Treatment approach

In the 2009 H1N1 influenza pandemic, most cases were mild and did not require treatment, with the exception of the early cases in Mexico. The reason for this disparity is not known.

With seasonal influenza, the use of neuraminidase inhibitors (oseltamivir, zanamivir) seems to confer a relatively modest benefit in terms of decreasing the duration of symptoms in outpatients with influenza-like illness, although the beneficial effects might be more evident in patients with confirmed influenza infection.

At the present time, treatment guidelines for 2009 H1N1 influenza essentially are those for seasonal influenza. [32] The goal of treatment is to shorten duration of symptoms, reduce risk of complications, and decrease hospital length of stay. If the availability of antiviral medications is limited, priority for treatment should be given to high-risk groups, including patients who require admission to the hospital, patients with comorbid conditions, pregnant women, and young children. The decision to treat should be based on clinical judgement in symptomatic outpatients without risk factors, if treatment can be started within 48 hours of symptom onset.

Once it is decided to treat, treatment should be given as soon as possible and should not be withheld pending test results. Ideally, treatment should be started within 48 hours of symptom onset, although hospitalised patients may benefit from treatment even if symptoms started more than 48 hours prior to admission. [56] [57] [58] One study demonstrated that initiation of treatment within the first 4 days of admission may still confer some benefit in terms of reducing severity of illness. [59]

Although oseltamivir resistance has been reported, this seems to be uncommon and should not influence treatment decisions.

Post-exposure chemoprophylaxis

The decision on whether to administer antivirals for chemoprophylaxis should be made on a case-by-case basis taking into account the exposed person’s risk for influenza complications, the type and duration of contact, recommendations from local or public health authorities, and clinical judgement.

HIV-positive patients who have been exposed to a person with an influenza-like illness or with probable or confirmed influenza should receive antiviral prophylaxis. Post-exposure antiviral prophylaxis can also be considered for pregnant women who are close contacts of people with suspected or confirmed H1N1 swine influenza virus infection. Theoretically, the drug of choice for influenza prophylaxis in pregnant women is zanamivir because of its limited systemic absorption. For women with respiratory disease (e.g., asthma) or at risk of respiratory complications, oseltamivir should be used for prophylaxis. Both drugs are classified as pregnancy category C by the Food and Drug Administration (FDA) in the US, although the limited evidence available contains no reports of adverse maternal events. In addition, it should be noted that oseltamivir is the drug of choice for treatment. Chemoprophylaxis for at-risk children depends largely on age. Zanamivir is FDA-approved for children ≥5 years of age while oseltamivir is approved for children ≥1 year of age. An emergency use authorisation (EUA) was issued by the FDA for the use of oseltamivir in children <1 year of age. This EUA expired June 23, 2010. [60] During this period chemoprophylaxis for infants aged <3 months was not recommended unless the exposure situation was critical because of lack of data on the use of oseltamivir in this age group. [32]

The recommended duration of chemoprophylaxis is for 7 to 10 days after the last known exposure. [32] For control of outbreaks in long-term care facilities and hospital settings, antiviral chemoprophylaxis is recommended for a minimum of 2 weeks and up to 1 week after the last known case has been identified. [32] Chemoprophylaxis is not recommended if >48 hours have elapsed since the last contact with an infectious individual.

Previously healthy children and adults, 5 to 64 years of age

In cases of mild illness, where symptoms can be managed in the outpatient setting, supportive care is recommended, with oral fluids and antipyretics. Children (<18 years of age) should not be given aspirin-containing medications when suspected of having H1N1 influenza A (or any viral) infection because of the risk of developing Reye's syndrome.

In more severe cases (with severe symptoms or if admission to the hospital is required), active treatment with antiviral agents is recommended. Although treatment is most effective when started early (within 48 hours of symptom onset), studies of seasonal influenza suggest that patients admitted to the hospital may still benefit from treatment started beyond 48 hours. [61] [32] Available agents are oseltamivir and zanamivir. Zanamivir is inhaled, so oseltamivir is the preferred treatment for patients with significant respiratory problems, such as asthma.

During the 2009 pandemic, the FDA in the US issued an EUA allowing the use of IV peramivir for hospitalised patients with severe cases of pandemic influenza that had failed to respond to oral or inhaled therapy, or in cases where IV administration was deemed to be preferable over other routes of administration (e.g., suspected poor oral absorption). The EUA was terminated in June 2010. [60] However, the drug continues to be tested in phase III clinical trials.

Previously healthy children <5 years of age

Children younger than 5 years of age, particularly those 2 years of age or younger, are at increased risk for complications of influenza infection. In this group, treatment with oseltamivir is recommended for symptom onset within 48 hours. Zanamivir is not recommended for this age group and is only approved for treatment in children aged ≥7 years.

For children <1 year of age, the safety of oseltamivir is unknown, although the available data suggest that oseltamivir has a relatively low rate of serious adverse events in this age group. [61] [32] Reports from the 2009 H1N1 pandemic suggest that aside from gastrointestinal symptoms, oseltamivir was well tolerated among this age group. [44] [62]

Children should not be given aspirin-containing medication when suspected of having H1N1 influenza A (or any viral) infection because of the risk of developing Reye's syndrome.

Breastfeeding infants should continue to be breastfed, because maternal antibodies may confer some degree of protection. If the mother is ill, breast milk should, if possible, be expressed and bottle-fed to the infant.

Patients admitted to the hospital

All patients admitted to the hospital with influenza-like illness or with probable or confirmed influenza should receive treatment regardless of when symptom onset occurred. Treatment should be given as soon as possible and should not be withheld pending test results.

Adults at high risk of influenza complications

All adults in high-risk categories should receive antiviral treatment. [32] Treatment should be given as soon as possible, and should not be withheld pending test results.

Groups at risk of complications include:

• People >65 years of age

• Pregnant women

• Residents of nursing homes or chronic-care facilities

• People with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, haematological (including sickle cell disease), metabolic (including diabetes mellitus), or neurological and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)

• People with immunosuppression, including that caused by medications or by HIV infection

• People aged <19 years who are receiving long-term aspirin therapy

• American Indians/Alaska Natives

• People who are morbidly obese (i.e., BMI ≥40).

All patients with chronic malnutrition or conditions that place them at risk for malnutrition with influenza-associated anorexia should be treated.

All HIV-infected adults with influenza-like symptoms should receive antiviral treatment.

High-risk children

In addition to children <5 years of age, older children with developmental disabilities and chronic medical conditions, particularly chronic neurological or neuromuscular and congenital metabolic disorders (who cannot tolerate anorexia associated with influenza illness), and patients <19 years of age who are receiving long-term aspirin therapy are at higher risk for complications.

HIV-infected adolescents with influenza-like symptoms should receive antiviral treatment.

Pregnant women

It is recommended that all women who are pregnant or within 2 weeks postpartum with influenza-like illness receive treatment. The recommendation to treat is based on observations from previous pandemics and from interpandemic seasonal influenza outbreaks, when an increased risk of death and adverse pregnancy outcomes were reported. Because the risks of infection are high and the apparent risk of treatment is low among pregnant women, pregnancy is not considered a contraindication to treatment. Because of its systemic activity, the drug of choice is oseltamivir. [63]

Fever should be treated promptly because of the association between hyperthermia and adverse outcomes from pregnancy, including birth defects. [64] The drug of choice is paracetamol.

Neuraminidase-resistant strains

Very few cases of neuraminidase resistance have been reported among H1N1 2009 strains of influenza A. Most are associated with an H275Y mutation and, to a lesser extent, an S247N mutation. [65] [66] The former confers resistance to only oseltamivir while the later confers resistance to both oseltamivir and zanamivir. Because the incidence of oseltamivir resistance is only 2.6%, it should not influence treatment decisions in patients with confirmed swine influenza at this time. [67] However, clinical selection criteria for antiviral susceptibility testing have been proposed and may become useful in the future. These include: [68]

• Failed therapy

• Positive test for influenza A while receiving or after receiving prophylaxis

• Positive test for influenza A in a patient returning from an area where resistance is endemic

• Persistent infection in an immunocompromised host

• Nosocomial transmission in clinical areas with immunocompromised hosts

• Positive test from a case in contact with immunocompromised host.

Oseltamivir resistance rates among seasonal influenza strains, on the other hand, are variable and generally increasing. The antiviral regimen should be tailored according to local resistance patterns among patients with influenza infection in whom a specific strain cannot be determined.