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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza



Treatment and Prophylaxis

C. Hoffmann, S. Korsman and B.S. Kamps



- Green links: Free full-text articles -

Most patients with uncomplicated human influenza, especially adolescents and young adults, can be treated symptomatically and need no specific intervention. In the elderly, however, treatment with antiviral drugs is a good option. These drugs should further be considered for high-risk individuals, especially patients with underlying medical conditions, as well as in a number of special situations.

Neuraminidase inhibitors are effective against all variants that have caused disease in humans, including the virus of the 1918 pandemic (Tumpey 2005). In human H5N1 influenza, treatment with an oral neuraminidase inhibitor, oseltamivir, seems to be effective in some cases, but may fail in others. Recently, resistant strains have been reported (de Jong 2005). In addition, the dosage and duration of treatment appear to be different in severe H5N1 cases.

In the case of a future pandemic, antiviral drugs may play an important role in the early phase, when vaccines against the new strain are not yet available or as long as the available vaccine is in short supply.

Antiviral Drugs

Of the four antiviral drugs currently available for the treatment of influenza A infection (two neuraminidase inhibitors and two M2 ion channel inhibitors), only the neuraminidase inhibitors oseltamivir and zanamivir are also active against influenza B. All drugs are most effective if started within a few hours of the onset of symptoms and are generally licensed for use within 48 hours of the first symptoms. They can modify the severity of illness, as well as reducing the intensity of influenza symptoms and decreasing the duration of illness by about 1 to 3 days. However, the extent to which antiviral treatment leads to a reduction of serious complications and hospitalisation is still subject to debate. Treatment success is, in part, a variable of the time between the onset of symptoms and the beginning of antiviral treatment: the sooner after onset treatment begins, the better.

The neuraminidase inhibitors, oseltamivir and zanamivir, have fewer side effects than the M2 ion channel inhibitors rimantadine and amantadine, and drug resistance seems to develop less frequently. The clinical pharmacology, adverse effects and resistance profiles of these drugs are discussed in detail in the Drugs chapter.

The neuraminidase inhibitor, oseltamivir (Tamiflu®), is currently the drug of choice for the treatment of human H5N1 influenza.

Neuraminidase Inhibitors

These drugs - introduced in 1999 and 2000 - interfere with the normal function of the influenza neuraminidase by mimicking sialic acid, the natural substrate of the neuraminidase (Varghese 1992, Varghese 1995). The viral neuraminidase is responsible for cleaving sialic acid residues on newly formed virions, playing an essential role in their release and facilitating virus spread within the respiratory tract. When exposed to neuraminidase inhibitors, the influenza virions aggregate on the surface of the host cell, limiting the extent of infection within the mucosal secretions (McNicholl 2001) and reducing viral infectivity (see Figure at http://content.nejm.org/cgi/content/full/353/13/1363/F1). Experimental evidence further suggests that influenza neuraminidase may be essential at the early stage of virus invasion of the ciliated epithelium of human airways (Matrosovich 2004). The design of the neuraminidase inhibitors was a result of the analysis of the three-dimensional structure of influenza neuraminidase which disclosed the location and structure of the catalytic site (Colman 1983).

Numerous treatment studies in healthy adults have shown that neuraminidase inhibitors, when taken within 36 to 48 hours after the onset of symptoms, decrease the symptomatic illness by one or two days (Hayden 1997, Monto 1999, Treanor 2000, Nicholson 2000, Hedrick 2000, Cooper 2003, Whitley 2001, Aoki 2003). Early initiation of treatment is decisive for treatment efficacy (Aoki 2003, Kawai 2005). When started within the first 12 hours following the onset of fever, neuraminidase inhibitors shortened the illness by more than three days, in comparison to treatment that was started at 48 hours. The duration of fever, severity of symptoms, and time to return to normal activity also correlated with the time of initiation of antiviral intervention.

A study in Canadian long-term care facilities showed that older nursing home residents who were treated with oseltamivir within 48 hours after the onset of symptoms were less likely to be prescribed antibiotics, to be hospitalised, or to die (Bowles 2002). Side effects were rare (4.1 %), the most common being diarrhoea (1.6 %), cough (0.7 %), confusion (0.5 %) and nausea (0.5 %). Another study suggested that oseltamivir treatment of influenza illness reduces lower respiratory tract complications, antibiotic use, and hospitalisation in both healthy and "at-risk" adults (Kaiser 2003).

Prevention trials have shown that neuraminidase inhibitors administered prophylactically reduce the risk of developing influenza by 60-90 % when given at the start of the influenza outbreak (Monto 1999b, Cooper 2003). When administered prophylactically to household contacts of an influenza index case, protective efficacy against clinical influenza was generally > 80 % (Hayden 2000, Kaiser 2000, Welliver 2001, Monto 2002).

Neuraminidase inhibitors are generally well-tolerated. Transient gastrointestinal disturbance (nausea, vomiting) is the major adverse effect of oseltamivir. In particular, the observed safety profile of oseltamivir and zanamivir compares favourably with the M2 inhibitors rimantadine and amantadine (Freund 1999, Doucette 2001).

Rarely, with oseltamivir, serious skin/hypersensitivity reactions may occur, and patients should, therefore, be cautioned to stop taking oseltamivir and contact their healthcare providers if they develop a severe rash or allergic symptoms (FDA 2005). Bronchospasm and a decline in lung function (FEV1 or peak expiratory flow) have been reported in some patients with underlying pulmonary conditions, such as asthma or chronic obstructive pulmonary disease, on zanamivir. Zanamivir is therefore not generally recommended for the treatment of patients with underlying airways disease, and should also be discontinued in patients who develop bronchospasm or who have a decline in respiratory function (Relenza 2003).

The potential for drug-drug interactions is low, both for oseltamivir and zanamivir. In oseltamivir, competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter may occur. Probenecid may more than double systemic exposure to oseltamivir carboxylate (Hill 2002).

Naturally occurring virus strains resistant to neuraminidase inhibitors are believed not to exist in human influenza A (McKimm-Breschkin 2003). In vitro, the NA mutations E119V, R292K, H274Y, and R152K were associated with resistance to oseltamivir (McKimm-Breschkin 2003). Some mutations, i.e., the R292K and H274Y mutation, lead to a functionally defective enzyme with compromised viral fitness, and it has been suggested that viruses carrying these mutations are unlikely to be of significant clinical consequence in man (Tai 1998, Carr 2002, Ives 2002, Herlocher 2004). However, a recent report describes a resistant H5N1 strain carrying the H274Y mutation causing viremia in two patients who subsequently died from avian influenza (de Jong 2005). Zanamivir seems to retain in vitro activity against some oseltamivir-resistant strains (McKimm-Breschkin 2003, Mishin 2005).

Following clinical use, the incidence of development of resistant strains is lower among adults and adolescents older than 13 years, than among children. One study found neuraminidase mutations in strains from 9/50 children (18 %) taking oseltamivir. (Kiso 2004). These findings are reason for concern, since children are an important transmission vector for the spread of influenza virus in the community. In the case of an H5N1 pandemic, the frequency of resistance emergence during oseltamivir treatment of H5N1 paediatric patients is uncertain, but it is likely to be no less than that observed in children infected with currently circulating human influenza viruses (Hayden 2005).

Neuraminidase inhibitors are effective against the virus that caused the 1918 pandemic (Tumpey 2002).

Indications for the Use of Neuraminidase Inhibitors

Oseltamivir (Tamiflu®) and zanamivir (Relenza®) are currently licensed for the treatment of influenza A and B. They should be used only when symptoms have occurred within the previous 48 hours and should ideally be initiated within 12 hours of the start of illness.

In addition, oseltamivir - but not zanamivir (with the exception of two countries) - is also licensed for prophylaxis when used within 48 hours of exposure to influenza and when influenza is circulating in the community; it is also licensed for use in exceptional circumstances (e.g. when vaccination does not cover the infecting strain) to prevent an influenza epidemic.

Oseltamivir and zanamivir seem to have similar efficacy, but they differ in their modes of delivery and tolerability. Zanamivir is delivered by inhalation and is well tolerated; however, children, especially those under 8 years old, are usually unable to use the delivery system appropriately and elderly people may have difficulties, too (Diggory 2001). Oseltamivir is taken in the form of a pill but may produce nausea and vomiting in some patients.

M2 Ion Channel Inhibitors

Amantadine and rimantadine are tricyclic symmetric adamantanamines. In the 1960s it was discovered that they inhibited strains of influenza (Stephenson 2001). They are active only against influenza A virus (influenza B does not possess an M2 protein), have more side effects than neuraminidase inhibitors, and may select for readily transmissible drug-resistant viruses.

M2 inhibitors block an ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991) and is required for viral uncoating (for more details see the Drugs chapter). Both drugs are effective as treatment if started within 24 hours of illness onset, reducing fever and symptoms by 1-2 days (Wingfield 1969, Smorodintsev 1970, van Voris 1981).

Daily prophylaxis during an influenza season reduces infection rates by 50-90 % (Dawkins 1968, Dolin 1982, Clover 1986). Post-exposure prophylaxis of households seems problematic, though. In one study, rimantadine was ineffective in protecting household members from influenza A infection (Hayden 1989).

Gastrointestinal symptoms are the major side effects associated with amantadine and rimantadine. In addition, amantadine has a wide range of toxicity which may be in part attributable to the anticholinergic effects of the drug. In addition, minor reversible CNS side effects may occur during a 5-day treatment in up to one third of patients (van Voris 1981). The same frequency of side effects was found when the drug was tested in young healthy volunteers over a four-week period. Among 44 individuals, side effects (dizziness, nervousness, and insomnia) were well tolerated by most subjects, but 6 volunteers discontinued amantadine because of marked complaints. Cessation of side effects occurred in more than half of those continuing amantadine. 16 volunteers had decreased performance in sustained attention tasks (Bryson 1980). When studied in 450 volunteers during an outbreak of influenza A, the prophylactic effects of rimantadine and amantadine were comparable. Influenza-like illness occurred in 14 % of the rimantadine group and in 9 % of the amantadine group (Dolin 1982). Withdrawal from the study because of central nervous system side effects was more frequent in the amantadine (13 %) than in the rimantadine group (6 %).

The potential for drug interactions is greater for amantadine, especially when co-administered with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. For more details see the chapter, "Drugs".

Point mutations in the M gene lead to amino acid changes in the transmembrane region of the M2 protein and may confer high-level resistance to amantadine. The genetic basis for resistance appears to be single amino acid substitutions at positions 26, 27, 30, 31 or 34 in the transmembrane portion of the M2 ion channel (Hay 1985). The mutants are as virulent and transmissible as the wild-type virus. In an avian model, they were also genetically stable, showing no reversion to the wild-type after six passages in birds over a period of greater than 20 days (Bean 1989). Such strains may develop in up to one third of patients treated with amantadine or rimantadine; in immunocompromised individuals the percentage may even be higher (Englund 1998). Drug-resistant influenza A virus (H3N2) can be obtained from rimantadine-treated children and adults as early as 2 days after starting treatment (Hayden 1991). Some H5N1 strains which have been associated with human 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.

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.).

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.


Special Situations


Oseltamivir: children 1 to 12 years of age clear the active metabolite oseltamivir carboxylate at a faster rate than older children and adults, resulting in lower exposure. Increasing the dose to 2 mg/kg twice daily results in drug exposures comparable to the standard 1 mg/kg twice daily dose used in adults (Oo 2001). Infants as young as 1 year old can metabolise and excrete oseltamivir efficiently (Oo 2003), but in younger children, use of oseltamivir is contraindicated (FDA 2005).

Zanamivir: In the EU, zanamivir is approved for use in children aged 12 years or older (US: 7 years).

Amantadine, rimantadine: Given the relatively low efficacy and the high risk of developing gastrointestinal and CNS adverse effects, the authors do not recommend administration of amantadine or rimantadine to children.

Impaired Renal Function

Oseltamivir: the terminal plasma elimination half-life is 1.8 h in healthy adults. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance, and averages 23 h after oral administration in individuals with a creatinine clearance < 30 ml/min (Doucette 2001). A dosage reduction to 75 mg once daily is recommended for patients with a creatinine clearance < 30 ml/min (1.8 l/h) (He 1999); in prophylaxis, a dosage of 75 mg every other day is recommended. No treatment or prophylaxis dosing recommendations are available for patients on renal dialysis treatment.

Zanamivir: the manufacturer declares that there is no need for dose adjustment during a 5-day course of treatment for patients with either mild-to-moderate or severe impairment in renal function (Relenza).

Rimantadine: renal insufficiency results in increased plasma concentrations of rimantadine metabolites. Haemodialysis does not remove rimantadine. A reduction to 100 mg/day is recommended in patients with a creatinine clearance < 10 ml/min. Supplemental doses on dialysis days are not required (Capparelli 1988). In patients with less severe renal insufficiency, and in older persons, rimantidine should be monitored for adverse effects.

Amantadine: a dose reduction is recommended for individuals > 60 years and with a creatinine clearance < 40 ml/min. Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Patients should be observed carefully for adverse reactions. In these cases, consider further dose reduction or discontinuation of the drug. Amantadine is not removed by haemodialysis.

Impaired Liver Function

Oseltamivir: the metabolism of oseltamivir is not compromised in patients with moderate hepatic impairment, and dose adjustment is not required in these patients (Snell 2005).

Zanamivir: has not been studied in persons with hepatic dysfunction.

Rimantadine: for persons with severe hepatic dysfunction, a dose reduction of rimantadine is recommended.

Amantadine: adverse reactions to amantadine have only rarely been observed among patients with liver disease.

Seizure Disorders

Seizures (or seizure-like activity) have rarely been reported among patients with a history of seizures who were not receiving anticonvulsant medication while taking amantadine or rimantadine.


All drugs mentioned above should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus (Pregnancy Category C).


Treatment of Human H5N1 Influenza

Experience with the treatment of H5N1 disease in humans is limited - until 8 March 2006, 175 confirmed cases had been reported to the WHO ( WHO 2006), and clinical reports published to date include only a few patients (Yuen 1998, Chan 2002, Hien 2004, Chotpitayasunondh 2005, WHO 2005, de Jong 2005).

Based on current data, the treatment of influenza disease caused by the currently circulating H5N1 strains seems to be somewhat different from the treatment of "classical" influenza. However, it should be noted that current recommendations are preliminary and modifications are likely as new data come in:

  • Patients with suspected H5N1 influenza should promptly receive a neuraminidase inhibitor pending the results of laboratory testing (WHO 2005).

  • Oseltamivir (Tamiflu®) is currently regarded as the drug of choice.
  • Oseltamivir dosage might need to be increased in severe disease to up to 150 mg twice daily in adults (WHO 2005).
  • In severe disease, oseltamivir might need to be given for longer periods, both for treatment (7-10 days or longer) and for prophylaxis (WHO 2005).
  • Resistance may occur and precede clinical deterioration (de Jong 2005).
  • Treatment with oseltamivir may be beneficial even when initiated as late as 8 days after the onset of symptoms, if there is evidence of ongoing viral replication (WHO 2005, de Jong 2005).

Corticosteroids have frequently been used, with conflicting results. In one series, six of the seven patients who were treated with corticosteroids died (Hien 2004). Ribavirin, interferon alpha and other immunomodulatory drugs have all been used, but without convincing results.

In severe cases, ventilatory support and intensive care may be needed within days of admission (Hien 2004, Chotpitayasunondh 2005).

Transmission Prophylaxis

As soon as a case of human H5N1 infection is suspected, precautions need to be taken to minimise nosocomial spread. If the diagnosis is confirmed, possible contacts of the index case must be identified to facilitate early intervention with antiviral therapy, in order to reduce morbidity and mortality and limit further spread of the disease (WHO 2004).

General Infection Control Measures

Infection control measures include the application of standard precautions (Garner 1996) to all patients receiving care in hospitals. If the diagnosis of H5N1 influenza infection is being considered on the basis of clinical features, additional precautions should be implemented until the diagnosis can be ruled out.

Special Infection Control Measures

Influenza virus is transmitted by droplets and fine droplet nuclei (airborne). In addition, transmission by direct and indirect contact is also possible. Although there is currently no evidence that the H5N1 virus is transmitted among humans, the WHO recommends the following precautions (WHO 2004):

  • Use of high-efficiency masks in addition to droplet and contact precautions.
  • Patients should be housed in a negative pressure room.
  • Patients should be isolated to a single room. If a single room is not available, cohort patients separately in designated multi-bed rooms or wards.
  • Patient beds should be placed more than 1 metre apart and preferably be separated by a physical barrier (e.g. curtain, partition).

To protect healthcare workers (HCWs) and other hospital personnel, the following recommendations have to be followed (WHO 2004):

  • HCWs should protect themselves with a high efficiency mask (European CE approved respirators or US NIOSH certified N-95), gown, face shield or goggles, and gloves. The use of masks by healthcare workers in pandemic settings has recently been clarified (WHO 2005b). A surgical mask, when consistently used, may also reduce the risk of infection, but not significantly (Loeb 2004).

  • Limit the number of HCWs who have direct contact with the patient(s); these HCWs should not look after other patients.
  • The number of other hospital employees (e.g. cleaners, laboratory personnel) with access to the environment of these patients should also be limited.
  • Designated HCWs should all be properly trained in infection control precautions. Restrict the number of visitors and provide them with appropriate personal protective equipment and instruct them in its use.

  • Ask HCWs with direct patient contact to monitor their own temperature twice daily and to report any febrile event to hospital authorities. HCWs who have a fever > 38ºC, and who have had direct patient contact, should be treated immediately.
  • Offer post-exposure prophylaxis (for example, oseltamivir 75 mg daily orally for 7 days) to any HCW who has had potential contact with droplets from a patient without having had adequate personal protective equipment.
  • HCWs who are unwell should not be involved in direct patient care since they are more vulnerable and may be more likely to develop severe illness when exposed to influenza A (H5N1) viruses.
  • Dispose of waste properly by placing it in sealed, impermeable bags which should be clearly labelled "Biohazard" and incinerated. Linen and reusable materials that have been in contact with patients should be handled separately and disinfected.

Contact Tracing

Identify contacts as well as those persons who may have been exposed to the common source of infection. Contacts are persons who have shared a defined setting (household, extended family, hospital or other residential institution, military barracks or recreational camps) with a person in whom the diagnosis of influenza A(H5N1) is being considered while this person was in his or her infectious period (i.e. from 1 day prior to the onset of symptoms to 7 days after the onset of symptoms, or to the date prescribed by national public health authorities, or to the date indicated in the section "Discharge policy") (WHO 2004).

These persons should be monitored for 7 days following the last exposure to the implicated patient, or to the common source, and asked to check their temperature twice daily. If a person who is being monitored develops fever (> 38ºC) and a cough or shortness of breath, he or she should be treated immediately (WHO 2004).

Discharge policy

The WHO recommends that infection control precautions for adult patients remain in place for 7 days after resolution of the fever. Previous human influenza studies have indicated that children younger than 12 years can shed virus for 21 days after the onset of illness. Therefore, infection control measures for children should ideally remain in place for this period (WHO 2004).

Where this is not feasible (because of a lack of local resources), the family should be educated on personal hygiene and infection control measures (e.g. hand-washing and use of a paper or surgical mask by a child who is still coughing). Children should not attend school during this period (WHO 2004).


Global Pandemic Prophylaxis

There is some evidence that containment and elimination of an emergent pandemic influenza strain at the point of origin is possible using a combination of antiviral prophylaxis and social distance measures (Ferguson 2005). The authors used a simulation model of influenza transmission in Southeast Asia to evaluate the potential effectiveness of targeted mass prophylactic use of antiviral drugs, and predicted that a stockpile of 3 million courses of antiviral drugs should be sufficient for elimination.

The WHO has recently started creating an international stockpile of antiviral drugs to be dispatched to the region of an emerging influenza pandemic (WHO 20000824). If the pandemic cannot be contained at its source, rapid intervention might at least delay international spread and gain precious time. For this strategy to work, a number of key criteria must be met to reach a high probability of success (Ferguson 2005):

  1. rapid identification of the original case cluster,
  2. rapid, sensitive case detection and delivery of treatment to targeted groups, preferably within 48 h of a case arising,
  3. effective delivery of treatment to a high proportion of the targeted population, preferably 90 %,
  4. sufficient stockpiles of drugs, preferably 3 million or more courses of oseltamivir (the WHO disposes currently of this stockpile),
  5. population co-operation with the containment strategy and, in particular, any social distance measures introduced,
  6. international co-operation in policy development, epidemic surveillance and control strategy implementation.

It should be noted that the idea of stopping a pandemic at its source or delaying its international spread, is an attractive, but as yet untested hypothesis. So far, no attempt has ever been made to alter the natural course of a pandemic once it has emerged in the human population. The logistic issues involved in delivering the drug to large populations are considerable. In addition, the first pandemic viral strains should not be highly contagious, and the virus should be limited to a small geographical area. There are many "ifs", and the outcome is all but certain. Nevertheless, given the potentially catastrophic consequences of an influenza pandemic, the WHO’s strategy of stockpiling antiviral drugs for rapid and early intervention is one of the numerous precious pieces of global pandemic preparedness planning.



The introduction of neuraminidase inhibitors was an important step for the more efficient control of human influenza infection. Today, neuraminidase inhibitors are the only drugs effective against recently isolated highly pathogenic avian influenza viruses in humans. However, reports on highly drug-resistant H5N1 strains underline the experience we have had with other viral infections such as HIV: we never have enough drugs to treat our patients and we will always need new and better ones. Great efforts lie ahead of us to develop more drugs and maybe even supervaccines that include antigens present in all subtypes of influenza virus, that do not change from year to year, and that can be made available to the entire world population (Osterholm 2005). These efforts will be costly, but only in terms of money: nothing compared to the loss of life associated with the next influenza pandemic.




  1. Air GM, Laver WG. The neuraminidase of influenza virus. Proteins 1989; 6: 341-56. Abstract: http://amedeo.com/lit.php?id=2482974
  2. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51: 123-9. Abstract: http://amedeo.com/lit.php?id=12493796 - Full text at http://jac.oxfordjournals.org/cgi/content/full/51/1/123
  3. Bean WJ, Threlkeld SC, Webster RG. Biologic potential of amantadine-resistant influenza A virus in an avian model. J Infect Dis 1989; 159: 1050-6. Abstract: http://amedeo.com/lit.php?id=2723453
  4. Bowles SK, Lee W, Simor AE, et al. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999-2000. J Am Geriatr Soc 2002; 50: 608-16. Abstract: http://amedeo.com/lit.php?id=11982659
  5. Bryson YJ, Monahan C, Pollack M, Shields WD. A prospective double-blind study of side effects associated with the administration of amantadine for influenza A virus prophylaxis. J Infect Dis 1980; 141: 543-7. Abstract: http://amedeo.com/lit.php?id=7373087
  6. Butler D. Wartime tactic doubles power of scarce bird-flu drug. Nature 2005; 438: 6. http://amedeo.com/lit.php?id=16267514
  7. Capparelli EV, Stevens RC, Chow MS, Izard M, Wills RJ. Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure. Clin Pharmacol Ther 1988; 43: 536-41. http://amedeo.com/lit.php?id=3365917
  8. Carr J, Ives J, Kelly L, et al. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res 2002; 54: 79-88. Abstract: http://amedeo.com/lit.php?id=12062393
  9. CDC 1999 - Centers for Disease Control. Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR Recomm Rep 1999; 48: 1-9. Abstract: http://amedeo.com/lit.php?id=10632443 - Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4814a1.htm
  10. CDC 2005 - Centers for Disease Control. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005; 54: 1-40. Abstract: http://amedeo.com/lit.php?id=16086456 - Full text at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5408a1.htm
  11. CDC 2006. CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005-06 Influenza Season. Available from http://www.cdc.gov/flu/han011406.htm - Accessed 13 February 2006.
  12. Chan PK. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002; 34: Suppl 2: Abstract: http://amedeo.com/lit.php?id=11938498 - Full text at http://www.journals.uchicago.edu/CID/journal/issues/v34nS2/010992/010992.html
  13. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005; 11: 201-9. Full text at http://www.cdc.gov/ncidod/eid/vol11no02/04-1061.htm
  14. Clover RD, Crawford SA, Abell TD, Ramsey CN Jr, Glezen WP, Couch RB. Effectiveness of rimantadine prophylaxis of children within families. Am J Dis Child 1986; 140: 706-9. Abstract: http://amedeo.com/lit.php?id=3521258
  15. Colman PM, Varghese JN, Laver WG. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983; 303: 41-4. Abstract: http://amedeo.com/lit.php?id=6188957
  16. Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003; 326: 1235. Abstract: http://amedeo.com/lit.php?id=12791735 - Full text at http://bmj.bmjjournals.com/cgi/content/full/326/7401/1235
  17. Dawkins AT Jr, Gallager LR, Togo Y, Hornick RB, Harris BA. Studies on induced influenza in man. II. Double-blind study designed to assess the prophylactic efficacy of an analogue of amantadine hydrochloride. JAMA 1968; 203: 1095-9. http://amedeo.com/lit.php?id=4870515
  18. de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005; 353: 2667-72. Abstract: http://amedeo.com/lit.php?id=16371632 - Full text at http://content.nejm.org/cgi/content/full/353/25/2667
  19. Demicheli V, Jefferson T, Rivetti D, Deeks J. Prevention and early treatment of influenza in healthy adults. Vaccine 2000; 18: 957-1030. Abstract: http://amedeo.com/lit.php?id=10590322
  20. Diggory P, Fernandez C, Humphrey A, Jones V, Murphy M. Comparison of elderly people´s technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. BMJ 2001; 322: 577-9. Abstract: http://amedeo.com/lit.php?id=11238150 - Full text at http://bmj.bmjjournals.com/cgi/content/full/322/7286/577
  21. Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 307: 580-4. Abstract: http://amedeo.com/lit.php?id=7050702
  22. Doucette KE, Aoki FY. Oseltamivir: a clinical and pharmacological perspective. Expert Opin Pharmacother 2001; 2: 1671-83. Abstract: http://amedeo.com/lit.php?id=11825310
  23. Englund JA, Champlin RE, Wyde PR, et al. Common emergence of amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis 1998; 26: 1418-24. Abstract: http://amedeo.com/lit.php?id=9636873 - Full text at http://www.journals.uchicago.edu/cgi-bin/resolve?CIDv26p1418PDF
  24. FDA - Food & Drug Administration. FDA Approves Tamiflu for Prevention of Influenza in Children Under Age 12. Accessed on 8 January 2006 from http://www.fda.gov/bbs/topics/news/2005/NEW01285.html
  25. Ferguson NM, Cummings DA, Cauchemez S, et al. Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature 2005; 437: 209-14. Epub 2005 Aug 3. Abstract: http://amedeo.com/lit.php?id=16079797
  26. Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir: a review of clinical safety. Drug Saf 1999; 21: 267-81. http://amedeo.com/lit.php?id=10514019
  27. Garner JS, and the Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Part II. Recommendations for isolation precautions in hospitals. Am J Infect Control 1996; 24: 32-52. Full text at at http://www.cdc.gov/ncidod/dhqp/gl_isolation_ptII.html
  28. Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH. The molecular basis of the specific anti-influenza action of amantadine. EMBO J 1985; 4: 3021-4. Abstract: http://amedeo.com/lit.php?id=4065098 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=4065098
  29. Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 1989; 321: 1696-702. Abstract: http://amedeo.com/lit.php?id=2687687
  30. Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine. Antimicrob Agents Chemother 1991; 35: 1741-7. Abstract: http://amedeo.com/lit.php?id=1952841 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=1952841
  31. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med 1997; 337: 874-80. http://amedeo.com/lit.php?id=9302301 - Full text at http://content.nejm.org/cgi/content/full/337/13/874
  32. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999; 341: 1336-43. Abstract: http://amedeo.com/lit.php?id=10536125 - Full text http://content.nejm.org/cgi/content/full/341/18/1336
  33. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med 2000; 343: 1282-9. Abstract: http://amedeo.com/lit.php?id=11058672 - Full text at http://content.nejm.org/cgi/content/full/343/18/1282
  34. Hayden FG. Perspectives on antiviral use during pandemic influenza. Philos Trans R Soc Lond B Biol Sci 2001; 356: 1877-84. Abstract: http://amedeo.com/lit.php?id=11779387 - Full text at http://www.influenzareport.com/link.php?id=11
  35. Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004; 189: 440-9. Abstract: http://amedeo.com/lit.php?id=14745701 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v189n3/31422/31422.html
  36. Hayden F, Klimov A, Tashiro M, et al. Neuraminidase inhibitor susceptibility network position statement: antiviral resistance in influenza A/H5N1 viruses. Antivir Ther 2005; 10: 873-7. Abstract: http://amedeo.com/lit.php?id=16430192
  37. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J 2000; 19: 410-7. Abstract: http://amedeo.com/lit.php?id=10819336
  38. Herlocher ML, Truscon R, Elias S, et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 2004; 190: 1627-30. Epub 2004 Sep 28. Abstract: http://amedeo.com/lit.php?id=15478068 - Full text at http://aac.asm.org/cgi/content/abstract/45/4/1216
  39. Holsinger LJ, Nichani D, Pinto LH, Lamb RA. Influenza A virus M2 ion channel protein: a structure-function analysis. J Virol 1994; 68: 1551-63. Abstract: http://amedeo.com/lit.php?id=7508997 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?pubmedid=7508997
  40. Ives JA, Carr JA, Mendel DB, et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 2002; 55: 307-17. Abstract: http://amedeo.com/lit.php?id=12103431
  41. Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet 2006; 367: 303-13. Abstract: http://amedeo.com/lit.php?id=16443037
  42. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003; 163: 1667-72. Abstract: http://amedeo.com/lit.php?id=12885681 - Full text at http://archinte.ama-assn.org/cgi/content/abstract/163/14/1667
  43. Kawai N, Ikematsu H, Iwaki N, et al. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season. Clin Infect Dis 2005; 40: 1309-16. Epub 2005 Mar 16. Abstract: http://amedeo.com/lit.php?id=15825034
  44. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364: 759-65. Abstract: http://amedeo.com/lit.php?id=15337401
  45. Leneva IA, Goloubeva O, Fenton RJ, Tisdale M, Webster RG. Efficacy of zanamivir against avian influenza A viruses that possess genes encoding H5N1 internal proteins and are pathogenic in mammals. Antimicrob Agents Chemother 2001; 45: 1216-24. Abstract: http://amedeo.com/lit.php?id=11257037 - Full text at
  46. Li KS, Guan Y, Wang J, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004; 430: 209-13. Abstract: http://amedeo.com/lit.php?id=15241415
  47. Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 2005; 437: 1108. Abstract: http://amedeo.com/lit.php?id=16228009
  48. Loeb M, McGeer A, Henry B, et al. SARS among critical care nurses, Toronto. Emerg Infect Dis 2004; 10: 251-5. Abstract: http://amedeo.com/lit.php?id=15030692 - Full text at http://www.cdc.gov/ncidod/EID/vol10no2/03-0838.htm
  49. Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 2004; 78: 12665-7. Abstract: http://amedeo.com/lit.php?id=15507653 - Full text at http://jvi.asm.org/cgi/content/full/78/22/12665
  50. McKimm-Breschkin J, Trivedi T, Hampson A, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother 2003; 47: 2264-72. Abstract: http://amedeo.com/lit.php?id=12821478 - Full text at http://aac.asm.org/cgi/content/abstract/47/7/2264
  51. McNicholl IR, McNicholl JJ. Neuraminidase inhibitors: zanamivir and oseltamivir. Ann Pharmacother 2001; 35: 57-70. Abstract: http://amedeo.com/lit.php?id=11197587
  52. Mishin VP, Hayden FG, Gubareva LV. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother 2005; 49: 4515-20. Abstract: http://amedeo.com/lit.php?id=16251290 - Full text at http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=16251290
  53. Moscona A. Oseltamivir resistance - disabling our influenza defenses. N Engl J Med 2005; 353: 2633-6. http://amedeo.com/lit.php?id=16371626 - Full text at http://content.nejm.org/cgi/content/full/353/25/2633 - Audio at http://content.nejm.org/cgi/content/full/353/25/2633/DC1
  54. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999; 180: 254-61. Abstract: http://amedeo.com/lit.php?id=10395837 - Full text at http://www.journals.uchicago.edu/JID/journal/issues/v180n2/990003/990003.html
  55. Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000; 160: 3243-7. Abstract: http://amedeo.com/lit.php?id=11088084 - Full text at http://archinte.ama-assn.org/cgi/reprint/160/21/3243
  56. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282: 31-5. Abstract: http://amedeo.com/lit.php?id=10404908 - Full text at http://jama.ama-assn.org/cgi/content/abstract/282/1/31
  57. Monto AS, Rotthoff J, Teich E, et al. Detection and control of influenza outbreaks in well-vaccinated nursing home populations. Clin Infect Dis 2004; 39: 459-64. Abstract: http://amedeo.com/lit.php?id=15356805 - Full text at http://www.journals.uchicago.edu/CID/journal/issues/v39n4/33140/33140.html
  58. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005; 353: 1363-73. http://amedeo.com/lit.php?id=16192481 - Full text at http://content.nejm.org/cgi/content/full/353/13/1363
  59. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 2000; 355: 1845-50. Abstract: http://amedeo.com/lit.php?id=10866439
  60. Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005; 352: 1839-42. Full text at http://content.nejm.org/cgi/content/full/352/18/1839
  61. Peiris JS, Yu WC, Leung CW, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004; 363: 617-9. Abstract: http://amedeo.com/lit.php?id=14987888
  62. Peters PH Jr, Gravenstein S, Norwood P, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001; 49: 1025-31. Abstract: http://amedeo.com/lit.php?id=11555062
  63. Relenza (zanamivir for inhalation). Research Triangle Park, NC: GlaxoSmithKline, 2003 (package insert). Accessed from http://www.InfluenzaReport.com/link.php?id=5
  64. Smorodintsev AA, Zlydnikov DM, Kiseleva AM, Romanov JA, Kazantsev AP, Rumovsky VI. Evaluation of amantadine in artificially induced A2 and B influenza. JAMA 1970; 213: 1448-54. http://amedeo.com/lit.php?id=4915518
  65. Snell P, Dave N, Wilson K, et al. Lack of effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir and its metabolite oseltamivir carboxylate. Br J Clin Pharmacol 2005; 59: 598-601. Abstract: http://amedeo.com/lit.php?id=15842560
  66. Stephenson I, Nicholson KG. Influenza: vaccination and treatment. Eur Respir J 2001; 17: 1282-93. Abstract: http://amedeo.com/lit.php?id=11491177 - Full text at http://erj.ersjournals.com/cgi/content/full/17/6/1282
  67. Sugrue RJ, Hay AJ. Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel. Virology 1991; 180: 617-24. Abstract: http://amedeo.com/lit.php?id=1989386
  68. Symmetrel (package insert). Endo Pharmaceuticals Inc., Chadds Ford, 2003. http://influenzareport.com/link.php?id=6
  69. Tai CY, Escarpe PA, Sidwell RW, et al. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother 1998; 42: 3234-41. Abstract: http://amedeo.com/lit.php?id=9835519 - Full text at http://aac.asm.org/cgi/content/full/42/12/3234?pmid=9835519
  70. Tamiflu (package insert). Gilead Sciences, Foster City, 2005. Accessed on 8 January 2005 from http://www.rocheusa.com/products/tamiflu/pi.pdf
  71. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283: 1016-24. Abstract: http://amedeo.com/lit.php?id=10697061 - Full text at http://jama.ama-assn.org/cgi/content/full/283/8/1016
  72. Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005; 310: 77-80. Abstract: http://amedeo.com/lit.php?id=16210530
  73. Tumpey TM, Garcia-Sastre A, Mikulasova A, et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc Natl Acad Sci U S A 2002; 99: 13849-54. Abstract: http://amedeo.com/lit.php?id=12368467 - Full text at http://www.pnas.org/cgi/content/full/99/21/13849
  74. Van Borm S, Thomas I, Hanquet G, et al. Highly pathogenic H5N1 influenza virus in smuggled Thai eagles, Belgium. Emerg Infect Dis 2005; 11: 702-5. Abstract: http://amedeo.com/lit.php?id=15890123 - Full text at http://www.cdc.gov/ncidod/EID/vol11no05/05-0211.htm
  75. Van Voris LP, Betts RF, Hayden FG, Christmas WA, Douglas RG Jr. Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA 1981; 245: 1128-31. Abstract: http://amedeo.com/lit.php?id=7007668
  76. Varghese JN, Epa VC, Colman PM. Three-dimensional structure of the complex of 4-guanidino-Neu5Ac2en and influenza virus neuraminidase. Protein Sci 1995; 4: 1081-7. Abstract: http://amedeo.com/lit.php?id=7549872 - Full text at http://www.proteinscience.org/cgi/content/abstract/4/6/1081
  77. Varghese JN, McKimm-Breschkin JL, Caldwell JB, Kortt AA, Colman PM. The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 1992; 14: 327-32. Abstract: http://amedeo.com/lit.php?id=1438172
  78. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001; 285: 748-54. Abstract: http://amedeo.com/lit.php?id=11176912 - Full text at http://jama.ama-assn.org/cgi/content/abstract/285/6/748
  79. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127-33. Abstract: http://amedeo.com/lit.php?id=11224828
  80. WHO 20000824. Donation of three million treatments of oseltamivir to WHO will help early response to an emerging influenza pandemic. http://www.who.int/mediacentre/news/releases/2005/pr36/en/index.html - Access 14 January 2006.
  81. WHO 2004. WHO interim guidelines on clinical management of humans infected by influenza A (H5N1). Available from http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage/en/index.ht ml - accessed on 14 January 2006.
  82. WHO 2005. The Writing Committee of the World Health Organization. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 353: 1374-85. - Full text at http://content.nejm.org/cgi/content/extract/353/13/1374
  83. WHO 2005b. Use of masks by health-care workers in pandemic settings. Available from http://www.who.int/entity/csr/resources/publications/influenza/Mask%20Clarification1 0_11.pdf - Accessed on 14 January 2006.
  84. WHO 2006. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. Accessed on 10 March 2006 from http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_03_08/en/ind ex.html
  85. Wingfield WL, Pollack D, Grunert RR. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. N Engl J Med 1969; 281: 579-84. http://amedeo.com/lit.php?id=4897137
  86. Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 2005; 192: 665-72. Epub 2005 Jul 15. Abstract: http://amedeo.com/lit.php?id=16028136
  87. Yuen KY, Chan PK, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351: 467-71. Abstract: http://amedeo.com/lit.php?id=9482437 - Full text at http://www.thelancet.com/journals/lancet/article/PIIS0140673698011829/fulltext



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