As featured in The American Journal for Nurse Practitioners.  

Impact on the 2009-2010 Influenza Season 

Influenza causes significant morbidity and mortality each year. Rapidly emerging influenza viruses resistant to available agents are a major cause for concern. Two classes of antivirals—adamantanes and neuraminidase inhibitors—are used in chemoprophylaxis and treatment of influenza. Although clinicians are under increasing pressure to prescribe antivirals for their patients, especially in the midst of the 2009 H1N1 pandemic, many flu viruses over the past few years have become resistant to these agents. To explain this phenomenon, the author discusses the biology of influenza viruses and the history of and causes for resistance to antiviral agents. The goal is for nurse practitioners to have a better understanding of the diagnosis, treatment, and prevention of influenza to better care for their patients during this 2009-2010 influenza season.

Influenza epidemics usually occur during the late fall through early spring of each year.¹  Influenza affects 5%-10% of persons of all ages in the United States per year, leading to an average of 226,000 hospitalizations and 36,000 deaths. In 2006, influenza/pneumonia was the eighth leading cause of death in this country.²  The economic burden of a flu epidemic in the United States is approximately $87.1 billion per year.³  Even though vaccination against influenza has been shown to be the single most effective way to protect against this infectious disease,¹ vaccination compliance has remained suboptimal.⁴ 

With only two classes of antiviral agents—adamantanes and neuraminidase inhibitors—used in chemoprophylaxis and treatment of influenza,⁵ rapidly emerging flu viruses resistant to available agents are a major cause for concern. In 2006, 92% of seasonal influenza A H3N2 viruses were resistant to the adamantanes amantadine (Symmetrel) and rimantadine (Flumadine).⁶  In the 2008-2009 influenza season, 99% of seasonal influenza A H1N1 viruses were resistant to oseltamivir (Tamiflu).⁷  In April 2009, a new influenza A 2009 H1N1 virus (also known as swine flu or novel H1N1 influenza) emerged.

This 2009 H1N1 virus, which differs from the seasonal influenza A H1N1 virus, has dominated as the circulating virus for the 2009-2010 season to date. More than 99% of all of 2009 H1N1 viruses have been resistant to the adamantanes.⁸  The news regarding 2009 H1N1 susceptibility/resistance to neuraminidase inhibitors is better, and will be discussed later in the article. This article explains the mechanism whereby flu viruses become resistant to various antiviral agents.

Biology of Influenza Viruses

Influenza viruses belong to the RNA virus family Orthomyxoviridae^9,10. These influenza viruses are categorized as A, B, or C, depending on their internal structural proteins, the nucleocapsid and matrix (M) proteins. Influenza A viruses infect humans, animals, and birds. Influenza B viruses infect humans only, and influenza C viruses infect humans and swine. Nomenclature of influenza viruses is based on the type, host of origin (except for human isolates), geographic origin, strain number, year of isolation, and subtype (for influenza A viruses). The proposed nomenclature for the 2009 H1N1 influenza virus, also known as the swine flu virus or novel H1N1 influenza virus, is A/California/07/2009(H1N1).¹¹  That is, this virus as an influenza type A virus that was first isolated in California in 2009; 07 is the strain number and H1N1 is the subtype. Because this novel virus infects humans only, the host of origin is not included in the nomenclature.

More About Influenza A Viruses—These viruses have a spherical lipid membrane with hemagglutinin (HA) and neuraminidase (NA) glycoproteins projecting from its surface (Figure).^9,10,12  These surface proteins determine a virus’s antigenic variability. Only influenza A viruses are subtyped: 16 subtypes of HA and 9 subtypes of NA have been recovered from birds, animals, or humans. Four HA glycoproteins (H1, H2, H3, and H5) and two NA glycoproteins (N1 and N2) have been found to infect humans. H1N1 and H3N2 are the two main viral subtypes causing seasonal influenza outbreaks each year.¹³  H5N1, also known as avian influenza or bird flu, can infect birds, animals, and humans.¹⁴

The M1 protein lies beneath the spherical lipid membrane that encloses the virion core.^9,10,11,12 Within the virion core, there are eight separate segments of ribonucleic acid (RNA) genome. Genetic reassortment may occur when a given cell is infected by two different viruses. A mixture of different parental RNA genome segments can occur, leading to creation of a new subtype of offspring with different surface antigens. For example, 2009 H1N1 is a quadruple reassortant virus containing genes from pigs in Europe and Asia and genes from birds and humans.¹⁵  Because hosts have no pre-existing immunity to these completely novel antigenic proteins, pandemic outbreaks may result, as in the 1918 Spanish flu and the 2009 H1N1 flu.

The M2 ion channels communicate between the surface of the virus and the virion core.^9,12 These M2 ion channels are unique to influenza A virus. Antivirals such as amantadine and rimantadine are also known as M2 ion channel inhibitors. They work by blocking viral entry into the host cell.

Antigenic Drifts and Shifts—Influenza viruses are highly versatile because of their ability to undergo antigenic drifts and shifts.^9,10,12 Antigenic drift denotes minor antigenic changes, usually as a result of point mutations that occur gradually. Antigenic shift is related to genetic reassortment that creates abrupt, drastic changes in the sequence of the surface protein that cannot be explained by genetic mutation. Antigenic drifts and shifts affect HA and/or NA surface proteins that pose a challenge for host immunity, in terms of the development of vaccines, and they are responsible for the emergence of antiviral drug resistance. Antigenic shift does not seem to occur in influenza B or C viruses.

Antiviral Agents for Influenza

Two classes of antiviral agents are available for chemoprophylaxis and treatment of influenza, the adamantanes and the neuraminidase inhibitors (Table 1).⁵ Adamantanes, also known as M2 ion channel inhibitors, block the M2 ion protein channel, preventing fusion of the virus with the host cell, thereby preventing viral entry and replication.¹⁶  Because the M2 ion protein channel is unique to influenza A, adamantanes are indicated for prevention and treatment of influenza A infections only. Adamantanes are 70%-90% effective when used as chemoprophylaxis and in treatment.¹⁷ When used to treat influenza infection, they can reduce duration of illness by 1.5 days when initiated within 48 hours of illness onset.¹⁸

Neuraminidase inhibitors, such as oseltamivir (Tamiflu) and zanamivir (Relenza),^9,19 work by binding to NA proteins and preventing release of viruses from infected cells.¹⁰ Neuraminidase inhibitors are indicated for both influenza A and B infections. These agents are 70%-90% effective in treating seasonal infections and as post-exposure chemoprophylaxis.¹⁷ When administered early in the disease process, neuraminidase inhibitors reduce illness duration by 1-3 days. These agents also reduce rates of complications such as bronchitis, pneumonia, and otitis media in children, as well as hospitalizations. Peramivir, a new, intravenously administered neuraminidase inhibitor, became available in November 2009. Peramivir received an emergency use authorization (EUA) by the US Food and Drug Administration for the treatment of hospitalized patients with confirmed or suspected 2009 H1N1 infection.²⁰ This agent is still undergoing clinical trials and is not approved to treat other types of influenza virus infections.²¹

Antiviral Resistance Pattern

Resistance to antiviral agents in the prevention and treatment of influenza is increasing at an alarming rate. Adamantanes had been effective against influenza A infections for decades, until around 2003, when a sharp rise in resistance was demonstrated by influenza A H3N2 viruses in Asia.^6,18,22 Isolates collected from 26 states from October through December 2005 showed that 193 (>92%) of 209 circulating influenza A H3N2 viruses were resistant to adamantanes.⁶ In addition, 2 (25%) of 8 circulating influenza A H1N1 viruses showed resistance to adamantanes. In 2006, the Advisory Committee on Immunization Practices recommended against the use of adamantanes (ie, amantadine and rimantadine) in the treatment of influenza.²³

Neuraminidase inhibitors were approved for use in the United States in 1999;^24,25 no significant resistance to these agents was noted until the 2007-2008 influenza season.¹⁹ In that season, 111 (10.9%) of 1020 seasonal influenza A H1N1 viruses analyzed were resistant to oseltamivir, a significant increase from 0.7% in the previous season.²⁶ In the 2008-2009 season, nearly all seasonal A H1N1 viruses were resistant to oseltamivir.⁷ A 2008 French study showed that, among 225 influenza B isolates, 1 was found resistant to both oseltamivir and zanamivir and 8 were outliers for oseltamivir and/or zanamivir.²⁷

The Centers for Disease Control and Prevention (CDC) FluView website (http://www.cdc.gov/flu/weekly/) provides weekly reports on influenza activities and resistance pattern to antivirals.⁸ Table 2 shows the antiviral resistance pattern for the influenza season ending on July 18, 2009. All of the influenza viruses tested were susceptible to zanamivir.⁷ More than 99% of circulating seasonal influenza A H1N1 viruses were resistant to oseltamivir, but fewer than 1% were resistant to adamantanes. Among the influenza A H3N2 viruses tested, all were susceptible to oseltamivir, but 100% were resistant to adamantanes. Among influenza B viruses, 100% were susceptible to both neuraminidase inhibitors. 

The 2009 H1N1 influenza viruses first appeared in the United States and Mexico in March/April 2009.¹⁵ The World Health Organization (WHO) declared a phase 6 pandemic, the highest level, on June 11, 2009, as the H1N1 flu spread to more than 70 countries.²⁸ The first cases of oseltamivir-resistant viruses were reported in July 2009.7 As of December 2, 2009, 79 cases of oseltamivir-resistant 2009 H1N1 infection have been reported worldwide.²⁹ In the United States, nearly all 2009 influenza A H1N1 viruses tested were resistant to adamantanes.⁸ Table 3 shows antiviral resistance testing results on samples collected since September 1, 2009; more than 99% of the samples tested have been of the 2009 H1N1 subtype.⁸

 

Possible Causes of Antiviral Resistance

The exact reasons that influenza viruses become resistant to antiviral agents are not well understood. Substantial resistance to antivirals was first observed in Asia after outbreaks of avian influenza A H5N1 in 1997, severe acute respiratory syndrome (SARS) in 2003, and influenza A H5N1 in 2005 (resistant to oseltamivir).³⁰ As with the phenomenon of bacterial resistance to antibiotics, inappropriate use of antiviral agents may lead to increased selection pressure on viruses, resulting in mutant strains that are resistant to certain antivirals. Many scientists, including Weinstock and Zuccotti³⁰ and Moscona,³¹ have ascribed antiviral resistance to inadequate dosing and duration of use of these agents, as well as to indiscriminate use (these medications can be purchased without a prescription in many countries). However, in a later publication, Weinstock and Zuccotti³² concluded that overuse of antivirals cannot fully explain resistance pattern because oseltamivir resistance was high in Norway, where oseltamivir was rarely used, and resistance was low in Japan, where oseltamivir was used routinely to treat influenza.

Dharan et al¹⁹ evaluated characteristics of patients with oseltamivir-resistant viral infections and compared them with patients whose viral infections were not resistant. These investigators found that both groups of patients experienced a similar clinical course and severity of illness. None of the patients with oseltamivir-resistant viral infections had taken oseltamivir prior to testing or had had household contact with anyone who took it. The authors found no association between oseltamivir use and resistance to seasonal influenza A H1N1 viruses in the United States. Nelson et al²² analyzed the origin and global emergence of adamantine-resistant A H3N2 influenza viruses, and concluded that resistance is likely the result of a complex evolutionary process. Antiviral resistance is related to geographically variable selection pressures, extensive global migration, and frequent viral reassortment. These scientists also theorize that resistant viruses can also mutate/reassort to a drug-sensitive phenotype.

Regardless of the exact mechanism for the emergence of antiviral-resistant viruses, it is known that antiviral resistant viruses can develop during chemoprophylaxis, emerge rapidly during treatment, and be transmitted from person to person.^5,6,17 A CDC Health Advisory issued on July 9, 2009, described three 2009 H1N1 flu cases resistant to oseltamivir: two patients had developed resistance while taking chemoprophylaxis and one patient had no previously known exposure to oseltamivir or to influenza.³³

Stephenson et al³⁴ analyzed sequential clinical nasopharyngeal samples obtained before and after oseltamivir therapy from 64 children aged 1-12 years with acute influenza in 2005-2007.  The researchers recovered antiviral-resistant viruses from 3 (27.3%) of 11 children with influenza A H1N1, 1 (2.9%) of 34 children with influenza A H3N2, and 0 (0%) of 19 children with influenza B, all of whom were treated with oseltamivir. However, none of the children infected with drug-resistant virus showed evidence of prolonged illness. DeJong et al³⁵ reported that resistant influenza A H5N1 developed as early as day 4 of oseltamivir treatment, and that the 2 patients with resistant viruses both died of the infection. These authors suggested that poor patient outcome is associated with the presence of detectable virus after completion of treatment.

Approximately 30% of patients treated with adamantanes for influenza are thought to shed resistant viruses.¹⁸ Development and shedding of resistant viruses are more likely in children and in immunocompromised populations (eg, patients with AIDS; organ or bone marrow transplant recipients; patients on long-term corticosteroid therapy or chemotherapy; patients with diabetes) than in healthy populations.⁵

Diagnosis, Treatment, and Prevention of Influenza

In July 2009, the WHO declared 2009 H1N1 viruses unstoppable.³⁶ Between April and November 14, 2009, the CDC estimated that 47 million cases of H1N1 flu occurred in the United States, with 213,000 hospitalizations and 10,000 deaths.³⁷ The CDC predicts that the 2009 H1N1 virus will likely cause significant morbidity and mortality, and have substantial economic impact in the 2009-2010 influenza season, affecting as many as 40% of the US workforce—that is, persons who will be unable to work because of their own illness or because they are caring for others with influenza.^38,39

Rapid emergence of influenza viruses resistant to adamantanes and oseltamivir makes selection of antiviral agents for clinical treatment or prevention more complicated. Antivirals need to be initiated within 48 hours from onset of influenza-like illness (ILI) to reap maximal benefit. However, the ability for clinicians to rapidly and accurately identify influenza virus is limited.^3,40 Current diagnosis, treatment, and chemoprophylaxis recommendations for seasonal and 2009 H1N1 are available at http://www.cdc.gov/flu/.

Diagnostic Tests—Collection of respiratory specimens for influenza testing should be done within the first 4-5 days of illness, when viral shedding is greatest. Viral culture is the gold standard for definitive diagnosis. Viral culture can identify viral type, subtype, and antiviral susceptibility, but results may take up to 7 days. Serology requires paired testing to measure a rise in titer and may take more than 2 weeks to receive results. Immunofluorescence assay (direct or indirect fluorescent antibody) can provide results in about 4 hours but it cannot identify subtypes of influenza A virus. Accuracy of testing also depends on individual technicians’ experience and expertise.

Reverse-transcription polymerase chain reaction (RT-PCR), one of the most sensitive tests, can identify type and subtype of flu virus, but this test is not widely available. Rapid antigen tests take about 30 minutes to perform; some of these tests can distinguish between influenza A and B, but none can distinguish viral subtypes. Sensitivity of these rapid tests ranges from 50% to 70%, and specificity ranges from 90% to 99% for seasonal influenza. Rapid tests are also highly specific in detecting 2009 H1N1 viruses; however, sensitivity is poor, ranging from 10% to 70%. A positive rapid test result tends to rule in influenza, but a negative test result cannot rule out influenza. Treatment decisions are not based on rapid test results alone; a patient’s clinical presentation must be carefully considered.

Treatment—Local and state surveillance can assist treatment decisions by identifying circulating virus type, subtype, and resistance pattern. To access local and state surveillance information, as well as international surveillance data, NPs can log on to http://www.cdc.gov/flu/weekly/fluactivity.htm. Information can also be obtained on the website of each state’s Department of Health or by performing an Internet search for H1N1 flu surveillance data for the desired state (eg, in Florida, one would log on to http://myflusafety.com/data.html). From Summer 2009 through December 2009, surveillance has demonstrated that most influenza A infections are due to 2009 H1N1 viruses, which is susceptible to both neuraminidase inhibitors.⁸

Under the threat of an H1N1 flu pandemic, clinicians are under increased pressure to prescribe antivirals for their patients. The CDC recommends that antiviral treatment be reserved for hospitalized patients with confirmed, probable, or suspected 2009 H1N1 infection and for persons categorized as being at high risk for complications²¹:

Persons younger than 2 years or aged 65 years or older; 

women who are pregnant or up to 2 weeks postpartum;

persons with chronic health conditions (eg, asthma, heart failure, chronic lung disease) or immunocompromised status; 

pediatric patients on chronic aspirin therapy; and persons who are extremely obese.^21,41

Most persons presenting with an uncomplicated febrile illness do not require antiviral medication, but clinical judgment is crucial in the decision to treat. Poland et al,⁵ concerned about resistance patterns, advocate the rational use of antiviral agents, stating that any antiviral pressure inevitably leads to mutational changes in viruses. Multidrug therapy (including combining drugs with different mechanisms of action), restriction of antiviral use to patients likely to have life-threatening complications, improved availability of point-of-care testing to guide selection of antivirals, and recommendation for universal influenza vaccination may be answers to prevent development of these resistant viruses.⁵

Prevention—Vaccination against influenza remains the single most effective way to protect individuals from contracting the disease.¹ Vaccination can be achieved with trivalent inactivated vaccine (TIV; known as the flu shot, and administered as an intramuscular injection) or live attenuated influenza vaccine (LAIV; called FluMist, and administered via nasal spray).¹ The influenza vaccine is indicated for more than 80% of the US population; however, fewer than 40% receive it. All healthcare personnel are advised to receive flu vaccination because of their greater risk of exposure and to prevent transmission to patients. However, immunization rates among healthcare professionals remain suboptimal, at about 50%.^1,42,43 Vaccination cost, concerns about vaccine safety/efficacy, lack of knowledge about influenza illness, fear of needles, and inconvenient vaccination distribution locations have been identified as potential barriers to influenza vaccination.^44,45

Vaccination against both seasonal and 2009 H1N1 influenzas is especially important in the 2009-2010 influenza season because of the 2009 H1N1 pandemic. Inability to rapidly and accurately diagnose viral subtypes may pose challenges to appropriately select antiviral agents to treat ILIs. Persons who rely on using antivirals in the prevention and treatment of the flu may be disappointed. These agents may not be available in pandemic outbreaks; in addition, resistance to antivirals may render their use ineffective. NPs need to be role models in receiving influenza vaccines and advocating for their use.

Conclusion

Influenza viruses are quite versatile, going through frequent antigenic drifts and shifts, and causing substantial morbidity and mortality worldwide. The recent trend of the rapid emergence of influenza viruses resistant to available antiviral agents is alarming and complicates influenza treatment and prevention. Furthermore, the emergence of the 2009 H1N1 influenza pandemic, combined with limited ability of healthcare practitioners to rapidly and accurately identify influenza viruses for the selection of medications, may pose special challenges for the 2009-2010 influenza season. Vaccination against influenza is the single most effective way to prevent the disease. NPs need to be role models by demonstrating a high influenza vaccination rate and advocating for its use. NPs also need to keep up to date with the latest developments and health advisories to most effectively care for their patients to reduce morbidity and mortality associated with influenza.

Ying Mai Kung is a full-time family nurse practitioner at Thagard Student Health Center at Florida State University (FSU) in Tallahassee; serves as adjunct faculty at the College of Nursing at FSU; and is a DNP candidate at the University of Florida in Gainesville. The author states that she does not have a financial interest in or any other relationship with any commercial product named in this article.

Note: Permission to reprint the figure above was granted by Elsevier LTD, publisher of Hayden FG. Influenza. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2007;chap 387, and by Robert G. Webster, PhD, FRS, who provided the illustration for this chapter.

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