This is a laboratory test which will assist physicians caring for patients who
have developed pulmonary (lung) scarring.

This policy provides limited coverage for the EnvisiaTM Genomic Classifier
(VeracyteTM, Inc., South San Francisco, CA), a tissue based multi-analyte assay
with algorithm analysis test (hereafter called EnvisiaTM) for interstitial lung
disease (ILD) patients who are suspected of having idiopathic pulmonary
fibrosis (IPF) and who do not have a definitive usual interstitial pneumonia
(UIP) pattern by high resolution computed tomography (HRCT) or other known
cause of ILD. IPF suspicion increases significantly in patients greater than
60 years of age when HRCT is not definitive, and comorbidities in this
population make clinicians reluctant to perform surgical lung biopsy to obtain
a diagnosis due to significant procedure morbidity and mortality. EnvisiaTM
testing is performed on less-invasive bronchoscopy transbronchial biopsy (TBB)
samples and is intended to provide a categorical UIP or non-UIP result that
along with clinical and radiographic information may guide treatment without
the need or risk of surgical lung biopsy.

ILD is a heterogenous group of lung disorders, for which an accurate diagnosis
is critical to determining appropriate intervention for a given patient.1 IPF
is one of the most common interstitial lung diseases and frequently implicated
when there is no other known cause of ILD, and often necessitates surgical
lung biopsy to obtain a diagnosis. The natural history of IPF is described as
progressive decline in pulmonary function until eventual death from
respiratory failure or complicating comorbidity. Patients with IPF under age
50 are rare, with disease typically presenting in the sixth and seventh
decades of life and incidence increasing with older age.2 The incidence of IPF
is estimated to be between 8-17 per 100,000 person years in the general
population,3 and mean survival after diagnosis is 2 to 5 years.2 A study
evaluating Medicare claims data from 2000 to 2011 found that the incidence of
IPF in the Medicare population is significantly higher, 93.7 per 100,000
person years, than observed in the general population.4

Historically, lung transplantation has been the only proven treatment for IPF,
but its use has been limited due to supply of donor organs and poor survival
for IPF patients relative to other candidates.5 Recent clinical trials
evaluating the efficacy of anti-fibrotic therapy in patients diagnosed with
IPF have demonstrated a 50% reduction in the proportion of patients that have
absolute pulmonary function decline of 10% or greater, an increase in the rate
of patients with no pulmonary function decline, and improved progression free
survival.6,7 These findings suggest an improvement in patient outcomes when
IPF is accurately diagnosed and treated.

The pattern of UIP is the hallmark of an IPF diagnosis. The development of
evidence based diagnostic criteria for IPF in 2011 by an international
consortium of pulmonary societies, including the American Thoracic Society
(ATS), requires exclusion of known causes of ILD, a definitive UIP pattern by
HRCT, or specific combinations of UIP by HRCT and surgical pathology.2 Despite
efforts to standardize these criteria, interobserver agreement of categorical
UIP diagnosis by HRCT following the ATS guideline is moderate (52%) among
expert thoracic radiologists.8 And recent studies suggest that a minority
(13%) of patients being evaluated for IPF obtain a definitive UIP diagnosis by
HRCT, necessitating surgical biopsy as the next diagnostic step.9

Diagnosis of IPF by HRCT alone is challenging. As shown in Table 1, a
diagnosis of UIP by HRCT requires the coexistence of multiple radiographic
features of a UIP pattern and absence of features inconsistent with UIP. Those
features consistent with IPF may also be found in patients with other common
ILDs of known cause, such as chronic hypersensitivity pneumonitis (HP).10
Although guidelines place significant importance upon a thorough clinical
history to identify ILDs of known cause, up to 30% of patients with HP are
ultimately diagnosed without identifying a known cause, further complicating
clinician's ability to distinguish these diseases.11 Additional non-surgical
biopsy approaches to diagnosing ILDs of known cause that may be utilized
include bronchoalveolar lavage (BAL) for the identification of lymphocytosis
which may suggest occult hypersensitivity pneumonitis, and TBB which is useful
in diagnosing granulomatous disorders, such as sarcoidosis.2 While highly
specific for these indications and significantly less risk than a surgical
biopsy, pathologic review of BAL and TBB specimens have not shown to be
sensitive for detecting a UIP pattern.12

A patient survey led by the Pulmonary Fibrosis Foundation suggests that at
least half of patients with IPF are misdiagnosed at least once, and for up to
4 in 10 patients it takes a year to reach a final diagnosis.13 These data
suggest that many patients with IPF are being missed by HRCT and non-surgical
biopsy alone.

Missing an IPF diagnosis can prove fatal. The PANTHER trial challenged the
paradigm of treating patients that may have IPF with steroid and
immunosuppressive combination therapy that is the standard of care for many
ILDs of known cause. The trial demonstrated that the use of prednisone,
azathioprine and N-acetylcysteine (NAC) combination therapy compared to
placebo had an increased rate of death (8 to 1, p=0.01) and hospitalization
(3.2 to 1, p<0.001) in patients with diagnosed IPF.14 These findings highlight
the need for more sensitive and specific diagnostic techniques to identify
IPF.

Table 1. High Resolution Computed Tomography Criteria for UIP Pattern2

UIP Pattern (All Four Features) | Possible UIP Pattern (All Three Features) |
Inconsistent with UIP Pattern (Any of the Seven Features)  
---|---|---  
  
  * Subpleural, basal predominance
  * Reticular abnormality
  * Honeycombing with or without traction bronchiectasis
  * Absence of features listed as inconsistent with UIP (see third column)  

|

  * Subpleural, basal predominance
  * Reticular abnormality
  * Absence of features listed as inconsistent with UIP pattern (see third column)   

|

  * Upper or mid-lung predominance
  * Peribronchovascular predominance
  * Extensive ground glass abnormality (extent > reticular abnormality)
  * Profuse micronodules (bilateral, predominantly upper lobes)
  * Discrete cysts (multiple, bilateral, away from areas of honeycombing)
  * Diffuse mosaic attenuation/air-trapping (bilateral, in three or more lobes)
  * Consolidation in bronchopulmonary segment(s)/lobe(s)

  
  
When a definitive UIP pattern cannot be established by HRCT, ATS guidelines
recommend physicians consider surgical lung biopsy as the next step and
require the multidisciplinary integration of clinical, radiographic and
pathologic features against a series of formal diagnostic criteria to make a
diagnosis of IPF.2 While this leaves only a minority of scenarios where
clinicians are unable to categorically assign a diagnosis, clinicians are
increasingly reluctant to perform surgical lung biopsy in patients with
unclassifiable ILD due to significant safety concerns.15 Among 5 clinical
trials conducted since the year 2000 utilizing predominantly video-assisted
thoracoscopy for surgical biopsy for the diagnosis of IPF, common
complications include prolonged airway leaks (6-12%), pneumothorax,
hemothorax, pleural effusion, and a 30-day mortality rate of 3-4%.16 Procedure
risks are increased in patients with high oxygen requirements, pulmonary
hypertension, rapid disease progression, severely reduced forced vital lung
capacity, multiple coexisting conditions, or frailty.17 ATS guidelines
recommend clinicians consider the unique clinical situation of each individual
patient as to whether the risks of surgical lung biopsy outweigh the benefits
of establishing a diagnosis of IPF.

Over the past decade transbronchial cryobiopsy has been investigated by major
lung disease centers as an alternative to surgical lung biopsy. Cryobiopsy
provides a larger biopsy specimen than TBB, which is generally associated with
a greater diagnostic yield. Cryoprobes work by applying cooling agents under
high pressure causing pulmonary tissue to adhere to the cold probe tip and the
tissue is then extracted. A recent meta-analysis of diagnostic yield using
cryobiopsy in the diagnosis of ILD showed a mean yield of 73% with significant
heterogeneity across 27 independent studies where diagnostic yield ranged from
40% to 95%.18 Complication rates of cryobiopsy are not insignificant and most
commonly include pneumothorax and significant bleeding. The pooled incidence
of pneumothorax was 9.4%, significant bleeding was 14.2%, and 30-day mortality
0.3%. The authors conclude that cryobiopsy when compared to TBB increases
diagnostic yield; however, there is a significant concomitant increase in the
risks of pneumothorax (from 0.7-2% to 9.4%) and significant bleeding (from
1-4% to 14.2%). The authors recommend patients be carefully selected and
cryobiopsy be performed at centers with considerable experience.

Significant investigation into genetic factors of familial IPF have shown
strong associations with specific gene variants. Familial forms of IPF
affecting 2 or more members of the same family contribute to only 5% of all
IPF cases, and therefore hereditary genetic testing is not currently
recommended. 2011 ATS guidelines called for greater research into gene
expression and the genomic factors contributing to IPF for earlier diagnosis
and treatment.2

****Professional Society Clinical Practice Guidelines****

The development of diagnostic criteria for IPF in 2011 by an international
consortium of guidelines including the ATS requires exclusion of known causes
of ILD, a definitive UIP pattern by HRCT, or specific combinations of UIP by
HRCT and histopathology obtained through surgical lung biopsy.2 ATS guidelines
recommend physicians consider surgical lung biopsy as the next step in
obtaining a diagnosis when patients do not meet all criteria to establish a
UIP diagnosis by HRCT. Further, ATS guidelines recommend clinicians consider
the unique clinical situation of each individual patient as to whether the
risks of surgical lung biopsy outweigh the benefits of establishing a secure
diagnosis of IPF.

In 2018, the Fleischner Society published a white paper on the diagnostic
criteria for IPF with an emphasis on radiographic features of UIP in
diagnosing IPF.22 The Fleischner Society recommendations and diagnostic
criteria are largely consistent with the 2011 ATS recommendations in
establishing categorical determinations of the presence of UIP by HRCT and
surgical pathology to distinguish IPF from other ILDs of known cause with an
emphasis on multidisciplinary assessment of clinical, radiographic and
pathological factors. The statement authors suggest that molecular diagnosis
with machine learning, with reference to EnvisiaTM, will play an increasing
role in the diagnosis of IPF when considered along with clinical and imaging
features.

This contractor consulted several ILD specialists in the development of this
policy including clinicians from:

  * Mayo Clinic
  * Columbia University
  * USC Medical Center

********T **est Description and Intended Use**********

The EnvisiaTM Genomic Classifier is a multianalyte assay with algorithm
analyses that analyzes gene expression of 190 genes to deliver a categorical
UIP or non-UIP result. The EnvisiaTM classifier is intended for patients with
ILD suspected of IPF, and who do not have a definitive UIP pattern by HRCT or
other known cause. The EnvisiaTM Genomic Classifier is intended to provide a
categorical UIP or non-UIP result that along with clinical and radiographic
information may guide treatment without the need for surgical lung biopsy
reducing patient risk.

**Analytical Validation**

The EnvisiaTM classifier was developed to identify UIP without the need for
surgical lung biopsy by assessing gene expression profiles from lung tissue
collected from non-surgical TBBs. The classifier was validated utilizing
patient samples obtained from the BRAVE trial (BRonchial sAmple collection for
a noVel gEnomic test). The BRAVE trial includes 26 study sites in the United
States (US) and Europe and is an institutional review board (IRB)-approved
study prospectively enrolling patients with suspected ILD undergoing a planned
lung biopsy procedure that consent to the collection of an additional 5 TBBs
for classifier development and validation. Final pathologic diagnoses used as
the reference standard were made by expert lung pathologists in each of the 3
study arms from surgical lung biopsy (BRAVE-1), TBB (BRAVE-2), or cryobiopsy
(BRAVE-3) against which the classifier performance is compared to calculate
test performance of sensitivity and specificity.

**Clinical Validation**

The first clinical validation of the genomic classifier by Pankratz et al19
included 140 enrolled patients. After predefined exclusion criteria, 84
eligible patients provided 283 TBB samples paired with same-patient final
reference pathology diagnoses. Machine learning was used to train an algorithm
with high specificity using TBB samples from 53 patients, and performance was
evaluated on an independent test set of 31 patients. The TBB classifier
distinguished UIP from non-UIP conditions with an area under the curve (AUC)
of 0.86, specificity of 86% [CI: 71%-95%] and sensitivity of 63% [CI:
51%-74%]. Importantly, this study explored the feasibility of a single
molecular test result per subject by combining multiple TBBs from upper and
lower lobes. Performance improved to an AUC of 0.92 when a minimum of 3 and up
to 5 TBB samples per subject are combined at the ribonucleic acid (RNA) level
for testing.19

A second clinical validation by Choi et al20 utilized 3-5 pooled TBB samples
from 139 patients enrolled in the BRAVE study. Samples from 90 patients were
utilized for classifier training, and the final EnvisiaTM classifier was
validated on an independent, blinded test set of 49 patients. In the
independent test set, final pathology diagnoses were assigned by expert ILD
pathologists using samples from surgical lung biopsy (53%, BRAVE-1), TBB (4%,
BRAVE-2) and cryobiopsy (43%, BRAVE-3). The EnvisiaTM classifier predicted
histopathologic UIP from TBB samples with a high specificity (88%; CI:
70%-98%) and modest sensitivity (70%; CI: 47%-87%), surpassing the ability of
both local and expert central HRCT evaluation to predict histopathologic UIP
suggesting this classifier has utility in clinical practice to guide patient
management in lieu of surgical lung biopsy.20

**Clinical Utility**

Investigators have sought to assess the utility of the EnvisiaTM classifier in
making a categorical IPF vs non-IPF clinical diagnosis. In a randomized,
blinded analysis of 98 prospectively enrolled patients from the BRAVE trial 2
independent, 3-member, central multidisciplinary teams (CMDTs) made up of
expert ILD clinicians received clinical information, centrally reviewed HRCT,
and either centrally reviewed histopathology or the EnvisiaTM classifier result
for each patient case. Cases were randomly assigned between CMDTs and each
subject is therefore reviewed twice, once each by the 2 CMDTs using
histopathology or EnvisiaTM classifier results. The primary objective was to
compare the intra-patient agreement for clinical diagnoses. Interim results
for approximately half of cases (n=56) showed a 92% categorical agreement in
IPF vs non-IPF diagnosis. These findings suggest that the EnvisiaTM classifier
is capable of informing a clinical diagnosis without the need for surgical
lung biopsy or expert pathology.21

**Criteria for Coverage**

The EnvisiaTM classifier is reasonable and necessary when all of the following
conditions are met:

  * That are healthy enough to undergo a bronchoscopy with TBBs, and
  * HRCT scan of the chest (defined by high kernel ~1mm axial reconstructions, including both inspiratory and expiratory imaging) showing 1 of the following: 
    * A "Probable UIP" pattern (see comment below) as defined by the 2018 Fleichner Society White paper (<https://www.ncbi.nlm.nih.gov/pubmed/29154106>), or
    * An "Indeterminate for UIP" pattern as defined by the 2018 Fleichner Society White paper (<https://www.ncbi.nlm.nih.gov/pubmed/29154106>)
  * Exclusion of autoimmune disease by clinical evaluation and serologic testing, including, when indicated, an evaluation by a rheumatologist
  * Absence of a definitive occupational, environmental, medication-related, or other cause of the patient's lung disease

**Situations in which Envisia TM should not be used:**

  1. "Typical UIP" pattern on HRCT as defined by the 2018 Fleischner Society White paper (<https://www.ncbi.nlm.nih.gov/pubmed/29154106>)
  2. "CT features most consistent with non-IPF diagnosis" on HRCT as defined by the 2018 Fleichner Society White paper (<https://www.ncbi.nlm.nih.gov/pubmed/29154106>).
  3. When a positive EnvisiaTM result is considered unlikely to lead to a confident diagnosis of IPF (>90% confidence)

**Comment regarding Probable UIP pattern on HRCT**

  * A "Probable UIP" pattern in an adult >70 years of age with extensive reticulation (>1/3 of the lung fields) is unlikely to benefit from EnvisiaTM since the likelihood of a histological pattern of UIP is already >90%.
  * A "Probable UIP" pattern in a man >50 years of age or a woman >60 years of age with moderate-to-severe traction bronchiectasis is unlikely to benefit from EnvisiaTM since the likelihood of a histological pattern of UIP is already >90%.

**Level of Evidence**

Quality: Moderate  
Strength: Limited  
Weight: Limited

The clinical utility of the EnvisiaTM Genomic Classifier to aid in the
diagnosis of patients with an ILD of unknown cause and suspected of IPF, as
defined in the intended use above, is quite promising. This contractor
believes that forthcoming clinical studies in these patients will demonstrate
improved patient clinical outcomes. Continued coverage for EnvisiaTM testing is
dependent on annual review by this contractor of such data and publications.