Influenza Diagnostic Testing Algorithm

Figure 1: Guide for considering influenza virus diagnostic tests for individual patients when influenza viruses are circulating in the community1

1. Confirmation of influenza virus infection by diagnostic testing is not required for clinical decisions to prescribe antiviral medications. Decisions to administer antiviral medications for influenza treatment or chemoprophylaxis, if indicated, should be based upon clinical illness and epidemiologic factors, and start of therapy should not be delayed pending testing results. Respiratory specimens should be collected from an ill patient as early as possible after onset of symptoms (ideally <48-72 hours after onset) to help maximize influenza testing sensitivity.
2. Influenza like-illness (history of feverishness or documented fever with either cough or sore throat), fever with other respiratory symptoms, etc. Note that some persons may have atypical presentations (e.g. elderly, very young infants, immunosuppressed, and patients with certain chronic medical conditions). Fever is not always present (e.g. premature infants, young infants, elderly, immunosuppressed). Other symptoms associated with influenza include myalgias, headache, fatigue. Complications include exacerbation of underlying chronic disease, (e.g. congestive cardiac failure, asthma), pneumonia, bacterial co-infection, bronchiolitis, croup, encephalopathy, seizures, myositis, and others.
3. e.g. Decisions on use of antibiotics or antiviral medications, on conducting further diagnostic tests, on recommendations for home care, or on recommendations for ill persons living with persons with high-risk conditions. Consult IDSA, ATS, AAP antibiotic guidance.
4. Persons ≥65 years or <2 years; pregnant women; persons with chronic lung disease (including asthma), heart disease, renal, metabolic, hematologic and neurologic disease; immunosuppression; and morbid obesity.
5. e.g. Decisions on changing infection control practices (such as in hospitalized patients); if a positive influenza test result is used for confirming influenza virus circulation in the community which might inform clinical practices related to home care guidance, hospital infection control practices, future testing practices, etc.

Figure 2: Guide to use of influenza virus diagnostic tests in investigating outbreaks in institutional or other closed settings1

1. Examples of institutional or closed settings include long-term care facilities, nursing homes, schools, correctional facilities, hospitals, ships.
2. In settings where persons at high-risk of influenza complications reside, a single case of suspected influenza is sufficient for triggering influenza testing and consideration of implementation of empiric control measures, including active surveillance for new illness cases.
3. e.g., Influenza like-illness (fever with either cough or sore throat), fever with other respiratory symptoms, etc. Note that some persons may have atypical presentations (e.g. elderly, very young infants, immunosuppressed, and patients with certain chronic medical conditions). Fever is not always present. Other symptoms associated with influenza include myalgias, headache, fatigue. Complications include exacerbation of underlying chronic disease, (e.g. congestive cardiac failure, asthma), pneumonia, bacterial co-infection, bronchiolitis, croup, encephalopathy, seizures, myositis, and others.
4. e.g., use of antivirals empirically for treatment or for chemoprophylaxis of influenza, changes in infection control practices (isolation or cohorting of ill, quarantine of exposed), changes in admission or staffing policies, or changes in social distancing recommendations, etc.
5. Persons ≥65 years or <2 years; pregnant women; persons with chronic lung disease (including asthma), heart disease, renal, metabolic, hematologic and neurologic disease; immunosuppression; and morbid obesity.
6. In an outbreak setting, because of the low sensitivity of RIDTs, use of the tests on specimens from more than one ill person is recommended. The presence of any influenza positives among persons with clinically compatible illnesses is supportive of influenza as the probable cause of the outbreak. Confirmation of RIDT results by more specific influenza testing is indicated.

Figure 3: Algorithm to assist in the interpretation of RIDT results and clinical decision-making during periods when influenza viruses are circulating in the community1

RIDT POSITIVE for one of the following:

• Influenza A
• Influenza B
• Influenza A and B (A/B)

Interpretation:
Influenza virus infection likely1,2

Actions:

Initiate antiviral treatment for influenza if clinically indicated.

• Consider additional influenza virus testing to confirm RIDT results, for subtyping of influenza A virus, to distinguish between influenza A and B viruses, or for more specific analyses, if indicated.
• Consider additional diagnostic testing for other pathogens and/or empiric antibiotic therapy for bacterial co-infection, if indicated.3

RIDT NEGATIVE for one or more of the following:

• Influenza A
• Influenza B
• Influenza A and B (A/B)

Interpretation:
Cannot rule out Influenza virus infection1,2

Actions:

Use clinical signs, symptoms, history, examination, information on local influenza activity in the community to decide if antiviral treatment is indicated.

• Do not use negative RIDT results exclusively for clinical decision-making, or for public health decisions, including identifying influenza outbreaks, or for decisions on infection control measures.
• Consider additional influenza testing if indicated. Consider additional diagnostic testing and/or empiric antibiotic therapy for bacterial infection if indicated.3

1. During periods when influenza activity is high and influenza viruses are circulating among persons in the community (see 3. below), the positive predictive value of a test result is high (that is, the chance that a positive result indicates that the patient has influenza is high), and the negative predictive value of a test result is low (the chance that a negative result is a true negative is low) due to low sensitivity of RIDTs to detect influenza virus in respiratory specimens compared to RT-PCR or viral culture: false negative results are common.
2. Influenza virus infection may include seasonal influenza A (H3N2), 2009 H1N1, influenza B, or rarely, a novel influenza A virus infection. The interpretation of RIDTs will, in part, depend on the test used – some will detect influenza A, some will detect influenza B and some will detect both A and B viruses. If tests for both influenza A and influenza B are positive, refer specimen to a public health laboratory for resolution, as dual infections are uncommon.
3. Consult local or state health departments or other sources (e.g. virology testing at a local hospital) for local activity on other respiratory pathogens associated with acute respiratory illness. Empiric antibiotic coverage should include coverage for Streptococcus pneumoniae, Staphylococcus aureus (including MRSA), Group A Streptococcus, and others, especially for hospitalized adult patients per IDSA/ATS CAP guidelines.

Figure 4: Algorithm to assist in the interpretation of RIDT results and clinical decision-making during periods when influenza viruses are not circulating or influenza activity is low in the community1

RIDT POSITIVE for one of the following:

• Influenza A
• Influenza B
• Influenza A and B (A/B)

Interpretation:
Cannot exclude false positive result1,2

Actions:

Use clinical signs, symptoms, history, examination, information on local influenza activity in the community to decide if antiviral treatment is indicated.

• Additional influenza virus testing is recommended to confirm RIDT results, for subtyping of influenza A virus, to distinguish between influenza A and B viruses, or for more specific analyses, if indicated.
• Consider additional diagnostic testing for other pathogens and/or empiric antibiotic therapy for bacterial co-infection, if indicated.3

RIDT NEGATIVE for one or more of the following:

• Influenza A
• Influenza B
• Influenza A and B (A/B)

Interpretation:
Influenza virus infection unlikely2

Actions:

Use clinical signs, symptoms, history, examination, information on local influenza activity in the community to decide if antiviral treatment is indicated.

• Do not use negative RIDT results exclusively for clinical decision-making, or for public health decisions, including identifying influenza outbreaks, or for decisions on infection control measures.
• Consider additional influenza testing if indicated. Consider additional diagnostic testing and/or empiric antibiotic therapy for bacterial infection if indicated.3

1. During periods when influenza activity is low and there is low influenza virus circulation among persons in the community, the positive predictive value of a rapid influenza diagnostic test is low (that is, the chance that a positive result indicates that the patient has influenza is low), and the negative predictive value is high (the chance that a negative result is a true negative is high). Even though RIDTs have high specificity, false positive RIDT results are more common when influenza activity is low.
2. Influenza virus infection may include seasonal influenza A (H3N2), 2009 H1N1, influenza B, or rarely, a novel influenza A virus infection. The interpretation of RIDTs will, in part, depend on the test used – some will detect influenza A, some will detect influenza B and some will detect both A and B viruses. If tests for both influenza A and influenza B are positive, refer specimen to a public health laboratory for resolution, as dual infections are uncommon.
3. Consult local or state health departments or other sources (e.g. virology testing at a local hospital) for local activity on other respiratory pathogens associated with acute respiratory illness. Empiric antibiotic coverage should include coverage for Streptococcus pneumoniae, Staphylococcus aureus (including MRSA), Group A Streptococcus, and others, especially for hospitalized adult patients per IDSA/ATS CAP guidelines.

Table 1: Influenza Virus Testing Methods

Method1	Types Detected	Acceptable Specimens3	Test Time3	CLIA Waived
Viral cell culture (conventional)	A and B2	NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum	3-10 days	No
Rapid cell culture (shell vials; cell mixtures)	A and B2	As above	1-3 days	No
Immunofluorescence, Direct (DFA) or Indirect (IFA) Antibody Staining	A and B2	NP swab or wash, bronchial wash, nasal or endotracheal aspirate	1-4 hours	No
RT-PCR4 (singleplex and multiplex; real-time and other RNA-based)	A and B2	NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum	Varied (Generally 1-6 hours)	No5
Rapid Influenza Diagnostic Tests6	A and B	NP swab, (throat swab), nasal wash, nasal aspirate	<30 min.	Yes/No

1. Serologic (antibody detection) testing is not recommended for routine patient diagnosis.
2. May be adapted to identification of specific subtypes
3. Ref: Leland, et al. 2007, Clin Micro Rev 20: 49-78. Approved respiratory specimens vary among FDA cleared influenza assays.
4. Reverse transcriptase polymerase chain reaction, including FDA-approved test systems, reference laboratory testing using ASR or lab-developed reagents
5. Random-access, single cartridge tests may be moderately complex
6. Immunochromatographic lateral flow and membrane-based immunoassays

Table 2: Characteristics of Rapid Influenza Diagnostic Tests1

1. 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.
2. NP = nasopharyngeal.
3. Does not distinguish between influenza A and B virus infections when used alone.
4. Moderately complex test – requires specific laboratory certification.
5. CLIA-waived test. Can be used in any office setting. Requires a certificate of waiver or higher laboratory certification.
6. Distinguishes between influenza A and B virus infections.

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.

References

Committee on Infectious Diseases, American Academy of Pediatrics. Policy Statement—Recommendations for Prevention and Control of Influenza in Children, 2010–2011.

Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG et al. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009 Apr 15;48(8):1003-32.

World Health Organization. WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) 2009 and other Influenza Viruses [540 KB, 32 pages]. Revised February 2010.

Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2:S27-72.

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 Feb;22(2):164-77.

Faix DJ, Sherman SS, Waterman SH. Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009 Aug 13;361(7):728-9.

Grijalva CG, Poehling KA, Edwards KM, Weinberg GA, Staat MA, Iwane MK, Schaffner W, Griffin MR. Accuracy and interpretation of rapid influenza tests in children. Pediatrics. 2007 Jan;119(1):e6-11.

Centers for Disease Control and Prevention (CDC). Evaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) Virus—United States, 2009. MMWR Morb Mortal Wkly Rep. 2009 Aug 7;58(30):826-9.