Response to Comments: Gastrointestinal Pathogen (GIP) Panels Utilizing Multiplex Nucleic Acid Amplification Techniques (NAATs)

A comment was received discussing the proposed changes in the context of the MolDX program. The commenter was concerned that the proposed changes were too restrictive of coverage for testing and could negatively impact patient care. The commenter stated that molecular testing in GI infectious disease greatly improves both the accuracy and turn-around-time of testing for microbial diagnosis. The commenter also stated that these test results are paramount to the clinical management of patients’ conditions and related concerns such as recommendations to return to work, school, and/or other activities. The commenter provided several examples and references in the literature to demonstrate how molecular testing, as compared to traditional laboratory testing, not only provides more comprehensive and accurate detection of potential infectious pathogens, but also allows more rapid modification of patient management such as selection of appropriate antimicrobials targeting the identified pathogen(s). The full-text articles cited were not included with the comment. The commenter also stressed that increased utilization of molecular infectious disease testing may reduce or eliminate post-infectious sequelae of acute infectious diarrhea. The commenter stated molecular testing may reduce subsequent utilization of healthcare resources and lower overall healthcare costs. The commenter expressed concern about restricting diagnostic possibilities to the four or five most likely pathogens and emphasized that molecular testing for acute diarrhea is recommended by current practice guidelines ACG 2016 and ISTM 2017.

Thank you for your comments. To avoid confusion, the proposed changes are not part of the MolDx program. Addressing the concern over restrictions in panel size, when coverage criteria are met, the policy generally allows 11 targets per test (not four to five targets) and additionally allows 12 or more targets in the context of acute or persistent diarrhea complicated by an immunocompromised state. While there were references included with your comment to demonstrate how molecular testing as compared to traditional laboratory testing and that it not only provides more comprehensive and accurate detection of potential infectious pathogens, but also allows more rapid modification of patient management such as selection of appropriate antimicrobials targeting the identified pathogen(s), full text literature was not submitted with this comment. Full text literature may be submitted via the reconsideration process outlined on our website when the LCD becomes effective.

After review of the comments, it has been decided that no changes will be made to the LCD as it is finalized.

The commenter stated their practice location has many travelers, many of whom travel internationally, and that the proposed LCD appears to be a game changer in the ability to identify the source of diarrhea precisely and efficiently.

Thank you for your comment. The revisions made in the proposed LCD were made based on the available literature. No changes to the LCD will be made as it is finalized. Full text literature may be submitted via the reconsideration process outlined on our website when the LCD becomes effective.

The commenter agreed with the proposed LCD’s limitation on repeat testing that uses the same GIP multiplex panel, such as following up a positive result for a single pathogen. However, the commenter disagrees on limiting the use of another, different, follow-up molecular test, like a single-analyte NAAT, to evaluate for clearance of an identified pathogen.

Thank you for your comment. In the summary of evidence in the LCD, there are a number of studies that support no testing of asymptomatic patients and no test for cure. Therefore, the intent of the LCD limitation is both single NAAT and multiplex NAATs are not considered medically reasonable and necessary when testing for clearance/cure. There will be clarifying language added upon finalization of the LCD to reduce confusion.

A comment was received regarding coverage criteria for GIP panels utilizing NAATs with 12 or more targets in the proposed LCD. The commenter expressed concern with limiting panels with 12 or more targets to patients with an immunocompromising medical condition. The commenter felt that these larger panels should also be available to elderly patients and patients with malignancies undergoing treatment, diabetes, malnutrition, and/or certain genetic disorders. The commenter was concerned these types of patients were not represented by the wording in the covered indications and requested that additional ICD-10 codes be added to Group 3 in the proposed Billing and Coding Article. The commenter included three studies with their comment that altogether are supportive of using larger panels with 12 or more targets to provide more rapid identification of a pathogen, allow earlier initiation of therapy, reduce misuse or overuse of antibiotics, optimize infection control, reduce use of unnecessary diagnostic services, inform time spent in infection isolation, and provide improved ruling-out of potential etiologies.

Thank you for your comment.

Regarding the request to clarify the Covered Indications for GIP panels with 12 or more targets: We believe the language written (“An immunocompromising medical condition with acute or persistent diarrhea”) in the LCD, which is further clarified by the listed ICD-10 codes for Group 3 in the Billing and Coding Article, adequately describes this category of patients.

Regarding the request to expand coverage for larger (12 or more targets) GIP panels: While the submitted literature does reinforce the usefulness of GIP panels, the provided articles do not clearly establish a minimum or maximum number of targets best suited for evaluation of patients in various clinical scenarios; instead, the studies utilized panels with established sizes (e.g., a 22 pathogen panel) and either compared these panels to standards of care (e.g., stool cultures) or other molecular tests that include different panels. Medicare only provides coverage for medically reasonable and necessary testing; thus, testing should be tailored to specific clinical circumstances and only ordered when it is expected to have an impact on clinical management of the patient. While large GIP panels may be able to encompass a broad differential diagnosis, often preliminary findings (e.g., history and physical) can rule out several potential etiologies, eliminating the need for indiscriminate testing. Additionally, please note that the proposed LCD only addresses testing in the outpatient setting. In the literature submitted by the commenter, the impact of GIP testing in the outpatient versus inpatient population was only briefly examined. One study stated, “In the outpatient population, we found no impact on either antibiotic therapy or the number of prevented diagnostic procedures (data not shown).” (Machiels JD, et al., 2020)

Regarding the request to add more ICD-10 codes to Group 3: ICD-10 codes for immunodeficiency, including secondary or other immunodeficiencies (D84.81 and D84.89 respectively), are provided in the Billing and Coding Article. It would not be correct coding to use the indications of diabetes, malnutrition, or certain genetic disorders as a primary diagnosis to support the use of GIP panel testing for infectious disease. These indications will not be added upon finalization of the proposed LCD and related proposed Billing and Coding Article.

Following review of the comments and the literature that was submitted, it has been determined that no changes will be made to the LCD as it is finalized.

Comments and suggestions were received from several professional societies via a group letter. The letter was organized into 3 comments with recommendations. The comments are summarized as follows:

Comment and Recommendation #1: The commenters expressed concern over the panel size limits imposed by the Covered Indications section found in the proposed LCD. They felt the panel size limits did not account for real-world testing availability and capabilities. The commenters pointed out that most practices would only use one platform and that manufacturers generally don’t provide more than one FDA cleared panel per platform. The commenters also stated that many laboratories do not have the resources needed to provide multiple platforms for various infectious disease panels. The commenters proposed removing the size limit distinction between immunocompromised populations and non-immunocompromised populations.

Comment and Recommendation #2: The commenters recommended allowing coverage for patients with significant evidence of a particular pathogen exposure (e.g., potential geographic outbreak) and for patients with acute diarrhea of less than seven days. They stated certain circumstances warranted earlier testing in order to control outbreaks or contaminated food sources. Additionally, earlier testing would protect others in the community who have health conditions or are in an immunocompromised state. Since the panels available to test for these indications are limited, the commenters recommended a 22-target panel be permitted for these indications.

Comment and Recommendation #3: The commenters agreed that retesting for the same GIP panel should not be covered. However, the commenters felt that in circumstances where two different panels are needed (e.g., testing with a small panel first and then using a larger panel if the former panel is negative but there is still a high degree of suspicion for an infectious etiology), the second panel should receive coverage. They recommended removing language prohibiting use of two different panels in the Limitations Section of the proposed LCD.

Finally, the following ICD-10 codes were suggested to be added to the related local coverage article:

A00.0 Cholera due to Vibrio cholerae 01, biovar cholera

A01.00 Typhoid fever, unspecified

A01.1 Typhoid meningitis

A01.2 Typhoid fever with heart involvement

A01.3 Typhoid pneumonia

A01.4 Typhoid arthritis

A02.0 Salmonella enteritis

A02.1 Salmonella sepsis

A02.20 Localized salmonella infection, unspecified

A02.22 Salmonella pneumonia

A02.8 Other specified salmonella infections

A02.9 Salmonella infection, unspecified

A03.0 Shigellosis due to Shigella dysenteriae

A03.1 Shigellosis due to Shigella flexneri

A03.2 Shigellosis due to Shigella boydii

A03.3 Shigellosis due to Shigella sonnei

A03.8 Other shigellosis

A03.9 Shigellosis, unspecified

A04.0 Escherichia coli enteropathogenic

A04.1 Escherichia coli enterotoxigenic

A04.2 Escherichia coli enteroinvasive

A04.3 Escherichia coli enterohemorrhagic

A04.4 Escherichia coli enteroaggregative

A04.5 Escherichia coli

A04.6 Yersinia enterocolitica

A04.7 Clostridium difficile

A04.9 Bacterial intestinal infection, unspecified

A05.0 Foodborne staphylococcal intoxication

A05.1 Botulism food poisoning

A05.2 Foodborne Clostridium perfringens [Clostridium welchii] intoxication

A05.3 Foodborne Vibrio parahaemolyticus intoxication

A05.4 Foodborne Bacillus cereus intoxication

A05.5 Foodborne Vibrio vulnificus intoxication

A05.8 Other specified bacterial foodborne intoxications

A05.9 Bacterial foodborne intoxication, unspecified

A06.0 Acute amebic dysentery

A07.1 Giardiasis [lambliasis]

A07.2 Cryptosporidiosis

A07.8 Other specified protozoal intestinal diseases

A08.0 Rotaviral enteritis

A08.2 Adenoviral enteritis

A08.11 Acute gastroenteropathy due to Norwalk agent

A08.19 Acute gastroenteropathy due to other small round viruses

A08.31 Calicivirus enteritis

A08.32 Astrovirus enteritis

A08.39 Other viral enteritis

A08.8 Other specified intestinal infections

A09 Infectious gastroenteritis and colitis, unspecified

A28.2 Extraintestinal yersiniosis

A49.1 Methicillin susceptible Staphylococcus aureus infection, unspecified site

A49.2 Methicillin resistant Staphylococcus aureus infection, unspecified site

A49.3 Mycoplasma infection, unspecified site

A49.9 Bacterial infection, unspecified

A87.0 Enteroviral meningitis

A87.8 Other viral meningitis

A87.9 Viral meningitis, unspecified

A88.8 Other specified viral infections of central nervous system

B08.4 Enteroviral vesicular stomatitis with exanthema

B15.0 Hepatitis A with hepatic coma

B15.9 Hepatitis A without hepatic coma

B19.0 Unspecified viral hepatitis with hepatic coma

B19.9 Unspecified viral hepatitis without hepatic coma

B33.8 Other specified viral diseases

B34.1 Enterovirus infection, unspecified

B34.9 Viral infection, unspecified

B95.0 Streptococcus, group A, as the cause of diseases classified elsewhere

B95.1 Streptococcus, group B, as the cause of diseases classified elsewhere

B95.2 Enterococcus as the cause of diseases classified elsewhere

B95.3 Streptococcus pneumoniae as the cause of diseases classified elsewhere

B95.4 Other streptococcus as the cause of diseases classified elsewhere

B95.5 Unspecified streptococcus as the cause of diseases classified elsewhere

B95.6 Staphylococcus aureus as the cause of diseases classified elsewhere

B95.7 Other staphylococcus as the cause of diseases classified elsewhere

B95.8 Unspecified staphylococcus as the cause of diseases classified elsewhere

B96.1 Klebsiella pneumoniae [K. pneumoniae] as the cause of diseases classified elsewhere

B96.2 Escherichia coli [E. coli] as the cause of diseases classified elsewhere

B96.3 Hemophilus influenzae [H. influenzae] as the cause of diseases classified elsewhere

B96.4 Proteus (mirabilis) (morganii) as the cause of diseases classified elsewhere

B96.5 Pseudomonas (aeruginosa) (mallei) (pseudomallei) as the cause of diseases classified elsewhere

B96.6 Bacteroides fragilis [B. fragilis] as the cause of diseases classified elsewhere

B96.7 Clostridium perfringens [C. perfringens] as the cause of diseases classified elsewhere

B96.81 Helicobacter pylori [H. pylori] as the cause of diseases classified elsewhere

B96.82 Vibrio vulnificus as the cause of diseases classified elsewhere

B96.89 Other specified bacterial agents as the cause of diseases classified elsewhere

B97.0 Adenovirus as the cause of diseases classified elsewhere

B97.10 Unspecified enterovirus as the cause of diseases classified elsewhere

B97.11 Coxsackievirus as the cause of diseases classified elsewhere

B97.12 Echovirus as the cause of diseases classified elsewhere

B97.89 Other viral agents as the cause of diseases classified elsewhere

B99.8 Other and unspecified infectious diseases

B99.9 Unspecified infectious disease

K52.0 Gastroenteritis and colitis due to radiation

K52.1 Toxic gastroenteritis and colitis

K52.2 Allergic and dietetic gastroenteritis and colitis

K52.81 Eosinophilic gastritis or gastroenteritis

K52.82 Eosinophilic colitis

K52.89 Other specified noninfective gastroenteritis and colitis

K52.9 Noninfective gastroenteritis and colitis, unspecified

Z51.11: Encounter for antineoplastic chemotherapy (i.e., associated with chemotherapy-induced immunosuppression)

Thank you for your comment.

Comment and Recommendation #1: Medicare only provides coverage for medically reasonable and necessary testing; thus, testing should be tailored to specific clinical circumstances and only ordered when it is expected to have an impact on clinical management of the patient. While large GIP panels may be able to encompass a broad differential diagnosis, often preliminary findings (e.g., history and physical) can rule out several potential etiologies, obviating the need for indiscriminate testing.

Comment and Recommendation #2: When a particular pathogen is suspected based on an exposure history, only a single organism test should be required. Panel testing would not apply to these clinical circumstances. Community outbreaks are usually caused by common infectious organisms, and thus these outbreaks would not require a GIP panel larger than 11 targets and/or a panel that tests for unusual infectious organisms. The health department and/or CDC would investigate and perform the testing for community outbreaks where an unusual infectious organism is suspected.

Comment and Recommendation #3: Circumstances where a second panel is medically necessary in the outpatient setting should be rare. Therefore, these situations will be evaluated on redetermination.

ICD-10-CM codes: The ICD-10-CM codes listed describe either a diagnosis of an infectious pathogen or a diagnosis of specific gastrointestinal condition. ICD-10-CM codes describing diagnoses of infectious pathogens would be expected to result from the infectious disease testing itself and would not be used to justify the ordering of infectious disease testing. The ICD-10-CM code diagnoses of specific gastrointestinal conditions represent non-infectious etiologies that would not be used to justify ordering infectious disease testing. Please note that several of the requested ICD-10-CM codes are invalid codes and the code descriptors for several of the codes were incorrect according to the ICD-10-CM Experts for Physicians 2022 manual.

Following review of the comments it has been determined that no changes will be made to the LCD as it is finalized.

The commenter is in agreement with and supports the Proposed Local Coverage Determination (LCD) for Gastrointestinal Pathogen (GIP) Panels Utilizing Multiplex Nucleic Acid Amplification Techniques (NAATs).

Thank you for your comment