key: cord-0711423-w8oh0maq authors: de St. Maurice, Annabelle; Martin‐Blais, Rachel; Halasa, Natasha title: Preparing for the 2020—2021 influenza season date: 2021-04-27 journal: Pediatr Transplant DOI: 10.1111/petr.14025 sha: faeb636afea0880eda0b610f4b2c2a0e43973275 doc_id: 711423 cord_uid: w8oh0maq The COVID‐19 pandemic has altered health seeking behaviors and has increased attention to non‐pharmaceutical interventions that reduce the risk of transmission of respiratory viruses including SARS‐CoV‐2 and influenza. While the potential impact of the COVID‐19 pandemic on influenza is not fully known, in the Southern hemisphere influenza infection rates appear to be very low. Influenza vaccine efficacy for 2019–2020 season was comparable to prior season and influenza vaccine recommendations for pediatric immunizations remain similar to prior years. Influenza treatments continue to include neuraminidase inhibitors as well as baloxavir for treatment and in some instances prophylaxis. The 2019-2020 influenza season was marked by decreased influenza transmission during the COVID-19 pandemic likely resulting from differences in health seeking behaviors, physical distancing, mask wearing, and attention to personal hygiene. 1 In the Northern hemisphere, influenza activity started to decrease by mid to late February 2020. 2 In tropical Africa, only Cote D'Ivoire and Mali reported cases of influenza. In Europe, influenza activity is at inter-seasonal levels, however, Ireland has seen increased influenza like illness activity likely related to SARS-CoV-2 circulation. East Asia has experienced baseline inter-seasonal levels of influenza like illness, however, in Southern, Central and Western Asia there were no or few influenza detections. In Cambodia and Lao PDR influenza like illness related to influenza A(H3N2) continued to increase. From September 2020 to October 2020, the National Influenza Centres and national influenza laboratories submitted 81 257 respiratory specimens to the WHO FluNet; of these 172 specimens were positive for influenza. 1 Influenza A accounted for the majority of cases worldwide, with 108 (63%) of cases typed as influenza A and 64 (37%) typed as influenza B. Of the influenza A cases, 6% were influenza A(H1N1)pdm09 and 94% were influenza A(H3N2). Of the B viruses, 8% belonged to the B-Yamagata lineage and 92% to the B-Victoria lineage. While inter-seasonal influenza rates remain low and influenza activity was very low in the Southern hemisphere during the peak of their flu season, it is difficult to extrapolate this to the Northern hemisphere since COVID-19 mitigation measures vary across countries. For example, in Australia a mandatory 14-day hotel quarantine was imposed for all returned travelers in March, later accompanied by lockdowns and bans on gatherings. 2 In Chile, curfews and lockdowns and mandatory masking were used as strategies to mitigate the spread of COVID-19. As regions in the United States, Europe, and Southeast Asia are experiencing increases in COVID-19 cases 3 it is unclear whether or not these regions will also have a mild flu season. Because SARS-CoV-2 (the virus that causes COVID-19) and influenza have similar modes of transmission and clinical presentation, differentiating between the two diseases is difficult. Epidemiologic data suggest that SARS-CoV-2 is more infectious than influenza. 4 Both SARS-CoV-2 and influenza can cause respiratory disease and gastrointestinal illness. A recent study found that more children with COVID-19 had evidence of fever, diarrhea or vomiting, headache, body ache, or chest tightness than children with influenza at the time of diagnosis. 5 Yet, one differentiating feature of COVID-19 is the loss of sense of taste or smell. Because of the similar clinical presentations of these respiratory viruses, it is important for providers to test for both influenza and SARS-CoV-2 infection when evaluating patients with influenza-like illness during the influenza season. Co-infection with influenza and SARS-CoV-2 is not infrequent in pediatric patients 6 ; therefore, patients with a positive influenza test should also be tested for SARS-CoV-2. Healthcare facilities should invest in combination platforms that diagnose both influenza and SARS-CoV-2 this season. 7 Zoonotic avian influenza cases in birds and humans are reported to the WHO in order to rapidly identify strains with pandemic potential. Several strains have been monitored by WHO including H5, H7, H9N2. From February 2020 to October 2020, no human cases of influenza A(H5) were identified, however, cases have been identified in wild birds and poultry. 8 Influenza A (H7) has been detected in poultry in the United States and Australia but no human cases have been identified. Flu vaccine efficacy is monitored by a variety of surveillance systems both nationally and globally. Efficacy can be determined by studying rates of infection in vaccinated individuals compared to unvaccinated individuals and can be stratified by populations at risk. 9 Additional estimates of vaccine efficacy can be obtained by studying mortality or hospitalization and comparing immunized to nonimmunized individuals. These estimates can be obtained through active (e.g. public health research collaboratives) or passive surveillance (e.g. mandatory reporting). According to the 2019-2020 CDC data, preliminary flu vaccine efficacy in the United States during the 2019-2020 influenza season was estimated to be 39% for all influenza A or B types). 10 Vaccine efficacy was 31% for influenza A(H1N1)pdm09 viruses and 44% for influenza B/Victoria viruses. In Europe, vaccine estimates were estimated to range from 29 to 61% in the primary care setting against all influenza types. 11 Data for the 2020 flu season in Australia has demonstrated a 44% influenza A(H1N1)pdm09 isolate match and 65% influenza A(H3N2) match. 12 Of the few influenza B isolates all were antigenically similar to the corresponding vaccine component. Although vaccine efficacy in Australia has not been estimated, it appears as though the circulating influenza strains are similar to those contained in the vaccine. Northern hemisphere by the WHO can be found in Table 1a ,b. The WHO SAGE working group recommends that governments work to ensure that influenza vaccine supply is sustainable given potential shortages associated with the COVID-19 pandemic. 13 Influenza vaccines that have been prequalified for use by different regulatory agencies can be found on the WHO website at: https://extra net. who.int/pqvda ta/Browse.aspx?nav=3 along with the national regulatory agency that has approved the vaccine. Two influenza vaccines were recently licensed for use in adults ≥65 years of age in the United States. 14 These two vaccines, Fluzone High-Dose Quadrivalent vaccine and Fluad Quadrivalent vaccine, effectively replace the high-dose trivalent vaccine. Immunogenecity and safety of these quadrivalent vaccines were compared to trivalent formulations and were found to be similar. FluAd has also been approved by the European Union for use in persons 65 years of age and older. 15 LAIV use varies globally. LAIV remains an option in the United States for individuals age 2 through 49 years 14 Union for individuals 2 through 17 years of age. 15 In Canada, LAIV is licensed for use in individuals 2-59 years of age. 16 Live attenuated flu vaccine has not been licensed in Australia. 17 In low and middle income countries in Asia and Africa, the efficacy of LAIV has been studied with variable results. 18 Numerous public health and transplant organizations recommend against live attenuated influenza vaccination in SOT and HSCT recipients due to the theoretical risk of infection, although the virus is cold-adapted and should not replicate at body temperature. [19] [20] [21] The American Society for Transplantation recommends that if a live influenza vaccine is inadvertently given to a SOT recipient, antiviral therapy and revaccination with an inactivated vaccine can be considered. 21 The AST states that live attenuated vaccine can be given prior to transplantation as long as the transplant is occurring two weeks or more following vaccination. Annual influenza vaccines are recommended annually at the beginning of the influenza season. However, optimal timing of vaccine administration post-transplant in SOT and HSCT recipients continues to be studied, but most experts recommend HSCT recipients receive inactivated influenza vaccine at least 3-6 months after HSCT and 2-6 months after SOT. [21] [22] [23] There is insufficient evidence to routinely recommend administering multiple influenza vaccine doses during a single influenza season or for administering high dose influenza vaccine to either SOT or HSCT recipients; however these continue to be studied. 24, 25 However, the European Conference on Infections in Leukemia suggests that a second dose of influenza vaccine may be considered in individuals with graft versus host disease or lymphopenia or during an influenza outbreak if individuals are immunized less than six months after transplant. 19 Children with influenza-like symptoms who are at high risk of complications from influenza infection (such as those who have received previous transplants) should all be offered antiviral medications as soon as the illness is suspected-before virologic confirmation. 26 While the greatest benefit will likely be achieved if (NAIs) are given within 48 h of onset of illness, there is likely still some benefit to administration ≥48 h after illness begins-particularly for immunocompromised patients who may have prolonged viral shedding-and the AAP recommends that this be offered. 26 For many years, the adamantane class of drugs was the only available treatment for influenza, and then only for influenza A (influenza B viruses being intrinsically resistant). 27 Amantadine and rimantadine, the primary agents of this class, act by inhibiting the M2 protein ion channel, preventing uncoating and viral assembly. 27 These drugs were relatively effective for susceptible strains of influenza A; however, resistance-conferring mutations occurred in large proportions of patients taking adamantane medications for ≥5 days. have been found to be resistant to the adamantanes, and so the use of these drugs are no longer recommended. 27, 28 Fortunately, the number and types of medications available for treatment of influenza have been expanding ( Table 2 ). The adamantanes have been largely replaced by newer drugs targeting different parts of the viral replication process, which have been developed using advancements in rational drug design, such as identifying active compounds based on a target enzyme's structure. 29 NAIs such as oseltamivir, zanamivir, and peramivir act as SA analogues, preventing viral budding by competitively inhibiting the NA-mediated cleavage of SA that results in viral particle release. 30 Each is given by a different route (oral, inhaled, and intravenous, respectively), and is approved for use in a different age group. Two of them, oseltamivir and zanamivir, may be given for both treatment and chemoprophylaxis. It is worth noting that several studies have shown reduced efficacy of neuraminidase inhibitors in children with asthma, although they are still recommended as treatment for patients with a history of asthma. 26 Oseltamivir is by far the most commonly used of the NAIs, and AAP guidelines identify oseltamivir as the first-line therapy for influenza infection in children. 26 If oseltamivir solution is not available, then capsules may be opened and mixed with simple syrup or sugar-free solution in the pharmacy or at home to form an easily administrable liquid formulation. 26, 31 In general, oseltamivir is well tolerated; the only adverse effect that exceeded those of placebo in trials was gastrointestinal distress and vomiting. 26 Post-marketing reports of neuropsychiatric effects (including fatal self-injury) in children from Japan have led to significant concern and FDA labeling changes. A clear link to oseltamivir as the cause has not been established, and some speculate that the neurologic effects may be due to influenza infection itself; nonetheless, caution is recommended in pediatric patients. 26, 32 Baloxavir marboxil is a cap-dependent endonuclease inhibitor which impairs the influenza virus's ability to "cap-snatch" (and thus doses. 40 However, clinical worsening may not necessarily be due to drug failure, as adverse effects of immunosuppressive medications may also mimic worsening infection in these patients. 40 Those who present with particularly severe disease or sudden decompensation after initial improvement should be evaluated and treated for bacterial superinfection. Fungal superinfection should also be considered, particularly in immunocompromised individuals. 40 The most common NAI resistance mutation-marked by a H275Y Table 3 . Doses for chemoprophylaxis are lower than treatment doses, and so any concern for true disease should prompt immediate increase to therapeutic doses. 26 Chemoprophylaxis should never be used as a substitute for vaccination-only as an adjunct measure-since immunization has significant benefits for individuals and the population as a whole, including decreased severity of illness if it does occur. 50 noted that all pediatric transplant societies recognize that influenza vaccination is important to prevent severe disease, and recommend its prioritization as soon as possible in the influenza season. 21, 52 Providers should note that use of antiviral medication at the time of LAIV (but not IIV) administration may impair response. 26 This is less likely to be a concern for pediatric transplant patients, as live virus vaccines are contraindicated for the majority of transplant recipients. For adults and children ≥3 months of age with very high risk of influenza-related complications and for whom vaccination is contraindicated or likely to be ineffective, chemoprophylaxis for the entire influenza season may be considered. Short-term chemoprophylaxis can also be given to high-risk individuals while awaiting response after vaccine administration, or to their close contacts if chemoprophylaxis of the immunocompromised individual is contraindicated and influenza is circulating in the community. 40 The impact of COVID-19 mitigation measures on influenza cases in the Northern hemisphere during the latter part of the 2019-2020 season was significant. 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