Clinical Policy Title: Seasonal influenza testing

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1 Clinical Policy Title: Seasonal influenza testing Clinical Policy Number: Effective Date: October 1, 2017 Initial Review Date: August 17, 2017 Most Recent Review Date: September 21, 2017 Next Review Date: September 2018 Policy contains: Seasonal influenza Related policies: None. ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas considers the diagnosis of seasonal influenza by laboratory assay (e.g., viral culture, rapid antigen, direct and indirect immunofluorescence assays, and reverse-transcriptase polymerase chain reaction [RT-PCR]-based testing) to be clinically proven and therefore medically necessary when: Results of the assay will influence management decisions such as initiating antiviral and/or antibacterial therapy, performing other diagnostic tests, and/or implementing infection control measures in patients including but not limited to (Center for Disease Control [CDC] 2016, Abraham 2016, Nicholson 2014, Pozo 2013, Petrozzino 2010, Infectious Diseases Society of America [IDSA] 2009) o Children <2 years of age. o Adults 65 years of age. o Persons with chronic illness. o Persons with immunosuppression (e.g., human immunodeficiency virus [HIV] infection) o Women who are pregnant or within 2 weeks postpartum. 1

2 o o o o Persons <19 years of age who are receiving long-term aspirin therapy. American Indians/Alaska Natives. Persons who are morbidly obese (i.e., BMI 40). Persons who are institutionalized (e.g. nursing homes). Limitations All other uses of laboratory assay for diagnosis of seasonal influenza in adults and children are not medically necessary. Alternative covered services: In-network routine and preventive health services by a primary care or specialty provider. Background Influenza is an acute respiratory illness caused by influenza A or B viruses that occurs in outbreaks and epidemics worldwide, mainly in the winter season. During an influenza outbreak, acute febrile respiratory illnesses can be diagnosed as influenza with a high degree of certainty by clinical criteria (Ebell, 2012). In comparison, sporadic cases of influenza cannot be differentiated from infections caused by other respiratory viruses on clinical grounds alone. Influenza diagnostic tests include viral culture, immunofluorescence assays, rapid antigen immunoassays, and reverse-transcriptase polymerase chain reaction (RT-PCR)-based testing (Petrozzino, 2010). Among these, RT-PCR is the most sensitive and specific though there are constraints of expense and adequate laboratory facility and personnel that can impact access. Rapid antigen and immunofluorescence testing (e.g., lateral flow tests such as QuickVu ) can be performed at the site of patient care such as the physicians office or emergency department. Early diagnosis at the point-of-care can have a positive impact on the efficacy of therapy (in general, earlier treatment is more effective than later) but these tests are constrained by a lack of test sensitivity (Abraham, 2016; Nicholson 2014, Petrozzino, 2010). Given the limited sensitivity of the rapid antigen tests for influenza, a negative result should be interpreted with caution given the potential for a false-negative result and empiric treatment for most symptomatic patients may be a foregone conclusion whether testing is conducted or not (Abraham, 2016). Searches AmeriHealth Caritas searched PubMed and the databases of: 2

3 UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on August 1, Search terms were: seasonal influenza. We included: Findings Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. There is scant medical evidence in support of routine point-of-care testing (POCT) for influenza in adults and children presenting with acute febrile respiratory conditions. Most analyses do not support routine or screening use of POCTs for influenza; nor do they find compelling evidence of efficacy with regard to improved prescribing of anti-viral medications, avoidance of organism resistance, or in improved clinical outcomes in either adult or child. The Centers for Disease Control and Prevention (CDC, 2016) and the Infectious Diseases Society of America (IDSA, 2009) have promulgated guidelines regarding influenza testing and treatment. The CDC identifies RT-PCR as a preferred testing method, and notes the current drawbacks of rapid testing modalities. The IDSA is more patient-focused and identifies who and when to test and treat. Summary of clinical evidence: Citation CDC (2016) Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection Influenza testing is not needed for all patients with signs and symptoms of influenza to make antiviral treatment decisions but is most appropriate for hospitalized patients if a positive test would result in a change in clinical management. Molecular assays such as RT-PCR are particularly useful to identify influenza virus infection as a cause of respiratory outbreaks in institutions (e.g., nursing homes, chronic care facilities, and hospitals). Although RT-PCR is the most sensitive influenza test and is highly specific, negative results can occur in persons with influenza for multiple reasons, so negative RT-PCR 3

4 Citation Abraham (2016) Influenza in the Emergency Department: Vaccination, Diagnosis, and Treatment: Clinical Practice Paper Approved by American Academy of Emergency Medicine Clinical Guidelines Committee. Nicholson (2014) Randomized controlled trial and health economic evaluation of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64-yearolds. results may not always exclude a diagnosis of influenza. Rapid molecular assays and some commercially available molecular assays can produce results in a reasonable time period to inform clinical management (ranging from approximately 20 minutes to less than 1.5 hours). Reported sensitivities of available rapid molecular assays range from %. As with other molecular diagnostic tests, if treatment is clinically indicated, antiviral treatment should not be withheld from patients with suspected influenza while awaiting testing results during periods of peak influenza activity in the community when the likelihood of influenza is high. A systematic review inclusive of 163 articles found rapid antigen detection for influenza is a simple bedside test with high specificity, but generally low sensitivity. The authors concluded that if a patient presents with a syndrome consistent with influenza and has negative rapid antigen detection, they should either receive a confirmatory reverse transcriptase polymerase chain reaction or be treated as if they have influenza. A systematic review and meta-analysis evaluated the diagnostic accuracy and clinical effectiveness and cost-effectiveness of rapid molecular and near-patient diagnostic tests for influenza, respiratory syncytial virus (RSV) and Streptococcus pneumoniae infections in comparison with traditional laboratory culture. The authors evaluated diagnostic accuracy for influenza and pneumococcal infection, RT-PCR for influenza and sputum culture for S. pneumoniae using samples collected during the RCT. There was no evidence of association between diagnostic group and prescribing or clinical outcomes. Using PCR as "gold standard," Quidel Influenza A + B POCT detected 24.4% [95% confidence interval (CI) 16.0% to 34.6%] of influenza infections (specificity 99.7%, 95% CI 99.2% to 99.9%); viral culture detected 21.6% (95% CI 13.5% to 31.6%; specificity 99.8%, 95% CI 99.4% to 100%). Using blood culture as "gold standard," BinaxNOW pneumococcal POCT detected 57.1% (95% CI 18.4% to 90.1%) of pneumococcal infections (specificity 92.5%; 95% CI 90.6% to 94.1%); sputum culture detected 100% (95% CI 2.5% to 100%; specificity 97.2%, 95% CI 94.3% to 98.9%). Overall, pooled estimates of sensitivity and specificity of POCTs for influenza from the literature were 74% (95% CI 67% to 80%) and 99% (95% CI 98% to 99%), respectively. Median intervals from specimen collection to test result were 15 minutes [interquartile range (IQR) minutes) for Quidel Influenza A + B POCT, 20 minutes (IQR minutes) for BinaxNOW pneumococcal POCT, 50.8 hours (IQR hours) for semi-nested conventional PCR, 29.2 hours (IQR hours) for real-time PCR, hours (IQR hours) for culture of influenza and 84.4 hours (IQR hours) and 71.4 hours (IQR hours) for culture of S. pneumoniae in blood and sputum, respectively. 4

5 Citation Pozo (2013) Guidance for clinical and public health laboratories testing for influenza virus antiviral drug susceptibility in Europe. Ebell (2012) Development and validation of a clinical decision rule for the diagnosis of influenza. Fiore (2011) Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). Ebell (2011) Costs and quality-adjusted life-years (QALYs) of each diagnostic strategy were similar. Guidelines from the European Union (EU) and other European Economic Area (EEA) countries on how and when to test for influenza virus antiviral drug susceptibility. Phenotypic neuraminidase enzyme inhibition assays are recommended to determine the level of inhibition of the neuraminidase enzyme by antiviral drugs as a measure of drug susceptibility of the virus. Genotypic assays are recommended to identify amino acid substitutions in the neuraminidase and M2 ion-channel proteins that have been associated with reduced antiviral susceptibility previously. Priority should be given to testing for neuraminidase inhibitor susceptibility. A narrative review promoted a clinical decision rule to improve the accuracy of a diagnosis of influenza that could help clinicians avoid unnecessary use of diagnostic tests and treatments. The simple heuristics (fever and cough; fever, cough, and acute onset) were helpful when positive but not when negative. The most useful and accurate clinical rule assigned 2 points for fever plus cough, 2 points for myalgias, and 1 point each for duration <48 hours and chills or sweats. The risk of influenza was 8% for 0 to 2 points, 30% for 3 points, and 59% for 4 to 6 points; the rule performed similarly in derivation and validation groups. Approximately two-thirds of patients fell into the low- or high-risk group and would not require further diagnostic testing. Recommendations from the CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of antiviral agents for the prevention and treatment of influenza summarizes chemoprophylaxis of influenza virus infection and provides a summary of the effectiveness and safety of antiviral treatment medications. The CDC advises on the use of: 1) Early antiviral treatment of suspected or confirmed influenza among persons with severe influenza (e.g., those who have severe, complicated, or progressive illness or who require hospitalization); 2) Early antiviral treatment of suspected or confirmed influenza among persons at higher risk for influenza complications; and 3) Either oseltamivir or zanamivir for persons with influenza caused by 2009 H1N1 virus, influenza A (H3N2) virus, or influenza B virus or when the influenza virus type or influenza A virus subtype is unknown; 4) Antiviral medications among children aged <1 year; 5) Local influenza testing and influenza surveillance data, when available, to help guide treatment decisions; and 6) Consideration of antiviral treatment for outpatients with confirmed or suspected influenza who do not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset. 5

6 Citation A systematic review of clinical decision rules for the diagnosis of influenza. Petrozzino (2010) Rapid diagnostic testing for seasonal influenza: an evidence-based review and comparison with unaided clinical diagnosis. Infectious Diseases Society of America (2009) Guidelines for the management of seasonal influenza A systematic review and meta-analysis evaluated the accuracy of multivariate models, clinical decision rules, or simple heuristics for the diagnosis of influenza. Simple heuristics such as the so-called fever and cough rule and the fever, cough, and acute onset rule were each evaluated by several studies in populations of adults and children. The areas under the receiver operating characteristic curves were 0.70 and 0.79, respectively. The authors could not calculate a single summary estimate as the diagnostic threshold varied among studies. A systematic review found that a proprietary assay (QuickVue ) diagnostic specificity exceeds that of unaided clinical diagnosis by 29 31%. False-positive results occur approximately 8.2 times more frequently by unaided clinical diagnosis than by the RFT alone. These findings were unaffected by seasonal variations in disease prevalence. RFTs reduce diagnostic testing, antibiotic use, and emergency department utilization while increasing antiviral prescription rates. No systematic relationship between the broadness of clinical diagnostic criteria for influenza and diagnostic performance was observed across studies. The authors concluded that use of RFTs improves seasonal influenza diagnostic specificity above that based on unaided clinical diagnosis irrespective of the broadness of clinical diagnostic criteria, and affects clinical decision-making. If the result will influence clinical management (decisions on initiation of antiviral treatment, impact on other diagnostic testing, antibiotic treatment decisions, and infection control practices), with consideration for the sensitivity and specificity of the test used and information about local influenza virus circulation, the following persons should be considered for influenza testing: o During influenza season a. Outpatient immunocompetent persons of any age at high risk for complications of influenza (e.g., hospitalization or death) presenting with acute febrile respiratory symptoms, within five days of illness onset, when virus is usually being shed. o Persons at high risk of complications from influenza who should be considered for antiviral therapy. b. Outpatient immunocompromised persons of any age presenting with febrile respiratory symptoms, irrespective of time from illness onset, because immunocompromised persons can shed influenza viruses for weeks to months. c. Hospitalized persons of any age (immunocompetent or immunocompromised) with fever and respiratory symptoms, including those with a diagnosis of community-acquired pneumonia, irrespective of time from illness onset. 6

7 Citation d. Elderly persons and infants presenting with suspected sepsis or fever of unknown origin, irrespective of time from illness onset. e. Children with fever and respiratory symptoms presenting for medical evaluation, irrespective of time from illness onset. f. Persons of any age who develop fever and respiratory symptoms after hospital admission, irrespective of time from illness onset. g. Immunocompetent persons with acute febrile respiratory symptoms who are not at high risk of developing complications secondary to influenza infection may be tested for purposes of obtaining local surveillance data. References Professional society guidelines/other: Abraham MK, Perkins J, Vilke GM, Coyne CJ. Influenza in the Emergency Department: Vaccination, Diagnosis, and Treatment: Clinical Practice Paper Approved by American Academy of Emergency Medicine Clinical Guidelines Committee. J Emerg Med Mar;50(3): doi: /j.jemermed Epub 2016 Jan 4. Review. PubMed PMID: Center for Disease Control (CDC). Seasonal influenza (flu). Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. CDC website: Accessed August 25, Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep Jan 21;60(1):1-24. PubMed PMID: Infectious Diseases Society of America (IDSA). Guidelines for the management of seasonal influenza. IDSA website: /Viruses/Influenza/#recommendations Accessed August 28, Peer-reviewed references: Ebell MH, Afonso AM, Gonzales R, Stein J, Genton B, Senn N. Development and validation of a clinical decision rule for the diagnosis of influenza. J Am Board Fam Med. 2012;25(1): Ebell MH, Afonso A. A systematic review of clinical decision rules for the diagnosis of influenza. Ann Fam Med. 2011;9(1):69-77 Nicholson KG, Abrams KR, Batham S, et al. Randomized controlled trial and health economic evaluation 7

8 of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64- year-olds. Health Technol Assess. 2014;18(36):1-274, vii-viii. Pozo F, Lina B, Andrade HR, et al; Community Network of Reference Laboratories for Human Influenza in Europe. Guidance for clinical and public health laboratories testing for influenza virus antiviral drug susceptibility in Europe. J Clin Virol. 2013;57(1):5-12. Petrozzino JJ, Smith C, Atkinson MJ. Rapid diagnostic testing for seasonal influenza: an evidence-based review and comparison with unaided clinical diagnosis. J Emerg Med. 2010;39(4): e1. CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): A Influenza diagnostic tests. Center for Medicare and Medicaid Services (CMS). Website: l&keyword=influenza&keywordlookup=title&keywordsearchtype=and&list_type=ncd&bc=gaaaaca AAAAAAA%3d%3d& Last accessed August 15, Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Infectious agent detection by nucleic acid (DNA or RNA); influenza virus, includes reverse transcription, when performed, and amplified probe technique, each type or subtype Infectious agent detection by nucleic acid (DNA or RNA); influenza virus, for multiple types or sub-types, includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, first 2 types or sub-types Infectious agent detection by nucleic acid (DNA or RNA); influenza virus, for multiple types or sub-types, includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, each additional influenza virus type or sub-type beyond 2 (List separately in addition to code for primary procedure) Infectious agent antigen detection by immunoassay with direct optical observation; Influenza 8

9 CPT Code Description Comments Infectious agent antigen detection by immunofluorescent technique; influenza B virus Infectious agent antigen detection by immunofluorescent technique; influenza A virus ICD-10 Code Description Comments N/A HCPCS Level II Code N/A Description Comments 9