Rapid Diagnostic Testing for Influenza: Information for Clinical Laboratory Directors
Information for Clinical Laboratory Directors
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- Rapid Diagnostic Tests for Influenza
- Table 1: Influenza Virus Testing Methods
- Table 2: Characteristics of Rapid Influenza Diagnostic Tests
The availability and use of influenza rapid diagnostic tests by laboratories and clinics have substantially increased in recent years.
- Rapid influenza diagnostic tests (RIDTs) are screening tests for influenza virus infection.
- They can provide results within 15 minutes.
- More than 10 RIDTs have been approved by the U.S. Food and Drug Administration (FDA) (seeInfluenza Diagnostic Table).
- Some rapid influenza diagnostic tests utilize an analyzer reader device to standardize result interpretation.
- One RIDT that uses an analyzer device is an immunoassay
- One rapid immunofluorescence assay uses an analyzer device
- RIDTs differ in some important respects:
- Some can identify influenza A and B viruses and distinguish between them in respiratory specimens.
- Some can identify influenza A and B viruses but cannot distinguish between them in respiratory specimens.
- Some tests are waived from requirements under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).
- Most tests can be used with a variety of respiratory specimen types (see Influenza Diagnostic Table), but the accuracy of the tests can vary based on the type of specimen collected (for example throat swab versus nasal swab).
- FDA approval is based upon specific specimen types.
- RIDTs vary in terms of sensitivity and specificity when compared with viral culture or RT-PCR. Product insert information and research publications indicate that:
- Sensitivities are approximately 50-70%
- Specificities are approximately 90-95%
- Specimens to be used with RIDTs generally should be collected as close as is possible to the start of symptoms (e.g., less than 4 days after illness onset). In very young children, influenza viruses can be shed for longer periods; therefore, in some instances, testing for a few days after this period may still detect influenza viruses. Immunosuppressed persons may have detectable influenza viruses in respiratory specimens for prolonged periods (weeks to months).
Predictive Value Depends Upon Prevalence
The positive and negative predictive values vary considerably depending upon the prevalence of influenza (level of influenza activity) in the patient population being tested.
- False-positive (and true-negative) influenza test results are more likely to occur when disease prevalence is low, which is generally at the beginning and end of the influenza season.
- False-negative (and true-positive) influenza test results are more likely to occur when disease prevalence is high, which is typically at the height of the influenza season.
Clinical Considerations of Testing When Influenza Prevalence is Low
When influenza prevalence is relatively low, the positive predictive value (PPV) is low and false-positive test results are more likely. By contrast, when influenza prevalence is low, the negative predictive value (NPV) is high, and negative results are more likely to be true.
| If Influenza Prevalence is... | And Specificity is... | Then PPV is... | False Pos. rate1 is... |
|---|---|---|---|
| VERY LOW (2.5%) | MODERATE (80%) | VERY LOW (6-12%) | VERY HIGH (88-94%) |
| VERY LOW (2.5%) | HIGH (98%) | LOW (39-56%) | HIGH (44-61%) |
| MODERATE (20%) | MODERATE (80%) | LOW (38-56%) | HIGH (44-62%) |
| MODERATE (20%) | HIGH (98%) | HIGH (86-93%) | LOW (7-14%) |
The false pos. rate is the number of false positives/number of total positives, or 1-PPV.
The interpretation of positive results should take into account the clinical characteristics of the case and the prevalence of influenza in the patient population being tested (e.g., level of influenza activity in the community). If an important clinical decision is affected by the test result, the rapid test result should be confirmed by another test, such as reverse transcription polymerase chain reaction (RT-PCR).
Top of PageClinical Considerations of Testing When Influenza Prevalence Is High
When influenza prevalence is relatively high, the NPV is low and false-negative test results are more likely. When influenza prevalence is high, the PPV is high and positive results are more likely to be true.
| If Influenza Prevalence is... | And Sensitivity is... | Then NPV is... | False Neg. rate2 is... |
|---|---|---|---|
| MODERATE (20%) | LOW (50%) | MODERATE (86-89%) | MODERATE (11-14%) |
| MODERATE (20%) | HIGH (90%) | HIGH(97-99%) | LOW (2-3%) |
| HIGH (40%) | LOW (50%) | MODERATE (70-75%) | MODERATE (25-30%) |
| HIGH (40%) | HIGH (90%) | HIGH (93-94%) | LOW (6-7%) |
The false neg. rate is the number of false negatives/number of total positives, or 1-NPV.
The interpretation of negative results should take into account the clinical characteristics of the patient and the prevalence of influenza in the patient population being tested (e.g., level of influenza activity in the community). If an important clinical decision is affected by the test result and influenza is still suspected, then the rapid test result should be confirmed by another test, such as RT-PCR.
Selecting Tests
Many factors should be considered when selecting a test, including the following:
- Tests with high sensitivity and specificity will provide higher positive and negative predictive values.
- Types of specimens that provide the most accurate results.
Information about these characteristics can be found in product inserts and scientific articles, and by contacting the manufacturers.
Changes in Recommended Procedures Can Affect Test Results
Modification by the user can affect test performances and increase false-positive and/or false-negative rates. Such modifications include:
- Using specimens for which the test is not optimized
- Using swabs that did not come with the rapid test kits [unless recommended (see package insert for specific instructions)].
When Is Use of Rapid Diagnostic Tests Beneficial?
- Testing during an outbreak of acute respiratory disease can determine if influenza is the cause.
- During influenza season, testing of selected patients presenting with acute respiratory illnesses compatible with influenza can help establish whether influenza is present in a specific patient population and help health-care providers determine how to use their clinical judgment for diagnosing and treating respiratory illness. (Testing need not be done for all patients.)
- Otherwise, RIDTs do not address the public health need for influenza virus isolates that can only be obtained through the collection of specimens for viral culture. Influenza virus isolates are essential for determining the match between circulating influenza virus strains and those virus strains contained in the vaccine and for aiding in the selection of new vaccine strains.
Table 1: Influenza Virus Testing Methods
| Method1 | Types Detected | Acceptable Specimens2 | Test Time | CLIA Waived3 |
|---|---|---|---|---|
| Viral cell culture (conventional) | A and B | NP4 swab, throat swab, NP2 or bronchial wash, nasal or endotracheal aspirate, sputum | 3-10 days | No |
| Rapid cell culture (shell vials; cell mixtures) | A and B | As above | 1-3 days | No |
| Immunofluorescence, Direct (DFA) or Indirect (IFA) Antibody Staining [antigen detection] | A and B | NP4 swab or wash, bronchial wash, nasal or endotracheal aspirate | 1-4 hours | No |
| RT-PCR5 (singleplex and multiplex; real-time and other RNA-based) and other molecular assays | A and B | NP4 swab, throat swab, NP2 or bronchial wash, nasal or endotracheal aspirate, sputum | Varied (Generally ≤15 minutes-6 hours)7 | No |
| Rapid Molecular Assay | A and B | NP4 swab, nasal aspirate, wash, swab | ≤15 minutes7 | Yes/No7 |
| Rapid Influenza Diagnostic Tests6 (antigen detection) | A and B | NP4 swab, (throat swab), nasal wash, nasal aspirate | <30 min. | Yes/No |
- Serologic (antibody detection) testing is not recommended for routine patient diagnosis.
- Ref: Leland, et al. 2007, Clin Micro Rev 20: 49-78. Approved respiratory specimens vary among FDA cleared influenza assays.
- Ref: http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html
- NP = nasopharyngeal
- Reverse transcriptase polymerase chain reaction, including FDA-approved test systems, reference laboratory testing using ASR or lab-developed reagents
- Chromatographic- and/or fluorescence-based lateral flow and membrane-based immunoassays
- Rapid molecular assays can provide results in 15 minutes or less. Alere i Influenza A&B was cleared by FDA for nasal swabs and viral transport media. Alere i Influenza A&B was CLIA-waived only for use with nasal swabs.
Table 2: Characteristics of Rapid Influenza Diagnostic Tests1
| Procedure (Manufacturer/Distributor) | Influenza Virus Types Detected | Approved Specimens2 | CLIA Waived3 | Uses Analyzer Reader Device |
|---|---|---|---|---|
| Alere™ i Influenza A/B (Alere Scarborough, Inc.) | A and B | Nasal swab (in VTM8) | No | Yes |
| Alere™ i Influenza A/B4 (CLIA Waived) (Alere Scarborough, Inc.) | A and B | Nasal swab (Direct) | Yes | Yes |
| BD Directigen™ EZ Flu A+B4 (Becton-Dickinson & Co.) | A and B | NP5 wash/aspirate/swab Throat swab | No | No |
| BD Veritor™ System for Rapid Detection of Flu A+B4 (CLIA-waived), (Becton Dickinson & Co.) | A and B | NP5 swab/ nasal swab | Yes | Yes |
| BD Veritor™ System for Rapid Detection of Flu A+B4 (Moderately Complex), (Becton Dickinson & Co.) | A and B | NP5 wash/aspirate | No | Yes |
| Binax NOW® Influenza A&B4 Test (Binax, Inc.) | A and B | NP5 swab, Nasal wash/aspirate/swab | Yes | No |
| BioSign® Flu A+B4 or OraSure QuickFlu Rapid A+B Test or Polymedco Poly stat Flu A&B Test or LifeSign LLC Status Flu A&B (Princeton BioMedtech Corp.) | A and B | NP5 swab/aspirate/wash, nasal swab | No | No |
| ClearView Exact II Influenza A&B Test or Alere Influenza A&B Test (Binax d/b/a Inverness Medical Alere Scarborough, Inc.) | A and B | Nasal swab | Yes | No |
| Genzyme OSOM® Influenza A&B4 Test (Genzyme Corp.) | A and B | Nasal swab | No | No |
| QuickVue® Influenza A/B Test6 (Quidel Corp.) | A and B | Nasal wash/aspirate/swab | Yes | No |
| QuickVue® Influenza A+B Test4 (Quidel Corp.) | A and B | NP5 swab Nasal wash/aspirate/swab | Yes | No |
| RAMP Influenza A/B Assay or 3M™ Rapid Detection Flu A+B Test4 (Response Biomedical Corp.) | A and B | NP5 swab/aspirate Nasal wash/aspirate | No | Yes |
| SAS™ FluAlert A&B Test (SA Scientific, Inc.) | A and B | Nasal wash/aspirate | No | No |
| SAS™ Influenza A4 Test (SA Scientific, Inc.) | A only | Nasal wash/aspirate | Yes | No |
| SAS™ Influenza B6 Test (SA Scientific, Inc.) | B only | Nasal wash/aspirate | Yes | No |
| Sofia® Analyzer and Influenza A+B FIA (CLIA-waived) (Quidel Corp.) | A and B | NP5 swab Nasal swab | Yes | Yes |
| Sofia® Analyzer and Influenza A+B4,7, FIA (Quidel Corp.) | A and B | NP5 aspirate/swab/wash Nasal swab | No | Yes |
| TRU FLU®4 (Meridian Bioscience, Inc.) | A and B | NP5 aspirate/swab Nasal wash/swab | No | No |
| XPECT™ Influenza A/B4 (Remel Inc./Thermo Fisher Scientific) | A and B | Nasal wash/swab Throat swab | No | No |
- List may not include all test kits approved by the U.S. Food and Drug Administration. Discontinued tests not included.
- Approved respiratory specimens according to manufacturer's package insert. Note that test performance may vary if other respiratory specimens are used.
- Ref: http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html
- Distinguishes between influenza A and B virus infections.
- NP = nasopharyngeal.
- Does not distinguish between influenza A and B virus infections when used alone.
- Requires use of a separate analyzer reader device.
- VTM = viral transport media
Disclaimer: Use of trade names or commercial sources is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention or the Department of Health and Human Services.
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