key: cord-0916680-q9mg6tki
authors: Jones, Warren A.; de Cassia Castro, Rita; Masters, Henry L.; Carrico, Ruth
title: Influenza Management During the COVID-19 Pandemic: A Review of Recent Innovations in Antiviral Therapy and Relevance to Primary Care Practice
date: 2021-08-14
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2021.07.005
sha: a857e8b06684d904ebd7645ed08dfb3eca9e0438
doc_id: 916680
cord_uid: q9mg6tki

Seasonal influenza requires appropriate management to protect public health and resources. Decreasing the burden of influenza will depend primarily on increasing vaccination rates as well as prompt initiation of antiviral therapy within 48 hours of symptom onset, especially in the context of the current COVID-19 pandemic. A careful approach is required to prevent health services from being overwhelmed by a surge in demand that could exceed capacity. This review highlights the societal burden of influenza and discusses the prevention, diagnosis, and treatment of influenza as a complicating addition to the challenges of the COVID-19 pandemic. The importance of vaccination for seasonal influenza and the role of antiviral therapy in the treatment and prophylaxis of seasonal influenza, including the most up-to-date recommendations from the Centers for Disease Control and Prevention for influenza management, will also be reviewed.

With the emergence of the COVID-19 pandemic, the medical community needs to prepare for the management of seasonal influenza and consider the coexistence with COVID-19. The complexities of prevention, diagnosis, management, and capacity across medical services have the potential to be exacerbated by the arrival of influenza season. Primary care clinicians have a critical role in the front-line management of both infections, to protect public health and prevent health services from being overwhelmed.

Influenza is an acute respiratory infection with variable degrees of systemic symptoms that can include fever, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue, vomiting, and diarrhea. 1, 2 Although influenza can present with wide-ranging symptomology, an additional 4% to 28% of influenza-infected patients are estimated to be asymptomatic. 3 Of the four types of influenza viruses, types A and B are responsible for causing yearly epidemics of respiratory disease, and occasionally, pandemics. 1, 4, 5 Influenza is transmitted mainly via respiratory droplets, but may also be transmitted by direct contact with an infected person, or indirect contact via surfaces. 1, 6 have to consider influenza virus infection, SARS-CoV-2 infection, and co-infection when making clinical decisions. Diagnostic testing can help to distinguish between influenza and SARS-CoV-2 infection, and subsequently inform clinical management. Accurate diagnosis is of particular importance for patients with suspected influenza who are being admitted to an emergency department, or to determine the cause of a respiratory illness outbreak within a closed setting. However, the CDC indicates that clinicians should not wait for the results of influenza and/or SARS-CoV-2 testing, to initiate empiric antiviral treatment for influenza in priority groups (i.e., hospitalized patients, patients with severe, complicated or progressive illness, or those at higher risk for influenza complications). 17 In addition, during periods of co-circulation of influenza and SARS-CoV-2 within the community, clinicians may consider, based on clinical judgement, early initiation of empirical antiviral treatment of non-high-risk outpatients with suspected influenza, which may include those assessed and evaluated via telemedicine. 17 The risk of exceeding the capacity of healthcare facilities has been a serious concern during the COVID-19 pandemic and will continue to be an issue in the coming months. Most recent estimates from the CDC, for the 2019 to 2020 influenza season, report 18 to 26 million medical visits, 410,000 to 740,000 hospitalizations, and 24,000 to 62,000 deaths due to influenza. 18 Therefore, early diagnosis, effective prevention, and management of influenza and influenzarelated complications will be crucial to decrease hospital bed usage. 19 Although diagnostic testing of respiratory infections across the United States was higher than normal during the 2019 to 2020 influenza season because of the COVID-19 pandemic, the coexistence of influenza and COVID-19 has led to difficulties in accurately attaining estimates for influenza versus influenzalike illnesses in the beginning of the COVID-19 pandemic. Following widespread adoption of community mitigation measures to reduce the transmission of COVID-19, the Southern J o u r n a l P r e -p r o o f Hemisphere has experienced low influenza activity in 2020. 20 In the United States, influenza activity in 2021 continues to be unpredictable, given the varying levels of influenza vaccination patterns and adherence to COVID-19 control measures currently being observed across the country, which may vary geographically over time.

Many of the same mitigation strategies are effective for the prevention of both influenza and COVID-19, including promotion of health habits to prevent viral transmission such as social distancing, staying at home when sick, hand hygiene, and sneeze and cough etiquette. Surgical masks and facial coverings, when used correctly, may also reduce the transmission of influenza and coronavirus in respiratory droplets, and in aerosols in the case of coronarvirus. 21 Healthcare providers have an important role to play in educating their patients on social distancing, mask use, hand hygiene and cough etiquette. The CDC recommends a combination of infection prevention control strategies that includes: covering the nose and mouth when coughing or sneezing, handwashing with non-antibacterial soap and water, and using universal source control such as appropriate use of masks or face coverings. 22 Patients should be educated to wear a mask or face covering over their nose and mouth, and perform hand hygiene before and after touching it. 23, 24 As the primary route of influenza transmission is via respiratory droplets, mask wearing may be particularly useful during the upcoming influenza season in public places or where close contact with other persons is expected. This may be of particular benefit for immunocompromised individuals.

Ensuring the uptake of the seasonal influenza vaccine among eligible individuals will be of utmost importance during the period in which influenza and COVID-19 are expected to cocirculate. Given the novelty of the current COVID-19 pandemic coupled with the uncertainty of continued public health mitigation measures, it is very important to plan for seasonal influenza.

Influenza is the most frequent cause of death from a vaccine-preventable disease in the United States, with highest infection rates from seasonal influenza observed among children. However, the risks for complications, hospitalizations, and deaths are higher among adults aged 65 years and older, children younger than 5 years of age, pregnant women, and people of any age who have medical conditions that place them at increased risk for complications from influenza. 25 Therefore, influenza vaccination for individuals 6 months of age and older remains the best method for influenza prevention, and it is particularly important this influenza season. 13 These recommendations note that vaccination coverage will be especially important for those at increased risk for severe illness and/or complications from influenza and for influenza-related outpatient/inpatient or emergency department visits.

Influenza vaccination has been estimated to prevent between 1.6 and 6.7 million illnesses, 790,000 to 3.1 million outpatient medical visits, 39,000 to 87,000 hospitalizations, and 3,000 to 10,000 deaths from respiratory and circulatory complications related to influenza each season. 26 Influenza vaccination is the first line of defense against influenza, and is of vital importance, particularly in the current environment. However, there are limitations to its effectiveness. The seasonal influenza vaccine is designed to protect against the three or four influenza viruses that research indicates are most likely to spread and cause illness during the J o u r n a l P r e -p r o o f upcoming influenza season. 27 Therefore, the effectiveness of the influenza vaccine varies annually.

Coverage and use of the influenza vaccination at the population level is difficult to manage. During the 2019-2020 influenza season, the CDC estimated vaccination coverage (≥1 dose of influenza vaccine) to be 63.8% among children (aged 6 months to 17 years) and 48.4% in adults aged >18 years, which is below national objectives. 28 This coverage varies greatly between states, from 51.9% to 78.3% in children and 41.4% to 56.8% in adults. 28 Across the states, lower vaccine coverage in children corresponded to lower vaccination rates among adults.

Increasing influenza vaccination coverage in children is especially important, as they have been identified as the main spreaders of influenza infection. 29, 30 Influenza vaccines are not 100% effective, and antiviral treatment may be needed for the management of acute influenza infection.

It is important to note that there is no change in the CDC's recommendation on timing of vaccination this influenza season. Vaccination in July or August was deemed to be too early, particularly for older people, due to the likelihood of reduced protection against infection later in the influenza season. Instead, September and October were deemed to be more optimal for vaccination. However, the CDC recommends that, as long as influenza viruses are circulating, vaccination should continue, even in January or later. 31 For travelers e.g., those visiting areas of year-round endemic influenza, the CDC recommends vaccination at least 2 weeks before travel. 32 J o u r n a l P r e -p r o o f

Both influenza and COVID-19 can result in severe illness and complications, particularly in high-risk individuals; therefore, rapid diagnosis is important to facilitate timely initiation of treatment and allow for appropriate isolation. 15 Given the overlap in symptoms between influenza and COVID-19, diagnostic testing may be necessary to better inform treatment decisions.

In the United States, a number of rapid influenza diagnostics tests (RIDT) are commercially available for the detection of influenza A and B. The acronym RIDT is synonymous with a test that detects an influenza antigen. Historically, these test have had low sensitivity in comparison to molecular-based tests. 33 Authorization the FDA has approved several tests that simultaneously detect influenza viruses and SARS-CoV-2 ( Table 1) . 41 It should be noted that empiric antiviral treatment should be initiated as soon as possible without waiting for laboratory confirmation of influenza virus infection for priority patients, when influenza is known to be circulating in the community ( Figure 1 and Supplemental Appendix). 17 Testing in tandem for these pathogens may be needed in some circumstances for appropriate patient management. (Figure 2b) . 44 Neuraminidase inhibitors have been shown to be effective for the treatment of influenza in clinical trials and in the real-world setting ( Influenza viruses can have reduced susceptibility to one or more influenza antiviral agents.

Reduced susceptibility to antivirals, which may be an indication of potential antiviral treatmentemergent resistance, occurs when an influenza virus changes the antiviral binding at the active site.

Consequently, some antiviral agents may not be as effective in the treatment of viruses with reduced susceptibility. 60 High levels of resistance continue to be observed with amantadine and rimantadine (>99%) among circulating influenza A(H3/N2) and A(H1N1)pdm09 viruses.

Therefore, these drugs are no longer recommended against currently circulating influenza A viruses.

To date, the majority of data regarding treatment-emergent resistance to neuraminidase inhibitors has been obtained with oseltamivir, as it has been available for decades and is the most widely used neuraminidase inhibitor (NAI Direct comparisons between oseltamivir and baloxavir treatment-emergent resistance rates should not be made due to differences in study design, study populations, and methodologies for viral detection. In addition, it is important to distinguish treatment-emergent resistance rates from rates of circulating resistant, which refers to a virus that is already resistant at the point of infection. Antiviral resistance and reduced susceptibility to the neuraminidase inhibitors and to baloxavir among circulating influenza viruses is currently very low (<1% and <0.1%, respectively, according to the most recent World Health Organization reports), 66-68 and J o u r n a l P r e -p r o o f the CDC and the World Health Organization will continue to monitor the occurrence of resistance. 69 In summary, the benefits of antiviral treatment far outweigh concerns of potential resistance, which in the vast majority of cases does not have a significant clinical impact. 58

As of January 25, 2021, the CDC recommends antiviral treatment as soon as possible (≤48 hours) for any patient with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications, including young children, adults 65 years of age and older, and people with comorbidities, e.g., asthma, diabetes, and heart disease. 17 Decisions regarding initiation of antiviral treatment should not be delayed for laboratory confirmation of influenza in priority patients. The CDC has also produced a guide for considering influenza testing and treatment when influenza viruses are circulating in the community regardless of influenza vaccination history (Figure 1 and Supplemental Appendix). This algorithm may be especially valuable for primary care providers managing influenza during the current COVID-19 pandemic.

In addition, the CDC notes that antivirals can be considered as a treatment option for J o u r n a l P r e -p r o o f

Influenza: Diagnosis and Treatment