Clearing the Air Around Influenza

Prevention

Prevention of transmission and infection with respiratory viruses focuses on specific interventions (vaccines) and aspecific interventions (physical and social).

Given the aspecific nature of the ILI syndrome and the ups and downs of circulation, the most sensible precautions to be used and prepared for are physician and social interventions such as barriers, distancing and personal hygiene.

The evidence base for these interventions is poor, as the story of the relevant Cochrane review shows.

TTE has often reported on the politicisation of these interventions, precluding large randomised controlled trials from identifying effective interventions and exploring their use either alone or as a mix in different age categories and settings. The bottom line is that hand washing is the only intervention showing a small but important decrease in risk, especially if carried out regularly.

Many vaccines against different agents have been developed over the years, but few are licensed. The most effective is the measles vaccine, a live attenuated product. Given their age, trials in the 1960s are difficult to interpret. Pertussis vaccines were effective when produced as whole-cell vaccines, but concerns were raised about potential harms. Hence, the current acellular variety is a gentler, probably less effective form, which is part of the basic childhood schedule. 

Four major Cochrane Reviews focus on preventing influenza in healthy adults, healthy children, and people who care for the elderly and in the elderly. They are all long-running reviews spanning twenty-plus years under the same senior author team. 

Over the years, the reviews have progressively accumulated evidence, leading to stability in their conclusions - The results are unlikely to change with the inclusion of new studies. The review updates reached a point where the evidence does not show anything different to what it has done for decades, despite governments claiming the contrary. The most significant gap in our understanding of how vaccines affect the consequences of influenza persists. Given what we have shown about their rarity, this is hardly surprising. This is also the main reason for the extensive interchangeable use of the F-words “Flu” and influenza.

Confusion hides reality.

The Cochrane authors pose several conditions for future updates of the reviews. The last one is the development and testing of a new causal paradigm for ILI and influenza. 

Producing new vaccines each year that effectively address viral antigen changes and the short duration of antibody responses in individuals requires substantial global machinery. However, the programs for selecting and producing vaccines rely on causal assumptions that are neither clear nor predictive.

Overall, the largest data comes from trials involving populations least likely to benefit from vaccines but most likely to develop immunity: healthy adults. There is a strong serological response in trials with healthy adults, but the clinical impact is minimal; it takes vaccinating 71 healthy adults to prevent just one case of influenza. 

The vaccine's weak effectiveness cannot be attributed solely to the mismatch between vaccine antigens and wild virus strains. A more notable effect is seen in children over the age of two; it is estimated that five children need to be vaccinated to prevent one case of influenza, although there is considerable uncertainty surrounding these estimates. Additionally, there is limited evidence regarding the vaccine's ability to prevent complications, reduce transmission, or decrease time off work. Other reviews have reached similar conclusions.

Observational data still appears in the Cochrane reviews, but only as a historical record of earlier versions. Over the past two decades, observational studies have been included in the hope that they can provide long-term and rare harm data and improve the external validity of the trial evidence. However, they have been of such low quality that any conclusions proved unreliable. 

Current yearly registration of candidate influenza vaccines is based on their ability to trigger a good antibody response. Yet, antibody responses are poor predictors of field protection. This is another example of surrogate outcomes in biomedicine, where effects on clinically important outcomes remain unmeasured or unproven from randomised trials: complications and death by influenza. Those who followed the “MHRA papers” series will recognise the logic behind the statement.

The simple answer is that we do not understand what the target is. What is the threat of influenza, and what can we expect from the vaccines?

The WHO Global Influenza Programme (GIP), with its backbone Global Influenza Surveillance and Response System(GISRS), is a complex network of 143 national reference centres and specialist laboratories in 113 states carrying out surveillance of circulating influenza viruses. GISRS was devised and developed to guide annual influenza vaccine production, emphasising influenza viruses, their variants, and emerging strains.

However, there is no reliable system to monitor and quantify the epidemiology and impact of ILI, the syndrome that is present clinically. Few states produce reliable data on the number of physician contacts or hospitalised cases due to ILI, and none tie these data to the proportion of ILI caused by influenza. 

We do not know for certain what the impact of ILI is, nor the impact of the proportion of ILI caused by influenza. PIE studies apportioning positivity to the scores of viruses probably causing ILI are rare, as interest is focused on influenza. The standard quoted figure of 36,000 yearly deaths in the US is based on the “respiratory and circulatory deaths” category including all types of pneumonia, including secondary to meconium ingestion or bacterial causes. More recently, the US Centers for Disease Control and Prevention (CDC) have proposed estimates of impact ranging between 3,000 and 49,000 yearly deaths. When actual death certificates are tallied, annual influenza deaths are little more than 1,000 yearly. So, the actual threat is unknown (but likely to be small,) and so is the estimation of the impact of vaccination.

The uncertainty over the aetiology of ILI, its capricious nature and the weak correlation between immunity and protection, point to possible causal or concurrent factors in the genesis of both ILI and influenza. In other words, virus positivity may only be one of the factors necessary for a case of influenza or ILI to manifest itself.

This is the seventh of the old geezers’ simplified recap of what is known about ILIs.

Readings

1. Demicheli V, Jefferson T, Ferroni E, Rivetti A, Di Pietrantonj C. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD001269. DOI: 10.1002/14651858.CD001269.pub6.

2. Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD004879. DOI: 10.1002/14651858.CD004879.pub5.

3. Demicheli V, Jefferson T, Di Pietrantonj C, Ferroni E, Thorning S, Thomas RE, Rivetti A. Vaccines for preventing influenza in the elderly. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD004876. DOI: 10.1002/14651858.CD004876.pub4.

4. Thomas RE, Jefferson T, Lasserson TJ. Influenza vaccination for healthcare workers who work with the elderly. Cochrane Database Syst Rev. 2010 Feb 17;(2):CD005187. doi: 10.1002/14651858.CD005187.pub3. Update in: Cochrane Database Syst Rev. 2013 Jul 22;(7):CD005187. doi: 10.1002/14651858.CD005187. (update imminent with no change to the conclusions).