may facilitate earlier appropriate targeted therapy. The LCD design is intended to allow clinicians to test for these organisms. In addition, recognizing that Clostridium difficile is also an infectious organism whose identification has clear implications for treatment, we allow testing of up to 11 organisms when Clostridium difficile is one of them.

Multiplex analysis of gastrointestinal infectious diseases

This analysis did not focus on Clostridium difficile colitis. Unfortunately, we now come to the panel test. I don't do this test without diarrhea. These infections are rare in my patients, but they can clear the antigen for a while. Viral testing in immunocompromised patients is necessary as they require isolation with norovirus, and oral immunoglobulin therapy is required for rotavirus, which does not always clear up in my patients. CMV colitis we do with invasive biopsy, but if we go to fecal CMV colitis test in immunocompromised and immunocompromised patients, treatment for CMV colitis is intravenous ganciclovir and high dose intravenous immunoglobulin. In addition, we often assess the viral etiology of diarrhea before performing colonoscopy in immunocompromised thrombocytopenic stem cell transplant patients to rule out viral infection before performing invasive biopsy to screen for graft-versus-host disease. C. difficile is a problem for immunocompromised or immunocompromised patients and frequent testing is required.

Thanks for the comment. We agree that testing for a wide range of gastrointestinal pathogens, including Clostridium difficile, is warranted in immunocompromised patients. Specific details on the CPT codes covered in the LCD allow for this, and we have made the LCD text explicit to recognize that testing for Clostridium difficile may be useful and necessary, and to recognize that testing for a broader range of organisms is required could be. useful and necessary in immunocompromised patients.