Search

Influenza is a highly contagious and debilitating disease that imposes an excess burden of complications and mortality. Antiviral therapy is the primary intervention for treatment and post-exposure prophylaxis (PEP) of influenza. Amantadine and rimantadine are members of the M2 class of antiviral agents and are moderately effective in influenza management. However, their utility is compromised by high levels of resistance, tolerability concerns and a lack of efficacy against influenza B. An alternative class of agents, the neuraminidase inhibitors (NIs), represent the most advanced form of antiviral therapy available, and act by specifically inhibiting the neuraminidase enzymes that are present on all influenza subtypes. Two NIs, oseltamivir and zanamivir, are currently available for clinical use. Oseltamivir, the most widely used NI, is administered orally as a prodrug (oseltamivir carboxylate) and systemically distributed to all potential infection sites. Zanamivir, a second NI, is administered by inhalation via a disk inhaler and deposited primarily in the respiratory tract. When administered within 48 hours of symptom onset, both agents significantly reduce illness duration and symptom severity, and decrease the rate of influenza-associated complications. With oseltamivir, greater benefits are detected with earlier treatment initiation (<12 hours). In PEP, both NIs effectively protect the close contacts of index cases from symptomatic influenza. Oseltamivir and zanamivir are generally well tolerated and associated with a low level of resistance. Emerging evidence supports the activity of both NIs against the H5N1avian influenza infection, which is a pandemic candidate. However, the WHO currently recommends the use of oseltamivir for the management of suspected cases, given the systemic nature of the H5N1 challenge. Ongoing studies are exploring the effectiveness of oseltamivir, zanamivir and other NIs for pandemic management.

Re-analysis of the influenza pandemic of 1918 has given reassurance about a rather low reproductive number (R(o)), a prolonged herald wave of virus and that the skewed mortality towards the young adult could be a singularly unique event dependent upon previous infection history, perhaps not to be repeated in a future pandemic. Over 99% of those who contracted the virus survived, in spite of the absence of antivirals, vaccine and antibiotics for the secondary bacteria infections which probably accounted for one-third of the 50 million deaths. Therefore, in spite of a three-fold population increase since 1918 and 100 thousand plane journeys daily, judicious and careful planning together with a stockpile of antiviral drugs, oseltamivir, zanamivir and M2 blockers and a generic H5N1 vaccine, and application of hygiene would be expected to reduce mortality in a new pandemic, to figures significantly less than 1918.

Sixteen EU scientists and doctors were interviewed about pandemic planning using psychometric methods applied to a scientific problem for the first time. Criticism was aimed at countries which have no plan whatsoever, the majority of nations. Many such countries have not invested in scientific infrastructure and public health. Amongst the 15 or so published pandemic plans a lack of detail was identified. Of particular need was investment into avian virus vaccine stocks (H1-15), prepared licenses of vaccine and pre purchase and agreed distribution, investment into stocks of antivirals, antibiotics and masks. Most but not all members of the group predicted a global outbreak within 5 years, most probably starting in SE Asia. However it was recognised that a pandemic could start anywhere in the world which had juxtaposition of young people, chickens, ducks and pigs. Mammalian cell culture production using wild type virus with the production factory at category III levels of security was exemplified. Antivirals would be essential to ameliorate the first wave of infection although significant quantities of cell grown vaccine could be produced if, as in 1918, 1957 and 1968 there is a long period between the first virus isolation and person to person spread. The wider scientific community is more energised than previously for very serious preparations to be in place way before the outbreak begins as this is a major public health problem, completely dwarfing concerns about bioterrorism.

The Great Influenza Pandemic of 1918-1919 was a cataclysmic outbreak of infection wherein over 50 million people died worldwide within 18 months. The question of the origin is important because most influenza surveillance at present is focussed on S.E. Asia. Two later pandemic viruses in 1957 and 1968 arose in this region. However we present evidence that early outbreaks of a new disease with rapid onset and spreadability, high mortality in young soldiers in the British base camp at Etaples in Northern France in the winter of 1917 is, at least to date, the most likely focus of origin of the pandemic. Pathologists working at Etaples and Aldershot barracks later agreed that these early outbreaks in army camps were the same disease as the infection wave of influenza in 1918. The Etaples camp had the necessary mixture of factors for emergence of pandemic influenza including overcrowding (with 100,000 soldiers daily changing), live pigs, and nearby live geese, duck and chicken markets, horses and an additional factor 24 gases (some of them mutagenic) used in large 100 ton quantities to contaminate soldiers and the landscape. The final trigger for the ensuing pandemic was the return of millions of soldiers to their homelands around the entire world in the autumn of 1918.

A method was developed for detection of influenza genes in formalin-fixed brains of mice that had been experimentally infected with influenza A/NWS/33 (H1N1) virus. Using this technique, messenger ribonucleic acid (mRNA) of the beta-actin gene was detected in eight clinical brain samples from the 1916-1920 outbreak of encephalitis lethargica, showing preservation of particular mRNAs. However, we did not detect influenza nucleotide sequences of M, NP, and NS genes from these same samples. We conclude either that influenza was not the causative agent of encephalitis lethargica or, possibly, that the virus had a hit-and-run mechanism and was no longer present in the brain at the time of death of the patients.

A small armentarium of anti-influenza drugs now exists, and includes the M2 blockers (amantadine and rimantadine) and the neuraminidase inhibitors (Relenza and Tamiflu). The neuraminidase inhibitors have certain advantages, including a broader spectrum of antiviral activity, including influenza A and B viruses. On the other hand, there is now much clinical experience with the M2 blockers, and these drugs are inexpensive. It is clear that influenza in different community groups needs to be managed in specific and targeted ways. For example, in the over-65-years and at-risk groups, vaccination will remain a mainstay of disease prevention. However, up to 40% of those in these groups may fail to receive vaccine, and therefore the antivirals can be used therapeutically, or, in defined circumstances, as prophylactics. At present, influenza is hardly managed in the community. The infrequent global outbreaks, pandemics, present further problems. The more extensive use of the two classes of antivirals, and also vaccines, in the important interpandemic years will provide a very significant investment in health benefits in the face of a new pandemic virus in an otherwise completely vulnerable population.

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.

In 1918, a great 'forgotten plague' wiped out fifty million people around the world - many of them young and healthy. The killer disease was flu. What was it that made this outbreak so deadly and would we be prepared if another pandemic struck?

The 1918 influenza pandemic caused 40 million deaths, and so dwarfed in mortality and morbidity the preceding pandemic of 1889 and the 1957 and 1968 pandemics. In retrospect, much can be learnt about the source, the possible subterranean spread of virus, and the genetic basis of virulence. The World Health Organization has urged every nation to prepare a pandemic plan for the first global outbreak of the 21st century. We present an appraisal of epidemiological and mortality evidence of early outbreaks of respiratory disease in France and the UK in the years 1915 to 1917. Certain of these earlier focal outbreaks--called epidemic bronchitis rather than influenza--occurred during the winter months when influenza was known to be in circulation, and presented with a particular heliotrope cyanosis that was so prominent in the clinical diagnosis in the world pandemic outbreak of 1918-1919 (the Great Pandemic). The outbreaks in army camps at Etaples in France and Aldershot in the UK in 1916-1917 caused very high mortality in 25-35 year olds. Increased deaths from bronchopneumonia and influenza were also recorded in England. We deduce that early focal outbreaks of influenza-like disease occurred in Europe and on the balance of probability the Great Pandemic was not initiated in Spain in 1918 but in another European country in the winter of 1916 or 1917. We suggest that the pandemic had its origins on the Western Front, and that World War I was a contributor.

This discussion piece examines the likely epicentre of the influenza pandemic of 1918-1919. Contrary to previous studies that have proposed a Chinese origin, there is documentation that suggests that, in this instance, the virus spread eastwards to China from Europe. Although more recent oubreaks of influenza have undoubtedly had an Oriental origin, the evidence indicates that future outbreaks could conceivably arise anywhere in the world.

Influenza A virus initiated worldwide epidemics (pandemics) in 1918, 1957, 1968 and 1977. A revised calculation of the 1918-1919 pandemic estimates that 40 million persons died and 500 million were infected. The mortalities in 1957 and 1968 were nearly 6 million. Biological and genetic characteristics of the causative agents of the more recent pandemics, have been well studied but little is known about the causative agent of the Great Pandemic in 1918. Genetic characterisation of the 1918 virus has been achieved by sourcing virus RNA from formalin fixed lung samples or by exhuming frozen victims of the outbreak from Arctic regions. Initial analysis of the HA gene from two USA sources indicates a virus related to swine and human influenza with no base insertion at the HA1-HA2 cleavage junction which, at least in avian influenza A, characterises high virulence. Important unanswered questions are whether the 1918 virus spread pantropically perhaps to include the brain and hence cause encephalitis including the later lethargic forms, or whether infection was confined to the respiratory tract. Re-examination of reports of respiratory disease in England and France in 1916-1917 may indicate a non-Spanish origin of the pandemic and a period of 2 years for the virus to be seeded worldwide. In contrast the other two pandemic viruses in 1957 and 1968 appeared to originate in Asia. New anti-neuraminidase drugs in conjunction with amantadine and novel developments with influenza vaccines would be expected to ameliorate the disease in a future pandemic., (Copyright 2000 John Wiley & Sons, Ltd.)

Eighteen influenza A (H3N2) viruses were isolated during a single outbreak in a closed community of Carmelite nuns. Serological analysis of the virus haemagglutinin (HAs), using a panel of monoclonal antibodies, demonstrated antigenic microheterogeneity. In contrast, no significant biochemical differences were detected in viral genes by RNA:RNA hybridisation or in structural or nonstructural polypeptides analysed by high-resolution polyacrylamide gel electrophoresis (PAGE) or by limited proteolysis followed by PAGE. Influenza A (H3N2) viruses isolated in the vicinity of the convent were distinguishable from each other and from the epidemic viruses isolated in the convent both antigenically and biochemically.

An electron microscopic immunogold labelling technique employing monoclonal antibodies has been applied to the antigenic analysis of influenza A and B viruses. Reassortant influenza A H3N2 viruses containing haemagglutinin molecules from viruses isolated between 1968 and 1982 were analysed with a panel of monoclonal antibodies raised against viruses which appeared over the same period. The immunogold labelling technique clearly demonstrated the antigenic drift in the haemagglutinin molecule that occurred between 1968 and 1982. When the technique was applied to the examination of viruses from a more geographically restricted influenza epidemic in a semi-closed community, antigenic variants were found. Furthermore the technique enabled the identification of distinct antigenic variant subpopulations within a single clinical isolate. Analysis of the HA of MDCK cell or egg grown virus by this procedure provided data to support the hypothesis that the host cell exerts selective pressure on subpopulations of virus resulting in the emergence of antigenic variants.

1-Adamantanamine hydrochloride (aminoadamantane) has been shown to inhibit the multiplication of influenza A viruses in cell cultures, organ cultures and experimentally infected mice. An epidemic of influenza in Great Britain in the winter of 1967-68 provided the opportunity to study the prophylactic effect of aminoadamantane in the family environment and this paper reports the results of further observations in January-March 1969 during an influenza epidemic due to A2/Hong Kong/68.In a double-blind, placebo-controlled investigation of aminoadamantane given prophylactically, in doses of 100 mg every 12 hours for 10 days, no protective effect of the drug was demonstrated. In view of the positive effect of the drug in the earlier study during the winter of 1967-68, and the apparent sensitivity of the virus strain, an explanation involving the very high incidence of individuals possessing HI antibody of less than 1:12 is offered.