2021–2022 AMMI Canada guidance on the use of antiviral drugs for influenza in the COVID-19 pandemic setting in Canada

Abstract

We provide an update to the Association of Medical Microbiology and Infectious Disease Canada seasonal influenza foundation guideline on the use of antiviral drugs for influenza for the upcoming 2021–2022 influenza season in Canada. Peramivir and baloxavir marboxil were licensed in Canada in 2017 and 2020, respectively, but neither is currently marketed. Thus, this guidance continues to focus on further optimizing the use of oseltamivir and zanamivir. Important issues for this year include the implications of co-circulation of severe acute respiratory syndrome coronavirus 2 and influenza viruses; the role of diagnostic testing in relation to impact on patient management; and dosing and administration recommendations for neuraminidase inhibitors for various at-risk age groups.

Background and Epidemiology

The coronavirus disease 2019 (COVID-19) pandemic has again generated many questions concerning influenza in Canada, including concern about the likelihood of co-circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses during the fall and winter in the northern hemisphere. During the 2019–2020 influenza season, influenza activity in Canada ended abruptly in week 13 at the end of March 2020, 8 weeks earlier than the average end of season on the basis of the previous five seasons. A similar abrupt decline was observed in other northern hemisphere countries. An increase in neither influenza vaccine uptake nor vaccine effectiveness during the 2019–2020 influenza season likely accounted for this observation. Vaccine uptake ranged from 30% in adults aged 18–64 years without chronic disease to 70% among older adults, and vaccine effectiveness was modest, ranging from 43% for influenza A (H1N1) to 65% for influenza B. The sharp decline in influenza detection was also not due to a decrease in influenza testing but rather corresponded to the implementation of stringent and widespread public health measures to limit the spread of SARS-CoV-2.1^,2

In 2020–2021, despite continued monitoring for influenza across Canada, there was no evidence of community circulation throughout the surveillance season.3 Thus, to date during the pandemic, there has been little to no co-circulation of SARS-CoV-2 and influenza viruses.

Notwithstanding the disappearance of epidemic influenza during 2019–2020 and 2020–2021 and the low rates of infection in the southern hemisphere during 2021, predicting the character and time course of this year’s (2021–2022) northern hemisphere influenza season remains difficult. Accordingly, it is appropriate to update our recommendations on the use of antiviral drugs for influenza for 2021–2022.

Role of Laboratory Testing

Influenza and COVID-19 cannot be reliably differentiated on the basis of clinical presentation because both viruses cause a range of overlapping respiratory and systemic symptoms, although anosmia and dysgeusia have been more frequently described with COVID-19.4^,5 In addition, co-infection with both influenza virus A or B and SARS-CoV-2 has been described but appears to be uncommon.6

For influenza viruses and SARS-CoV-2, laboratory-based nucleic acid amplification tests (NAAT), which generally consist of reverse transcriptase polymerase chain reaction (RT-PCR) assays, are the gold-standard diagnostic test.7^,8 The ideal specimen depends on the clinical picture. Use of a flocked nasopharyngeal swab (NPS) to enhance the collection and release of cellular material is the preferred specimen type, but mid-turbinate nasal or combined nasal–throat samples are also acceptable, depending on institutional testing algorithms and other factors such as patient age. In suspected cases of influenza and SARS-CoV-2 with progressive respiratory illness, lower-tract specimens should be obtained if the NPS is negative, using the appropriate personal protective equipment and necessary precautions to minimize aerosol generation. Testing of alternative specimens such as saline gargles or saliva has been validated for SARS-CoV-2 detection in several Canadian laboratories9^,10 but is not currently validated for influenza.

Rapid point-of-care antigen detection tests and molecular assays for SARS-CoV-2 have been approved for use in Canada; their clinical utility and how they should be used continues to evolve.11 Although their diagnostic accuracy is insufficient for use as a stand-alone diagnostic test in a hospital setting, they are increasingly being used in the community in several provinces to access hard-to-reach populations and for surveillance. Rapid NAAT assays or antigen detection tests (RADTs) have been available for influenza detection for many years. Because of their simplicity and speed, they are potentially valuable influenza diagnostic tools, especially if deployed at the point of care. However, test sensitivity can vary substantially across commercial platforms;12 thus, their use should be limited to the outpatient setting. Traditional RADTs without an automated digital reader are generally no longer recommended because they have poor sensitivity for influenza A and B viruses in adults (42.6% and 33.2%, respectively) and children (61.2% and 65.7%, respectively) compared with RT-PCR.12

Results of influenza testing can be used to inform decisions on antiviral and antibiotic stewardship, need for ancillary diagnostic testing, additional hospital and institutional infection control measures, or recommendations for household contacts of index cases that are at higher risk for complications of influenza infection.13 All hospitalized patients with suspected influenza should be tested with highly accurate NAAT assays (see Box 1). In contrast to COVID-19, public health interventions such as contact tracing are not generally warranted for influenza; thus, influenza testing for ambulatory patients is not routinely recommended but may be considered when results will guide management. The ability to provide expanded influenza testing will depend on molecular testing capacity, given the massive demand that SARS-CoV-2 testing has placed on laboratories. Although laboratory testing may determine the underlying etiology of those presenting with respiratory symptoms and identify uncomplicated community cases of influenza, which may mitigate further spread and reduce the burden of influenza-like illness (ILI), this must be weighed against the risk of further straining human resources, supply chains, and other limited resources. The cost and practicality of bundled testing for both influenza and SARS-CoV-2 viruses for all cases is prohibitive and does not necessarily benefit individual patient management. However, multiplex tests that can detect influenza and SARS-CoV-2 in a single test may increase the ability to deliver both influenza virus and SARS-CoV-2 testing. The availability of multiplex testing continues to evolve and will vary by jurisdiction. Clinicians should check with their local laboratories to determine the influenza testing strategy used.

Box 1:

Testing for respiratory viruses in patients with influenza-like illness when influenza is circulating in the community

• For hospitalized patients of all ages and disease severity, clinicians should use multiplex nucleic acid amplification test assays (if available) that target a panel of respiratory pathogens, which at minimum should include both influenza and severe acute respiratory syndrome coronavirus 2 viruses.

• In the outpatient setting, if test results will alter clinical management, clinicians may consider testing for influenza, but the availability of testing in the outpatient setting will vary by jurisdiction.

• Clinicians should consult with their local laboratory to determine what testing strategies are available to them.

Antiviral Treatment

The following guidance is provided to assist practitioners and is based on currently available information. There are no changes from our most recent recommendations.

Use of influenza antivirals

Early empiric antiviral therapy

When influenza is circulating in the community, the decision to initiate therapy with influenza antivirals for individuals with possible influenza or COVID-19 should be based on their risk factors and the severity of their clinical presentation (Box 2).

Box 2:

Adults and children with influenza-like illness for whom early empiric antiviral therapy for influenza should be considered when influenza is circulating in the community

Early empiric antiviral therapy for influenza should be prescribed for adults and children who

1. have severe, complicated, or progressive illness,^*

2. are hospitalized,^* and

3. are at higher risk of complications of influenza, which include the following age groups, chronic medical conditions, and persons:

   • Asthma and other chronic pulmonary disease, including asthma, bronchopulmonary dysplasia, cystic fibrosis, chronic bronchitis, and emphysema
   • Cardiovascular disease (excluding isolated hypertension; including congenital and acquired heart disease, such as congestive heart failure and symptomatic coronary artery disease)
   • Renal disease
   • Chronic liver disease
   • Diabetes mellitus and other metabolic diseases
   • Anemia and hemoglobinopathies, such as sickle cell disease
   • Cancer, immunosuppression, or immunodeficiency due to disease (eg, HIV infection, especially if CD4 is <200 × 10⁶/L) or management of underlying condition (solid organ transplant or hematopoietic stem cell transplant recipients)
   • Neurological disease and neurodevelopmental disorders that compromise handling of respiratory secretions (cognitive dysfunction; spinal cord injury; neuromuscular, neurovascular, neurodegenerative, and seizure disorders; cerebral palsy; metabolic disorders)
   • Children aged younger than 5 years^*
   • Individuals aged 65 years or older
   • People of any age who are residents of nursing homes or other chronic care facilities
   • Pregnancy and up to 4 weeks postpartum regardless of how the pregnancy ended^†
   • Obesity with a BMI ≥40 or a BMI >3 z-scores above the mean for age and gender
   • Children and adolescents aged younger than 18 years undergoing treatment for long periods with acetylsalicylic acid because of the potential increase in Reye’s syndrome associated with influenza
   • Indigenous peoples

Our recommendations for early empiric antiviral therapy remain unchanged from the 2019 update to the AMMI Canada Foundation document.¹⁴ Antiviral therapy should be prescribed for adults and children who belong to priority groups with suspected or confirmed mild or uncomplicated influenza illness regardless of time elapsed since onset of symptoms.14 Initiation of antiviral therapy should not wait for laboratory confirmation of influenza infection. If the NAAT test for influenza is negative, therapy can be discontinued.

For those with mild, uncomplicated influenza illness, consider the following:

• For adults with mild disease with or without risk factors for complications and illness of less than or more than 48 hours duration, consult the 2019 update to the AMMI Canada Foundation document.14

• For children who have mild, suspected or confirmed influenza, consult the 2019 update to the AMMI Canada Foundation document.14

Paediatric considerations

For children with mild disease and no risk factors other than age, consider the following:16

• Aged younger than 1 year: In Canada, neuraminidase inhibitors (NAIs) are currently not approved for the routine treatment of seasonal influenza illness in this age group. Because infants aged younger than 6 months are not vaccinated for influenza, it is important to immunize their household and other close contacts to indirectly protect them from disease. Influenza immunization during pregnancy should be promoted to protect infants during their first 6 months of life.

• Aged 1 to <5 years: Antiviral use is optional for this group. In this regard, although children aged younger than 5 years are classified as high risk and those aged younger than 2 years at highest risk, children who are otherwise healthy, whose influenza is mild, and who do not require hospitalization do not routinely require antiviral therapy. For these children, treatment (using oseltamivir) is optional.

• Aged 5 years or older: Antiviral therapy is not routinely recommended for children and youth with mild influenza illness who are otherwise healthy.

For children with mild disease and risk factors other than age, consider the following:

• Aged younger than 1 year: NAIs are not currently approved for the routine treatment of seasonal influenza illness.17

• Aged 1 year or older: Within 48 hours of illness onset, treat with oseltamivir or, when age-appropriate (≥7 y), inhaled zanamivir.

• Aged 1 year or older: Beyond 48 hours of illness onset, treatment with oseltamivir may be considered on a case-by-case basis. When age appropriate, inhaled zanamivir may be used instead of oseltamivir.

Available antiviral agents

Since 2017, two additional antiviral drugs for influenza have been licensed by Health Canada: intravenous peramivir,18 another member of the NAI class of drugs, such as oseltamivir and zanamivir, and oral baloxavir marboxil. Baloxavir inhibits influenza A and B virus replication by inhibiting viral endonuclease, a mechanism of action distinct from the NAIs.19 As of September 2021, neither peramivir nor baloxavir is being marketed in Canada. Therefore, this guidance focuses on the use of oseltamivir, zanamivir, and amantadine. Amantadine continues to not be recommended because of widespread resistance to it in contemporary influenza A viruses (influenza B viruses are inherently resistant to adamantanes).

Since the publication of the updated 2019 Association of Medical Microbiology and Infectious Disease (AMMI) Canada Foundation guidance document,14 new data on the effectiveness of oseltamivir have been published that further support use of oral oseltamivir as the primary agent in Canada for treatment of suspected or confirmed influenza.20

Treatment with zanamivir orally inhaled powder should be considered for patients not responding to oseltamivir therapy, those who have developed influenza while receiving oseltamivir prophylaxis, or those in whom influenza B infection is confirmed or strongly suspected. Unfortunately, no safe and effective formulation of zanamivir for administration to intubated patients is available in Canada (an intravenous formulation is available in the United Kingdom). Accessing intravenous peramivir via the Special Access Program of Health Canada may be an option.

Antiviral dosage regimens

Please refer to the AMMI Canada Foundation document for details on dosing regimens. The standard adult dose of oseltamivir is 75 mg orally twice per day. Increasing the dose of oseltamivir to more than the standard recommended dose is unlikely to provide added benefits. In critically ill ventilated patients receiving oseltamivr via oro- or nasogastric tube and those who are receiving renal replacement therapy or extracorporeal membrane oxygenation, oseltamivir appears to be well absorbed. Oseltamivir dose regimens only need to be adjusted for patients with renal insufficiency. No adjustment is required for obesity or pregnancy. Oseltamivir is considered safe to use during pregnancy. Oseltamivir dosing regimens for patients with renal impairment are detailed in Table 3 of the foundation document.14

Antiviral resistance to neuraminidase inhibitors

Resistance to oseltamivir in circulating viruses in Canada during the 2019–2020 influenza season was very low. However, this can change. Current Canadian drug resistance surveillance data can be found on Flu Watch.21

From September 2019 to August 2020, 733 influenza viruses underwent genotypic testing for oseltamivir resistance at the National Microbiology Laboratory. All 164 A (H3N2) and all 286 B viruses were sensitive. Among 283 A (H1N1) viruses, only 1 had a mutation (H257Y) consistent with oseltamivir resistance. All 733 viruses were susceptible to zanamivir. No viruses from the 2020–2021 influenza season were available for antiviral drug susceptibility testing. Since the 2009 pandemic, nearly all circulating strains have been sensitive to oseltamivir and zanamivir. Thus, at this time, oseltamivir and zanamivir resistance is not considered to be a significant concern.

During therapy, resistance to oseltamivir is more likely to emerge among immunocompromised patients of all ages as well as among young healthy children, so treatment failure as a result of drug resistance among such patients should be considered as a possible explanation. Resistance to zanamivir among such patients has been less commonly reported. If resistance is suspected, it is important to repeat testing on a new upper or lower respiratory tract sample, and any positive specimens should be sent for antiviral resistance testing. Consult your local laboratory for guidance.

Treatment duration

Among patients with mild uncomplicated influenza illness, the recommended duration of oseltamivir therapy is 5 days. The optimal duration of therapy for patients with laboratory-confirmed influenza without or with concurrent SARS-CoV-2 infection who are hospitalized or have severe, progressive, or complicated disease has not been established. If treatment is being continued for longer than 5 days among severely ill individuals, consulting an expert in infectious disease should be considered.

Among patients whose influenza test is negative and whose SARS-CoV-2 virus test is positive, influenza antiviral therapy should be stopped. Among patients for whom tests for both influenza and SARS-CoV-2 are negative but respiratory disease is continuing or progressing, further diagnostic testing and expert input from an infectious disease specialist should be considered before influenza antiviral therapy is discontinued.

Influenza and COVID-19 co-infection

Patients with both influenza virus and SARS-CoV-2 co-infection who are receiving remdesivir or other SARS-CoV-2 antivirals should also receive oseltamivir as per the criteria outlined earlier. Whether significant drug–drug interactions occur with co-administration is presently uncertain.

Antiviral prophylaxis

Guidance on the use of chemoprophylaxis to protect individuals against influenza was published in the AMMI Canada Foundation document and continues to be appropriate (Appendix Figure A1).14 When influenza and COVID-19 are circulating in the community, the authors recommend early empiric presumptive therapy in preference to pre-exposure prophylaxis when contacts who are at higher risk of influenza complications are exposed to an index case with acute respiratory tract illness even though it is uncertain that illness in the index case might be COVID-19 disease rather than influenza. Such early empiric influenza antiviral therapy may be continued or stopped as outlined above in the “Treatment Duration” section.

Appendix

Figure A1:

Algorithm for oseltamivir and zanamivir prophylaxis or early treatment in close contacts of suspected or lab-confirmed cases of influenza

*Presumptive treatment is therapy with twice-daily doses of oseltamivir or zanamivir initiated before the onset of influenza symptoms in close contact of individual with suspected or lab-confirmed influenza illness

Ethics Approval:

N/A

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Funding:

No funding was received for this work.

Disclosures:

TF Hatchette has received an investigator-initiated grant from GlaxoSmithKline/Pfizer for the Severe Outcome Surveillance Network of influenza and community-acquired pneumonia in hospitalized adults, received payment from Sanofi for a coronavirus disease vaccine presentation, received payment for expert testimony from the Peter C. Ghiz Law Corporation, and is a board member of the Halifax Sexual Health Centre and past president of AMMI Canada. J Papenburg has received grants or contracts from MedImmune, Sanofi, AbbVie, and Merck, and has received consulting fees from Merck and honoraria for presentations from AbbVie and AstraZeneca.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A