2020–2021 AMMI Canada guidance on the use of antiviral drugs for influenza in the setting of co-circulation of seasonal influenza and SARS-CoV-2 viruses in Canada

Abstract

We provide an update to the Association of Medical Microbiology and Infectious Disease Canada foundation guidance for the upcoming 2020–2021 influenza season in Canada. Important issues for this year include the implications of co-circulation of SARS-CoV-2, the role of diagnostic testing, and a restatement of dosing and administration recommendations for neuraminidase inhibitors in various age groups and underlying health conditions. Although peramivir and baloxivir are now licensed in Canada, neither is currently marketed, so this guidance focuses on further optimizing the use of oseltamivir and zanamivir.

Background and Epidemiology

The ongoing coronavirus disease 2019 (COVID-19) pandemic has generated many questions concerning the upcoming influenza season in Canada. The high 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 has the potential to create unforeseen challenges for diagnostic testing, clinical care, and public health management.

The implications of co-circulation of both viruses are uncertain. However, data from the Southern Hemisphere influenza season after the start of the COVID-19 pandemic revealed marked reductions in laboratory-confirmed seasonal influenza cases and hospitalizations (1,2). Measures deployed to reduce the spread of COVID-19 likely contributed to these reductions. However, other factors such as increased influenza vaccine uptake and vaccine efficacy may also have contributed.

Predicting the character and time course of this year’s Northern Hemisphere influenza season based on the Southern Hemisphere experience is difficult. Among the uncertainties will be the uptake and efficacy of this season’s influenza vaccine. Increased influenza vaccine uptake in the general population in Australia has been reported (3). However, the extent to which this applies to high-risk communities in the so-called COVID-19 hot zones is unclear. In addition, the constituents of the influenza vaccine for the Southern Hemisphere are different than those of the vaccine for the Northern Hemisphere.

Like other vaccines, influenza vaccine protection is specific for the target pathogen, namely influenza viruses with no expected effect on other non-influenza respiratory viruses, and the balance of available evidence reinforces this principle (4–11). More recently, several studies have also reported no effect of influenza vaccination on the risk of COVID-19 hospitalization or mortality (12,13)

As of early November, influenza activity in Canada was at exceptionally low levels. As of week 46 of 2020, the percentage of tests positive for influenza (0.04%) remained at the lowest level recorded for the past nine seasons (14).

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 (15,16). In addition, co-infection with both influenza virus A or B and SARS-CoV-2 has been described.

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 (17,18). The ideal specimen depends on the clinical picture. A nasopharyngeal swab (NPS) using a flocked swab 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. In suspected cases of both influenza and SARS-CoV-2 with progressive illness involving the lower respiratory tract, lower tract specimens should be obtained if the NPS is negative, although procedures such as bronchoalveolar lavage can generate aerosols and may be associated with increased risk to health care workers. Testing of alternative specimens such as saline gargles or saliva has been validated for SARS-CoV-2 detection in several Canadian laboratories but are 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. However, diagnostic accuracy may be insufficient for their use as stand-alone tests; their clinical utility is unclear at this point, and how they should be used continues to evolve (19). Rapid NAAT assays or rapid 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 (20), and their use should be limited to the outpatient setting (11). Traditional RADTs without an automated digital reader are generally no longer recommended because they have poor sensitivity for influenza A and B in adults (42.6% and 33.2%, respectively) and children (61.2% and 65.7%, respectively) compared with RT-PCR (14).

Results of influenza testing can be used to inform decisions on antiviral and antibiotic treatments, need for ancillary diagnostic tests, 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 (21). All hospitalized patients with suspected influenza should be tested with highly accurate NAAT assays (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. However, 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 identifying uncomplicated community cases of influenza may mitigate further spread and reduce the burden of influenza-like illness, 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.

• In hospitalized patients of all ages and disease severity, clinicians should use multiplex nucleic acid amplification tests assays targeting a panel of respiratory pathogens, including 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 depending on laboratory capacity.

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

Antiviral Treatment

Notwithstanding the substantial uncertainties concerning the influenza season this fall and winter, the following guidance is provided to assist practitioners on the basis of currently available information. Evolving experience may necessitate changes in these suggestions.

Early empiric antiviral therapy

The decision to initiate therapy with influenza antivirals in individuals with possible influenza or COVID-19 should be based on their risk factors and 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.

^* It is strongly encouraged that these groups be prescribed early empiric antiviral therapy

^† Children aged 2–4 years also have a higher rate of complications than older children; however, the risk for these children is lower than the risk for children aged younger than 2 years. For the latter, the risk of hospitalization is substantially higher than for older children (22).

^‡ The risk of influenza-related hospitalization increases with length of gestation; that is, it is higher in the third trimester than in the second trimester.

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:

   • Asthma and other chronic pulmonary disease, including 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)
   • Malignancy
   • Chronic renal insufficiency
   • Chronic liver disease
   • Diabetes mellitus and other metabolic diseases
   • Hemoglobinopathies such as sickle cell disease
   • Immunosuppression or immunodeficiency as a result of disease (eg, HIV infection, especially if CD4 is <200 × 10⁶/L) or iatrogenic because of medication
   • Neurological disease and neurodevelopmental disorders that compromise handling of respiratory secretions (cognitive dysfunction, spinal cord injury, seizure disorders, neuromuscular disorders, cerebral palsy, metabolic disorders)
   • Age younger than 5 years^†
   • Age 65 years or older
   • Residents of nursing homes or other chronic care facilities
   • Pregnancy and up to 4 weeks postpartum regardless of how the pregnancy ended^‡
   • Age younger than 18 years on chronic aspirin therapy
   • Obesity with a BMI of 40 kg/m² or more or a BMI more than 3 z-scores above the mean for age and gender
   • Children and adolescents (aged 6 mo–18 y) undergoing treatment for long periods with acetylsalicylic acid because of the potential increase in Reye’s syndrome associated with influenza
   • Indigenous Canadians

Early empiric antiviral therapy should be prescribed for adults and children who belong to priority groups with suspected or confirmed mild or uncomplicated influenza illness (Appendix A) or who have severe, complicated, or progressive illness (Appendix B) regardless of the time that has elapsed since onset of symptoms. 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.

Mild, uncomplicated influenza illness

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 algorithm in Appendix A. For children who have mild, suspected, or confirmed influenza, consult the algorithm in Appendix C.

Pediatric considerations (23)

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

• 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 (18). Because infants aged younger than 6 months are not vaccinated for influenza, it is important to immunize their household and other close contacts to protect them from disease and, thereby, reduce the need for antiviral therapy. Influenza immunization of pregnant women should be promoted to protect infants during their first 6 months of life.

• Aged 1 to less than 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 younger than 2 years as 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 is optional.

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

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

• Aged younger than 1 year: NAIs are currently not approved for the routine treatment of seasonal influenza illness (24).

• Aged 1 year or older: Within 48 hours of illness onset, treat with oseltamivir or, when age appropriate (≥7 years), 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 2018, two additional antiviral drugs for influenza have been licensed by Health Canada: intravenous peramivir (25), 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 that of the NAIs (26). As of September 2020, 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 amantadine).

Since the publication of the updated 2019 Association of Medical Microbiology and Infectious Disease (AMMI) Canada foundation guidance document (27), new data on the effectiveness of oseltamivir have been published, further supporting use of oral oseltamivir as the primary agent in Canada for treatment of suspected or confirmed influenza.

Treatment with zanamivir orally inhaled powder should be considered for patients not responding to oseltamivir therapy, for those who have developed influenza while receiving oseltamivir prophylaxis, or for 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 (27) for details on dosing regimens. The standard adult dose of oseltamivir is 75 mg by mouth twice a day. Increasing the dose of oseltamivir in excess of the standard recommended dose is unlikely to provide added benefits. Oseltamivir dose regimens do not need to be adjusted for patients with a BMI of more than 40 kg/m² or who are pregnant at any stage of gestation. Oseltamivir is considered safe to use during pregnancy. Dosing should be adjusted according to degree of renal impairment. Oseltamivir dosing regimens for patients with renal impairment are detailed in Table 3 of the foundation document (27).

In critically ill ventilated patients receiving oseltamivir via oro- or nasogastric tube and those who are receiving renal replacement therapy or extracorporeal membrane oxygenation, oseltamivir appears to be well absorbed.

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 (28).

During therapy, resistance to oseltamivir is more likely to emerge among immunocompromised patients of all ages and among young children so treatment failure resulting from 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 the upper respiratory tract specimen (NPS) or lower respiratory tract specimen testing (endotracheal secretion or bronchoalveolar lavage specimen), and positive specimens should be sent for antiviral resistance testing. Consult your local laboratory for further guidance.

Treatment duration

In 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 is not established. Treatment may be continued for longer than 5 days for 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 in 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. Currently, it is uncertain whether significant drug–drug interactions occur with co-administration.

Antiviral prophylaxis

Guidance on the use of chemoprophylaxis to protect individuals against influenza was published in the AMMI foundation document (27) and continues to be appropriate (Appendix D). Early empiric presumptive therapy continues to be recommended in preference to post-exposure prophylaxis. Presumptive therapy should be considered 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 whether illness in the index case might be COVID-19 rather than influenza.

Such early empiric influenza antiviral therapy may be continued or stopped as outlined in the ‘Treatment Duration’ section.

Appendix A

Figure A.1:

Algorithm for oseltamivir and zanamivir treatment of mild or uncomplicated suspected or confirmed influenza in adults

Appendix B

Figure B.1:

Algorithm for oseltamivir and zanamivir treatment of severe, progressive, or complicated suspected or confirmed influenza in adults

BID = Twice daily

Appendix C

Figure C.1:

Children or youth aged younger than 18 years with suspected or confirmed influenza

* In children of any age with mild or uncomplicated illness, antiviral treatment is not routinely recommended and should not be used if symptoms have been present for more than 48 hours. Treatment with oseltamivir or, if appropriate, zanamivir may be considered on a case-by-case basis even if symptoms have been present for more than 48 hours. In Canada, antivirals are not authorized for infants aged younger than 1 year but may be considered on a case-by-case basis. An infectious diseases physician or a pharmacist should be consulted.

† If antivirals are being used, the following apply: no recent oseltamivir exposure, oseltamivir or zanamivir (if age appropriate); recent oseltamivir exposure for treatment or prophylaxis, zanamivir, and consider testing for oseltamivir resistance.

Appendix D

Figure D.1:

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

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

Ethics Approval:

N/A

Informed Consent:

N/A

Funding:

No funding was received for this work.

Disclosures:

Papenburg reports grants and personal fees from BD Diagnostics, Seegene, Janssen Pharmaceutical, and AbbVie and grants from MedImmune and Sanofi Pasteur, outside the submitted work. Hatchette reports grants from GSK and Pfizer, outside the submitted work.

Peer Review:

This manuscript has been peer reviewed.