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Clinical Policy Bulletin:
Influenza Rapid Diagnostic Tests
Number: 0476


Policy

Aetna considers rapid diagnostic tests for viral influenza (e.g., Directigen Flu A, Directigen Flu A+B, Flu OIA, Quickvue Influenza Test, and Z Stat Flu) medically necessary.

See also CPB 0035 - Influenza Vaccine.



Background

In the context of an epidemic, the clinical diagnosis of influenza in a patient with fever, malaise, and respiratory symptoms can be made with some certainty.  In the absence of an epidemic of influenza, however, the diagnosis may be uncertain.  In these cases, rapid diagnostic tests (which take less than 1 hour to perform) may be helpful in distinguishing influenza from infection with a number of other viruses (and occasionally streptococcal pharyngitis) that produce headache, muscle aches, fever, and/or cough.  The results of these rapid diagnostic tests for influenza may be useful in selecting appropriate antiviral therapy, avoiding inappropriate antibiotic therapy, and in promptly initiating measures to decrease the spread of disease.

Most of the rapid diagnostic tests that can be done in a physician's office are approximately greater than 70 % sensitive for detecting influenza and approximately greater than 90 % specific (CDC, 2005).  Thus, as many as 30 % of samples that would be positive for influenza by viral culture may give a negative rapid test result.  In addition, some rapid test results may indicate influenza when a person is not infected with influenza.

Guidelines from the Centers for Disease Control and Prevention (CDC) (Harper et al, 2005) explain that commercial rapid diagnostic tests can detect influenza viruses within 30 mins.  Some tests are approved for use in any outpatient setting, whereas others must be used in a moderately complex clinical laboratory.  These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types.  Different tests can detect: (i) only influenza A viruses; (ii) both influenza A and B viruses, but not distinguish between the 2 types; or (iii) both influenza A and B and distinguish between the two.

Centers for Disease Control and Prevention guidelines explain that none of the tests provide any information about influenza A subtypes.  The types of specimens acceptable for use (i.e., throat, nasopharyngeal, or nasal aspirates, swabs, or washes) also vary by test.  The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test.  The CDC recommends that, because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means because of the possibility of false-negative rapid test results, especially during periods of peak community influenza activity.  In contrast, false-positive rapid test results are less likely, but can occur during periods of low influenza activity.  Therefore, when interpreting results of a rapid influenza test, physicians should consider the positive- and negative-predictive values of the test in the context of the level of influenza activity in their community (Harper et al, 2005).  Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests.

Centers for Disease Control and Prevention guidelines state that, despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only culture isolates can provide specific information regarding circulating strains and subtypes of influenza viruses.  The guidelines explain that this information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year.  Virus isolates also are needed to monitor the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.

Although widely used in emergency departments and physicians' offices, antigen-based rapid assays have shown poor sensitivity for the H1N1 virus compared with culture or molecular diagnostic techniques.  Drexler et al (2009) found only 11 % sensitivity of a rapid antigen test with reverse transcription polymerase chain reaction (RT-PCR).  Investigators compared the sensitivity of a commercially available antigen-based rapid test (BinaxNOW Influenza A & B Rapid Test) with that of a real-time RT-PCR (rRT-PCR)assay specific for the hemagglutinin gene of the 2009 H1N1 virus.  Of 1,838 clinical specimens tested, 221 were confirmed as H1N1 positive by RT-PCR.  When 144 of these PCR-positive specimens were evaluated using the rapid-antigen test, results were positive for only 16 (11.1 %).  The "gold standard" PCR also demonstrated poor sensitivity, detecting the 2009 H1N1 virus in just 12 % of 1,838 respiratory specimens submitted at a time when this virus was pandemic and probably responsible for most influenza-like illness.

During May 2009, a few weeks after 2009 pandemic influenza A (H1N1) infection was first detected in the United States, outbreaks among students from 2 schools were detected in Greenwich, Connecticut (CT).  Staff members from Greenwich Hospital and the CT Department of Public Health collected data on symptoms for 63 patients and submitted naso-pharyngeal washings for testing using a rapid influenza diagnostic test (RIDT) for influenza A and B and rRT-PCR assay, thus affording an opportunity to assess the field performance of the RIDT.  A total of 49 patients had infections with pandemic H1N1 confirmed by rRT-PCR (CDC, 2009).  The findings of this performance assessment indicated that, compared with rRT-PCR, the sensitivity of the RIDT for detecting infection in patients with 2009 pandemic H1N1 was 47 %, and the specificity was 86 %.  Sensitivity and specificity did not vary markedly by the presence or absence of CDC-defined influenza-like illness (ILI) or by time from symptom onset to specimen acquisition.  In this group of patients, although positive RIDT results performed well in predicting confirmed infection with pandemic H1N1 virus (positive predictive value: 92 %), negative tests did not accurately predict the absence of infection (negative predictive value: 32 %).  These findings affirm recent CDC recommendations against using negative RIDT results for management of patients with possible 2009 pandemic H1N1 infection.

Hawkes et al (2010) examined the diagnostic accuracy of a RIDT and direct fluorescent antibody (DFA) assay for swine-origin H1N1 virus (S-OIV) by using rRT-PCR as the reference standard.  These investigators prospectively recruited children (aged 0 to 17 years) assessed in the emergency department of a pediatric referral hospital and a community pediatric clinic for ILI between May 22 and July 25, 2009.  RIDT (performed on-site) and DFA were compared with rRT-PCR to determine their sensitivity and specificity for S-OIV.  They also compared the sensitivity of RIDT for S-OIV to that for seasonal influenza over 2 preceding seasons.  Of 820 children enrolled, 651 were from the emergency department and 169 were from the clinic.  Sensitivity of RIDT was 62 % (95 % confidence interval [CI]: 52 % to 70 %) for S-OIV, with a specificity of 99 % (95 % CI: 92 % to 100 %).  Sensitivity of DFA was 8 3% (95 % CI: 75 % to 89 %) and was superior to that of RIDT (p < 0.001).  Sensitivity of RIDT for S-OIV was comparable to that for seasonal influenza when using DFA supplemented with culture as the reference standard.  Sensitivity of RIDT for influenza viruses was markedly higher in children 5 years of age or younger (p = 0.003) and in patients presenting less than or equal to 2 days after symptom onset (p < 0.001).  The authors concluded that the sensitivity of RIDT for detection of S-OIV is higher than recently reported in mixed adult-pediatric populations but remains suboptimal.

Cruz and associates (2010) evaluated the performance of a RIDT in detecting H1N1 2009 influenza A virus in respiratory samples from pediatric patients in comparison to that of rRT-PCR and viral culture.  Patients for whom the RIDT, viral culture, and rRT-PCR results were known were included.  Sensitivity, specificity, and likelihood ratios (LRs) were calculated.  A total of 3,030 specimens had RIDT results paired with both rRT-PCR and viral culture results.  With rRT-PCR as the reference, overall test sensitivity was 45 % (95 % CI: 43.3 % to 46.3 %) and specificity was 98.6 % (95 % CI: 98.1 % to 99 %).  Positive and negative LRs were 32.9 (95 % CI: 22.9 to 45.4) and 0.56 (95 % CI: 0.54 to 0.58), respectively.  Sensitivity of RIDT was significantly higher in young infants and children younger than 2 years than in older children.  Using viral culture as the reference standard, RIDT sensitivity was 55.5 % (95 % CI: 51.9 % to 95.6 %) and specificity was 95.6 % (95 % CI: 95 % to 96.1 %).  The positive and negative LRs were 12.6 and 0.47, respectively.  The authors concluded that the RIDT had relatively poor sensitivity but excellent specificity in this consecutive series of respiratory specimens obtained from pediatric patients.  Although a positive RIDT result was highly accurate in predicting infection with influenza type A H1N1 2009 in children, a negative RIDT result did not preclude a child having H1N1.  Thus, for children at high-risk with ILI during high prevalence periods of influenza, empiric initiation of antiviral therapy should be considered for patients with a negative RIDT result.

Parida et al (2011) stated that the recent emergence of the S-OIV poses a serious global health threat.  Rapid detection and differentiation of S-OIV from seasonal influenza is crucial for patient management and control of the epidemics.  These researchers reported a 1-step, single-tube accelerated and quantitative S-OIV-specific H1 reverse transcription loop-mediated isothermal amplification (RTLAMP) assay for clinical diagnosis of S-OIV by targeting the H1 gene.  A comparative evaluation of the H1-specific RTLAMP assay vis-a-vis the World Health Organization (WHO)-approved rRT-PCR, involving 239 acute-phase throat swab samples, demonstrated exceptionally higher sensitivity by picking up all of the 116 H1N1-positive cases and 36 additional positive cases among the negatives that were sequence-confirmed as S-OIV H1N1.  None of the rRT-PCR-positive samples were missed by the RTLAMP system.  The comparative analysis revealed that S-OIV RTLAMP was up to 10-fold more sensitive than the WHO rRT-PCR; it had a detection limit of 0.1 tissue culture infectious dosage of (50)/ml.  One of the most attractive features of this isothermal gene amplification assay is that it seems to have an advantage in monitoring gene amplification by means of SYBR Green I dye-mediated naked-eye visualization within 30 mins compared to 2 to 3 hours for a eRt-PCR.  This suggested that the RTLAMP assay is a valuable tool for rapid, real-time detection and quantification of S-OIV in acute-phase throat swab samples without requiring sophisticated equipment.

Su and colleagues (2012) applied the developed paired surface plasma waves biosensor (PSPWB) in a dual-channel biosensor for rapid and sensitive detection of S-OIV.  In conjunction with the amplitude ratio of the signal and the reference channel, the stability of the PSPWB system is significantly improved experimentally.  The theoretical limit of detection (LOD) of the dual-channel PSPWB for S-OIV is 30 PFU/mL (PFU, plaque-forming unit), which was calculated from the fitting curve of the surface plasmon resonance signal with a S-OIV clinical isolate concentration in phosphate-buffered saline (PBS) over a range of 18 to 1.8 × 10(6) PFU/ml.  The LOD is 2 orders of magnitude more sensitive than the commercial rapid influenza diagnostic test at worst and an order of magnitude less sensitive than rRT-PCR whose LOD for S-OIV in PBS was determined to be 3.5 PFU/ml in this experiment.  Furthermore, under in-vivo conditions, this experiment demonstrates that the assay successfully measured S-OIV at a concentration of 1.8 × 10(2) PFU/ml in mimic solution, which contained PBS-diluted normal human nasal mucosa.  Most importantly, the assay time took less than 20 mins.  The authors concluded that from thees findings, the dual-channel PSPWB potentially offers great opportunity in developing an alternative PCR-free diagnostic method for rapid, sensitive, and accurate detection of viral pathogens with epidemiological relevance in clinical samples by using an appropriate pathogen-specific antibody.

Additional information concerning diagnostic testing for influenza is available at http://www.cdc.gov/flu/professionals/diagnosis/.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
87804
ICD-9 codes covered if selection criteria are met:
079.99 Unspecified viral infection
487.0 - 487.8 Influenza
729.1 Myalgia and myositis, unspecified
780.60 Fever, unspecified
780.79 Other malaise and fatigue
784.0 Headache
786.05 Shortness of breath
786.2 Cough
Other ICD-9 codes related to the CPB:
462 Acute pharyngitis


The above policy is based on the following references:
  1. Betts RF. Influenza virus. In: Principles and Practice of Infectious Diseases. 4th ed. GL Mandell, JE Bennett, R Dolin, eds. New York, NY: Churchill Livingstone; 1995;1546-1567.
  2. Cate TR. Influenza. In: Conn’s Current Therapy. 50th ed. RE Rakel, ed. Philadelphia, PA: WB Saunders Co; 1998;90-93.
  3. Dolin R. Influenza. In: Harrison’s Principles of Internal Medicine. 14th ed. AS Fauci, E Braunwald, KJ Isselbacher, et al., eds. New York, NY: McGraw-Hill; 1998:1112-1116.
  4. Hayden FG. Influenza. In: Cecil Textbook of Medicine. 20th ed. JC Bennett, F Plum, eds. Philadelphia, PA: WB Saunders Co; 1996:1753-1757.
  5. Treanor JJ Hall CB. Influenza and infections of the trachea, bronchi, and bronchioles. In: Practical Approach to Infectious Diseases. 4th ed. RE Reese, RF Betts, eds. Philadelphia, PA: Lippincott-Raven Publishers; 1996:240-246.
  6. Wright P. Influenza viral infections. In: Nelson Textbook of Pediatrics. 15th ed. RE Behrman, RM Kliegman, AM Arvin, eds. Philadelphia, PA: WB Saunders Co; 1996;901-903.
  7. Neuzil KM, Griffin MR, Schaffner W. Influenza vaccine: Issues and opportunities. Infect Dis Clin North Am. 2001;15(1):123-141, ix.
  8. Poehling KA, Edwards KM. Prevention, diagnosis, and treatment of influenza: Current and future options. Curr Opin Pediatr. 2001;13(1):60-64.
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  10. Rodriguez WJ, Schwartz RH, Thorne MM. Evaluation of diagnostic tests for influenza in a pediatric practice. Pediatr Infect Dis J. 2002;21(3):193-196.
  11. Uyeki TM. Influenza diagnosis and treatment in children: A review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J. 2003;22(2):164-177.
  12. National Institute for Clinical Excellence (NICE). Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza. Technology Appraisal No. 58. London, UK: NICE; 2003.
  13. Hueston WJ, Benich JJ. A cost-benefit analysis of testing for influenza A in high-risk adults. Ann Family Med. 2004;2(1):33-40.
  14. Mundy L, Parrella A. ZstatFlu: Point-of-care influenza test. Horizon Scanning Prioritising Summary - Volume 7. Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); 2004.
  15. Call SA, Vollenweider MA, Hornung CA, et al. Does this patient have influenza? JAMA. 2005;293(8):987-997.
  16. Vega R. Rapid viral testing in the evaluation of the febrile infant and child. Curr Opin Pediatr. 2005;17(3):363-367.
  17. Harper SA, Fukuda K, Uyeki TM, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-8):1-40.
  18. Centers for Disease Control and Prevention (CDC). Influenza (Flu). Diagnosis. Information for Healthcare Professionals. Atlanta, GA: CDC; updated October 12, 2005. Available at: http://www.cdc.gov/flu/professionals/diagnosis/. Accessed June 20, 2006.
  19. Poehling KA, Zhu Y, Tang YW, Edwards K. Accuracy and impact of a point-of-care rapid influenza test in young children with respiratory illnesses. Arch Pediatr Adolesc Med. 2006;160(7):713-718.
  20. Smit M, Beynon KA, Murdoch DR, Jennings LC. Comparison of the NOW Influenza A & B, NOW Flu A, NOW Flu B, and Directigen Flu A+B assays, and immunofluorescence with viral culture for the detection of influenza A and B viruses. Diagn Microbiol Infect Dis. 2007;57(1):67-70.
  21. Hurt AC, Alexander R, Hibbert J, et al. Performance of six influenza rapid tests in detecting human influenza in clinical specimens. J Clin Virol. 2007;39(2):132-135.
  22. Cruz AT, Cazacu AC, Greer JM, Demmler GJ. Rapid assays for the diagnosis of influenza A and B viruses in patients evaluated at a large tertiary care children's hospital during two consecutive winter seasons. J Clin Virol. 2008;41(2):143-147.
  23. de La Rocque F, Lécuyer A, Wollner C, et al. Impact of influenza rapid diagnostic tests (IRDT) on the diagnosis of influenza and on the management of influenza in children in ambulatory pediatric setting. Arch Pediatr. 2009;16(3):288-293.
  24. Gaspard P, Mosnier A, Cohen JM, et al. Immunoassay rapid test for influenza diagnosis in institutions for elderly people: A four-year surveillance with the GROG Géronto-Alsace. Pathol Biol (Paris). 2009;57(1):90-96.
  25. Paulson J. 3M Rapid Detection Flu A + B Test: A new diagnostic test for rapid detection of influenza A and influenza B. Mol Diagn Ther. 2009;13(1):15-18.
  26. Ginocchio CC, Lotlikar M, Falk L, et al. Clinical performance of the 3M Rapid Detection Flu A+B Test compared to R-Mix culture, DFA and BinaxNOW Influenza A&B Test. J Clin Virol. 2009;45(2):146-149.
  27. Drexler JF, Helmer A, Kirberg H, et al. Poor clinical sensitivity of rapid antigen test for influenza A pandemic (H1N1) 2009 virus. Emerg Infect Dis. 2009;15(10):1662-1664.
  28. Centers for Disease Control and Prevention (CDC). Performance of rapid influenza diagnostic tests during two school outbreaks of 2009 pandemic influenza A (H1N1) virus infection - Connecticut, 2009. MMWR Morb Mortal Wkly Rep. 2009;58(37):1029-1032.
  29. Hawkes M, Richardson SE, Ipp M, et al. Sensitivity of rapid influenza diagnostic testing for swine-origin 2009 a (H1N1) influenza virus in children. Pediatrics. 2010;125(3):e639-e644.
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  32. Parida M, Shukla J, Sharma S, et al. Development and evaluation of reverse transcription loop-mediated isothermal amplification assay for rapid and real-time detection of the swine-origin influenza A H1N1 virus. J Mol Diagn. 2011;13(1):100-107.
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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