Influenza Treatment & Management

Prehospital care is predominantly supportive. Supplemental oxygenation to manage respiratory symptoms or objective hypoxia may be needed. Ventilatory support with a bag-valve-mask device and/or with field intubation may be required if the patient is in respiratory failure. Intravenous access should be obtained, and a bolus of a crystalloid can be administered to support hemodynamic stability.

Attention should be given to the appropriate use of personal protective equipment (PPE) by the prehospital providers and advance notification should be given to the hospital regarding the potential need for patient respiratory isolation. General guidelines in low-risk areas are that patients with fever and respiratory complaints should wear a standard mask, if tolerated, to decrease airborne droplets.

Most frequently, hospitalization is necessary when influenza exacerbates underlying chronic diseases. Some patients, especially elderly individuals, may be too weak to care for themselves alone at home.

On occasion, the direct pathologic effects of influenza may require hospitalization. Most commonly, this is influenza pneumonia.

As with other diseases, prevention of influenza is the most effective strategy. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) publishes recommendations for high-risk groups, including all health care personnel, who should be vaccinated.

Public health measures are effective in limiting influenza transmission in closed environments.^[32] Enhanced surveillance with daily temperature taking and prompt reporting with isolation through home medical leave and segregation of smaller subgroups decrease the spread of influenza. In one study, symptomatic illness attributable to influenza decreased from 12% to about 4% with the use of these measures.^[33]

The ACIP also publishes recommendations on the use of antiviral agents for prevention and treatment of influenza.^[34]

In the United States, 4 prescription antiviral drugs (oseltamivir, zanamivir, amantadine, rimantadine) are approved for treatment and chemoprophylaxis of influenza. Since January 2006, only the neuraminidase inhibitors (oseltamivir, zanamivir) have been recommended because of widespread resistance to the adamantanes (amantadine, rimantadine) among influenza A (H3N2) virus strains. The neuraminidase inhibitors have activity against influenza A and B viruses (including H1N1), while the adamantanes have activity against influenza A viruses only.

Oseltamivir (Tamiflu) resistance emerged in the United States during the 2008-2009 influenza season. In 2007-2008, a significant increase in the prevalence of oseltamivir resistance was reported among influenza A (H1N1) viruses worldwide. During the 2007-2008 influenza season, 10.9% of H1N1 viruses tested in the United States were resistant to oseltamivir.

Oseltamivir is taken orally (75 mg bid), and zanamivir [Relenza] is taken via an inhalation apparatus (10 mg bid for 5 d). Multiple studies have demonstrated their efficacy. These agents work by inhibiting influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus envelope; this spike is needed for successful cellular release of virus and transmission within the body.

To be effective, these agents must be administered within 40 hours of symptom onset. For critically ill patients with H5N1 infection, evidence suggests that initiation of oseltamivir up to 6-8 days from onset of symptoms may reduce the mortality rate.^[35]

Studies also demonstrate the efficacy of these agents in preventing influenza A and B. The prophylactic dose is one half the acute treatment dose.

In a study of 445 patients by the Management of Influenza in the Southern Hemisphere Trialists (MIST) group 1, zanamivir reduced the duration and severity of illness.^[36] Zanamivir was administered to one half of patients and placebo to the others within 36 hours of symptom onset. Duration of the flu was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk groups. A significant decrease in the severity of illness in patients treated with zanamivir allowed them to resume normal activities much sooner.

A placebo-controlled study of oseltamivir by Treanor et al demonstrated the ability of that agent to decrease the duration and severity of influenza.^[37] This analysis included patients with laboratory-based diagnoses of influenza and those with clinical diagnosis based on symptoms. The 629 patients were enrolled and randomized into 1 of 3 treatment arms: (1) standard-dose oseltamivir, (2) high-dose oseltamivir, and (3) placebo. In both oseltamivir groups, the mean illness duration was reduced from 103 to 70 hours. The symptom severity decreased in the treated group by 40%.

Additional studies have demonstrated the benefit of neuraminidase inhibitors both in acute disease and in prevention. In a study of 837 relatives of family members infected with influenza, 20% of those treated with placebo became ill, compared with only 4% of those who received prophylactic zanamivir.^[38] In addition, this study provided treatment to the index case family member, resulting in a 2.5-day reduction in illness over placebo. Recombinant DNA viral sequences were performed in this study, and no resistant influenza strains developed.

A novel study documented the prophylactic and therapeutic effects of oseltamivir in experimentally induced influenza in humans.^[39] In a controlled laboratory environment, volunteers were inoculated intranasally with influenza A/Texas/36/91 (H1N1). In the prophylaxis arm of the study, subjects received either oseltamivir or placebo 26 hours before virus inoculation; in the treatment arm, subjects received oseltamivir or placebo 28 hours after inoculation.

In the prophylactic group, 38% of patients developed influenza, versus which 67% in the placebo group. In the treatment group, oseltamivir reduced the duration of illness from 95 to 53 hours and reduced the severity reduced by 50%, compared with placebo.^[39]

Hayden et al also documented the prophylactic efficacy of oseltamivir. In this study, 1559 healthy nonimmunized patients were treated with either placebo or oseltamivir for 6 weeks; at the end of the period, 4.8% of the placebo group had laboratory-confirmed influenza, compared with only 1.2% of the oseltamivir group.^[40]

In a randomized, double-blind, placebo-controlled trial of children aged 1-3 years (n=408) with influenza A or B, Heinonen et al found that oseltamivir decreased the incidence of acute otitis media by 85% when treatment began within 12 hours of symptom onset. When treatment began within 24 hours of symptom onset, no significant reduction in incidence of acute otitis media was observed.^[41]

When oseltamivir treatment started within 24 hours for children with influenza A, the median time to resolution of illness was decreased by 3.5 days in all children and reduced parental work absenteeism by 3 days. Efficacy was not demonstrated against influenza B infections.^[41]

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.^[42]

Lam et al suggested that cases of suspected severe influenza infection should be treated early and aggressively, even before diagnostic tests can be confirmed.^[43] In their study, a higher dose of oseltamivir and nonconventional methods of ventilation improved outcome in patients with pandemic H1N1 2009 infection.

Whether to prescribe one of the newer neuraminidase inhibitors should depend on the patient, the probable type of influenza involved (A or B), and the potential benefit. Advantages for prescribing these agents include significantly reducing illness severity and duration. In elderly and high-risk patients who receive these agents, the secondary complications of influenza are also decreased.

Disadvantages include potential adverse effects and costs. Some patients may be willing to pay $100 to have a less severe episode of the flu. Adverse effects include potential bronchospasm with inhaled zanamivir and nausea, vomiting, and headache from oseltamivir. The bronchospasm associated with zanamivir has received attention from national media. Until more data are available, physicians should not prescribe zanamivir to patients prone to bronchospasm.

Although oseltamivir is approved for use up to 48 hours after the initiation of symptoms, one study suggested that the most significant effect occurs when taken within 6 hours of symptom onset and only limited effects when therapy is begun more than 24 hours after symptom onset.

Probenecid, a uricosuric, approximately doubles the effective dose of oseltamivir by disrupting renal excretion of the drug and may have a role in a pandemic or in severe infections.^[44] No studies have yet been performed to confirm the appropriate dosing regimen in this situation.

Antiviral drug recommendations

The CDC has made the following recommendations regarding the use of antiviral drugs in influenza^[34] :

• Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization
• Antiviral treatment is recommended as soon as possible for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions; clinical judgment should be an important component of outpatient treatment decisions
• Recommended antiviral medications include oseltamivir and zanamivir
• Oseltamivir may be used for treatment or chemoprophylaxis of influenza among infants younger than 1 year, when indicated
• Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset.
• Because antiviral resistance patterns can change over time, clinicians should monitor local antiviral resistance surveillance data

Investigational antiviral agents

Investigational antiviral agents for influenza include laninamivir octanoate and peramivir. In a double-blind, randomized controlled trial, the median time to illness alleviation with a 40-mg dose of laninamivir octanoate was similar to that with oseltamivir. A single inhalation of laninamivir octanoate is effective for the treatment of seasonal influenza, including that caused by oseltamivir-resistant virus, in adults.^[45]

A single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, time to alleviation of symptoms was significantly reduced compared with that of placebo.^[46]

Treatment of avian influenza

Initial interventions depend on the severity of the presenting illness. Administration of neuraminidase inhibitors is currently the only specific therapy for human H5N1 disease. Early administration agent appears to be critical for clinical benefit. Because diagnostic uncertainty is likely, management may include the administration of broad-spectrum antibiotics and aggressive fluid resuscitation to manage clinical signs of sepsis.

Guidelines from the World Health Organization (WHO) from 2007 recommend therapy regimens with a neuraminidase inhibitor, preferably oseltamivir.^[47] Studies are ongoing as to the relative effectiveness of high-dose and/or prolonged courses of therapy with oseltamivir.^[26] If high-dose regimens prove to be more effective, the availability of antiviral medication in the event of a massive outbreak, as well as treatment considerations for mildly versus severely ill people, would be affected.

Although most H5N1 influenza cases are resistant to amantadine or rimantadine (reflecting mutations in the M2 gene segment^[2] ), combination therapy is recommended unless the patient was exposed in an area known to contain virus strains resistant to the other antiviral agents. Treatment failures due to resistance to single-drug oseltamivir regimens have been reported.^[26]

Zanamivir has not yet been tested in people with H5N1 disease, but animal studies are promising and the resistance mutations to oseltamivir do not cause cross-resistance. Some researchers have recommended dual therapy with both existing neuraminidase inhibitors. One concern is that inhaled zanamivir is unlikely to reach distal airways in severe disease.^[26]

Two experimental drugs exist; arbidol is available in China and Russia, and peramivir is still being studied. Neither is yet available in the United States.

Steroids have not been shown to be beneficial, except perhaps in the setting of septic shock with adrenal insufficiency.^[26]

Supportive care such as oxygen therapy, intravenous fluids, and parenteral nutrition may be needed. Severe cases may require ventilatory support with intubation and low-volume (high-frequency) ventilation.

Infection control and prevention of transmission to other patients and health care workers are important. Droplet precautions should be used, including eye protection. No evidence shows that airborne spread is possible, but if fine aerosols are expected because of specific procedures, a particulate respirator should be properly fitted and used.

Adults and children older than 12 years require 1 week of infection-control precautions, from the initial onset of symptoms. Children younger than 12 years may shed high titers of human influenza virus for up to 21 days after the illness onset, and the World Health Organization (WHO) recommends the same duration for avian influenza precautions.^[26]

If proper handling of biologic specimens can be ensured, repeat studies of the viral load, susceptibilities, and drug levels can be used to monitor the response to therapy.

Patients with influenza generally benefit from bed rest.

Most patients with influenza recover in 3 days; however, malaise may persist for weeks.

Influenza vaccine provides good protection against immunized strains. The vaccination becomes effective 10-14 days after administration.

Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during the winter flu season is produced. Two strains of influenza A and one of influenza B are included. For example, during 2010-2011, recommended components were an A/California/7/2009 (H1N1)–like virus (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens.^[48]

The vaccine is available in a variety of dosage forms. The intramuscular injection contains 45 mcg of hemagglutinin of influenza per 0.5 mL and utilizes a 1- to 1.5-inch needle. A microinjection system for intradermal delivery (Fluzone Intradermal) is now available in the United States and features an ultrafine needle that is 90% shorter than the typical needle used for IM injections. The intradermal dosage form contains 27 mcg/0.1 mL of influenza hemagglutinin.

Influenza vaccine is also available as a nasal spray (FluMist) for healthy children aged 2 years or older, adolescents, and adults aged younger than 50 years. Clinical trials are limited in scope regarding the protective effects of live vaccine. The live virus is attenuated by cold; therefore, only very limited viral replication occurs at temperatures of more than 95°F.

The FDA approved a quadrivalent form of the vaccine (FluMist Quadrivalent) in March 2012. Like the already approved FluMist (trivalent), the quadrivalent vaccine contains weakened forms of the virus strains and is administered as a spray into the nose. However, this new formulation includes a second B strain, which increases the likelihood of adequate protection against circulating influenza B strains. The recommended components for this vaccine include A/California/7/2009 (H1N1)–like virus (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Yamagata/16/88 and B/Victoria/2/87. Additional quadrivalent seasonal influenza vaccines are pending FDA-approval.

Specific recommendations for individuals who should be immunized can be obtained from the CDC, which publishes regular updates of this information (see Seasonal Influenza Vaccination Resources for Health Professionals). Groups recommended for immunization include elderly individuals, those with certain chronic diseases, and health care workers. The vaccination of high-risk pregnant patients also provides some protective immunity for newborns and reduces subsequent hospitalizations in the infants.^[49]

A recent CDC analysis stresses 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.^[42]

It is safe to administer attenuated influenza vaccine in children with cancer.^[50]

Early use of glucocorticoids

Although glucocorticoids increase the risk of developing critical disease from viral infections, primary care practitioners in China use them as antipyretics, potentially exposing hundreds of millions to this risk. In one retrospective study from China the absolute risk increase was 32% for critical illness in patients who received steroids. Using glucocorticoids to reduce fever and prevent pneumonia increases the risk for critical disease or death from pH1N1 infection.^[51]

Prevention in elderly persons

In order to improve the immunogenicity of influenza virus vaccine in elderly adults, a high-dose trivalent inactivated influenza vaccine has been developed. In a multicenter, randomized, double-blind controlled trial in elderly adults (≥65 y), a statistically significant increase in seroconversion rate was found in those who received the high-dose vaccine (n=2575) compared with the standard-dose vaccine (n=1262).^[52]

The high-dose vaccine met superiority criteria for both strains of influenza A, and noninferiority criteria were met for influenza B strains. Seroprotection rates were higher for the high-dose vaccine compared with the standard-dose vaccine. The authors suggest that the high-dose vaccine may provide improved immunity for elderly adults.^[52]

Dual vaccination with pneumococcal and influenza vaccine is effective in protecting elderly persons with chronic illness from developing complications due to respiratory, cardiovascular, and cerebrovascular diseases, thereby reducing hospitalization, coronary or intensive care admissions, and death.^{[53, 54]}

Woods et al found that, in sedentary older adults, cardiovascular exercise extends influenza vaccine seroprotection. A randomized controlled trial in 144 sedentary but healthy older (age 69.9 +/- 0.4 y) adults who underwent either cardiovascular exercise or flexibility and balance training showed that peak (3 and 6 wk) postvaccine anti-influenza hemagglutination inhibition (HI) titers were similar in both groups, but participants randomized to cardiovascular exercise were significantly more likely to have seroprotective HI titers at 24 weeks, suggesting enhanced influenza seroprotection throughout the entire influenza season.^[55]

Prevention of avian influenza

Some data from animal studies suggest that the standard inactivated influenza vaccine may confer some partial immunity toward avian influenza. Therefore, recommendations are that poultry workers receive annual influenza vaccination to prevent illness and to prevent viral reassortment through simultaneous infection with the two types of influenza.

No avian influenza vaccine is currently available to the public, although various products are in clinical trials and appear immunogenic. One complication is that the highly pathogenic viruses cannot be easily grown using the traditional embryonated chicken egg method, as the embryos often die during incubation.

Alternative methods for producing immunogenic particles include tissue culture and reverse-genetic approaches using recombinant viruses. One option for increasing the immunogenicity (and hence potentially lowering the dose needed to vaccinate) is to use an adjuvant agent such as aluminum hydroxide. All of these methods are being evaluated for an avian influenza vaccine.

An H5N1 monovalent killed-virus vaccine produced by Sanofi-Pasteur has been approved by the FDA in the United States but is available only to government agencies and for stockpiles.^[56] It is derived from the influenza A/Vietnam/1203/2004 strain isolated from humans, and is a formalin-inactivated/detergent-disrupted, purified virus grown in embryonated chicken eggs.

The vaccine was approved based on a limited safety and immunogenicity study of 500 adults aged 18-64 years. Fewer than half of those receiving the highest dose of vaccine responded and achieved antibody titers expected to be fully effective (ie, hemagglutination inhibition antibody titers >1:40) based on experience with seasonal influenza. The vaccine contains thimerosal (unlike many other seasonal influenza vaccines) because of the need for multidose vials.^[57]

In a study of vaccination against Vietnamese- and Indonesian-origin H5N1 strains using a prime-boost strategy, which included 491 subjects, optimal antibody titers required at least a 14-day interval between doses, and results were no better at 28 days.^[58]

Some cross-reactivity was documented, but this was minimal at 1 month and was much better when 6 months had elapsed between doses. Although the use of a 6-month interval between vaccine doses is questionable in the setting of a pandemic, the authors suggest that priming at-risk individuals with an antigenically distant H5 influenza vaccine may have some effect in reducing the need for a 2-dose series later on.^[58]

A newer recombinant H5N1 vaccine is also available from the WHO.^[59] The CDC provides additional information about Avian Influenza Vaccines.

Avian influenza and travelers

Because avian influenza is rare in humans, the CDC does not currently recommend against travel to any country affected by H5N1.

Prophylactic antivirals are not indicated for patients who plan to travel to areas where avian influenza has been reported. Travelers who plan to travel to areas of the world affected by avian influenza outbreaks in birds and/or humans are advised to avoid close contact with poultry, especially diseased or dead birds, and to consume only adequately cooked meat.

If contact with birds in enclosed spaces is unavoidable, an N-95 respirator mask (or equivalent), gloves, and goggles should be used to minimize contact with droplets or particulates. For additional information, see the Avian Flu Travel Information from the CDC.

Controlling H5N1 influenza in birds

At present, highly pathogenic H5N1 avian influenza is predominantly a disease of birds. However, controlling the disease in birds is important because of its potential economic effects on poultry farming. Control may also decrease the opportunity for a pandemic flu strain to emerge. In addition, control of the H5N1 strain in birds decreases the likelihood of direct human exposures to infected birds and, thus, zoonotic cases in humans.

Control methods include the following:

• Culling of infected and exposed birds
• Sanitation
• Quarantine

In the 1997 outbreak of H5N1 disease in Hong Kong, aggressive government-ordered culling of chickens is believed to have limited the initial expansion and spread of the virus. Vietnam is similarly praised for having more success than its adjacent countries in containing the disease with aggressive testing and culling of poultry.

Proper disposal of carcasses and bird excrement are critical in limiting bird-to-bird and bird-to-human spread of disease. High concentrations of virus have been demonstrated in droppings obtained from chickens infected with H5N1. Bathing in water contaminated with droppings is suspected to be one mechanism of human exposure. In economically poor, rural settings, death of individual chickens is common, and H5N1 illness may be frequently unrecognized and unreported.

In the past, strict quarantining of commercial farms has limited the spread of highly pathogenic avian influenza virus (HPAIV) strains other than H5N1. Today, the importation of any bird from affected countries is prohibited. Quarantines work relatively poorly in rural settings, where animals are allowed to run free among human living quarters and between farms. Furthermore, the presence of H5N1 in wild birds, especially migratory species, limits the extent to which quarantining can be effective over the long term.^[12]

Containing pandemic influenza

Preparedness for pandemic influenza is widely considered to be grossly inadequate. The following 5 areas are important to managing a surge in severe illness^[60] :

• Surveillance and diagnostic services
• Information sharing and dissemination
• Community support
• Hospital and physician capacity
• Availability of vaccines and drugs

Even in the absence of a pandemic illness, the lack of capacity in US emergency departments has been described as a crisis by the Institute of Medicine. For more information about preparedness for epidemic influenza, see the WHO Global Influenza Preparedness Plan.

Consultation with an infectious disease specialist is prudent in some cases of seasonal influenza. Intensive care specialists need to be involved to manage severe disease.

In suspected H5N1 influenza, a pulmonary specialist, a critical care specialist, an infectious disease specialist, and the staff of the local public health department may all be consulted. Clinical laboratory personnel should also be informed before potential H5N1 isolates are sent to them. In addition, hospital infection-control officers should be involved early in the care of any patient who might have avian flu. Ultimately, the WHO and/or CDC should be contacted; the CDC can safely perform serotyping for suspected avian influenza strains.

Early involvement of the local public health department and hospital infection control is necessary to contain any outbreaks.

Patients with influenza who do not improve should return for further evaluation. Patients diagnosed with influenza should be educated about potential complications and encouraged to return for evaluation if concerned. This is especially true of patients with underlying chronic disease or those who are immunocompromised.