Urgent care clinicians should be aware of the most current diagnostic and therapeutic recommendations for influenza and the resources available for guiding management. This review outlines the classification of these viruses, their pathophysiology, the identification of high-risk patients, and the importance of influenza vaccination. Seasonal variations of influenza are discussed, as well as the considerations regarding which patients to test based on the current local prevalence of disease. Given the significant overlap in clinical presentations, co-evaluation for COVID-19 is also briefly discussed in the context of the evaluation and management of influenza. Differences between strains of influenza are reviewed. Recommendations for use of the currently available antiviral treatments are discussed, as well as how to engage in shared decision-making with patients regarding risks and benefits of testing and treatment.
During the 1918-1919 influenza pandemic, approximately one-third of the world’s population was infected and approximately 50 million people died.1 Influenza pandemics were not new occurrences, but their morbidity and mortality had not been well documented, and the causative organisms had not yet been identified. A half century later, the 1968 “Hong Kong” influenza pandemic (H3N2) resulted in an estimated 1 million deaths worldwide.2 Despite now having a much better understanding of influenza as well as multiple options for its treatment, influenza remains a major cause of mortality that results in more than 30,000 deaths annually in the United States, partly related to the aging of the population.3 The COVID-19 pandemic has demonstrated the potential for outbreaks of respiratory viruses, such as influenza, to become pandemics quickly during this era of global interconnectedness and air travel. Urgent care (UC) plays a key role in mitigating disease outbreaks, since containment of a potential epidemic relies on early and rapid identification, treatment, and—in some cases—prophylaxis.
The medical costs and lost wages from influenza are substantial. According to the United States Centers for Disease Control and Prevention (CDC), influenza epidemics cost $10.4 billion per year in direct medical expenses and an additional $16.3 billion in lost earnings annually in the United States.4,5 The average influenza epidemic is responsible for 3.1 million hospitalized days, and 31.4 million outpatient visits annually with a total economic burden of $87.1 billion in the United States alone.5
This issue of Evidence-Based Urgent Care reviews recent studies on the clinical presentation, diagnosis, and treatment of influenza, and provides recommendations on the evaluation and management of patients with suspected symptoms of influenza.
Although precise data for influenza-like illness (ILI) and sequelae are difficult to obtain, historically, up to 20% of the United States population has been estimated to be infected with the influenza virus during any given winter season.3 Since the emergence of COVID-19, tracking of ILI has become significantly more complicated as healthcare-seeking behaviors for ILI symptoms has markedly changed. Overall, however, rates of seasonal influenza have been much lower than historic comparisons during the COVID-19 pandemic.6
Influenza disproportionately affects young children and elderly persons, and influenza deaths have increased substantially in the last 2 decades, in part due to the aging of the population.3 Annual mortality in the United States from influenza typically ranges from 12,000 to 56,000 deaths with 140,000 to 710,000 patients hospitalized each year and 9.2 to 35.6 million patients presenting to various healthcare settings for treatment.5,7
Morbidity and mortality from influenza can vary depending on a given population’s immunity to previous strains.8 Historically, mortality from seasonal outbreaks disproportionately affects the elderly, with up to 90% of deaths occurring in people aged ≥65 years However, this is not the case with every influenza strain. The pandemic of 2009, for example, resulted in more significant outbreaks of disease among the younger population who had no (or weaker) immunity.8,9
Seasonal influenza is defined as the typical outbreak of the infection that occurs at varying times in a given year. An epidemic is declared when the number of cases of influenza exceeds what would normally be expected within a circumscribed region.10 According to the World Health Organization (WHO), the term pandemic is reserved for the occurrence of worldwide disease outbreaks and not for the emergence of a new strain (as was previously the case). Declaration of a pandemic by the WHO raises global awareness of a disease outbreak and supports more aggressive efforts for preparedness among local public health agencies.7,11 In the United States, the CDC publishes a weekly report that includes laboratory surveillance data on the regional incidence of ILI.12
Influenza cases occur throughout the year with varying frequencies based on geography. In the Northern Hemisphere, the virus is most prevalent between November and March. In tropical regions, cases occur steadily throughout the year.10 Influenza is spread predominantly by close person-to-person contact via respiratory secretions. This may explain, in part, the more rapid transmission during the colder months, when people are often confined indoors in poorly ventilated spaces.11
The influenza virus is a spherical, RNA-based organism of the Orthomyxoviridae family. The RNA core of the virus particle is associated with a nucleoprotein (NP) antigen. Variations of this nucleoprotein have led to categorization of influenza viruses into 3 primary subgroups known as influenza types A, B, and C. Influenza A is the most common subtype of influenza and is most frequently associated with pandemic events. Influenza B virus infection occurs with less frequency but sometimes results in epidemics.7-11 Influenza C is the form of the virus least likely to infect humans. Influenza C illness is typically milder than A or B, so few assays used in clinical settings test for this subgroup.
Influenza A viruses are further grouped based on specific transmembrane or surface proteins: hemagglutinin (H or HA) and neuraminidase (N or NA).13 (See Figure 1.) There are 16 different hemagglutinin subtypes and 9 different neuraminidase subtypes, of which 3 subtypes of hemagglutinin (H1, H2, and H3) and 2 subtypes of neuraminidase (N1 and N2) have caused epidemic disease in the human population.14 Viral strains are classified based on the type of influenza, site of origin for that particular strain, isolate number, year of isolation, and subtype. For example, the influenza pandemic of 1968 was designated “A/Hong Kong/03/1968(H3N2).”
The surface proteins hemagglutinin and neuraminidase play a defining role in antigenic variation of the influenza viruses over time. These variations are responsible for the occurrence of influenza epidemics.
There are 2 types of antigen variation: antigenic drift and antigenic shift. All 3 virus subgroups (influenza A, B, and C) undergo antigenic drift, which involves small point mutations to the viral genes that code for hemagglutinin and neuraminidase. Antigenic drift is caused by minor mutations affecting the structure of viral antigens. Having some preserved immunity from prior vaccination and/or infection limits the virulence of repeat exposures when antigenic drift occurs. Antigenic shift, by contrast, is a much more radical change defined by the reassortment of the viral genes such that the surface proteins change in a more dramatic fashion. When antigenic shift occurs, immunity against a previous strain generally proves insufficient for preventing clinical disease. Antigenic shift can occur when cells are infected by 2 or more different influenza strains at once. Genetic reassortment in these cases allows for the production of a new strain.
The reassortment of genes that results in the production of new influenza strains often involves an animal host. Pigs, horses, and birds are some of the most common intermediate hosts, hence the nomenclature of “swine,” “equine,” and “avian” influenza strains. This explains why influenza epidemics involving novel strains have often begun in China, where close living conditions between animals and humans facilitate co-infection and genetic reassortment. Because animal co-infection with influenza types B and C is infrequent, the phenomenon of antigenic shift is limited to influenza type A, which accounts for the more frequent epidemics and pandemics involving this viral subtype. Historically, pandemics have emerged at intervals of approximately 15 to 30 years.1,15 (See Table 1.)
The primary route of transmission for influenza is through respiratory secretions released during coughing or sneezing. The virus initially infects the epithelial cells of the upper respiratory tract and the alveolar cells of the lower respiratory tract. The typical incubation period is 18 to 72 hours, depending on the size of the initial inoculum.13 Peak viral replication is typically reached by the second or third day, with viral shedding usually complete approximately 7 days after infection. However, in children and immunocompromised hosts, viral shedding can last up to 2 weeks.17,18
During active infection, pathologic changes can be found throughout the respiratory tract. Changes in the lower respiratory tract are most significant; bronchoscopy typically reveals diffuse mucosal inflammation and edema of the bronchi. Subsequent epithelial cell necrosis leads to desquamation of the epithelial cells that line the respiratory tract. The virus can then affect the lung parenchyma, leading to viral pneumonia and increasing the risk for secondary bacterial pneumonia.
The most common secondary bacterial pathogens associated with influenza infections are Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae. Although uncommon, community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has been found in fatal cases of pneumonia in patients with confirmed skin CA-MRSA or in patients living with someone who had the infection, with most reported cases leading to fatality within 4 days.19 These organisms often colonize the respiratory tract and can affect the lung parenchyma opportunistically when bronchopulmonary defenses are depleted.13 In fact, H influenzae was found with such frequency in the respiratory secretions of influenza patients during the 1918 epidemic that it was initially thought to be the primary pathogen.20
Vaccination initiatives are fundamental to preventing and/or reducing illness. The WHO recommended an influenza vaccine for the 2021-2022 season that was comprised of antigenic representations from the 4 major circulating strains, namely influenza A (H3N2), influenza A (H1N1), influenza B/Yamagata, and influenza B/Victoria.7,21 H1N1 and H3N2 were the predominant strains during the 2009 and 1968 pandemics, respectively; however, since the 2009 H1N1 pandemic, H3N2 has been the most dominant strain, with the exception of the 2015-2016 season.7,22 (See Figure 2.)
The CDC has implicated the H3N2 strain as being the most virulent, volatile, and mutagenic of all the dominant strains, and vaccines are least effective at preventing clinical disease when H3N2 is the dominant strain.7 H3N2-dominant seasons are associated with the highest rates of influenza cases, hospitalizations, and deaths.22 A meta-analysis on influenza vaccine effectiveness in ambulatory care settings from 2004 to 2015 found that the pooled vaccine effectiveness for influenza B was 54%. The effectiveness of vaccination against H1N1 was 61% but only 33% for the H3N2 viruses.7,23
Despite the poor protection from the H3N2 strain specifically, vaccination still prevents many influenza cases, hospitalizations, and deaths. The goal vaccine effectiveness is ≥50% in order to prevent most cases of severe influenza and consequent morbidity and mortality.16 (See Figure 3.) While the 2018-2019 season vaccine effectiveness was only 29%, this still resulted in many fewer cases of influenza than would have been the case with no vaccination.7,16
There are currently 3 methods approved by the United States Food and Drug Administration to produce influenza vaccines: egg-based, cell-based, and recombinant influenza vaccine. For egg-based formulations (eg, Fluzone™, Fluad™), the candidate vaccine viruses identified for that season are introduced into fertilized hens’ eggs and incubated for several days, allowing the virus to replicate; the influenza viruses are then inactivated and the viral antigen is purified and made available for injection. An egg-based method is also used to make the live attenuated virus for nasal spray vaccines (eg, FluMist™).24 In cell-based vaccines (eg, Flucelvax™), the viruses are harvested from mammalian cells instead of hens. In recombinant-based vaccines (eg, Flublok™), manufacturers isolate specific proteins from a naturally occurring candidate virus, which are then combined with another virus that grows well in insects, and they are allowed to replicate. These viral proteins are then harvested and purified for vaccine use.
The CDC recommends that all persons aged ≥6 months be vaccinated for influenza each year with “rare exception.”25,26 The CDC recommends vaccination for people who have egg allergy, with special considerations based on the severity of the allergy;26 however, the American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology Joint Task Force specifically advises that egg allergy “of any severity” should not influence decisions about whether to vaccinate or which vaccine formulation to use.27 The CDC also recommends caution in patients with a history of a true adverse reaction or allergy to a prior influenza vaccine, or a history of Guillain-Barré Syndrome; specialist consultation is advisable for these patients.25,26
Special consideration for vaccine selection should also be given to pediatric patients, patients aged >65 years, and patients with conditions that cause immunocompromise. Patients aged >65 years benefit from receiving the higher dose vaccine formulations due to immunosenescence that occurs with normal aging.28 Pediatric patients should be vaccinated annually with whatever formulation is approved and most acceptable to the caregiver.24 Live attenuated vaccine formulations should be avoided in patients with significant immunocompromise (eg, history of solid organ or bone marrow transplant).24
Influenza vaccination should be administered in the Northern Hemisphere before the end of October.29 Patients can be vaccinated safely in the setting of concomitant illness as long as symptoms are mild; however, vaccination should be postponed in patients with moderate or severe respiratory illness or COVID-19 (any severity) until clinical resolution of the illness.30 The influenza vaccine can safely be administered at the same time as vaccination for COVID-19, but injections should be given at distant anatomic sites (eg, contralateral deltoids).31
The CDC defines ILI as a temperature >37.8˚C (100˚F), plus either cough or sore throat, in the absence of a known cause other than influenza.32 The signs and symptoms of influenza are fairly nonspecific, hence the broad CDC definition of ILI. Influenza should be included in the differential diagnosis of any febrile patient who presents to UC with symptoms of an upper respiratory infection. Given the nonspecific symptoms of influenza, the differential diagnosis must also include a wide range of bacterial and viral infectious processes. Infectious pathogens to consider include Mycoplasma pneumoniae, S pneumoniae, Legionella species, and respiratory tract viral pathogens including SARS-CoV-2, adenovirus, respiratory syncytial virus, rhinovirus, and parainfluenza viruses. Myocarditis, bacteremia, endocarditis, and noninfectious causes of fever (eg, thyrotoxicosis, neuroleptic malignant syndrome) should also be included in the differential of patients presenting with ILI, especially during influenza season, to minimize the risk of missing these potentially life-threatening diagnoses.
Evaluation and management of patients with ILI in the UC setting begins with an accurate, age-appropriate assessment of vital signs, appropriate isolation (as feasible), and stabilization for patients with compromised respiratory status. Efforts to stabilize may range from simple oxygen supplementation to activation of emergency medical services via 911. The use of face masks by patients and clinicians alike is indicated to minimize viral spread. Because influenza is contagious and spread by respiratory droplets, care should be taken to isolate patients presenting to UC centers with ILI from other patients, especially patients with advanced age and/or comorbidities. Diligent use of personal protective equipment by staff when caring for patients with ILI is also critical for protecting healthcare workers and patients.33 All patients with suspected influenza should be managed according to standard droplet isolation and contact precautions.34 See the Clinical Pathways for summaries of the clinical approach to patients who present with ILI.
Influenza infections are associated with a range of symptoms and presentations that vary by age. (See Table 2.) The typical history of influenza is 2 to 5 days of fever, nasal congestion, sore throat, cough, chills and myalgias. Usual signs include fever and tachycardia. Van Wormer et al performed a prospective analysis of subjective symptoms of patients presenting with acute respiratory illness to determine correlation with laboratory-confirmed influenza illness and severity. They found that the most common symptoms were cough (92%), fatigue (91%), and nasal congestion (84%) (P < .001), whereas sneezing was identified as a negative predictor of influenza in adults.35 The presence of cough and fever during periods of high local influenza infections is strongly predictive of influenza (positive predictive value [PPV] 79%-87%).36,37 Previously, during times when influenza was circulating within the community (ie, “flu season”), patients with an ILI who had both cough and fever within 48 hours of symptom onset had a very high pretest probability of having influenza.33 Since the start of the COVID-19 pandemic, the value of cough and fever for predicting influenza has varied greatly depending on current SARS-CoV-2 positivity rates in the community.38 Numerous potential complications can result from a primary influenza infection.39 (See Table 3.)
A study of children aged ≤13 years found that the predominant symptoms among those with influenza were fever, cough, and rhinitis, which were reported in 95%, 77%, and 78% of the study population, respectively.40 This study also suggested that the range of fever (>39˚C [102.2°F]) was significantly higher in children with influenza. Associated gastrointestinal symptoms (ie, vomiting and diarrhea) also occur more frequently in children than in adults.41
Most communities have strategic plans for the evaluation and management of large numbers of patients in the event of a major influenza outbreak. Local, state, and federal protocols are designed to facilitate effective triage, stabilization, and transport of patients in the prehospital setting. These protocols are published by the National Highway Traffic Safety Administration.
Laboratory testing is indicated in cases for which test results may affect management (eg, decrease ancillary testing, influence decisions about antibiotic or antiviral use). The diagnostic tests for influenza include viral culture, immunofluorescence studies, molecular assays (including reverse transcription polymerase chain reaction [RT-PCR]), and rapid antigen tests. During an epidemic, formal testing may not be indicated because the decision to treat can be based on treatment criteria such as age, comorbidities, severity of illness, etc. The reliability of laboratory tests varies greatly, depending on the type of test performed, the quality of the sample, and the laboratory.42 All clinical testing can typically differentiate between influenza A and B, but will not specify influenza A subtypes (eg, H1N1, H3N2).43
Rapid diagnostic testing at the point of care (POC) is preferred in the UC setting, where clinical decisions based on test results need to be made immediately. RT-PCR testing has become the preferred “gold standard” given its improved sensitivity and specificity as compared to commercial rapid antigen testing, as well as faster turnaround times than viral culture.42 In recent years, POC rapid RT-PCR tests have emerged as the most attractive option for influenza testing in the acute care setting with turnaround times generally <30 minutes. These POC RT-PCR tests have better test characteristics than antigen tests with sensitivities ranging from 77% to 97% and specificities ranging from 97.5% to 100% depending on the study and device manufacturer.44,45
Regardless of testing modality, numerous studies support the effect of obtaining a positive influenza test result on decision-making surrounding additional testing and prescribing antibiotics and/or antiviral medications for both pediatric and adult populations. However, during times of high rates of infections, testing may not be helpful, especially given the variable sensitivity of rapid tests, which may mean that influenza cannot be excluded even in the setting of a negative test result.46-52
In periods of low influenza activity (ie, summertime), a rapid test will have its lowest PPV and its highest negative predictive value (NPV) and is more likely to yield false-positive results—up to 50%, in 1 study—when the disease prevalence drops below 5%.53 Conversely, in times of peak influenza activity (during an epidemic or pandemic), a rapid test will have a higher PPV and lower NPV and is more likely to produce a false-negative result. Because all modalities of influenza testing are highly specific, most positive test results can be trusted to be true positives regardless of pretest probability of influenza.54,55 (See Table 4 and Table 5.)
In a prospective study of adults who presented with ILI when the prevalence of seasonal influenza was high, rapid testing was found to be no better than clinical judgment alone in making the diagnosis of influenza.55 Testing should be reserved for cases where the test result will affect management in some discernible manner. Not even the “gold standard” tests will reliably exclude influenza virus infection 100% of the time, since the quality of the specimen and the experience of the technician can also affect the accuracy of the assay. Thus, empiric treatment of seriously ill and/or very high-risk patients should be considered if a clear alternative etiologic explanation cannot be found.
While rare, co-infection with SARS-CoV-2 and influenza can occur, and a positive COVID-19 test does not exclude the possibility of simultaneous influenza infection.56 In generally healthy, low-risk patients presenting with ILI and a positive COVID-19 test, presumption of isolated COVID-19 infection is reasonable and separate testing for influenza is unlikely to change management.
Not all patients with influenza require antiviral treatment. For patients with evidence of mild-to-moderate disease severity and no underlying high-risk conditions, treatment with supportive therapy alone is reasonable as these patients are unlikely to directly benefit from antiviral medications. Antiviral therapy is best reserved for those with more severe disease and/or those with high-risk underlying conditions including extremes of age, chronic pulmonary disease, pregnancy, or immunosuppressive conditions. (See Table 6.) Early treatment with antiviral medications for patients with high-risk chronic medical conditions has been shown to reduce the rate of influenza-related complications in both children and adults. Antiviral medications offer the greatest chance for benefit when started as early as possible in the disease course, especially within the first 48 hours. However, in higher-risk patients, use of antiviral treatment is prudent regardless of duration of symptoms.57-59
There are 2 primary classes of antiviral medications for influenza: adamantane derivatives and neuraminidase inhibitors. However, the FDA has also approved a single-dose oral antiviral medication, baloxavir marboxil (Xofluza™), which is in a new class, called the polymerase acidic endonuclease inhibitors. The oldest class of antivirals is the adamantane derivatives: amantadine and rimantadine. The neuraminidase inhibitors are a newer class of antiviral drugs and include oseltamivir (Tamiflu™), zanamivir (Relenza™), and peramivir (Rapivab™). Oseltamivir is taken by mouth, zanamivir is inhaled orally, and peramivir is administered intravenously. Oseltamivir and zanamivir can be used for influenza prophylaxis in certain clinical situations. (See the “Chemoprophylaxis for Influenza” section.)
The neuraminidase inhibitors— oseltamivir, zanamivir, and peramivir—inhibit the spread of newly formed virus particles within the host cell by blocking the function of neuraminidase, a viral cell surface protein. This enzyme is necessary to cleave newly formed viral particles that are bound by their hemagglutinin surface proteins. Since these medications inhibit neuraminidase, they are effective in patients infected with either type A or type B influenza virus. These drugs tend to be reasonably well tolerated; the most frequently noted side effects of oseltamivir include nausea, vomiting, and headache; zanamivir commonly causes diarrhea.
Oseltamivir is taken orally and is currently approved for the treatment of influenza in patients of all ages and pregnant patients. (See Table 7.) In a 2015 meta-analysis by Dobson et al, the intention-to-treat infected population had a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio, 0.79; 95% confidence interval [CI], 0.74-0.85; P < .0001). The median times to alleviation were 97.5 hours for oseltamivir and 122.7 hours for placebo groups (difference -25.2 hours; 95% CI, -36.2 to -16.0). For the intention-to-treat population, the estimated treatment effect was attenuated but remained highly significant (median difference -17.8 hours. In the intention-to-treat population, they found fewer lower respiratory tract complications requiring antibiotics >48 hours after randomization (risk ratio [RR], 0.56, P = .0001; 4.9% oseltamivir vs 8.7% placebo; risk difference, -3.8%; number needed to treat [NNT] = 26) and also fewer admissions to hospital for any cause (RR, 0.37, P = .013; 0.6%, oseltamivir; 1.7%, placebo; risk difference, -1.1%; NNT = 91). Regarding safety, oseltamivir increased the risk of nausea (RR, 1.60, P < .0001; 9.9% oseltamivir vs 6.2% placebo; risk difference, 3.7%; number needed to harm [NNH] = 27) and vomiting (RR, 2.43; P < .0001; 8.0% oseltamivir vs 3.3% placebo; risk difference, 4.7%; NNH = 21). While NNH for oseltamivir are lower than NNT for benefit, the “harms” are typically mild, whereas the possible benefits studied (hospitalization and secondary bacterial infections) are more clinically significant.60
Zanamivir is administered via inhalation because of its poor bioavailability. It is approved for the treatment of influenza in patients aged ≥7 years and for prevention of the disease in patients aged ≥5 years. Due to its possible association with bronchospasm, the manufacturer of zanamivir has recommended it not be used in patients with underlying reactive airway disease. However, in a multicenter randomized clinical trial, no direct causality between zanamivir use and bronchospasm was found.61,62
Peramivir is the newest drug of this class and is administered intravenously as a single dose for patients with uncomplicated influenza with <48 hours of symptoms. It is approved for use in patients aged ≥2 years. Efficacy has not yet been established in patients with influenza B. The single-dose intravenous medication was shown to be cost-effective for symptom reduction when compared to placebo or oseltamivir.59,63-65
Amantadine and rimantadine inhibit activity of the M2 protein within the influenza A virus. This protein is a transmembrane polypeptide involved in the viral replication process. Because the genetic sequence of this protein channel within the influenza B virus is significantly different, this class of medications is only active in the treatment and prevention of influenza A.66 However, even among influenza A isolates, high rates of resistance exist and adamantane derivatives are not recommended for treatment of influenza in the United States.
In 2018, the FDA approved a new orally administered, single-dose influenza antiviral drug, baloxavir marboxil (Xofluza™). A polymerase acidic endonuclease inhibitor, it is effective for treatment of influenza A and B. Its safety for use in pregnant and lactating patients has not been established.67
The recent discovery of increasing mutations in the gene that encodes the M2 protein in avian influenza viral isolates has suggested the potential for human pandemics with drug-resistant strains.68 This was a concern during the influenza season of 2005–2006, during which up to 92% of viral isolates were found to have point mutations within the M2 gene, conferring resistance to the adamantane class of medications.69 The restriction of these medications to the treatment of influenza A, the rapid emergence of drug resistance, and their side-effect profiles have limited the usefulness in clinical practice of the adamantane class of medications.70 Two 2006 systematic reviews discouraged the primary use of these medications in the treatment and prophylaxis of influenza.71,72
When the neuraminidase inhibitors were first developed and used in clinical practice, the emergence of resistant viral isolates was rare. However, continuous changes in gene sequences within the influenza viral genome have led to an increase in the number of drug-resistant viral strains. During the 2007-2008 influenza season, oseltamivir-resistant H1N1 seasonal influenza emerged globally at rates of up to 68% in some regions.72 This led to a resurgence of the adamantane derivatives as the recommended primary agent in regions of the world where the rates of oseltamivir-resistant H1N1 seasonal virus isolates were high. However, more recent flu seasons have demonstrated relatively low resistance to oseltamivir and the other neuraminidase inhibitors, and the CDC continues to recommend treatment with only the neuraminidase inhibitors.59 Cross-resistance between the most recently FDA-approved antiviral drug, baloxavir marboxil, and neuraminidase inhibitors, or between baloxavir marboxil and M2 proton pump inhibitors (adamantanes), is not expected because these drugs target different viral proteins.67
Close, consistent monitoring of local influenza strain prevalence and susceptibility patterns is paramount. See the Appendix for links to online resources to monitor influenza activity and susceptibility.
| Organization | Topic |
|---|---|
| CDC | Up-to-date information on influenza |
| CDC | Weekly flu activity and surveillance |
| CDC | Influenza infection in pregnancy |
| CDC | Antiviral medication treatment recommendations and susceptibility information |
| American College of Emergency Physicians | Strategic plan for ED management of outbreaks of novel H1N1 influenza |
| National Highway Traffic Safety Administration | Strategic plan for prehospital evaluation and management of an influenza pandemic |
Although the CDC and the Infectious Diseases Society of America do not recommend routine seasonal or pre-exposure antiviral prophylaxis for influenza, chemoprophylaxis with oseltamivir or zanamivir can be considered for adults and children aged >3 months who:
Chemoprophylaxis dosing for oseltamivir is 75 mg daily for adults. Patients for whom prophylaxis is recommended should receive an antiviral as soon as they are deemed eligible or at risk, but no more than 48 hours after an exposure. Post exposure chemoprophylaxis should be prescribed for 7 days. Chemoprophylaxis for the duration of influenza season is recommended in the highest-risk patients (eg, hematopoietic stem cell transplant recipients).42 This long-term chemoprophylaxis is best managed by a primary care clinician or other continuity specialist to follow very high-risk patients. For more information, go to Centers for Disease Control and Prevention - Interim Guidance for Influenza Outbreak Management in Long-Term Care and Post-Acute Care Facilities
According to the CDC, oseltamivir is the recommended treatment for pregnant women.59 The use of oseltamivir as postexposure prophylaxis among household contacts had an efficacy rate of 58.5%, with a range of efficacy of 68% to 89% among direct contacts of index cases.71 Oseltamivir also led to a statistically significant decrease in viral nasal titers as well as a reduction in secondary lower respiratory tract complications, particularly bronchitis and pneumonia.73
There is some controversy regarding the cost versus benefit of antiviral medications in treating influenza; however, as antiviral medications are generally well tolerated, most recommendations favor treatment (or at least offering treatment) for all cases of influenza. In a 2014 meta-analysis by Muthuri et al that compared no treatment with neuraminidase inhibitor treatment, the antivirals were associated with a reduction in mortality risk (adjusted odds ratio [OR], 0.81, P = .0024).74 When compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR, 0.48, P < .0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR, 0.50, P < .0001). These investigators also found that there was an increase in the mortality hazard rate with each day’s delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR], 1.23, P < .0001 for the increasing HR with each day’s delay).74 A similar review of neuraminidase inhibitor therapy in children aged <12 years found that the duration of clinical symptoms was reduced by 36 hours among previously healthy children taking oseltamivir and by 30 hours among those taking zanamivir.18,33,75
Use of neuraminidase inhibitors was found to be associated with decreased duration of symptoms and complications, especially among the elderly and when started within 2 days of symptom onset.76 Therefore, neuraminidase inhibitor therapy should be recommended most strongly in older patients who present early in the course of illness, as they are likely to receive the greatest benefit. Treatment remains reasonable, but benefits are less assured, in younger, healthy patients, especially if they present >48 hours after symptom onset.42
Final disposition of the patient with a suspected or confirmed influenza infection will depend on many clinical factors, including (but not limited to) respiratory status and work of breathing, oxygen saturation, age, comorbid medical conditions, and reliability of obtaining follow-up care. Patients with hypoxemia, respiratory distress, hypotension, altered mental status, and/or inability to tolerate oral fluids warrant immediate referral to the emergency department (ED).
For patients who can be safely discharged from UC, clinicians should engage with the patient in shared decision-making regarding the risks and benefits of available treatments and review return precautions and reasons to seek care in the ED. For patients with mild-to-moderate illness who can be discharged directly home, encourage good general health practices and review supportive care and symptom management. Patients should be reminded about the highly infectious nature of influenza and the need for isolation and masking while symptomatic. The CDC recommends that patients stay home for at least 24 hours after their fever has dissipated and that patients be reminded that they may be contagious for up to 7 days after the onset of illness.34
Because influenza infections can present with a wide range of nonspecific clinical signs and symptoms and numerous possible complications, UC clinicians must remember to consider this possible diagnosis while simultaneously maintaining a broad differential. A knowledge of the local seasonal incidence of influenza is crucial for appropriate diagnostic and treatment decisions and will help to limit unnecessary testing when empiric therapy would be more appropriate. Such considerations will improve clinic efficiency while still ensuring that patients who are at increased risk for a more severe disease course receive timely and appropriate therapy. With the evolution of new influenza strains and increased global interconnectedness and mobility, the threat of pandemic influenza continues to rise. UC clinicians serve an important frontline role for public health in the recognition of new trends in influenza and in the evidenced-based management of individual patients.
1. “My patient recently tested positive for COVID-19, so I’m sure his cough and fever are related to that and I don’t have to worry about influenza.” While currently rare, co-infection with SARS-CoV-2 and influenza can occur; presence of COVID-19 infection does not rule out influenza. Because different antiviral treatments are recommended for the 2 distinct viruses, consider testing for influenza in patients with COVID-19 who have more severe symptoms or risk factors for progression to serious illness. Some manufacturers produce rapid molecular tests which simultaneously test for both viruses. However, if this is not available to you, it is important to keep both diagnoses in your differential and remember that they can co-exist.
2. “The patient had an infiltrate on chest x-ray, so bacterial pneumonia appeared to be the clear diagnosis.” Numerous secondary complications can stem from a primary influenza infection. When addressing and treating these complications, do not overlook the possibility of a primary influenza infection and the need for medical management. In certain high-risk patients, testing for influenza and treatment with simultaneous antivirals and antibiotics may be indicated.
3. “I thought I would just let it run its course.” Many previously healthy people can be treated with supportive therapy alone; however, clinicians should be aware of the numerous risk factors for more severe disease. For patients deemed well enough to be safely discharged from UC, utilize shared decision-making with patients about testing and treatment.
4. “It’s summer. Influenza occurs in the fall and winter, so I do not need to be concerned about it at this time of the year.” Although influenza certainly exhibits seasonal fluctuations and regional outbreaks, the disease can occur year-round. Testing decisions for patients with ILI should be influenced by the regional prevalence of disease. UC clinicians should monitor data from agencies that track the prevalence of influenza, such as the CDC.
5. “My patient is pregnant and has influenza. The side-effect profile of antiviral medications concerns me, so I feel better treating her with supportive care.” Pregnancy is a risk factor for more severe influenza infection. Initial CDC epidemiologic data from recent influenza seasons indicate high rates of morbidity and mortality among pregnant women, which confirms the importance of antivirals in this population.
6. “Medical knowledge has advanced over the past few decades, and now we have great antiviral medications. I do not need to worry about a devastating influenza infection today.” While it is true that medical science has advanced considerably since the pandemic of 1918, influenza remains a significant threat. The ability of the virus to undergo genetic reassortment allows for the rapid development of new influenza strains to which the population has little or no immunity. Resistance to antiviral medications has been known to develop quickly for certain influenza strains.
7. “The WHO has declared a pandemic. I feel better giving all my suspected influenza patients antiviral therapy, since I don’t want anyone to have a poor outcome.” Declaration of a pandemic does not necessarily mean that the particular infectious organism is more virulent. It merely recognizes that the disease is spreading worldwide. Pandemics can occur during both mild and more severe disease outbreaks.
8. “The fever was low grade; I thought the baby just had a cold.” The presenting signs and symptoms of influenza infection are nonspecific, and a diagnosis based on clinical presentation alone becomes less accurate in children aged <3 years. Although many children will experience a mild disease course and can be managed with supportive therapy, patients aged <2 years are at higher risk for severe disease. Be vigilant and have a high index of suspicion for possible influenza infection in young children and other high-risk populations, especially when disease prevalence is high.
9. “Flu is everywhere. I don’t have the time to consult the CDC website. I will just give oseltamivir to my patient and be done with it.” Even in times of epidemic influenza infection, numerous strains can be circulating at a given time within a particular region. In past epidemics, there have been reports of influenza strains resistant to oseltamivir. Thus, without knowing the prevalence of local strains, one might mistakenly choose an antiviral agent that will prove less effective on those strains. Treatment with more than 1 agent may even be indicated in some regions until more formal strain-specific diagnostic testing can be undertaken. Since certain medications are effective against only influenza type A, the local prevalence of any type B influenza should be determined in order to select the appropriate drug therapy.
10. “I performed a rapid influenza test and it was negative, so I am safe sending my patient home on supportive therapy alone.” Numerous forms of testing are available to detect influenza infection. Rapid diagnostic tests help guide clinicians in their immediate management decisions, but the quality of the specimen and the skill of the technician performing the assay can influence results. Certain rapid assays are specific for influenza type A, so knowing which strains are circulating locally is important. In times of high disease prevalence, the chance that a given patient with an ILI actually has influenza is increased, as are the number of false-negative results obtained from rapid diagnostic testing. At such times, empiric therapy based on clinical presentation alone is advised for patients at high risk.
PubMed, ISI Web of Knowledge, and the Cochrane Database of Systematic Reviews resources from 2012 to 2022 were accessed using the keywords: emergency department, urgent care, epidemic, pandemic, influenza, novel H1N1, and H3N2. The CDC12 and the WHO78 websites were accessed. Guidelines from the American College of Emergency Physicians,79 the Infectious Diseases Society of America,33 and the American Academy of Pediatrics75 were also reviewed. References from the literature were searched to identify additional content.
You recalled that the CDC has guidelines for the evaluation and treatment of patients who present with an ILI. A review of the CDC website confirmed your impression that your area was experiencing an epidemic of influenza. You noted that children aged <2 years are at an increased risk for a more severe disease course if infected with influenza, and that an influenza A strain sensitive to oseltamivir was most prevalent in your region. You decided that initiating treatment with this antiviral agent would be appropriate for your 20-month-old patient, in addition to prescribing amoxicillin for his secondary acute otitis media.
Given the information you just uncovered about a recent spike in local cases of influenza, and after considering that this patient did not have risk factors for endocarditis or bacteremia, you suspected he had influenza. You recalled that neuraminidase inhibitors are most effective if started <48 hours after onset of symptoms; based on this patient’s relatively mild illness, duration of symptoms, and excellent underlying health status, you suspected he would not greatly benefit from antiviral treatment. You had a conversation with the patient about shared decision-making regarding testing for influenza when the test is unlikely to change management. He agreed that forgoing testing and antiviral treatment made the most sense, and he was discharged with instructions for supportive care and isolation, along with clear return precautions.
Flu season is here—or is it? Based on the experience of the past few years, the 2022-2023 season is likely to be unpredictable. While much about this influenza season remains to be seen, we can be certain that patients with influenza will continue to present to UC. The appropriate evaluation and management codes for these patient encounters will depend on the level of service, as guided by the elements of medical decision making. (See Table 8.)
The clinician must determine whether patients who are positive for influenza have acute, uncomplicated illness or injury or acute illness with systemic symptoms. See Table 9 for definitions of these terms. This determination will guide selection of the appropriate Problems Addressed grouping. Most upper respiratory infections, otitis media, otitis externa, urinary tract infections, nonsystemic rashes, and mild orthopedic injuries fit within the definition of acute, uncomplicated illness or injury. Typically, these scenarios meet the criteria for Level 3 (Low) in the category of Problems Addressed. A patient who is at high risk for more severe disease (eg, an elderly patient with a history of diabetes mellitus, heart disease, and asthma) and has influenza with a fever >101°F, nausea and vomiting, body aches, fatigue, or confusion, would be considered to have acute illness with systemic symptoms, and the criteria would be met for Level 4 (Moderate) in the category of Problems Addressed.
When determining the appropriate level in the Complexity of Data category, consider whether testing (eg, for SARS-CoV-2, group A beta-hemolytic Streptococcus, respiratory syncytial virus, or other agents) was performed, with or without influenza testing. For pediatric patients, all or part of the history of present illness may have been elicited from a parent or caregiver; data from these “independent historians“ do not need to be obtained in person, but must be obtained directly from the historian providing the independent information. Two POC tests (eg, SARS-CoV-2 and group A beta-hemolytic Streptococcus) plus the use of an independent historian results in Level 4 (Moderate) in Complexity of Data category; 3 or more laboratory tests (which may include POC testing as well as blood work) would also meet the criteria for Level 4 in this category.
Risk of Complications is the last category for consideration. A young, healthy patient with no systemic symptoms who tests positive for influenza has a much lower level of risk than an elderly patient who smokes and has systemic symptoms, diabetes mellitus, and a history of chronic obstructive pulmonary disease. In the UC setting, risk is most often determined by treatment decisions (eg, over-the-counter medication vs prescription drug management) and/or any comorbidities that directly affect the patient’s current condition and are addressed during the UC visit. (See Table 8.)
Proper documentation is crucial in all patient encounters. This should include an accurate description of the patient’s current condition; a record of the data that were collected, reviewed, and/or analyzed; documentation that an independent historian was utilized (if applicable); and documentation of the risk management of the patient, including whether the patient was directed to take over-the-counter medication or prescription medication, any comorbidities addressed that could have a direct impact on the patient’s current management plan, and any social determinants of health (SDOH). SDOH include but are not limited to lack of stable housing, employment, quality education, transportation, and access to nutritious food.
—Brad Laymon, PA-C, CPC, CEMC
Content on the FOAMed blog is not eligible for CME credit.
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.
Keith Pochick, MD, FACEP
Editor-in-Chief; Attending Physician, Urgent Care
Joshua Russell, MD, MSc, FCUCM, FACEP
Update Author; Supervising Physician, Legacy-GoHealth Urgent Care; Staff Physician, NorthShore University Immediate Care, Vancouver, WA
Michael Kim, DO;
Huai Lee Phen, MD
Brad Laymon, PA-C, CPC, CEMC
December 1, 2022
December 1, 2025 CME Information
4 AMA PRA Category 1 Credits™. 4 AOA Category 2-A or 2-B Credits. Specialty CME Credits: Included as part of the 4 credits, this CME activity is eligible for 2 Pharmacology CME credits
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