Pandemic and seasonal influenza:

therapeutic challenges

Matthew J. Memoli1, David M. Morens2 and Jeffery K. Taubenberger1

1 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

2Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Influenza A viruses cause significant morbidity and mortality annually, and the threat of a pandemic

underscores the need for new therapeutic strategies. Here, we briefly discuss novel antiviral agents

under investigation, the limitations of current antiviral therapy and stress the importance of

secondary bacterial infections in seasonal and pandemic influenza. Additionally, the lack of new

antibiotics available to treat increasingly drug resistant organisms such as methicillin-resistant

Staphylococcus aureus, pneumococci, Acinetobacter, extended spectrum beta-lactamase producing

gram negative bacteria and Clostridium difficile is highlighted as an important component of

influenza treatment and pandemic preparedness. Addressing these problems will require a

multidisciplinary approach, which includes the development of novel antivirals and new antibiotics,

as well as a better understanding of the role secondary infections play on the morbidity and mortality

of influenza infection.

Introduction

Influenza viruses are among the most common causes of respiratory

infections in humans [1] and are associated with high morbidity

and mortality, especially in infants, the elderly and people

with chronic diseases. In the USA alone, influenza results in

approximately 200,000 hospitalizations and 36,000 deaths in a

typical endemic season [2]. In addition to annual winter outbreaks,

antigenically novel strains of influenza virus occasionally

emerge causing pandemics on an average of three times per

century [3,4]. Although the impact of past pandemics has been

highly variable, up to 50% or more of a population can be infected

in a single pandemic year and the number of deaths caused by

influenza can dramatically exceed what is normally expected in an

endemic season [5,6]. For example, in the past 120 years there were

pandemics in 1889, 1918, 1957 and 1968 [7]. The 1957 pandemic

caused 66,000 excess deaths in the USA [6]. The 1918 pandemic,

the worst in recorded history, caused approximately 675,000

deaths in the USA [4] and killed up to 50 million people worldwide

[8].

It is highly likely that influenza will return in pandemic form

[4,9]. Concern about a future influenza pandemic caused by

human infection with a highly pathogenic avian influenza (HPAI)

virus of H5N1 subtype [9–12] has prompted renewed interest in

influenza pandemic preparedness planning and in basic and

applied influenza virus research.

After its re-emergence in 2003, the ongoingH5N1HPAI epizootic

continues to producehuman spillover infections [13]. As ofDecember

2007, 336 confirmed cases of human H5N1 infection had been

documented, of which 207 were fatal [14], yielding a case fatality

rate of 62%. Concerns about the emergence of an H5N1 pandemic

virus hinges not only upon sporadic transmission events between

infected poultry and exposed humans, but also crucially upon its

potential for sustained person-to-persontransmission. Severalsmall

case clusters of H5N1 infections have been reported [15,16].

Although epidemiologic information has been limited, person-toperson

transmission of H5N1 has been suggested in a few instances,

usually involving family members [17]. It is unknown whether this

represents infection associated with particularly intimate or prolonged

contact, or shared but unidentified host factors affecting

infection risk or virus transmissibility [18,19].

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Corresponding author: Memoli, M.J. (memolim@niaid.nih.gov)

590 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter. Published by Elsevier Ltd. doi:10.1016/j.drudis.2008.03.024

Challenges of therapy

Effective pharmacological treatment of influenza virus infection

must take into account the rapid time-course of acute viral infection.

Influenza A viral replication peaks approximately 48 h after

inoculation into the nasopharynx and declines slowly, with little

virus shed after about six days. The virus can replicate in the upper

and lower respiratory tract. Even after infectious virus can no

longer be recovered, viral antigen can be detected in cells and

secretions of infected individuals for several additional days [1].

Human influenza infection is an acute respiratory disease characterized

in its full form by the sudden onset of fever, coryza,

cough, headache, myalgia, prostration, malaise and inflammation

of the upper respiratory tree and trachea. Acute symptoms and

fever often persist for 7–10 days and weakness and fatigue can

linger for weeks. People with chronic pulmonary or cardiac disease,

diabetes mellitus or other chronic illnesses have a higher risk

of developing severe complications from influenza, which may

include hemorrhagic bronchitis, pneumonia (both primary viral

and secondary bacterial) and death. Hemorrhagic bronchitis and

pneumonia can develop within hours and fulminant, fatal influenza

viral pneumonia, may present with rapid onset of dyspnea,

cyanosis, hemoptysis and pulmonary edema. Death can follow in

as little as 48 h after the onset of symptoms, but most influenza

fatalities occur later, after the development of secondary bacterial

pneumonias and other complications [20].

Effective measures currently available against influenza infection

include prevention by either vaccination with inactivated or

live attenuated vaccines, or administration of antiviral drugs

prophylactically or therapeutically [21]. The role of novel vaccines

which target highly pathogenic influenza viruses in preparedness

for future pandemics has been extensively reviewed elsewhere [22–

26]. Given concerns about a deadly new pandemic and the inevitable

delays in producing and administering large quantities of

vaccines, pandemic planning initiatives have also focused on the

possible use of antiviral drugs as a component of pandemic mitigation

and response [27]. To prevent disease, antiviral drugs must

be administered promptly and continuously at times of influenza

exposure. However, the use of available antiviral drugs in an

influenza pandemic can have limitations [28], including the development

of drug resistance with retention of virulence and transmissibility

properties [29].

New therapeutic strategies are needed to lessen the impact of

seasonal influenza as well as to prepare for another influenza

pandemic. Particularly in developed nations, the population is

aging and persons are living longer with higher rates of chronic

diseases that put them into a high-risk category for influenza

complications and fatality [2,30]. Immunosuppressive therapies

and immunomodulating drugs are being used to treat many such

patients. Neither the population impact of a pandemic nor the

effectiveness of current therapies can be predicted. The relative

paucity of intensive care unit beds, invasive positive pressure

ventilation systems, emergency room facilities and staff are all

problems that could have a major impact during a pandemic. The

emergence of multi-drug resistant bacteria, both nosocomial and

community acquired, including methicillin-resistant Staphylococcus

aureus (MRSA), resistant pneumococci, Acinetobacter, extended

spectrum beta-lactamase (ESBL)-producing gram negative organisms

and Clostridium difficile, could all be major factors in the

morbidity and mortality of a future pandemic. It is clear that a

multidisciplinary approach is required in preparing for an influenza

pandemic, and that prevention and mitigation strategies

must address many issues.

Current pharmacotherapy and drug development

Most influenza pandemic plans consider drug therapy as a key part

of the initial response. In the event of a pandemic, not only could

primary viral pneumonia, respiratory distress and other syndromes

secondary to the influenza virus play a major part in

morbidity and mortality, but it is also highly likely that secondary

infections such as pneumonias and other community acquired

and nosocomial infections will contribute as well. Anti-influenza

drug availability is limited, and there is an obvious need for

development of new classes of antivirals. In addition, drug therapies

targeting the wide array of complications associated with

influenza infection and hospitalization, such as secondary pneumonias,

healthcare-associated infections, ventilator-associated

lung injury and others are also important.

Currently there are two major classes of drugs that target the

influenza virus: matrix 2 ion channel inhibitors and neuraminidase

(NA) inhibitors. These drugs have been extensively evaluated

[28] but their efficacy in a pandemic or highly pathogenic influenza

situation is still unknown. Matrix 2 ion channel blockers

(amantadine and rimantadine) are only effective against influenza

A viruses. Resistant viral strains develop rapidly and have been

recognized in 15–92% of patients in a given year [31–33]. Interestingly,

a dramatic increase in the frequency of resistance to

adamantanes by human influenza A (H3N2) viruses has occurred

in recent years, now up to 90%, associated with a single S31N

amino acid replacement in the viral matrix M2 protein [34]. The

more recently developed NA inhibitors, zanamivir and oseltamivir,

are effective against influenza A and B viruses. Both classes of

drugs are effective in preventing influenza when administered

prophylactically [28,29]. To be clinically effective, early administration

within the first 12 hours of disease onset of each of these

drugs is important [28,35]. Drug resistance to NA inhibitors has

also been reported [36]. Prevalence of drug resistant strains of

seasonal influenza viruses could be increasing, as suggested by

European reports that 14% of H1N1 influenza A isolates were

resistant to oseltamivir during the 2007–2008 season [37]. Recent

reports have also documented the development of resistance

mutations in H5N1 strains following treatment with NA inhibitors

[39].

Unfortunately, neither class of drug has been proven to be of

value in pandemic mitigation nor has been shown to be efficacious

for highly pathogenic influenza viruses, such as H5N1 [38,39]. A

third class of drug being assessed is the inosine monophosphate

(IMP) dehydrogenase inhibitors, such as ribavirin. Small controlled

studies have shown some efficacy in decreasing fever

and influenza A virus shedding when IMP inhibitors are given

by aerosol, but no efficacy when given orally [40]. Further study

needs to be undertaken to examine the possibility that combinations

of the available drugs would increase efficacy.

Research efforts are also focusing on development of new drug

classes that target unique aspects of influenza virus replication and

infection. Antiviral therapies currently under investigation

include viral receptor blockers, viral release inhibitors, viral poly-

Drug Discovery Today  Volume 13, Numbers 13/14  July 2008 REVIEWS

www.drugdiscoverytoday.com 591

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