Noninvasive Testing for Helicobacter Pylori - eviCore
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Lab Management Guidelines V2.0.2021
Noninvasive Testing for Helicobacter
Pylori
MOL.CS.318.X
v2.0.2021
Introduction
Helicobacter Pylori (H. pylori) testing is addressed by this guideline.
Procedures Addressed
The inclusion of any procedure code in this table does not imply that the code is under
management or requires prior authorization. Refer to the specific Health Plan's
procedure code list for management requirements.
Procedure addressed by this guideline Procedure code
Infectious agent antigen detection by 87338
immunoassay technique, (eg, enzyme
immunoassay [EIA], enzyme-linked
immunosorbent assay [ELISA],
immunochemiluminometric assay [IMCA])
qualitative or semiquantitative, multiple-
step method; Helicobacter pylori, stool (H
pylori Stool antigen)
Infectious agent antigen detection by 87339
immunoassay technique, (eg, enzyme
immunoassay [EIA], enzyme-linked
immunosorbent assay [ELISA],
immunochemiluminometric assay [IMCA])
qualitative or semiquantitative, multiple-
step method; Helicobacter pylori
Helicobacter pylori, blood test analysis for 83009
urease activity, non-radioactive isotope
(eg, 13C)
Helicobacter pylori; breath test analysis 83013
for urease activity, non-radioactive isotope
(eg, 13C)
Helicobacter pylori; drug administration 83014
Helicobacter pylori antibody 86677
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Procedure addressed by this guideline Procedure code
Helicobacter pylori detection and antibiotic 0008U
resistance, DNA, 16S and 23S rRNA,
gyrA, pbp1, rdxA and rpoB, next
generation sequencing, formalin-fixed
paraffin embedded or fresh tissue or fecal
sample, predictive, reported as positive or
negative for resistance to clarithromycin,
fluoroquinolones, metronidazole,
amoxicillin, tetracycline, and rifabutin
Culture, typing; identification by nucleic 87149
acid (DNA or RNA) probe, direct probe
technique, per culture or isolate, each
organism probed
Culture, typing; identification by nucleic 87150
acid (DNA or RNA) probe, amplified probe
technique, per culture or isolate, each
organism probed
Culture, typing; identification by pulse field 87152
gel typing
Infectious agent detection by nucleic acid 87797-87799
(DNA or RNA), not otherwise specified
What Is H. Pylori
Definition
Helicobacter pylori (H. pylori) is a microaerophilic human pathogen that causes acid
peptic diseases of the stomach and duodenum, affecting 20%-80% of the population
worldwide.1-3
H. pylori Testing
The prevalence varies widely by geographic area, age, race, and socioeconomic
status. Infection with H. pylori causes more than 80% of peptic ulcer disease, and is
associated with mortality related to peptic ulcers and gastric cancer: 3
“Gastric cancer is the third leading cause of cancer-related death worldwide and H.
Pylori infection is responsible for 74.7% of all non-cardia gastric cancer cases.”
The presentation of H. pylori infection varies between patients. It is a chronic infection
usually acquired during childhood.4 According to the American College of
Gastroenterology (ACG) guidelines, patients with any of the following should be tested
for H. pylori infection, and treated if testing is positive: 5
"Active peptic ulcer disease (PUD)
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Past history of PUD (unless previous cure of H. pylori infection has been
documented)
Low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma
History of endoscopic resection of early gastric cancer (EGC)”
The following conditions are reasonable to evaluate for H. pylori infection, although
these are considered “conditional recommendations” by the ACG: 5
"Patients taking long-term, low-dose aspirin
Patients initiating chronic treatment with a non-steroidal anti-inflammatory drug
(NSAID)
Patients with unexplained iron deficiency anemia despite an appropriate evaluation
Adults with idiopathic thrombocytopenic purpura (ITP)”
Test Information
Introduction
Testing for H. pylori includes noninvasive tests, invasive tests, and molecular assays.
There are several methods of diagnostic testing for H. pylori, and the ACG has pointed
out that the most appropriate test depends upon the clinical situation: 6
“There is no single test that can be considered the gold standard for the diagnosis
of H. Pylori. Rather, the most appropriate test for any specific situation will be
influenced by the clinical circumstances, pretest probability of infection, as well as
the availability and costs of the individual diagnostic tests.”
The diagnostic methods can be divided into those that require endoscopy, and those
that do not.
Those that require endoscopy include histology, culture identification using the rapid
urease test, and molecular methods.
H. pylori Testing
Testing options that do not require endoscopy, referred to as noninvasive H. Pylori
testing in this policy, include H. pylori antibody testing, H. pylori ( 13C) breath test, H
Pylori stool antigen, and molecular methods. There are several advantages to
avoiding endoscopic diagnostic methods, including avoiding an invasive procedure,
procedural costs, and sampling bias due to uneven distribution of H. pylori in the
stomach.3
Noninvasive Tests for H. Pylori Infection
H. Pylori Antibody (Serological) Test: This test is performed by enzyme-linked
immunoassay (ELISA) or latex agglutination. There are several commercially available
kits, although none have Food and Drug Administration (FDA) clearance. 7H. pylori has
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a diverse antibody profile, primarily an IgG response, reported by immunoblot methods.
The strain that was used to create the diagnostic antigen can impact the performance
of the test in different geographical regions; local strains should be used to prepare kits
for detection of H. pylori specific antibodies.2 Additionally, antibodies to H. pylori persist
beyond infection and should not be used as a test for cure.
H. Pylori (13C) Breath Test: The breath test has been around for over 30 years, and is
the most popular and accurate noninvasive test to diagnose H. pylori infection and
confirm eradication. The patient ingests 13C-labeled urea (non-radioactive), and the H.
pylori’s urease activity hydrolyzes the urea to CO2. The patient’s breath contains the
labeled 13CO2 which can be measured by several FDA-cleared methods, including gas
chromatography mass spectrometry (GC-MS), infrared spectrophotometer, or laser-
assisted ratio analyzer.8 The test has near 95% sensitivity and specificity.9
H. Pylori Stool Antigen: H. pylori antigen in stool is the newest clinically available test,
and has the advantage of testing for eradication of H. pylori infection. Antigen detection
in stool is performed by ELISA using monoclonal capture antibodies adsorbed to the
wells or immunochromatography assay available at the point of care. There are several
manufacturers that provide FDA-cleared kits.
H. Pylori (13C) Blood: Similar to the breath test, the patient ingests 13C-labeled urea,
and the H. pylori’s urease activity hydrolyzes the urea to 13CO2.
H Pylori Antigen (not stool): Similar to the H. pylori stool antigen test, this test uses
immunofluorescence to detect H. pylori antigen in blood. This test is rarely used, and is
considered obsolete because of the superiority of the stool antigen test.
Invasive Tests for H. Pylori Infection
H. pylori antimicrobial resistance in DNA, biopsy: There are numerous molecular
methods to detect the identified point mutations in 23S and 16S ribosomal RNA known
to lead to resistant organisms. These methods offer several advantages compared to
the gold standard, antibiograms or MIC determination, using Etest: they do not require
culture or living organisms, simplifying transportation, and have a faster turnaround
time because waiting for culture is not necessary.10
The methods include polymerase chain reaction (PCR), fluorescent in situ hybridization
H. pylori Testing
(FISH), and next generation sequencing. These methods can be performed on fresh or
formalin-fixed tissue from biopsy and gastric juices. Both PCR and FISH-based
methods are targeted, and require known mutations to design primers. PCR-based
methods are the most common and are used in commercially available PCR kits. 10
Next generation sequencing is the newest technology and has the advantage that it
can sequence large gene regions. 11
Molecular Tests for H. Pylori Infection and Antibiotic Resistance
Molecular tests are not standardized across laboratories and it is an unreliable
reference standard for the detection of H. pylori infection. 6
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In addition to traditional diagnostic methods, molecular methods (including, but not
limited to, PCR and next generation sequencing) are being developed to detect the H.
pylori bacterium and assess antimicrobial resistance on both invasive and non-invasive
sample types.
Recommended first-line treatment is clarithromycin triple therapy: 5
o “…consisting of a PPI, clarithromycin, and amoxicillin or metronidazole for 14
days…in regions where H. pylori clarithromycin resistance is known to beLab Management Guidelines V2.0.2021
While urea breath testing and stool antigen testing are the preferred noninvasive
diagnostic tests by professional societies, the sensitivity and specificity of the H. pylori
antibody test is only marginally worse than stool antigen testing. 13
Since the initial analyses that evaluated serological kit performances, several new tests
have been marketed and older tests have been reformulated. The most recent
comparison of 29 commercial assays found that there are a few superior assays with
characteristics similar to the urea breath test.14
H. Pylori (13C) Breath Test (CPT 83013, 83014)
Urea breath test is a highly accurate noninvasive test for the diagnosis of H. pylori
infection. Specificity and sensitivity >95% make this assay extremely useful when
performed with standardized procedures.3,9
There is significant heterogeneity in how the urea breath test is performed, including
time after ingestion of 13C-labeled urea to breath collection, measurement technique
(radioisotope mass spectrometry vs. infrared spectrometry), urease activity of the oral
flora, and the cut-off value used at the laboratory. 9
Treatment of H. pylori can cause false negative urea breath test results: 9
“…results can be affected by exposure to H. pylori therapy such as, antibiotics,
proton pump inhibitors or bismuth.”
PPI administration and H. pylori treatment can also affect results: 3
“Patient should stop taking PPI 2 wk and antibiotic 4 wk before exam to avoid false
negative results.”
False positive urea breath test results, although rare, have been linked to urease
activity of the oral flora:8
“Urease-producing oropharyngeal bacteria may rarely cause false positive results if
breath samples are taken within 10 min of urea administration. To overcome this
problem, some investigators have encapsulated the urea or administered it as a
tablet.”
The urea breath test can also be used for confirmation of disease eradication after
treatment.15 The ACG recommends:5
H. pylori Testing
“Whenever H. pylori infection is identified and treated, testing to prove eradication
should be performed using a urea breath test, fecal antigen test or biopsy-based
test at least 4 weeks after the completion of antibiotic therapy and after PPI therapy
has been withheld for 1-2 weeks.”
H. Pylori Stool Antigen (CPT 87338)
Stool antigen test for H. pylori is a noninvasive test for the diagnosis of infection, with
>90% sensitivity and specificity.3
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There are several advantages to using stool antigen testing for the diagnosis of H.
pylori, including cost (it is less expensive than urea breath testing), ease of
collection (it does not require fasting or ingestion of labeled-urea), and it can be
used to test for eradication.3
The stool antigen test can also be used for confirmation of disease eradication after
treatment. The ACG states:5
o “Whenever H. pylori infection is identified and treated, testing to prove
eradication should be performed using a urea breath test, fecal antigen test or
biopsy-based test at least 4 weeks after the completion of antibiotic therapy and
after PPI therapy has been withheld for 1-2 weeks.”
Several studies have evaluated the effectiveness of stool antigen testing for
diagnosing H. pylori infection in children. A meta-analysis determined pooled
sensitivity of 92% and specificity of 94%. 16
H. Pylori Detection and Antimicrobial Resistance in DNA, Biopsy (PLA 0008U)
There is a documented sharp increase of antimicrobial resistance globally, and this is
decreasing the efficacy of first and second-line treatments. However, there is not
enough evidence to support susceptibility-guided therapies. 12
“Recent systematic reviews demonstrated that the overall results are insufficient to
recommend the widespread use of susceptibility-guided therapies as a first-line or
rescue treatment regimen for H. pylori treatment. Further studies demonstrating
strong evidence-based outcomes are needed.”
Furthermore, there is a lack of clinical trials documenting treatment efficacy and
antimicrobial resistance patterns in North America: 5
“A Europe-wide effort is currently registering thousands of cases per year, thereby
providing real-time data on H. pylori antibiotic resistance which can be leveraged to
guide the most appropriate treatment recommendations. The dearth of knowledge
about antibiotic resistance in the United States is in sharp contrast to this approach
and remains an unfortunate barrier to making evidence-based treatment
recommendations.”
H. pylori Testing
Criteria
Introduction
This guideline addresses noninvasive testing of blood, breath, and stool for the
diagnosis and monitoring of H. pylori infection, as well as molecular testing for H. pylori
regardless of the sample type. It does not address endoscopy-based testing for H.
pylori, such as histology, and rapid urease test performed on positive cultures.
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Coverable H. Pylori Testing
H. pylori antibody test (CPT 86677), H. pylori ( 13C) breath test (CPT 83013 with or
without 83014), H. pylori stool antigen (CPT 87338)
Medical necessity requirements
H. pylori diagnostic testing through antibody testing, 13C breath test, or stool antigen
is indicated in the following circumstances:
o Active peptic ulcer disease
o Past history of peptic ulcer disease
o Low-grade gastric mucosa-associated lymphoid tissue lymphoma
o History of endoscopic resection of early gastric cancer
o Patients taking long-term, low-dose aspirin
o Patients initiating chronic treatment with a non-steroidal anti-inflammatory drug
(NSAID)
o Patients with unexplained iron deficiency anemia despite an appropriate
evaluation
o Adults with idiopathic thrombocytopenic purpura (ITP)
H. pylori diagnostic testing through 13C breath test or stool antigen is indicated in
the following circumstances:
o Before starting proton pump inhibitor therapy for dyspepsia
Testing for eradication of H. pylori infection is indicated using H. pylori 13C breath
test or stool antigen testing. H. pylori antibody testing should not be used to test for
eradication of H. pylori infection.
Test Frequency: H. pylori testing for any purpose should not be necessary on more
than six dates of service per year.
H. pylori Testing
Billing and reimbursement
When H. pylori testing is medically necessary, the following limitations apply:
o Only one H. pylori test is allowed per date of service. If more than one H. pylori
test is billed on the same date of service, the single payable test will be
determined based on the following:
When H. pylori stool antigen (CPT 87338) is billed with other H. pylori tests,
it will be the payable test. H. pylori (13C) breath test (CPT 83013 with or
without 83014) and/or H. pylori antibody test (CPT 86677) will not be
payable.
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H. pylori (13Cbreath test (CPT 83013 with or without 83014) will be the single
payable code when billed with H. pylori antibody test (CPT 86677).
o No more than 1 unit of a coverable H. pylori test may be billed for the same date
of service. One unit of 83013 (with or without 83014), 87338, or 86677 is
payable per date of service
H. Pylori (13C) Blood
CPT 83009
Medical necessity requirements
H. pylori (13C) blood test analysis for urease activity is not medically necessary for
any indication and is considered investigational and/or experimental
H. Pylori Antigen (blood)
CPT 87339
Medical necessity requirements
H. pylori antigen test in blood is not medically necessary for any indication and is
considered investigational and/or experimental
H. Pylori Molecular Detection and Antimicrobial Resistance
CPT 0008U, Other nonspecific procedure codes
Medical necessity requirements
H. pylori detection, with or without antimicrobial resistance testing using molecular
methods (such as PCR or next generation sequencing), is not medically necessary
for any indication and is considered experimental and investigational.
Note that H. pylori molecular testing does not have a single test-specific procedure
code and can be billed with a variety of procedure codes that represent general
H. pylori Testing
testing methods, including but not limited to 87797-87799, 87149-87152, etc.
Molecular H. pylori testing is not a coverable service regardless of which procedure
codes are used for billing.
References
Introduction
These references are cited in this guideline.
1. Brown LM. Helicobacter pylori: Epidemiology and Routes of Transmission.
Epidemiologic Reviews. 2000;22(2):283–297.
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400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.comLab Management Guidelines V2.0.2021
2. Patel SK, Pratap CB, Jain AK, et al. Diagnosis of Helicobacter pylori: What should
be the gold standard? World J Gastroenterol. 2014; 20(36): 12847 – 12859.
3. Wang Y, Kuo F, Liu C, Wu M, et al. Diagnosis of Helicobacter pylori infection:
Current options and developments. World J Gastroenterol. 2015;21(40):11221–
11235.
4. Malaty HM, El-Kasabany A, Graham DY, et al. Age at acquisition of Helicobacter
pylori infection: a follow-up study from infancy to adulthood. The Lancet.
2002;359(9310):931-935.
5. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: treatment
of Helicobacter pylori infection. Am J Gastroenterol. 2017;112:212–238.
6. Chey WD, Wong CY. American College of Gastroenterology guideline on the
management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808–
1825.
7. Theel ES, Johnson RD, Plumhoff E, Hanson CA. Use of the Optum Labs Data
Warehouse to assess test ordering patterns for diagnosis of Helicobacter pylori
infection in the United States. J Clin Microbiol. 2015;53(4):1358–1360.
8. Gisbert JP, Pajares JM. Review article: 13C-urea breath test in the diagnosis of
Helicobacter pylori infection – a critical review. Aliment Pharmacol Ther.
2004;20:1001–1017.
9. Ferwana M, Abdulmajeed I, Alhajiahmed A, et al. Accuracy of urea breath test in
Helicobacter pylori infection: metanalysis. World J Gastroenterol. 2015;21:1305-
1314.
10. Megraud F, Benejat L, Ngoyi EN, Lehours P. Molecular approaches to identify
Helicobacter pylori antimicrobial resistance. Gastroenterol Clin North Am.
2015;44(3):577-96.
11. Nezamia BG, Jani M, Alouani D, et al. Helicobacter pylori mutations detected by
next-generation sequencing in formalin-fixed, paraffin-embedded gastric biopsy
specimens are associated with treatment failure. J Clin Microbiol; 2019:57(7).
12. Arslan N, Yilmaz O, Demiray-Gurbuz, E. Importance of antimicrobial susceptibility
testing for the management of eradication in Helicobacter pylori infection. World J
H. pylori Testing
Gastroenterol. 2017;23(16):2854-2869.
13. Best LMJ, Takwoingi Y, Siddique S, et al. Non‐invasive diagnostic tests for
Helicobacter pylori infection. Cochrane Database of Syst Rev. 2018;Issue 3.
14. Burucoa C, Delchier JC, Courillon-Mallet A, et al. Comparative evaluation of 29
commercial Helicobacter pylori serological kits. Helicobacter. 2013;18(3):169–179.
15. Perri F, Manes G, Neri M, et al. Helicobacter pylori Antigen Stool Test and 13C-
Urea Breath Test in Patients After Eradication Treatments. Am J Gastroenterol.
2002;97(11):2756–2762.
16. Zhou X, Su J, Xu G, Zhang G. Accuracy of stool antigen test for the diagnosis of
Helicobacter pylori infection in children: A meta-analysis. Clin Res Hepatol
Gastroenterol. 2014;38(5):629–638.
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