174 Treatment and Prophylaxis

disease in Southeast Asia are resistant against amantadine and rimantadine (Peiris 2004, Le 2005), while isolates from strains circulating in Indonesia and, more recently, in China, Mongolia, Russia, Turkey and Romania are amantadine sensitive (Hayden 2005).

Recently, adamantanes have come under pressure, since it was discovered that 91 % of influenza A H3N2 viruses, isolated from patients in the US during the current influenza season, contained an amino acid change at position 31 of the M2 protein, which confers resistance to amantadine and rimantadine. On the basis of these results, the Centre for Disease Control recommended that neither amantadine nor rimantadine be used for the treatment or prophylaxis of influenza A in the United States for the remainder of the 2005–06 influenza season (CDC 2006). Some authors have suggested that the use of amantadine and rimantadine should be generally discouraged (Jefferson 2006).

Indications for the Use of M2 Inhibitors

Comparative studies indicate that rimantadine is tolerated better than amantadine at equivalent doses (Stephenson 2001). The advantage of amantadine is that it is cheap, 0.50 €/day in some European countries, compared to 5 €/day for rimantadine and 7 €/day for oseltamivir.

Treatment of “Classic” Human Influenza

In uncomplicated cases, bed rest with adequate hydration is the treatment of choice for most adolescents and young adult patients. If needed, treatment with acetylsalicylic acid (0.6–0.9 g every 3–4 hours) may be considered – headache, fever, and myalgia usually improve within hours. However, salicylates must be avoided in children of 18 years or younger because of the association of salicylate use and Reye’s syndrome. In these cases, acetaminophen or ibuprofen are common alternatives.

Nasal obstruction can be treated with sprays or drops, and cough with water vaporisation. Cough suppressants are needed only in a minority of patients. After the fever subsides, it is important to return to normal activity gradually. This is particularly true for patients who have had a severe form of the disease.

Antibiotic treatment should be reserved for the treatment of secondary bacterial pneumonia. Ideally, the choice of the drug should be guided by Gram staining and culture of respiratory specimens. In daily practice, however, the aetiology cannot always be determined, and so treatment is empirical, using antibacterial drugs effective against the most common pathogens in these circumstances (most importantly S. pneumoniae, S. aureus, and H. influenzae).

In more severe cases, supportive treatment includes fluid and electrolyte control, and finally supplemental oxygen, intubation, and assisted ventilation.

For more detailed information about the management of human H5N1 influenza, please see below.

Treatment of “Classic” Human Influenza 175

Antiviral Treatment

Oseltamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients aged 1 year and older, who have been symptomatic for no more than 2 days. The recommended duration of treatment with oseltamivir is 5 days (but may be longer in severe H5N1 infection). A 7-day course of oseltamivir is also indicated for the prophylaxis of influenza in the same age group (EU: ≥ 13 years).

Zanamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients aged 7 years and older and who have been symptomatic for no more than 2 days. With the exception of two countries, zanamivir has not been licensed for prophylactic use. The treatment duration is usually 5 days.

Rimantadine and amantadine are ineffective against the influenza B virus and are, therefore, indicated for prophylaxis and treatment of illness caused by influenza A virus only. To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine treatment should be discontinued as soon as clinically warranted, typically after 3–5 days of treatment or within 24–48 hours after the disappearance of signs and symptoms (CDC 2005).

Please note, that in the US, the CDC has recommended that neither amantadine nor rimantadine be used for the treatment or prophylaxis of influenza A in the United States for the remainder of the 2005–06 influenza season (CDC 2006).

Antiviral Prophylaxis

Several studies have shown neuraminidase inhibitors to be effective in preventing clinical influenza in healthy adults following exposure to close contacts (Hayden 2000, Welliver 2001, Hayden 2004). They have also been used in seasonal prophylaxis (Monto 1999, Hayden 1999). In all these studies, neuraminidase inhibitors are 70 to 90 percent effective in preventing clinical disease caused by influenza A and B infection. With the exception of two countries, oseltamivir is the only neuraminidase inhibitor currently approved for prophylactic use. The adamantanes may be considered for prophylaxis if the circulating strain is influenza A.

Cost, compliance, and potential side effects must all be considered when deciding on the timing and duration of antiviral prophylaxis against influenza infection. To be effective as seasonal prophylaxis, the drugs should be taken throughout the entire period of a community outbreak, generally over 6 weeks. This approach might not be cost-effective, especially when compared to annual vaccinations (Patriarca 1989).

In a pandemic situation, there may even be fewer opportunities for prophylaxis if the next pandemic strain is resistant to M2 inhibitors (as was the case with certain serotypes of the H5N1 strain circulating in Southeast Asia in 2004 and 2005), and if neuraminidase inhibitors continue to be in short supply. If this happens, most of the available drug will probably be reserved for treatment, and prophylaxis might be limited to target groups with enhanced risk of exposure (health personnel, etc.).

176 Treatment and Prophylaxis

In seasonal influenza, prophylaxis should be considered in the following situations (adapted from CDC 2005):

•Persons at high-risk who are vaccinated after influenza activity has begun

When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis for 2 weeks should be considered for persons at high risk. Children aged < 9 years, receiving influenza vaccine for the first time, may require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose).

•Persons who provide care to those at high risk

Healthcare personnel, if infected with influenza virus, can spread the disease. During the peak of influenza activity, prophylaxis with antiviral drugs can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status.

•Persons who have immune deficiencies

Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to the influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease.

•Other persons

Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated.

•Institutions that house persons at high risk

There are several lines of evidence that institution-wide prophylaxis in nursing homes, given as soon as possible after influenza activity is detected, might be a valuable addition to institutional outbreak-control strategies (Peters 2001, Bowles 2002, Monto 2004). When confirmed or suspected outbreaks of influenza occur, chemoprophylaxis should, therefore, be started as early as possible, administered to all residents, regardless of whether they received influenza vaccinations during the previous fall, continued for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine.