Seasonal Influenza: An Overview and Treatment Plan

ABSTRACT: Influenza is a serious and common viral infection of the respiratory system that carries a major global healthcare burden. It can result in several complications, including bacteria pneumonia and even death, especially among those who at highest risk (eg, elderly individuals and those with chronic comorbidities). Despite advances in vaccination and antiviral treatment, outbreaks of novel strains remain a public health dilemma. This article provides an overview of the potentially lethal viral illness, including an understanding of the virology, epidemiology, and diagnosis. It also discusses the recommended vaccination and treatment practices for the 2015-2016 influenza season.
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Influenza is a serious respiratory illness and a major global health burden. It is estimated to affect approximately 20% to 30% of children and 5% to 10% of adults worldwide each year.¹ Furthermore, approximately 3 to 5 million cases of severe seasonal influenza and up to 500,000 influenza-related deaths are recorded each year worldwide.² The average annual direct medical care costs for influenza A is estimated at $10 billion, with the total annual economic burden being approximately $87 billion.^3,4 Influenza viruses are extremely versatile and adaptable, which pose a challenge to infection control and treatment. Despite advances in vaccination and antiviral treatment, outbreaks of novel strains remain a public health dilemma. This article provides an overview on this potentially lethal viral illness and is intended to educate clinicians about the recommended practices as the 2015-2016 influenza season rapidly approaches. 
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Virology 

Influenza viruses, which belong to the orthomyxoviridae family, are enveloped, negative-strand ribonucleic acid (RNA) viruses, each one differing in pathogenicity.⁵ The 3 main types of influenza are A, B, and C. Type A virus has been the focus of many epidemiologic studies because it infects a variety of mammals, birds, and animals, unlike type B and C viruses. This characteristic of the type A virus makes it a potential source of pandemics. 

Influenza viruses contain gene segments that code for surface glycoproteins, such as hemagglutinin (HA) and neuraminidase (NA). There are 15 HA and 9 NA subtypes.⁶ These glycoproteins not only encapsulate the viral RNA, but they also play a role in attacking host cells. HA proteins attach the virus to host cells by binding sialic acid receptors; hence, a determinant of infectivity. NA proteins, on the other hand, determine the virulence of the viral strain. They cleave the glycosidic linkages to sialic acid, thereby assisting in the release of virions after replication inside infected cells.⁶ 

Influenza viruses have the following 2 mechanisms for developing defensive responses against the human immune system—antigenic drift and antigenic shift—and they serve as a driving force in evolving new variants. Like many viruses, influenza viruses accumulate mutations during replication due to lack of proofreading mechanisms. These point mutations can result in surface glycoproteins with selective defensive advantages against human immunity. A mutation, for example, can lead to the formation of an HA protein that is not identified by human antibodies and is therefore more successful at invading host cells. 

This mechanism of mutation-driven advantage is known as antigenic drift. The second mechanism, antigenic shift, describes the process of 2 influenza A viruses re-assorting and exchanging different glycoproteins. This can lead to the introduction of novel HA proteins to the human immune system from viruses that infect swine, birds, and other animals. These novel proteins pose a bigger threat to human immunity and can lead to pandemics.⁵ 

Transmission 

Influenza viruses are typically transmitted via inhalation of the virus or direct contact with the respiratory secretion of an infected person through coughing or sneezing.⁶ There is a risk of transmission to others if the virus is being shed from the respiratory tract, mainly within 2 to 3 days of illness onset.^7,8 Shedding of the virus can be more prolonged in children and in immunocompromised patients which increases the risk of infection in these households.^9,10 As the viral load grows, the host immune and inflammatory responses propagate, leading to alveolar inflammation, airway hyperreactivity, bronchoalveolar obstruction, and impaired diffusion capacity. These mechanisms, along with other cytopathic effects, explain the symptoms of influenza.¹¹ 

Epidemiology 

Historically, the influenza virus has demonstrated the following 2 epidemiological patterns: seasonal local outbreaks (epidemics) and global outbreaks (pandemics).⁹ The worst influenza pandemic occurred in 1918 and had devas tating effects. It claimed more lives than World War I, killing at least 40 to 50 million people worldwide.¹²

 Since then, there have been 4 to 5 pandemics, occurring with intervals of 9 to 39 years in between each outbreak; the most recent pandemic of 2009 caused between 123,000 and 203,000 fatalities.^6,13-15 A pandemic occurs when a completely new genetic strain of the virus emerges (antigenic shift) and affects various countries at the same time. The burden is much more severe and widespread than in an epidemic, which are usually caused by the continuous change of existing virus strains (antigenic drift).⁷ 

The disease is known to hit during specific times of the year (ie, winter months) and is an important cause of hospitalizations and deaths occurring during this season. This is especially true in individuals 65 years and older and in those with cardiac, pulmonary, or renal comorbidities.¹⁶ However, sporadic outbreaks are not uncommon during any time of the year.¹⁷ Data from the 1997 flu season in the United States showed a steady increase in influenza reporting in January, which peaked during the end of January.¹⁷ Conversely, influenza activity during the 2014-2015 season increased during late November and early December before peaking during late December.¹⁸ The probability of infection varies according to the prevalence, the match between the vaccination strain and the prevalent strain (see below for additional information), and the vaccination status of the individual.¹⁹ Data have shown that the demography of affected groups differ by the scale of the outbreak; for example, patients who were affected by the 2009 pandemic were more likely to be younger, African American, obese, or have experienced complications if they were pregnant as compared with individuals affected by the seasonal outbreak of influenza.⁹ 

Clinical Presentation

After the exposure to influenza and an incubation period of 2 to 5 days, symptoms begin with an abrupt onset of fever, rigors, nonproductive cough, myalgia, headache, coryza, and/or sore throat, with cough and fever being the most predictive symptoms for influenza.^6,20 In healthy individuals, these symptoms are usually mild and typically subside within 5 to 8 days.⁹ In addition to the aforementioned symptoms, otitis media, nausea, and vomiting are common among children with influenza. While not as common, febrile seizures can also occur in this population as a result of spiking fevers.^21,22 Some of the more common complications of influenza include laboratory-confirmed lymphopenia, viral pneumonia, secondary bacterial pneumonia (mostly due to Staphylococcus aureus, Streptococcus pneumonia, or S pyogenes), and compromise to cardiopulmonary preexisting conditions.^9,19 Severe bacterial pneumonia are more likely to complicate pandemic influenza infections.²³ Rare complications include encephalopathy, transverse myelitis, myositis, myocarditis, pericarditis, Guillain-Barré syndrome, and Reye syndrome.^9,21 Between 1976 and 2007, the estimated number of annual influenza-associated deaths with underlying respiratory and circulatory causes in the United States ranged from 3349 to 48,614, and the annual rate of influenza-associated deaths in the United States ranged from 1.4 to 16.7 deaths per 100,000 persons.²⁴ Risk factors for complications and poor outcomes
include old age and young age (age ≥65 or <16 years), pregnancy, preexisting pneumonia, asthma, chronic obstructive pulmonary diseases (COPD), obesity, diabetes mellitus, immunosuppression, and occupational exposure (eg, healthcare workers).^6,25-29 

Diagnosis 

Influenza should be suspected in patients who present with a febrile respiratory illness during the months of November to April. Outside of the usual seasonal time frame, influenza should be considered in recent travelers or in close contacts of recent travelers and in individuals who are exposed to institutional outbreaks. Because of the overlap in symptoms with other common conditions (eg, adenovirus, rhiovirus, and respiratory syncytial virus), the diagnosis of influenza is of limited accuracy based on symptoms alone. Polymerase chain reaction is the most sensitive and specific method to diagnose influenza.¹⁹ Results are usually available between 1 and 6 hours.³⁰ Viral culture from nasal or throat swaps offer high sensitivity or specificity for detection, however, the results often take several days and is therefore not practical in an outpatient setting. Rapid antigen diagnostic tests are another option. These commercially available immunoassays can provide results within 30 minutes, albeit with variable sensitivity ranging from 10% to 70%.²¹ Most available rapid tests can distinguish between types A and B strains.⁶ These tests should be conducted within 24 to 48 hours of symptom onset to coincide with maximal viral shedding. A 2012 meta-analysis of 159 studies evaluating 26 rapid influenza diagnostic tests concluded that the sensitivity is higher for influenza A than for influenza B, and that these tests can help rule in—but not rule out—infection.³¹ 

Prevention and Vaccination

Risk-based strategy focusing on vaccinating populations at highest risk of mortality and morbidity (eg, elderly people) does not seem effective in preventing influenza-related deaths and hospitalizations.^32,33 This could be attributed to poor immunologic response to vaccination in the elderly.³ Given these findings, recommendations for annual vaccination was extended to caretakers and household contacts of high-risk individuals in an attempt to limit exposure. Currently, the Advisory Committee on Immunization Practices (ACIP) recommends annual vaccination of all persons aged 6 months and older (Table 1).²¹ Although this strategy was implemented several years ago, the prevention of seasonal influenza remains a challenge due to poor compliance with these recommendations.³ For example, only 43% of healthcare workers and 21% of household contacts of high-risk persons were vaccinated during the 2003-2004 influenza season.- 

Seasonal vaccines are a product of collaboration between advisory committees of the World Health Organization, CDC, and FDA. Epidemiologic and surveillance data are utilized to determine the 3 prevalent virus variants that are most likely to cause outbreaks in the upcoming season. In the 2015-2016 season, the US-licensed trivalent vaccine will encompass HA derived from H1N1-like virus, H3N2-like virus, and a Yamagata lineage-like virus. A quadrivalent vaccine also available, will include an additional B virus from the B/Victoria lineage. The efficacy of influenza vaccines vary based on the seasonal match between the vaccine antigen and seasonal virus strains. Studies suggest that vaccine efficacy can range from 70% to 90% with a good match and from 0% to 50% with a poor match.^21,34 Live attenuated influenza vaccine (LAIV) has better efficacy than the trivalent inactivated vaccine in elementary school children.³ Both vaccines are well-tolerated and have mild side effects, such as transient nasal congestion and sore throat, as well as tenderness at injection site with the trivalent inactivated vaccine. Starting this season, ACIP no longer expresses a preference between LAIV and the trivalent inactivated vaccine.³⁵ This update aims to minimize delays in vaccinations to procure a specific vaccine preparation if an appropriate one is already available. LAIV should not be used in pregnant or immunocompromised patients or in those who have allergic reactions to egg or other vaccine components. Although previously an issue, vaccination supply and infrastructure for delivery are expanding to improve access and bridge the compliance gap.³ 

An emerging approach to influenza prevention is the use of antiviral prophylaxis for the duration of the season for certain risk groups (eg, healthcare workers who have direct patient care responsibilities and who have been unable to obtain vaccine, when the prevailing strain does not match the vaccine), but there is conflicting evidence at this time. The Infectious Diseases Society of America (IDSA) issued clinical guidelines in 2009 that recommend antiviral chemoprophylaxis for several individuals, including high-risk patients during the first 2 weeks after vaccination before they develop an adequate immune response to inactivated vaccine; and adults and children aged 1 year and older who are at high risk of experiencing influenza complications and in whom the influenza vaccination is contraindicated, unavailable, or may have low effectiveness (Table 2).³⁶ Randomized trials have demonstrated that the antiviral medications, oseltamivir and zanamivir, reduced the risk of influenza in unvaccinated healthy adults, household contacts, elderly individuals, and nursing home residents.⁹ Conversely, a 2012 Cochrane review of NA inhibitors for influenza prophylaxis and treatment in healthy adults and children concluded that there is little evidence on the benefits of prophylaxis; in addition, while oseltamivir did not decrease hospitalizations, it did shorten the duration of influenza symptoms by 21 hours.^37,38 Pre-exposure prophylaxis is another option, but it is not yet recommended, especially with ongoing concerns of viral resistance. 

Antiviral Treatment

Influenza continues to carry a large healthcare burden, and controlling influenza outbreaks continues to be a significant challenge due to high antigenic variations each season. Therefore, the need for antiviral treatments to alleviate infection burden is inevitable. Along with supportive care, there are 2 classes of antiviral drugs available for treatment and prevention: NA inhibitors and adamantanes. The 2009 IDSA guidelines recommend starting antiviral treatment within the first 48 hours of illness in patients at high risk for poor outcomes,³⁶ which, as previously mentioned, include children younger than 2 years of age, adults age 65 years and older, immunocompromised patients, nursing home residents, pregnant women, and those with chronic comorbidities (eg, chronic kidney disease, diabetes, COPD, asthma). Treatment after the initial 48 hours of illness should also be considered if a novel strain is suspected or if no improvement is noted. Antiviral therapy has been shown to reduce the duration of illness by an average of 1 day, nasal shedding of the virus, the rates of serious illness, the risk of secondary bacterial infections, and the risk of death if started promptly.^3,39,40 

The timing of antiviral initiation is not the only treatment-related challenge that physicians face when treating patients with influenza. Older adamantanes (amantadine and rimantadine) are not effective against influenza B and almost all influenza A viruses have developed resistance against them. Therefore, they are no longer recommended in the United States for H1N1 outbreaks unless combined with an NA inhibitor. In its 2015 guidelines, the CDC recommended the NA inhibitors oseltamivir, zanamivir, and peramivir for the treatment of uncomplicated influenza (Table 3).⁴¹ Resistance to oseltamivir is increasing steadily, which makes alternative antivirals favorable, if appropriate. Zanamivir is administered by inhalation, which makes it a poor choice in debilitated patients, children younger than 7 years of age, and those with reactive airway disease. Other agents that have shown promise in animal models and/or humans include conjugated sialidase, HA inhibitors, small interfering RNA, polymerase inhibitors, protease inhibitors, monoclonal antibodies, and a sphingosine analog.⁴² Furthermore, symptomatic treatment with acetaminophen, various NSAIDs, hydration, and antibiotics to treat secondary bacterial infection is recommended. However, adequate handwashing and various other infection control measures (eg, respiratory hygiene, cough etiquette, masking of person with respiratory symptoms) remain key in controlling the spread of the influenza virus.

The world witnessed the devastating consequences of an influenza pandemic in 1918 when an extremely virulent virus strain claimed the lives of nearly 40 to 50 million people.^11,12 Other major pandemics occurred in 1957 and 1968. It is impossible to predict when the next pandemic will happen, given how unpredictable the antigenic variation of the viral strains is. Preparedness for seasonal outbreaks, however, should be a priority for public health organizations. Physicians—specifically primary care providers—play a vital role in implementing these public health strategies by increasing awareness about preventive measures, treating individual cases in a timely manner, and bridging gaps in access to vaccination.

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