H1N1 Influenza (Swine Flu)

Swine influenza is a highly contagious respiratory disease in pigs caused by one of several swine influenza A viruses, as recently reviewed.[1, 2] In addition, influenza C viruses may also cause illness in swine. Strategies to control swine influenza virus (SIV) in animals typically include one of several commercially available bivalent swine influenza virus vaccines.

Transmission of swine influenza viruses to humans is uncommon. However, the swine influenza virus can be transmitted to humans via contact with infected pigs or environments contaminated with swine influenza viruses. Once a human becomes infected, he or she then can spread the virus to other humans, presumably in the same way as seasonal influenza is spread (ie, via coughing or sneezing).

History

The ability to trace outbreaks of swine flu in humans dates back to investigation of the 1918 Spanish influenza pandemic, which infected one third of the world’s population (an estimated 500 million people) and caused approximately 50 million deaths. In 1918, the cause of human influenza and its links to avian and swine influenza was not understood. The answers did not begin to emerge until the 1930s, when related influenza viruses (now known as H1N1 viruses) were isolated from pigs and then humans.[6]

In humans, the severity of swine influenza can vary from mild to severe. From 2005 until January 2009, 12 human cases of swine flu were reported in the United States; none were fatal. In 1988, however, a previously healthy 32-year-old pregnant woman in Wisconsin died of pneumonia as a complication of swine influenza.

A 1976 outbreak of swine influenza in Fort Dix, New Jersey, involved more than 200 cases, some of them severe, and one death.[7] The first discovered case involved a soldier at Fort Dix who complained of feeling weak and tired. He died the next day.

The fear of an influenza pandemic in 1976 led to a national campaign in the United States designed to immunize nearly the entire population. In October 1976, approximately 40 million people received the A/NewJersey/1976/H1N1 vaccine (ie, swine flu vaccine) before the immunization initiative was halted because of the strong association between the vaccine and Guillain-Barré syndrome (GBS).[8, 9] About 500 cases of GBS were reported, with 25 deaths due to associated pulmonary complications.[10]

A recent investigation sought to determine the link between GBS and the 1976 swine flu vaccine, because subsequent influenza vaccines did not have this strong association. Nachamkin et al found that inoculation of the 1976 swine flu vaccine, as well as the 1991-1992 and 2004-2005 influenza vaccines, into mice prompted production of antibodies to antiganglioside (anti-GM1), which are associated with the development of GBS. They proposed that further research regarding influenza vaccine components is warranted to determine how these components elicit antiganglioside effects.[11]  

This preliminary negative stained transmission electron micrograph depicts some of the ultrastructural morphology of the A/CA/4/09 swine flu virus. Courtesy of CDC/ C. S. Goldsmith and A. Balish.

This preliminary negative stained transmission electron micrograph depicts some of the ultrastructural morphology of the A/CA/4/09 swine flu virus. Courtesy of CDC/ C. S. Goldsmith and A. Balish.

2009-2010 H1N1 influenza (formerly called swine influenza) outbreak

Human cases of influenza A (H1N1) were reported worldwide. In 2009, cases of influenzalike illness were first reported in Mexico on March 18; the outbreak was subsequently confirmed as H1N1 influenza A.[12] Suspected clinical cases had been reported in 19 of the country's 32 states, although only 97 of the Mexican cases had been laboratory-confirmed as influenza A/H1N1[13] (12 of them genetically identical to influenza A/H1N1 viruses from California.[12] ) As of May 5th, 2009, nearly 600 H1N1 influenza cases had been confirmed in Mexico, including 25 deaths.[14]

On April 17, 2009, the CDC determined that 2 cases of febrile respiratory illness in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus.[15] By April 26, 2009, the US Department of Health and Human Services (HHS) declared a national public health emergency involving H1N1 influenza A, citing its significant potential to affect national security.[16] By June 25, 2009, 27,717 lab-defined cases of H1N1 influenza had been confirmed in the United States.[13, 17, 18, 19]

Estimates in the United States for the first 6 months of the pandemic reported approximately 22 million people in the United States became ill from the H1N1 influenza, nearly 100,000 were hospitalized, and about 3900 died. Deaths include an estimated 540 children younger than 18 years, 2900 adults aged 18-64 years, and about 440 elderly individuals. These estimates are from the CDC's Emerging Infection Program, rather than using only laboratory-confirmed cases.[20]

For an updated tally and case counts in specific states, see the CDC's H1N1 Flu (Swine Flu) Web page.

On June 11, 2009, the WHO raised the pandemic alert level to phase 6 (indicating a global pandemic) because of widespread infection beyond North America to Australia, the United Kingdom, Argentina, Chile, Spain, and Japan.[13] As of September 1, 2009, the WHO reported that H1N1 influenza had been confirmed in over 200,000 people in more than 100 countries and that they were aware of at least 2185 confirmed deaths. For an updated tally of affected countries and counts, see WHO's Influenza A (H1N1) Web page.

On October 24, 2009, President Obama declared the 2009 H1N1 influenza pandemic a national emergency, explaining that "...the rapid increase in illness across the Nation may overburden health care resources and that the temporary waiver of certain standard Federal requirements may be warranted in order to enable U.S. health care facilities to implement emergency operations plans, the in the United States 2009 H1N1 influenza pandemic constitutes a national emergency." This declaration made way for waiving certain requirements of the Medicare, Medicaid, and State Children's Health Insurance programs and of the Health Insurance Portability and Accountability Act Privacy Rule throughout the duration of the public health emergency.[21]

Government and public health officials are monitoring this situation worldwide to assess the threat from H1N1 influenza and to provide guidance to health care professionals and the public. Because the situation is changing rapidly, it is important to check regularly for changes in recommendations as new information becomes available. Online resources for daily guidance include the Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and Medscape's H1N1 Influenza A (Swine Flu) Alert Center.

Domínguez-Cherit et al (2009) conducted an observational study of consecutive critically ill patients in Mexican hospitals that treated most patients with confirmed, probable, or suspected H1N1 influenza during the 2009 epidemic. Critical illness occurred in 58 (6.5%) of 899 patients. The median age of critically ill patients was 44 years (range, 10-83 y). All presented with fever, and all but one with respiratory symptoms. Few patients had comorbid respiratory disorders, but 36% were obese. All patients but 2 received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia. By 60 days, 24 patients had died (41.4%). Patients who died had greater initial severity of illness, worse hypoxemia, higher creatine kinase and creatinine levels, and ongoing organ dysfunction. Treatment with neuraminidase inhibitors was associated with improved survival (odds ratio, 8.5).[22]

See Medscape's H1N1 influenza algorithm adaptation for guidance in managing suspected cases.

A WHO report on the 2009 influenza pandemic indicated that nearly all countries reported cases of H1N1 virus infection, with more than 17,000 deaths worldwide. In the United States, the number of clinical illnesses was estimated at 59 million, 265,000 hospitalizations, and 12,000 deaths.[23]  H1N1 strains are still prevalent in India, whose Health Ministry has reported over 2500 deaths to date.

In the second half of 2011, a novel swine influenza virus emerged. Twelve cases from 5 states were reported by the CDC in January 2012. The new strain, dubbed A (H3N2)v, includes a gene from the human pandemic strain and affects mostly children. In 3 of the 5 states where the virus emerged (Pennsylvania, Maine, and Indiana), the virus was a result of pig-to-human transmission.[24]

Mortality/Morbidity

H1N1 influenza (swine flu) tends to cause high morbidity but low mortality rates (1%-4%).

Age

Belongia et al provide an excellent epidemiologic comparison of the clinical characteristics of the 2009 influenza A H1N1 versus other seasonal influenza A strains.[25] In their study, the clinical manifestations and risk for hospitalization were similar between the 2009 H1N1 strain and other seasonal influenza A strains. However, children were disproportionately affected by the 2009 H1N1 strain but not necessarily by severity of illness.

A review of medical records from the 2009 US pandemic found hospitalized patients with pandemic H1N1 and pneumonia were at risk for severe outcomes including ARDS, sepsis, and death. However, patients often received delayed antiviral treatment (>2 days after illness onset). Patients with H1N1 and pneumonia should receive early and aggressive treatment with antibiotics and influenza antiviral agents.[26]

In a multicenter study in Britain consisting of over 1500 patients, independent predictors of severe outcome included age 55 to 64 years, certain chronic lung diseases, underlying neurological disease, obesity, delayed admission (≥5 days after illness onset), pneumonia, and others.[27]

See the patient education article Swine Flu.

Manifestations of H1N1 influenza (swine flu) are similar to those of seasonal influenza. Patients present with symptoms of acute respiratory illness, including at least 2 of the following:

• Fever
• Cough
• Sore throat
• Body aches
• Headache
• Chills and fatigue
• Diarrhea and vomiting (possible)

Persons with these symptoms should call their healthcare provider promptly. If an antiviral agent is warranted, it ideally should be initiated with 48 hours from the onset of symptoms (see Medication). The duration of illness is typically 4-6 days. The infectious period for a confirmed case is defined as 1 day prior to the onset of symptoms to 7 days after onset.

In children, signs of severe disease include apnea, tachypnea, dyspnea, cyanosis, dehydration, altered mental status, and extreme irritability.[4]

In children hospitalized for influenza, neurologic complications are common and sometimes life-threatening. In an effort to assess the extent and range of such complications in this population, Australian investigators in 6 tertiary pediatric referral centers carried out active hospital-based surveillance of 506 children younger than 15 years who had laboratory-confirmed pandemic influenza A (H1N1) 2009 infection (pH1N1'09).[28] Of the 506, 49 (9.7%) had neurologic complications.

Further study findings were as follows:

• Patients with neurologic complications tended to be slightly older than those without (median age, 4.8 years versus 3.7 years)
• Of patients with neurologic complications, 55.1% had preexisting medical conditions and 42.8% had preexisting neurologic conditions
• On presentation, only 36.7% had cough, fever, and coryza or runny nose; 38.7% had only 1 respiratory symptom or none at all
• Neurologic complications, in descending order of frequency, included seizure (7.5%), encephalitis or encephalopathy (1.4%), confusion or disorientation (1.0%), loss of consciousness (1.0%), and paralysis or Guillain-Barré syndrome (0.4%)
• Intensive care unit (ICU) admission was required in 30.6% of the patients, mechanical ventilation in 24.5%
• Mean hospital stay was 6.5 days, mean ICU stay 4.4 days
• Two (4.1%) of the 49 patients died

Specific treatment for influenza-related neurologic complications generally is unavailable. Consequently, early diagnosis of influenza, appropriate use of antiviral therapy, and universal influenza vaccination in children are vital. Influenza should be considered as a diagnosis in children with neurologic symptoms, even when few or even no respiratory symptoms are noted.

Outbreaks of H1N1 influenza (swine flu) are common in pigs year-round. Historically, when humans have become infected, it is a result of close contact with infected pigs (but not consumption of pork). In major outbreaks, human-to-human transmission occurs.

In the 2009-2011 outbreak, the WHO raised its pandemic alert level for H1N1 influenza to phase 6, indicating that a global pandemic was identified. 

Phase 6 criteria: In addition to the criteria defined in Phase 5, the same virus has caused sustained community-level outbreaks in at least one other country in another WHO region. Courtesy of the WHO.

In the 2009-2010 outbreak in the United States, preliminary testing showed that, in all cases, the viruses had the same genetic pattern. The virus is being described as a new subtype of influenza A/H1N1 not previously detected in pigs or humans.

Clinicians should consider the possibility of H1N1 influenza virus infections in patients who present with febrile respiratory illness. The CDC criteria for suspected H1N1 influenza are as follows[5] :

• Onset of acute febrile respiratory illness within 7 days of close contact with a person who has a confirmed case of H1N1 influenza A virus infection, or
• Onset of acute febrile respiratory illness within 7 days of travel to a community (within the United States or internationally) where one or more H1N1 influenza A cases have been confirmed, or
• Acute febrile respiratory illness in a person who resides in a community where at least one H1N1 influenza case has been confirmed.

In September 2011 the FDA approved a new CDC-developed test to diagnose seasonal flu as well as the influenza viruses that could become pandemic. The Human Influenza Virus Real-Time RT-PCR Detection and Characterization Panel (rRT-PCR Flu Panel) is an in vitro laboratory diagnostic test that can provide results within 4 hours. It is the only in vitro diagnostic test for influenza that is cleared by the FDA for use with lower respiratory tract specimens and will be given at no cost to qualified international public health laboratories.

Laboratories should send all influenza A specimens that they are unable to subtype to the Viral Surveillance and Diagnostic Branch of the CDC's Influenza Division as soon as possible for further diagnostic testing.[29]

Since the outbreak, multiple methods of diagnosing influenza have been reported. Influenza tests may include the following:

• Molecular tests: These may include conventional reverse-transcriptase PCR, office-based rapid molecular testing, and multiplex molecular platforms that can detect influenza in addition to several other common respiratory pathogens. RT-PCR yields the best performance based on sensitivity and specificity data.
• Rapid antigen or antibody immunoassays: Although these are available, most choose molecular testing over these immunoassays owing to their lower sensitivity.
• Viral culture: Although viral culture is available, it not very useful in clinical practice.
• Serology: Serologic testing is not recommended for diagnosis because paired sera (acute and convalescent) are required, thereby limiting the timeliness of these tests in patient care. They may be more useful in epidemiologic studies.

Viral tracking and research

Internationally, scientists have been collaborating on genetic analysis of current animal and human influenza viruses. These researchers have created a human/swine A/H1N1 influenza wiki to facilitate rapid dissemination of the results of this work. The collaboration is producing insights on the origin of the H1N1 virus and should enable scientists to track its evolution as the outbreak spreads around the world. Information from the National Institute of Allergy and Infectious Disease regarding influenza genome sequencing is available to researchers studying how influenza viruses evolve and those developing new and improved ways to prevent, diagnose, and treat influenza disease.[30, 31]

Treatment is largely supportive and consists of bedrest, increased fluid consumption, cough suppressants, and antipyretics and analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs) for fever and myalgias. Severe cases may require intravenous hydration and other supportive measures. Antiviral agents may also be considered for treatment or prophylaxis (see Medication).

Patients should be encouraged to stay home if they become ill, to avoid close contact with people who are sick, to wash their hands often, and to avoid touching their eyes, nose, and mouth. The CDC recommends the following actions when human infection with H1N1 influenza (swine flu) is confirmed in a community[4] :

• Patients who develop flulike illness (ie, fever with either cough or sore throat) should be strongly encouraged to self-isolate in their home for 7 days after the onset of illness or at least 24 hours after symptoms have resolved, whichever is longer.
• To seek medical care, patients should contact their health care providers to report illness (by telephone or other remote means) before seeking care at a clinic, physician's office, or hospital.
• Patients who have difficulty breathing or shortness of breath or who are believed to be severely ill should seek immediate medical attention.
• If the patient must go into the community (eg, to seek medical care), they should wear a face mask to reduce the risk of spreading the virus in the community when coughing, sneezing, talking, or breathing. If a face mask is unavailable, ill persons who need to go into the community should use tissues to cover their mouth and nose while coughing.
• While in home isolation, patients and other household members should be given infection control instructions, including frequent hand washing with soap and water. Use alcohol-based hand gels (containing at least 60% alcohol) when soap and water are not available and hands are not visibly dirty. Patients with H1N1 influenza should wear a face mask when within 6 feet of others at home.
• Antiviral therapy may be indicated. Available medications are discussed in the Medication section.

Vaccination campaign

The 2009 influenza A (H1N1) monovalent vaccine was released in mid October. The immunization series consisted of 2 doses for children younger than 10 years, consisting of an initial dose and a booster to be administered several weeks later. Adults and children 10 years and older received a single dose. Targeted populations recommended to receive the 2009 H1N1 vaccine included pregnant women, household contacts and caregivers of children younger than 6 months, healthcare and emergency medical services personnel, children aged 6 months to 18 years, young adults aged 19-24 years, and persons aged 25 through 64 years with conditions associated with higher risk of medical complications from influenza.[32, 33]

A separate seasonal influenza vaccine was needed for the 2009/2010 influenza season because it was too late to incorporate the new strain into the regular influenza vaccine already in production. Now H1N1 is a component of the trivalent and quadrivalent influenza vaccines.

A 2011 CDC analysis reaffirms the importance of vaccinating pregnant women regardless of trimester and prompt treatment with a neuraminidase inhibitor (ie, within 2 d of symptom onset) if influenza occurs during pregnancy.[34]

There are only a limited number of studies that describe the safety of giving influenza vaccine to pregnant women. A 2012 study in Denmark found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.[35]

Community precautions

The CDC recommends the following actions when human infection with H1N1 influenza (swine flu) is confirmed in a community[4] :

Household contacts who are not ill

• Remain home at the earliest sign of illness.
• Minimize contact in the community to the extent possible.
• Designate a single household family member as caregiver for the patient to minimize interactions with asymptomatic persons.

School dismissal and childcare facility closure

• Strong consideration should be given to close schools upon a confirmed case of H1N1 flu or a suspected case epidemiologically linked to a confirmed case.
• Decisions regarding broader school dismissal within these communities should be left to local authorities, taking into account the extent of influenzalike illness within the community.
• Cancelation of all school or childcare related gatherings should also be announced.
• Encourage parents and students to avoid congregating outside of the school if school is canceled.
• Duration of schools and childcare facilities closings should be evaluated on an ongoing basis depending on epidemiological findings.
• Consultation with local or state health departments is essential for guidance concerning when to reopen schools. If no additional confirmed or suspected cases are identified among students (or school-based personnel) for a period of 7 days, schools may consider reopening.
• Schools and childcare facilities in unaffected areas should begin preparation for possible school closure.

Social distancing

• Large gatherings linked to settings or institutions with laboratory-confirmed cases should be canceled (eg, sporting events or concerts linked to a school with cases); other large gatherings in the community may not need to be canceled at this time.
• Additional social distancing measures are currently not recommended.
• Persons with underlying medical conditions who are at high risk for complications of influenza should consider avoiding large gatherings.

Preventive measures for health care personnel

The CDC has issued interim recommendations for controlling the spread of H1N1 influenza in health care settings.[36] Recommended measures for care of patients with suspected or confirmed H1N1 influenza include the following:

• Place patients in a single-patient room with the door kept closed. An airborne-infection isolation room with negative-pressure air handling can be used, if available. Air can be exhausted directly outside or can be recirculated after filtration by a high efficiency particulate air (HEPA) filter.
• Suctioning, bronchoscopy, or intubation should be performed in a procedure room with negative-pressure air handling.
• Patients should wear a surgical mask when outside their room.
• Encourage patients to wash their hands frequently and to follow respiratory hygiene practices. Cups and other utensils used by the ill person should be washed with soap and water before use by other persons.
• Routine cleaning and disinfection strategies used during influenza seasons can be applied.
• Standard, droplet, and contact precautions should be used for all patient care activities and maintained for 7 days after illness onset or until symptoms have resolved.
• Health care personnel should wash their hands with soap and water or use hand sanitizer immediately after removing gloves and other equipment and after any contact with respiratory secretions.
• Personnel providing care to or collecting clinical specimens from patients should wear disposable nonsterile gloves, gowns, and eye protection (eg, goggles) to prevent conjunctival exposure.
• As per previous recommendations regarding mask and respirator use during influenza pandemics, personnel engaged in aerosol-generating activities (eg, collection of clinical specimens, endotracheal intubation, nebulizer treatment, bronchoscopy) and/or resuscitation involving emergency intubation or cardiac pulmonary resuscitation should wear a fit-tested disposable N95 respirator.
• Pending clarification of transmission patterns for the 2009 H1N1 influenza A (swine flu) virus, personnel providing direct patient care for suspected or confirmed cases should wear a fit-tested disposable N95 respirator when entering the patient's room.

2009 H1N1 vaccine efficacy and adverse effects

Zhu et al (2009) assessed the safety and immunogenicity of the 2009 H1N1 vaccine in a randomized clinical trial in populations ranging in age from 3-77 years. In the study, 2200 individuals received one dose, 2103 (95.6%) of whom received a second dose or placebo. A single 15-mcg dose of hemagglutinin antigen without alum adjuvant induced a typically protective immune response in most participants aged 12-60 years. Severe adverse effects were not observed. Mild injection-site reactions were reported in up to 16% of individuals.[37]

Communication from the US FDA Commissioner, Margaret Hamburg, summarized safety data after 11.3 million doses of intranasal and 34.9 million doses of injectable vaccine were distributed. Analysis of 3783 reports of adverse events was reported to the vaccine adverse event reporting system (VAERS) through November 24, 2009, based on 438,376 people vaccinated. The vast majority (94%) of adverse events described were classified as nonserious (eg, soreness at site of injection). No cases of Guillain-Barré syndrome have been reported. As of December 30, 2009, nearly 100 million doses of H1N1 vaccine had been distributed.[38]

Both the CDC and the IDSA practice guidelines (2019)[39] collectively provide thorough discussions on the epidemiology, clinical manifestations, diagnosis, and treatment of influenza.

Laboratory testing has found the H1N1 influenza A (swine flu) virus susceptible to the prescription antiviral drugs oseltamivir and zanamivir. Other antiviral agents (eg, amantadine, rimantadine) are not recommended because of recent resistance to other influenza strains documented over the past several years. Limited zanamivir resistance was reported for the H1N1 influenza strain in the 2007-2009 pandemic. Oseltamivir resistance was also noted (see below).

Basic supportive care (ie, hydration, analgesics, cough suppressants) should be prescribed. Empiric antiviral treatment should be considered for confirmed, probable, or suspected cases of H1N1 influenza. Treatment of hospitalized patients and patients at higher risk for influenza complications should be prioritized.

WHO guidelines

WHO guidelines recommend treating serious cases immediately.[40] The guidelines represent an international panel of experts who reviewed all available studies regarding antiviral agents (with emphasis on oseltamivir and zanamivir). Evidence indicates that oseltamivir, when properly prescribed, significantly decreases risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.

In the 2009 H1N1 pandemic, oseltamivir-resistant strains were observed in a small number of patients (especially among strains bearing the H275Y mutation). Most oseltamivir resistance occurred in severely immunocompromised patients with prior exposure to oseltamivir.[41]

For patients who initially present with severe illness or whose condition begins to deteriorate, initiate oseltamivir as soon as possible. For patients with severe or deteriorating illness, treatment should be provided even if started later. Where oseltamivir is unavailable or cannot be used for any reason, zanamivir may be given. This recommendation applies to all patient groups, including pregnant women, and all age groups, including young children and infants.

For patients with underlying medical conditions that increase the risk of more severe disease, WHO recommends treatment with either oseltamivir or zanamivir. These patients should also receive treatment as soon as possible after symptom onset, without waiting for the results of laboratory tests. Pregnant women are included among groups at increased risk, and WHO recommends that pregnant women receive antiviral treatment as soon as possible after symptom onset.

At the same time, the presence of underlying medical conditions will not reliably predict all or even most cases of severe illness. Worldwide, around 40% of severe cases are now occurring in previously healthy children and adults, usually younger than 50 years. Some of these patients experience a sudden and very rapid deterioration in their clinical condition, usually on day 5 or 6 following the onset of symptoms.

Clinical deterioration is characterized by primary viral pneumonia, which destroys the lung tissue and does not respond to antibiotics, and the failure of multiple organs, including the heart, kidneys, and liver. These patients require management in intensive care units using therapies in addition to antivirals.

Peramivir, an investigational, intravenous neuraminidase inhibitor in Phase 3 clinical trials, has been used successfully in adults and children under an emergency investigational new drug program in the United States. It was well tolerated and associated with recovery in the majority of patients hospitalized with severe H1N1 infection.[42]

Baloxavir marboxil is an antiviral agent approved for the treatment of uncomplicated conventional influenza. Whether it would be an appropriate choice for the 2007-2009 pandemic H1N1 strain is unknown.

Initiate antiviral agents within 48 hours

Prompt initiation of antiviral agents within 48 hours of symptom onset is imperative for providing treatment efficacy against influenza virus. In studies of seasonal influenza, evidence for benefits of treatment is strongest when treatment is started within 48 hours of illness onset. However, some studies of treatment of seasonal influenza have indicated benefit, including reductions in mortality or duration of hospitalization, even in patients in whom treatment was started more than 48 hours after illness onset. The recommended duration of treatment is 5 days.[43, 44]

Prophylaxis with antiviral agents should also be considered in the following individuals (pre-exposure or postexposure):

• Close household contacts of a confirmed or suspected case who are at high risk for complications (eg, chronic medical conditions, persons >65 y or < 5 y, pregnant women)
• School children at high risk for complications who have been in close contact with a confirmed or suspected case
• Travelers to Mexico who are at high risk for complications (eg, chronic medical conditions, persons >65 y or < 5 y, pregnant women)
• Healthcare providers or public health workers who were not using appropriate personal protective equipment during close contact with a confirmed or suspected case
• In September 2009, the CDC updated recommendations concerning the use of antiviral medications for prevention because of reported oseltamivir resistance; antivirals should not be used for postexposure chemoprophylaxis in healthy children or adults to manage outbreaks in the community, school, camp, or other settings. ^[45]
• Reserve antiviral chemoprophylaxis for persons at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza.

Pre-exposure prophylaxis can be considered in the following persons:

• Any health care provider who is at high risk for complications (eg, persons with chronic medical conditions, adults >65 y, pregnant women)
• Individuals not considered to be at high risk but who are nonetheless traveling to Mexico, first responders, or border workers who are working in areas with confirmed cases
• Oseltamivir ring prophylaxis can be considered for outbreaks of pandemic H1N1 influenza A, especially among closed populations such as military personnel; ring prophylaxis involved the use of oseltamivir 75 mg once daily to members of the same military unit where contact opportunities were substantial. ^[46]

Pediatric considerations

Aspirin or aspirin-containing products (eg, bismuth subsalicylate [Pepto Bismol]) should not be included in the treatment of confirmed or suspected viral infection in persons aged 18 years or younger because of the risk of Reye syndrome. For relief of fever, other antipyretic medications (eg, acetaminophen, nonsteroidal anti-inflammatory drugs) are recommended.

Pregnant women

Oseltamivir and zanamivir are "Pregnancy Category C" medications, indicating that no clinical studies have been conducted to assess the safety of these medications in pregnant women.

Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, oseltamivir or zanamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the embryo or fetus; the manufacturers' package inserts should be consulted. However, no adverse effects have been reported among women who received oseltamivir or zanamivir during pregnancy or among infants born to women who have received oseltamivir or zanamivir.

Prompt use of antiviral drugs during the 2009 H1N1 influenza pandemic improved survival among severely ill pregnant women. The CDC examined reports of severe flu (resulting in death or ICU admission) in 347 pregnant women during the pandemic, including 272 who were admitted to the ICU and survived and 75 who died. Severely ill postpartum women (n=15), including 9 who died, also were reported.

Of the 307 pregnant women for whom information regarding the presence of underlying medical conditions was available, half had underlying conditions such as asthma, diabetes, or hypertension. Among those who died, 86.1% received antiviral treatment with oseltamivir or zanamivir, compared with 94.8% of survivors. Time to initiate treatment from symptom onset was significantly different for women who died, compared with those who survived (P< .01). Only 4 women (7%) of those who died received an antiviral within 2 days of symptom onset, compared with 41% of survivors.

This analysis reaffirms the importance of prevention (ie, vaccination of pregnant women regardless of trimester) and prompt treatment with a neuraminidase inhibitor (ie, within 2 d of symptom onset) if influenza occurs during pregnancy.[34]

Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Because zanamivir is an inhaled medication and has less systemic absorption, some experts prefer zanamivir over oseltamivir for use in pregnant women, when feasible.[43, 47] Others recommend that, because pregnant women may have a decreased ability to inhale zanamivir, they should be given oseltamivir.

Prevention

A systematic review and meta-analysis has reported on the immunogenicity and safety of the 2009 influenza A (H1N1) vaccine. No death or case report of Guillain-Barre syndrome was reported, and the vaccine, with or without adjuvant, appeared to be generally seroprotective after one dose among patients older than 36 months.[48]

After the initial year H1N1 influenza reappeared in 2009, the A/California/7/2009 (H1N1)pdm09-like strain has been incorporated into seasonal influenza vaccines. All persons aged 6 months or older should receive influenza vaccine annually. 

Influenza vaccines are discussed more broadly in other reviews.

Class Summary

Drugs indicated for treatment of H1N1 influenza A virus include neuraminidase inhibitors (ie, oseltamivir and zanamivir).

Oseltamivir and zanamivir inhibit neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, these agents decrease the release of viruses from infected cells and, thus, viral spread.

These antivirals are effective in the treatment of influenza A or B and must be administered within 48 hours of symptom onset to provide optimal treatment. The sooner the drug is administered after symptom onset, the better the likelihood of a good outcome. However, some studies of treatment of seasonal influenza have indicated benefit, including reductions in mortality or duration of hospitalization even for patients whose treatment was started more than 48 hours after illness onset.[43] Antivirals reduce the length of illness by an average of 1.5 days. (In a subgroup of high-risk patients, illness was reduced by 2.5 d.) In addition, the severity of symptoms is also reduced.

On October 23, 2009, the FDA announced emergency-use authorization of the investigational intravenous neuraminidase inhibitor, peramivir. In an observational study of 31 patients, intravenous peramivir was administered to patients with progressive H1N1 pneumonia despite treatment with oseltamivir.[42] Peramivir was well-tolerated, and the 56-day survival rate was 59%. Peramivir gained full FDA approval in 2014 for treatment of acute uncomplicated influenza in patients who have been symptomatic for less than 2 days. 

Oseltamivir (Tamiflu)

Inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, decreases release of viruses from infected cells and thus viral spread. Effective to treat influenza A or B. Start within 40 h of symptom onset. Available as 30-mg, 45-mg, and 75-mg oral capsules and as a powder for suspension that contains 12 mg/mL after reconstitution.

Zanamivir (Relenza)

Inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, release of viruses from infected cells and viral spread are decreased. Effective against both influenza A and B. Inhaled through Diskhaler oral inhalation device. Circular foil discs containing 5-mg blisters of drug are inserted into supplied inhalation device.

Individuals with asthma or other respiratory conditions that may decrease ability to inhale the drug should be given oseltamivir (eg, asthma, pregnancy). Severe respiratory failure caused by H1N1 influenza has been reported in the southern hemisphere during July and August 2009; therefore, in severely ill patients, the ability to inhale zanamivir may be impaired.

Peramivir (Rapivab)

Elicits antiviral activity by inhibiting influenza virus neuraminidase, an enzyme that releases viral particles from the plasma membrane of infected cells. It is indicated for treatment of acute uncomplicated influenza in patients aged 6 months and older who have been symptomatic for less than 2 days. 

Class Summary

Influenza vaccine is administered each year before flu season. The vaccines may contain either 3 virus strains (2 influenza A and 1 influenza B) or 4 virus strains (2 influenza A strains and 2 influenza B strains), which antigenically represent the influenza strains likely to circulate the next flu season, in the formulation each year. The US Food and Drug Administration (FDA) makes the final decision about vaccine strains for influenza vaccines to be sold in the United States, based on year-round surveillance conducted by the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).

Influenza virus vaccine trivalent (Fluzone, Agriflu, Flucelvax, Fluarix, Fluvirin, Fluzone High-Dose, Fluzone Intradermal)

Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The FDA determines influenza vaccine contents annually. Carefully check the indications and age ranges for various brands of influenza vaccine. For example, Fluzone is approved for children as young as 6 months, whereas Fluvirin is approved for children aged 4 years or older. Fluzone High-Dose is specifically formulated to provide a higher antigen content to evoke a stronger immune response in patients aged ≥65 years.

Influenza virus vaccine quadrivalent (Afluria Quadrivalent, Fluarix Quadrivalent, Flucelvax Quadrivalent)

Quadrivalent vaccines contain 2 strains of influenza A and 2 strains of influenza B. The vaccine induces antibodies specific to virus strains contained in the vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season. It is administered as an IM injection and approved for adults and children 3 years or older.

Influenza virus vaccine trivalent, recombinant (Flublok)

This vaccine is made from recombinant hemagglutinin proteins that are not derived from egg or chick embryo. Influenza vaccine is indicated for active immunization to prevent infection from influenza A and B viruses. The vaccine induces antibodies specific to virus strains contained in the vaccine. The US Public Health Service determines influenza vaccine contents annually. Typically, 3 live attenuated virus strains, which antigenically represent the influenza strains likely to circulate the next flu season, are included in the formulation each year. It is administered as an IM injection and approved for adults aged 18-49 years.

Influenza virus vaccine quadrivalent, recombinant (Flublok Quadrivalent)

This vaccine is made from recombinant hemagglutinin proteins that are not derived from egg or chick embryo. Contains 4 viral strains (2 influenza A strains and 2 influenza B strains), which antigenically represent the influenza strains likely to circulate the next flu season.

Influenza virus vaccine trivalent, adjuvanted (Fluad)

Contains 3 viral strains (2 influenza A and 1 influenza B) which antigenically represent the influenza strains likely to circulate the next flu season, in the formulation each year.

Influenza virus vaccine quadrivalent, intranasal (FluMist Quadrivalent)

Discontinued for 2016/2017 Northern Hemisphere season because of low efficacy during several preceding years. The intranasal influenza vaccine is indicated for active immunization to prevent influenza A and B viruses in healthy children, adolescents, and adults. Quadrivalent vaccines contain 2 strains of influenza A and 2 strains of influenza B. The vaccine induces antibodies specific to virus strains contained in the vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season.