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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 ( 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. 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.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. 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).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):
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).
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.
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.
Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated.
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,
Children 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. Pregnancy 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:
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):
To protect healthcare workers (HCWs) and other hospital personnel, the following recommendations have to be followed ( WHO 2004):
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).
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):
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.
Conclusion 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.
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