Volume 8 Issue 3, November 2023, pp. 176-185

Following the near absence of circulating seasonal influenza in 2020–2021 and the late, brief 2021–2022 season, the 2022–2023 season’s influenza epidemic was characterized by early onset and high rates of transmission (14). The concomitant circulation of SARS-CoV-2 and significant fall respiratory syncytial virus (RSV) activity posed challenges for clinicians dealing with the multi-pathogen respiratory virus season. In addition, rising concerns around highly pathogenic avian influenza (HPAI) virus and the role of respiratory virus multiplex testing inform this review and update to existing AMMI Canada guidance on seasonal influenza for 2022–2023.

In this update we overview:

1.

Characteristics of the 2022–2023 influenza season.

2.

Prevention of influenza.

3.

Influenza antiviral use to reduce the impact on the health care system.

4.

The potential role of multiplex respiratory testing.

5.

Emerging issues related to HPAI virus.

Without question the 2022–2023 fall/winter season saw an unprecedented very early rise in seasonal influenza cases which had been substantially reduced in the preceding 2 years, most likely attributable to public health measures to tackle the COVID-19 pandemic (5). This resulted in a dramatic increase in influenza-associated hospitalizations, particularly among young children, a population concurrently experiencing high levels of severe RSV disease. Although the prevalence of COVID-19 decreased, ongoing viral evolution and the generation of new variants continue to pose risk for sustained and potentially increasing SARS CoV-2 transmission.

This 2022–2023 seasonal influenza surge mirrored that seen in the southern hemisphere where an early onset of seasonal influenza was also noted, with a predominance of influenza A (H3N2) infections (6,7). Part of the high level of absolute numbers of cases reported may have been due to the more widespread use of multiplex respiratory virus testing which includes the detection of not only SARS-CoV-2 but also influenza virus and RSV. Nevertheless, other markers of influenza activity during the fall of 2022 such as influenza hospitalization rates and outbreaks were also above expected levels (4), and the sheer volume of cases due to all three of these viruses continued to challenge a health system still impacted by the COVID-19 pandemic.

Although the impact of seasonal influenza was seen primarily in pediatric age groups this season, it has also impacted the older age groups that traditionally account for a significant degree of morbidity and mortality from seasonal influenza, especially during influenza A (H3N2) dominant seasons (4,8). This has continued to create challenges across the health system as provision of health care for patients at higher risk of progressive, severe, and complicated influenza disease draws heavily on resources and impacts patients and their families. Ensuring prevention measures (such as immunization) are utilized and timely access to influenza treatment with neuraminidase inhibitors (eg, oseltamivir) when indicated can reduce illness and health system strain (9).

Influenza immunization

The risks for severe disease and death from influenza or influenza-related complications, and the current challenges inherent in rapidly confirming influenza virus infection (through diagnostic testing) or exposure to someone with influenza virus infection, underscore the importance of primary prevention through immunization. Influenza immunization may also help to mitigate on-going health system strain (10). Influenza vaccination is recommended annually by Canada’s National Advisory Committee on Immunization (NACI) for all Canadians 6 months of age and older. Additional details can be found in the NACI Statement on Seasonal Influenza Vaccine for 2022–2023 (11). The NACI statement further highlights the groups for whom immunization is particularly important because risks are higher in some settings and for some individuals.

Information regarding immunization for protection against influenza in the context of the COVID-19 pandemic is published by the Public Health Agency of Canada (12). The Canadian Immunization Guide outlines that influenza vaccines can be co-administered at the same visit as COVID-19 immunizations when applicable to facilitate recommended immunizations (13).

To date, in the United States and Canada, the dominant clade (99.9%) of circulating A (H3N2) is 3C.2a1b.2a.2 which is antigenically similar to the A/Darwin/6/2021 (H3N2)-like virus included in the current season influenza vaccine (4,14). A report from the Canadian Sentinel Practitioner Surveillance Network (SPSN) found vaccine effectiveness (VE) reduced the risk by about half against medically attended A/H3N2 illness (54% [95% CI 38% to 66%]) (4,15). Consistent with the SPSN data, VE reported from the 2022 southern hemisphere influenza season in Chile was 49% at preventing hospitalizations during a predominantly A (H3N2) clade 3C.2a1b.2a.2 season (6).

Antiviral post-exposure chemoprophylaxis

Guidance on the use of chemoprophylaxis with neuraminidase inhibitors to protect individuals against influenza after exposure was published in the 2013 AMMI Canada Foundation document (16), and updated in 2019 (9). While the recommendations therein remain appropriate, questions remain and include: How effective is chemoprophylaxis when used in facility-based outbreak settings? What is the optimal duration of post-exposure chemoprophylaxis in those settings? What is advised in the event of exposure to novel influenza A infections or the currently circulating HPAI (H5N1) virus?

Evidence regarding the effectiveness of chemoprophylaxis with neuraminidase inhibitor therapy post-exposure to influenza or during influenza outbreak settings overall remains limited. Existing recommendations have been extrapolated in part from household studies (17,18), and retrospective analyses of chemoprophylaxis use in care settings where multiple outbreak prevention measures have typically been employed all at once (19,20). In these settings, chemoprophylaxis has been associated with shorter duration of the outbreak and fewer cases. Ten days of neuraminidase inhibitor chemoprophylaxis was evaluated in two multi-season randomized controlled trials conducted in long-term care facility outbreak settings. The studies yielded mixed results, and both reported being underpowered (21,22).

Recent analyses, and expert opinion support the potential effectiveness of chemoprophylaxis post-exposure (23,24), but highlight that focussed, limited and timely short-term use is advised (24,25). With seasonal influenza, early therapy is preferred over post-exposure prophylaxis in community settings (9).

Retrospective analyses from Canadian settings focussed on long-term care outbreaks have suggested that durations shorter than 10 days of oseltamivir chemoprophylaxis may be adequate (20) and highlight the relevance of timely administration in relation to declaration of a closed facility outbreak (24,25).

Use of chemoprophylaxis should be balanced against the recognized risk for the emergence of anti-viral resistance when prophylactic neuraminidase inhibitors are used for prolonged periods of time or when the chemoprophylaxis is initiated late post-exposure relative to the short incubation period of influenza viruses (26,27). Incubation periods are typically 1–4 days (mean 2 days) for seasonal influenza, and on average estimated to be a little longer for human infections with avian influenza ranging from 2 to 17 days for H5N1 (mean 2–) and 1–10 days for H7N9 (mean 5 d) or 2–7 days for influenza virus of swine origin (28).

Immunization for protection against seasonal influenza, and stewardship of available anti-viral therapies is underscored by the potential for human infection with emerging zoonotic strains of influenza virus. Ensuring susceptibility of infecting strains to anti-viral therapies is an important priority given the pandemic potential for severe disease and transmission among humans when population immunity to a novel pathogen is lacking. Robust evaluation of post-exposure chemoprophylaxis for HPAI exposure is lacking, but expert opinion, and animal study in ferrets suggest that higher dose chemoprophylaxis post-exposure (eg, oseltamivir 75 mg orally, twice daily) and a duration of therapy sufficiently long enough to cover an incubation period and peak viral shedding from infection should it occur would be prudent (29).

Refer to Figure 1 “Algorithm for oseltamivir and zanamivir prophylaxis or early treatment in close contacts of suspected or laboratory-confirmed case” which builds upon the AMMI Canada 2019 Guidance (9) by incorporating the chemoprophylaxis recommendations for HPAI exposures as detailed in the section Emerging issues related to highly pathogenic avian Influenza virus.

Figure 1: Algorithm for oseltamivir and zanamivir prophylaxis or early treatment in close contacts of suspected or laboratory-confirmed case.

This algorithm has been expanded from the original version as seen in Appendix D of the Use of Antiviral Drugs for Influenza: A Foundation Document for Practitioners to include emerging zoonotic influenza exposure events.* Table 3 as published in The Use of Antiviral Drugs for Influenza: A Foundation Document for Practitioners 2013 (16). Presumptive treatment is therapy with twice daily doses of oseltamivir or zanamivir initiated before the onset of influenza symptoms in close contact of individuals with suspected or lab-confirmed influenza illness. Early treatment is therapy with twice daily doses of oseltamivir or zanamivir initiated ideally within 48 hours of the onset of influenza symptoms.
Non-pharmaceutical interventions (NPI) for prevention

While a detailed review of NPI is beyond the scope of this guidance document, COVID-19 has highlighted their use in preventing respiratory disease. The use of masks and hand hygiene are foundational components to the response to COVID-19. While debate over added benefits of N95 respirators versus surgical masks continues (3032), masks have been shown to reduce the transmission of SARS-CoV-2. Data for preventing the transmission of influenza are less clear (3336). A non-inferiority randomized controlled trial found that surgical masks were non-inferior to N95 for protection against influenza in nurses working in tertiary care hospitals (35). A recent systematic review found that, while there was a trend towards a reduction in laboratory confirmed infection with influenza infection with mask use, it was not significant compared to the data for prevention of SARS-CoV-2 infection (36). However, most data are pre-pandemic when adherence to mask wearing may have been lower. A recent umbrella review suggested that while the quality of data to support non-pharmaceutical interventions for the prevention of viral respiratory infections in the community are of varying quality, the evidence for the use of facemasks and hand hygiene is the strongest (38). Similarly, a recent retrospective cross-sectional study suggested that individuals who used NPIs used to prevent COVID-19 in Lebanon in April 2021 including hand hygiene, mask use, and cough etiquette were less likely to develop influenza-like illness (39). However, it did not take into account lockdowns and school closures or restrictions in gathering which also had a significant impact in reducing the burden of respiratory viral illness.

Although the quality of data varies, NPI interventions like hand hygiene and wearing masks when in poorly ventilated crowded places are safe and can be considered reasonable options for individuals to choose to reduce risk this respiratory virus season.

There are no significant changes to the seasonal influenza antiviral indications and dosing as outlined in the foundation documents (9,16). To review, as outlined in the AMMI Canada Foundations documents (2013 and 2019) (9,16), and detailed in Appendices A through C, indications for influenza therapy with anti-viral medication factor in clinical or laboratory confirmed diagnoses of influenza, the time that has elapsed since the onset of the symptoms, and the risk factors for severe disease or death based on the age and health and immune status of the infected person.

Currently only the neuraminidase inhibitors oseltamivir and zanamivir are available and effective against currently circulating strains. Although baloxavir marboxil (XOFLUZA) was approved by Health Canada in 2020 for the treatment of uncomplicated influenza in patients 12 years of age and older, at the time of writing (February 2023) this agent is not yet marketed in Canada.

When influenza is circulating in the community, the decision to initiate therapy with influenza antivirals for outpatients with possible influenza should be based on their risk factors and the severity of their clinical presentation, for example, pneumonia, or exacerbation of underlying chronic medical conditions (9,16). Antiviral therapy should be prescribed as soon as possible when indicated.

Behavioural changes and non-pharmaceutical interventions during the COVID-19 pandemic led to reduced circulation of respiratory viruses and a subsequent larger proportion of susceptible individuals in the population, especially among children (40). With the lifting of interventions, increased circulation of respiratory viruses such as influenza virus and RSV has caused a considerable strain on health care systems during the 2022–2023 winter season. Ambulatory antiviral treatment, when indicated, has the potential to help to ease that burden. Early treatment with oseltamivir has been shown to lead to shorter duration of symptoms and less complications requiring antibiotics in adults and children (41,42). There are a number of observational studies reporting that ambulatory antiviral therapy reduces the risk of hospitalization compared to regular care, particularly when prescribed earlier in the course of infection (4348). The results of systematic reviews on the use of oseltamivir to prevent hospitalization have been mixed. Although a Cochrane review and systematic review of RCTs by Jefferson et al did not show any reduction in hospitalization with oseltamivir, it was noted that the outcome of hospitalization was poorly defined and inconsistently reported in the included studies (49,50). Some systematic reviews and meta-analyses have demonstrated oseltamivir has a beneficial effect in reducing hospitalizations (5153). A systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies including both adults and children found that oseltamivir treatment reduced hospitalization by 52% (51). Another meta-analysis of RCTs in adults treated with oseltamivir found a 63% reduction in hospitalization (50), however, a recent large pragmatic RCT did not replicate this effect (42).

While not definitive, suggestion that oseltamivir may reduce hospitalizations, thus potentially alleviating health system strain, remains important consideration. The effectiveness of oseltamivir is optimized when administered early in laboratory-confirmed infection. To facilitate this, consideration should be given to increasing access to both influenza testing and timely oseltamivir treatment to individuals at higher risk and as outlined previously (9,16) (see Appendices A–C).

Influenza virus, SARS-CoV-2, and RSV infections cannot be reliably differentiated based on clinical presentation since they cause a range of overlapping respiratory and systemic symptoms, making management challenging when all three viruses are circulating. Consistent with previous recommendations, all hospitalized patients with acute febrile respiratory illness should be tested using a highly accurate nucleic acid amplification test (NAAT) (4). Many commercial assays have moved away from detection of SARS-CoV-2 alone to multiplex NAAT testing that can identify any of these viruses in a single reaction and the use of these multiplex tests in community-based patients who are eligible for COVID-19 therapy has also increased the identification of influenza in these patients. At present, although influenza testing may not be routinely recommended for ambulatory patients in many jurisdictions, in part due to cost considerations, given the overlapping risk factors for complications and severe disease, many of those being tested for COVID-19 treatment would also potentially benefit from anti-viral treatment for influenza if it was identified. 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 or who have severe, complicated, or progressive illness regardless of time elapsed since onset of symptoms (9,16). Initiation of antiviral therapy should not wait for laboratory confirmation of influenza infection. If the NAAT test for influenza is done and the results are negative, therapy can be discontinued.

The use of multiplex testing offers the opportunity to identify more individuals who could benefit from treatment, shorten duration of illness, and relieve pressures on the health system; developing pathways to ensure easy access to therapy should be considered. In summary, the use of multiplex testing among the highest risk individuals would facilitate early use of antivirals for influenza or COVID-19. For this approach to be optimized, easy and equitable access to testing and treatment would need to be addressed. To improve outpatient access to influenza testing and treatment going forward, health systems across the country could consider leveraging the processes developed and used to enable efficient patient access to testing and therapeutics for COVID-19.

In December 2021, the Canadian Food Inspection Agency (CFIA) reported the first avian cases of highly pathogenic avian influenza (HPAI) virus in Canada since 2015. In the ensuing months, 11 provinces and territories reported subtype H5N1 HPAI virus activity in domestic poultry (backyard flocks and larger production facilities) and wild birds, including shorebirds and raptors. In 2022, the Canadian Wildlife Health Cooperative documented 1460 H5 PCR positive live and dead wild birds from 11 provinces/territories (54). Nearly 200 infected premises (backyard poultry flocks or production facilities) with over seven million birds have been identified across nine provinces, and over two million poultry have been depopulated, according to CFIA (55).

The extent of HPAI activity in North America in 2021–2022 has far exceeded that witnessed in the 2014–2015 intercontinental wave, bearing substantial concern for human and animal health, and heralding a fifth intercontinental wave of HPAI. Viral reassortment in Canada has been detected and further underscores the potential risk for intra- and interspecies spillover (56). H5N1 viral spillover to mammalian species has already been detected in a substantial number of free-ranging terrestrial and marine mammals in Japan, Europe, and the Americas, and the transmission among mammals is demonstrated by outbreaks among captive mink in Spain (5759).

Confirmed human infection and illness with HPAI viruses is uncommon and typically associated with direct exposure to birds or environments known to be contaminated with the virus. As of December 2022, there have been 977 H5Nx and 1569 H7Nx laboratory-confirmed human cases globally to date (60). Although historically these have been associated with high mortality (up to 59%), true infection rates are not well established, thus biasing these estimates (61).

The predominant H5N1 viruses now circulating among birds globally are different from earlier H5N1 viruses. In North America, prior to the 2022 American H5N1 human case, there has only been one confirmed human H5N1 case (Alberta, Canada, December 2013) (62). The patient was diagnosed after presenting with pulmonary symptoms and meningoencephalitis upon return from travel to China. The diagnosis was made post-mortem, highlighting that timely clinical recognition, diagnostic testing, and reporting to public health are integral to treatment interventions for patients or those in close contact and exposed to ill patients. H7N9 has also been rarely reported in humans, including in returning travellers to Canada (63). To date there has been no sustained human-to-human transmission of HPAI (64).

Clinical and laboratory diagnosis of HPAI in humans

The presentation of HPAI viral infections in humans range from asymptomatic to severe influenza-like illness, and may include conjunctivitis or meningoencephalitis, and may result in death (62,63,65). Timely diagnosis and reporting are key factors for successful outcomes with use of antiviral therapy or chemoprophylaxis and thus clinical assessments require a low index of suspicion in individuals with an exposure history. Routine diagnostic testing platforms commonly used in Canadian settings can detect HPAI strains, but many cannot differentiate them from human seasonal strains. Thus, when HPAI is suspected based on potential epidemiological risk factors, non-typeable samples must be forwarded to regional public health laboratories to rule out HPAI (see Infographic in this issue).

In Canada, the Public Health Agency of Canada defines severe acute respiratory infection (SARI) (67). The definition includes occupational and environmental risk factors for HPAI and should trigger diagnostic testing. At the time of writing, there is no specific national case definition for HPAI infection among humans, regardless of severity of illness. Individuals for whom there is sufficient concern for HPAI infection based upon the clinical presentation and epidemiologic factors should be tested, regardless of severity of illness.

Clinical samples for influenza testing should be submitted as soon as possible after onset of symptoms. Samples should include those approved for seasonal influenza, with consideration for additional lower respiratory tract sampling in severe cases, under institutional guidance by Infection Prevention and Control (IP&C).

Antiviral recommendations for avian influenza

A.

Treatment recommendations for HPAI infection in adults:

Oseltamivir 75 mg orally twice daily for 5 days (68).

B.

Chemoprophylaxis recommendations after exposure to HPAI

1.

Exposure* to a person infected with HPAI:

Oseltamivir 75 mg orally twice daily x 10 days.

2.

Discrete time-limited exposure to poultry or other zoonotic source of HPAI:

Oseltamivir 75 mg orally twice daily for 10 days.

3.

Chemoprophylaxis should be limited to discrete exposure events to confirmed cases and prolonged long-term use is not advised at this time.

*Exposure as defined by local public health and infection prevention and control.

Key considerations when prescribing for HPAI prevention or treatment:

Use neuraminidase inhibitor treatment dose for chemoprophylaxis and not once daily dosing.

10 days for chemoprophylaxis is recommended aiming to cover a slightly longer incubation period than seasonal influenza strains, and to ensure an adequate course of therapy to prevent viral shedding in the event infection occurs.

In the event of human HPAI infection, consideration should be given to initiating therapy even if >48 hours from symptom onset has elapsed due to the potential severity of illness and the risks of ongoing viral replication or transmission.

Zanamivir may be considered an alternative to oseltamivir for chemoprophylaxis or treatment and should be used according to the treatment dosing outlined in the AMMI Canada Foundations document (9,16).

The 2022–2023 influenza season has proven to be a unique season that shed light on the opportunities to hone existing prevention strategies across a range of respiratory viral infections including influenza and SARS-CoV-2 as they co-circulate. Going forward, additional health system advances that ensure consistent and timely access to influenza testing and treatment for those at highest risk will remain important and can be seen as tools to assist patients, populations, and the health system. Emerging risks such as the current global circulation of H5N1 HPAI strains underscore the importance of preventing and treating seasonal influenza to limit the potential for co-infections and reassortment. They also serve to reinforce the critical importance of surveillance, therapeutics, and the basics of infection prevention through immunization, NPIs, testing and focussed post-exposure interventions when necessary.

Acknowledgements:

The authors wish to acknowledge and thank Ms Riccarda Galioto and Ms Jenna Wong for their assistance in coordinating this work and preparing the final manuscript.

N/A

N/A

N/A

No funding was received for this work.

The authors have nothing to disclose

This manuscript has been peer reviewed.

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