Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
**History/Background and/or General Information**  
  
Diagnostic testing for identification of pathogens that are causative for
respiratory infections has evolved over the years. The aim is for rapid,
accurate, and sensitive identification in an effort to improve patient
outcomes through improved clinical decision making. These new technologies
include nucleic acid-based amplification techniques. The focus of this LCD is
respiratory pathogen panel testing, which typically includes detection for
multiple virus pathogens by amplification of target DNA and is currently the
most popular technique that can provide rapid, accurate, and sensitive
results.1  
  
Even with the widespread use of respiratory pathogen panel testing, only a few
methods are available that not only detect respiratory pathogens but are also
U.S. Food and Drug Administration (FDA) approved. Please see the FDA link for
approved/cleared respiratory pathogen panel tests. https://www.fda.gov/.2 It
is recognized that labs may not have FDA approval/clearance of their products,
i.e., laboratory developed tests (LDTs). At the time of this publication,
tests are not limited to FDA approved/cleared products only. Coverage for
tests is based on demonstration of analytical and clinical validity and
clinical utility at a level that meets the Medicare medically reasonable and
necessary requirement.  
  
**Covered Indications**  
  
Respiratory pathogen panel testing in the outpatient setting by a Part B
provider (e.g., physician's office, independent clinical laboratory) will be
considered medically reasonable and necessary when all of the following are
met:

  1. Panels with 5 respiratory pathogens are performed, and **BOTH** of the following criteria are met:
    * The outpatient setting is equipped to deliver timely reporting of results to providers **AND** ,
    * For patients where the test result aids clinical management with the goal of an improved health outcome for the patient.

**Limitations**  
  
The following is considered not medically reasonable and necessary:

  1. Panels with >5 respiratory pathogens performed in the Part B outpatient setting.3

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

**Introduction**  
  
This evidence review focuses on respiratory pathogen panel testing in the
outpatient setting and whether the evidence is adequate to draw conclusions
about improved health outcomes for the Medicare population. In general,
improved health outcomes of interest include patient mortality and morbidity,
as well as patient quality of life and function. The current clinical evidence
is based on guideline recommendations and clinical studies that demonstrate
the clinical utility of this testing. Specific outcomes of these trials in the
outpatient setting are focused on accurate detection and identification of the
pathogens in an effort to help guide clinical decision making. In other words,
does performance of this test in the outpatient setting affect patient care,
and ultimately, lead to reduced morbidity and mortality from respiratory
infections in the Medicare population. Accurate, rapid test results have the
potential to alter clinical management, such as initial medication
prescription and safe medication de-escalation, which will result in improved
patient health outcomes.  
  
**Internal Technology Assessment**  
  
PubMed was searched for prospective clinical trials that included the terms
molecular and respiratory. The studies that were found using these terms were
then screened for applicability to the adult outpatient population. Only two
studies were found that met the inclusion criteria. A search utilizing the
terms molecular and pneumonia found no new studies. The terms panel and
respiratory had 121 results and respiratory and immunocompromised had 59
results. The studies were then screened for inclusion of adults and outpatient
settings. Guidelines were searched for respiratory infections, especially
those which included patients who are immunocompromised. Additional studies
were found upon review of the bibliographies within other search criteria. For
inclusion in review, studies must be published in the English language and be
specific to the human population. All countries of origin were included if
broad inclusion for the clinical studies met the criteria. Ultimately,
prospective studies that included adults, had identifiable outpatients, and
had clinical utility outcomes for respiratory pathogen panel tests that
primarily change the clinician decision making as the surrogate for patient
outcomes of morbidity and mortality were included.  
  
**Systematic Review**  
  
Vos et al 20183 systematically reviewed evidence on diagnostic accuracy and
clinical utility for rapid (results < 3 hours) molecular diagnostics in
comparison to conventional molecular tests for respiratory viruses. The review
was conducted in a standardized, systematic manner and followed the guidance
of the Cochrane DTA Working Group. Inclusion, exclusion, and statistical
analysis plan are listed in the article and supplementary materials. In
estimating diagnostic accuracy, 63 separate reports were included in the meta-
analysis from 56 individual DTA publications. The median sample size in these
reports was 95 patients. Reports evaluated 14 commercial molecular rapid
diagnostic tests. Viruses evaluated include 29 studies of influenza A and B,
20 studies of influenza A, B, and RSV, and 14 studies of panels. Study
populations included both children and adults, but ages were not reported.
Results revealed the pooled sensitivity of all the tests was 90.9% (95% CI,
88.7% - 93.1%) and the pooled specificity was 96.1% (95% CI, 94.2% - 97.9%).
For clinical impact evaluation, 15 studies met inclusion criteria. The authors
note that these studies had large variation in design and quality. Study
design included 5 studies that were randomized diagnostic impact trials, 6
studies using a nonrandomized before-after design, and 4 observational non-
comparative studies. Seven studies were manufacturer sponsored. Most studies
included only adult patients. The Film Array test was the most frequent
diagnostic intervention. Clinical outcomes are listed and categorized in Table
4 of the article. Results show implementation of rapid molecular tests did not
decrease the number of antibiotic prescriptions or duration of antibiotic
treatment. The number of hospital admissions was not reduced by rapid
molecular testing. Safety outcomes did not differ between the intervention and
control groups. There was an increased appropriate use of oseltamivir in
influenza positive patients. The authors concluded: "In conclusion, rapid
molecular tests for viral pathogen detection provide accurate results. Even
though results on clinical impact of rapid diagnostic tests are conflicting,
there is high-quality evidence that rapid testing might decrease the length of
hospital stay and might increase appropriate use of oseltamivir in influenza
virus-positive patients, without leading to adverse results. We therefore
suggest considering implementation of rapid molecular tests within hospital
settings and recommend performance of high-quality randomized studies."3  
  
**Additional Clinical Trials**  
  
Brittain-Long 20114 designed a randomized study to determine if multiplex
testing for respiratory pathogen identification in adult patients with
symptoms of acute respiratory infections would have an impact on antibiotic
prescription rate in primary care settings. The patients had to have a
diagnosis of an acute respiratory infection, defined as a history of at least
two of the following symptoms: coryza/nasal congestion/sneezing, sore
throat/odynophagia, cough, pleuritic chest pain, shortness of breath or fever
for which the physician found no other explanation, with a duration of less
than 14 days. The sample size included 447 patients, though 406 were available
for analysis. Nasopharyngeal and throat swabs were collected and a multiplex
polymerase chain reaction (PCR) test with 13 viruses and 2 bacteria was
performed, at 12 outpatient sites in Sweden. Samples were collected at the
initial visit and at the follow-up visit 10 days later. Patients were
randomized to one of two cohorts. In the rapid cohort, clinicians received the
results on the day following patient inclusion into the study (within 24 hours
for the majority of patients), or the delayed cohort, where clinicians
received the results eight to twelve days later. The primary outcome was
antibiotic prescription rate at the initial visit and the secondary outcome
was the total antibiotic prescription rate during the study period. Patient
management was treating physician discretion. For the rapid result, 5.4% (9 of
202) patients received antibiotics at the initial visit compared to 12.3% (25
of 204) (P = 0.0005) of patients in the delayed result group. Upon
stratification by symptom duration 5 days, patients in the rapid result group
received fewer antibiotic prescriptions than patients in the delayed result
group. At follow-up there was no difference between the groups: 13.9% (28 of
202) in the rapid result group and 17.1% (35 of 204) in the delayed results
group received antibiotics. The authors conclude, "In conclusion we have shown
that access to a multiplex RT-PCR assay for the aetiologic diagnosis of ARTIs
may reduce the prescription rate of antibiotics at the initial visit in an
outpatient setting. To sustain the effect, it sees necessary to define how to
follow and manage the patient according to the result of the test, which
warrants further investigation."4  
  
Echavarria et al 20185 aimed to determine if timely diagnosis of respiratory
infection etiology could have an impact on medical management in the emergency
department, in Buenos Aires, Argentina. The study design was a randomized,
non-blinded study in children and adults with signs/symptoms of acute
respiratory infection with onset within the preceding 7 days that compared two
methods of testing. Patients were randomized to either the Film Array
respiratory panel or immunofluorescence assay (IFA) over two seasons. Median
time from sample collecting to reporting was under two hours for the
FilmArray-RP and 26 hours by IFA. A total of 156 children and 276 adults were
included. Changes in medical management included any change between the
initial intention to treat with antibiotics or oseltamivir and/or to order
complementary studies and the final decision, after test results were
available. Results were reported by telephone to the physician who initially
saw the patient, and at that moment the study team questioned the physician
about any changes in medical management between the original plan previously
documented on the standardized form and the final management plan that
included the test results. Changes in medical management were observed in both
groups, however patients in the FilmArray respiratory panel group were
associated with changes in medical management with an odds ratio of 15.52, 95%
CI; 1.99 - 120.83, in adults. This study was partially funded by a stakeholder
grant.  
  
May et al 20196 is a randomized clinical trial designed to evaluate the impact
of a multiplex respiratory test versus usual care control in an emergency
department. Pediatric and adult patients were included, and 191 patients were
enrolled (61 patients age 18 or older in the intervention arm and 59 age 18 or
older in the control arm) that met upper respiratory infection or influenza-
like illness inclusion criteria. Average age of the adult patients is not
listed, but comorbidities are listed. The primary outcome was an antibiotic
prescription, with the secondary outcomes as antiviral prescription, emergency
department disposition, and length of hospital stay. Clinicians and patients
were not blinded. The goal of test result reporting to the clinicians was
within 2 hours. Power calculations were done; however, enrollment did not
reach goal due to budgetary constraints. Some patients in the intervention arm
received antibiotics despite having a virus detected. "The magnitude of
antibiotic reduction was greater in children (-19%) vs adults (-9%, post hoc
analysis). There was no difference in antiviral use, length of stay or
disposition." The authors concluded, "Further evaluation of rapid multiplex
testing in the ED could see changes in outcomes if the limitations of this
study were addressed. This mainly includes identifying the right patient
population where testing can alter patient care (vs targeted testing or no
testing) and focusing on implementing comprehensive stewardship strategies
alongside diagnostic tools to ensure that testing is utilized appropriately
and effectively."6  
  
**Guidelines**  
  
The American Thoracic Society (ATS) and Infectious Diseases Society of
America's (IDSA) clinical practice guideline7 addresses high priority
questions using systematic reviews of high-quality studies. It is noted that
the evidence base was often insufficient and emphasizes the continued
importance of clinical judgment and experience, and the great need for
research. "Community-acquired Pneumonia (CAP) is an extraordinarily
heterogeneous illness, both in the range of responsible pathogens and the host
response." The need for individualized patient management is stressed. The
guideline focuses on patients in the U.S. who have not recently completed
foreign travel and do not have an immunocompromising condition, such as
inherited or acquired immune deficiency or drug-induced neutropenia, including
patients actively receiving cancer chemotherapy, patients infected with HIV
with suppressed CD4 counts, and solid organ or bone marrow transplant
recipients. In the conclusion it is stated: "Unfortunately, microbiological
testing has yet to deliver fast, accurate, and affordable testing that result
in proven benefit for patients with CAP in terms of more rapid delivery of
targeted therapy or safe de-escalation of unnecessary therapy. Exceptions
include rapid testing for MRSA and influenza. Until we have such widely
available (and affordable) tests, therapy for many or most patients with CAP
will remain empiric. Therefore, clinicians need to be aware of the spectrum of
local pathogens, especially if they care for patients at a center where
infection with antibiotic-resistant pathogens such as MRSA and P. aeruginosa
are more common."7  
  
The CHEST Guideline and Expert Panel Report8 is a 2019 systematic review that
developed recommendations related to acute cough due to suspected pneumonia or
influenza. Literature search did not identify an article addressing the
question of whether microbiological testing in addition to clinical judgment
rather than clinical judgment alone should be used to confirm pneumonia in
outpatients with acute cough. The below suggestion is offered:

"For outpatient adults with acute cough and suspected pneumonia, we suggest
that there is no need for routine microbiological testing (Ungraded Consensus-
based statement)  
 _Remarks:_ Microbiologic testing should be considered if the results may
result in a change of therapy."8

The IDSA's 2018 evidence-based clinical practice guideline for seasonal
influenza9 notes that timely diagnosis of influenza may increase the
appropriate use of antivirals and decrease the inappropriate use of
antibiotics. The grading of evidence is based on the U.S. Public Health
Service Grading System for ranking recommendations in clinical guidelines. The
recommendations for outpatient testing and panel testing include the following
statements:

  * "Clinicians should use rapid molecular assays (i.e., nucleic acid amplification tests) over rapid influenza diagnostic tests (RIDTs) in outpatients to improve detection of influenza virus infection (A-II)."
  * "Clinicians should use multiplex RT-PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized immunocompromised patients (A-III)."
  * "Clinicians can consider using multiplex RT-PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized patients who are not immunocompromised if it might influence care (e.g., aid in cohorting decisions, reduce testing, or decrease antibiotic use) (B-III)."9

**Consensus Statements**  
  
Ramirez et al's 2020 Treatment of Community-Acquired Pneumonia in
Immunocompromised Adults10 is a consensus document addressing initial
treatment of the immunocompromised patient who presents to the hospital with
community acquired pneumonia. It is noted that the number of immunocompromised
people at risk for CAP is increasing and is estimated to be 3% of the U.S.
population. The document includes a table (Table 2)10 that identifies patient
conditions qualifying patients as immunocompromised, which is listed below.

  * Primary immune deficiency diseases
  * Active malignancy or malignancy within 1 yr of CAP, excluding patients with localized skin cancers or early-stage cancers (e.g., stage 1 lung cancer)
  * Receiving cancer chemotherapy
  * HIV infection with a CD4 T-lymphocyte count <200 cells/L or percentage,14%
  * Solid organ transplant
  * Hematopoietic stem cell transplantation
  * Receiving corticosteroid therapy with a dose 20mg prednisone or equivalent daily for 14d or a cumulative dose >700mg of prednisone
  * Receiving biological immune modulators
  * Receiving disease-modifying antirheumatic drug or other immunosuppressive drugs (e.g., cyclosporin, cyclophosphamide, hydroxychloroquine, methotrexate)

They note patients with common comorbid conditions such as diabetes, chronic
lung disease, liver disease, kidney disease and the elderly and frail are
relatively immunocompromised; however, these patients are typically infected
with the same spectrum of organisms that cause CAP in younger or healthier
adults, with their treatments covered in the current guidelines. For the
immunocompromised, as defined in this article, they recommend a low threshold
for hospitalization, with the suggestion of a comprehensive microbiological
workup with the goal to perform pathogen-directed therapy and de-escalation of
therapy. The microbiologic workup should be individualized and includes a
table with specific immune deficiencies and associated respiratory pathogens.
Additionally, a negative nasopharyngeal PCR result does not rule out a viral
pneumonia, and with high suspicion the PCR should be done on bronchoscopy
samples. Furthermore, finding a virus by PCR does not rule out a bacterial
infection. The document does not address outpatient microbiological studies.  
  
**Contractor Adviosry Committee (CAC) Advisory Panel Meeting**  
  
General consensus from the CAC panel is that there is accuracy and reliability
in these respiratory pathogen panels and that the results of this testing may
improve patient health outcomes. The CAC panel also noted that there is a gap
in the literature when it comes to patient health outcomes related to the
results and how it affects patient treatment and/or management especially with
pathogens of lower prevalence that some of the respiratory pathogen panels
include.

Most respiratory infections are self-limited in immunocompetent hosts, with
some exceptions. For more serious infections such as CAP, patients can present
with a variety of symptoms, and it can be difficult to make the correct
diagnosis and enact appropriate treatment such as medication or
hospitalization. Clinicians use information obtained from a detailed patient
history and physical, and then may require additional information such as
chest x-ray and complete blood count with differential to help in decision
making. A particular concern is identifying pathogens that have targeted
therapies. Clinician decision making for patient management includes a
compilation of an array of information. In order to avoid the consequences of
a potential serious untreated infection, empirical treatment with antibiotics
is common even though viruses are in many instances the causative agents.  
  
In an attempt to provide appropriate targeted therapies, a diagnostic work-up
could include tests aimed at pathogen identification. Respiratory pathogen
panel testing has the advantage of rapid detection of multiple organisms,
which in theory would improve patient care via improved clinician decision-
making. However, limitations exist in understanding ideal testing strategies
and test interpretation.11 Sensitivity and specificity appear to be
established in respiratory pathogen panel testing, though there may be
important differences within panels for individual
pathogens.1,12,13,14,15,16,17,18 Infection occurrence by a particular pathogen
varies by region and time, in addition to patient specific risk factors.19
Predictive value is the tool that would better help the clinician narrow
pathogen identification and select the appropriate course of management.20
Pathogen prevalence as a causative organism varies as noted and prevalence is
related to predictive value; the test panels are static and may not include
the organism causing the infection. Additionally, it remains unclear how to
interpret a panel with multiple positive results; for instance, co-infection,
which does occur with varying frequency, versus contaminant, versus false
positives.19 These limitations may serve to lessen clinician confidence in
panel results and decrease the value of these panels as a decision-making
tool.  
  
Data of good quality for the clinical utility of multiplex respiratory
pathogen testing is limited.21 The strongest evidence comes from Vos 2017,3 a
systematic review and meta-analysis that examined clinical impact. The 15
studies examining clinical utility met broad inclusion criteria, and included
various study designs, pediatric and adult patients, outpatient and inpatient
settings, and different healthcare systems. The authors concluded that rapid
molecular tests for viral pathogen detection provide accurate results, but
that results on clinical impact were conflicting. They do suggest
consideration of rapid molecular tests within hospital settings. Brittain-Long
20114 is a study in the Swedish healthcare system that did not show a total
reduction in appropriate outpatient antibiotic therapy with panel testing.
Echavarria 20185 aimed to compare timely patient management by comparing two
diagnostic tests. It is a study in a different healthcare system as is
Brittain-Long4; the generalizability to the U.S. healthcare system is unclear.
The May6 study was limited in small sample size making it difficult to draw
conclusions. Summarizing the clinical evidence: in the outpatient
immunocompetent population, results from respiratory pathogen identification
via the current panels appears to be insufficient to assist in clinical
decision making to improve health outcomes, with the exception of testing to
identify influenza.3,22 Additionally, it is recognized that it is important to
identify COVID-19 as a cause of infection.  
  
Clinical practice guidelines are helpful in assisting clinicians in patient
management. The CAP guideline by ATS and IDSA7 recommends empiric treatment,
stressing the need for clinicians to be aware of the current pathogens in
their locality and to treat appropriately. They note rapid testing for MRSA
and influenza as being helpful in decision making, but that other
microbiological testing has yet to result in proven benefit as far as rapid
targeted therapy, or safe de-escalation of apparent unnecessary therapy. The
CHEST guideline8 and expert panel report for acute cough due to suspected
pneumonia or influenza suggests that there is no need for routine
microbiological testing and that it could be considered if the results may
result in a change of therapy. The IDSA guideline9 on management of seasonal
influenza recommends multiplex testing in hospitalized immunocompromised
patients and in those hospitalized but not immunocompromised if it might
influence care. There is no current support in guidelines for outpatient
multiplex testing for respiratory pathogens.  
  
In the immunocompromised, where concerns are great for poor outcomes, the data
comes primarily from the inpatient setting. In the inpatient setting, results
are inconsistent.23,24 To further help clinical decision-making, Ramirez
202010 addresses initial treatment of the immunocompromised, as defined in the
document, and recommends a low threshold for hospitalization, with the
suggestion of a comprehensive individualized microbiological work-up. The
document does not address outpatient microbiological studies.  
  
The CAC advisory panel meeting discussion reflected current literature. They
noted accuracy and reliability in these multiplex panels and that the results
of this testing may improve patient health outcomes, however there is a gap in
the literature when it comes to patient health outcomes related to the results
and how it affects patient treatment and/or management.  
  
In contrast, there is evidence to support influenza testing in appropriate
patients, particularly in the hospital inpatient setting.9,25 The importance
of differentiating COVID-19 from influenza, cannot be understated, which is
reflected in the CDC26 development of a 3 -pathogen respiratory pathogen panel
assay to differentiate COVID-19 from influenza A and B.  
  
The implementation of rapid molecular diagnostics to directly affect patient
outcomes and tackle antibiotic resistance requires a thoughtful approach.
Timely reporting, clinician education, decision support and evidence-based
guidelines based on test results are some of the processes that may improve
patient outcomes and lessen antibiotic resistence.3,20,27 Antibiotic
resistance is a critical concern and parallels appropriate patient management.  
  
New diagnostic tools aimed at rapid and accurate pathogen identification hold
great promise for patient management, and meaningfully address the critical
issue of antibiotic resistance. In consideration of improving patient
outcomes, high-quality research is critically needed to fulfill this promise.  
  
In summary, the studies demonstrate that other than testing for influenza and
recognition of the importance of identifying COVID-19, testing for multiple
pathogens using respiratory pathogen panel tests have not been proven to
impact clinical decision making resulting in improved patient outcomes.
Therefore, respiratory pathogen panel tests for greater than 5 respiratory
pathogens are not medically reasonable and necessary for the purposes of
Medicare coverage.