Influenza

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Colorised transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold) grown in MDCK cells (seen in green).
This 1919 photograph showed rows of tents that had been set up on a lawn in Massachusetts where victims of the 1918 influenza pandemic were treated.

RNA viruses with a segmented genome, hence prone to mutation. The WHO's system of nomenclature for flu viruses was updated in 2011.[1] Seasonal 'flu occurs owing to minor mutations, pandemic 'flu (ie affecting more than one continent) occurs as a result of more major mutations and tends to cause more burden upon the population as it affects the young and middle aged more. Spanish 'flu in 1918 caused 20-50 million deaths worldwide.

The most significant surface molecules are the haemagglutinin and neuraminidase proteins. The former latch on to host cells in the process of infection, the latter cleave bonds after exocytosis of daughter virus particles, releasing them from the parent.

Immunisation and drugs against influenza are directed against these two molecules, and the classification of different strains depends on them.

While there are just 2 types of neuraminidase, the appearance of a new haemagglutinin strain is usually associated with a pandemic eg Spanish 'flu (1918, H1N1), Asian 'flu (1957, H2N2), Hong Kong 'flu (1968, H3N2). Hence the appearance and continued spread of avian H5N1 will almost certainly result in another pandemic in due course even if Swine flu (2009, A(H1N1)pmd09) is first in the 21st century.[2][3]

Seasonal influenza has direct and indirect mortality impacts across the world. Early 2015 Northern Hemisphere influenza activity had peaked in North America the last week of December, Eastern Asia by mid January and Europe by mid February. This was associated with the largest excess mortality in those over 65 for 4 years. Active strains included a vaccine resistant but neuraminidase inhibitor sensitive influenza A(H3N2) and A(H1N1)pdm09. In Southern Hemisphere winter 2017 the active strains there and in Asia were again influenza A(H3N2) and some A(H1N1)pdm09. The later in India was reported to have killed thousands. While in 2017 Avian influenza outbreaks have not caused significant human disease, with most deaths being due to avian influenza A(H7N9) virus in China, such outbreaks can be locally very virulent as with the Egyptian outbreak of avian influenza A(H5N1) in December 2014 which had the most human cases ever reported in one month.

Contents


Aetiology

QuotationMarkLeft.png Coughs and sneezes - spread diseases QuotationMarkRight.pngOld health posters

QuotationMarkLeft.png Catch it. Bin it. Kill it!  QuotationMarkRight.pngNew health posters

Influenza virus is a negative-strand RNA virus transmitted by droplets and fomites.

Clinical

The incubation period is relatively short, just 1-3 days, but does vary. Onset of illness is sudden, with fever and prostration. Every muscle aches. Initial infection, and signs, are respiratory. Headache and gastrointestinal upset are common. Benign myositis (with raised muscle enzymes eg creatine kinase) especially affecting the calves is seen in type B infection.

Children under 2 have the highest risk for complications and/or hospitalization, although morbidity and mortality is also very high in the institutionalised elderly.

Complications of influenza

Severe complications are primary influenza pneumonia, staphylococcal or pneumococcal pneumonia pneumonia, invasive bacterial sepsis, encephalopathy, myocarditis. There is evidence that immunity to bacterial pathogens eg haemophilus, staphylococcus, pneumococcus is reduced.

Meningoencephalitis can occur, as can necrotizing encephalopathy (characterized by normal CSF and negative PCR). The latter is rare over 10 yrs of age - MRI shows bilateral high intensity T2 signals in thalamus, brainstem and cerebellum.

There is evidence that some complications such as Guillain-Barre syndrome[4] or narcolepsy are caused by shared epitopes in strains of the virus (including those used in immunisation) activating autoimmunity such as expression of CD4+ T cell clones[5].

Death from influenza

Death occurs rapidly in 50% of fatal cases (underlying disease common, but not essential). Death may be owing to influenza per se, or (often) to complications such as bacterial superinfections.

In a pandemic deaths are likely to occur in young people, whereas in other years old age or lowered resistance is more usually associated with death. With improved management of bacterial co-infection, historical mortality rates may not be valid. The death rate does vary depending on the viruses individual characteristics and other issues such as hygiene practices. The total population death burden can be modelled for influenza[6].

See also immunology and Influenza

Epidemiology

The burden of influenza has been shown to be underestimated due to the large number of asymptomatic infections and imperfect case ascertainment. During the 2015 southern hemisphere flu season a study in Auckland New Zealand attempted to qualify this in a large city. At the peak the virus type distribution was approximately half type B and half type A with one of subtyped strains of A, A(H3N2) predominating and there had been a fair vaccine match. For every death, 4.6 were admitted to ITU, 120 were hospitalised, 2000 visited their GP, 16,000 became sick with symptoms and 45,000 were infected with no noticeable symptoms (ie they seroconverted)
PMID link to reference awaited
.

Morbidity also reflects secondary infection and individual characteristics.

Detection probability of 2009 A/H1N1 in second wave[7]
Detection probability 95% CI
Symptomatic infection 36% 19-57%
On hospitalisation 20% 15-25%
If death 90% 80-96%
Proportion infections asymptomatic 65% 55-74%

Surveillance of influenza

The WHO and ECDC relate to national organs such as the Health Protection Agency's Centre for Infections which collaborates with others including the Royal College of General Practitioners' Birmingham-based research unit to monitor laboratory reports of influenza, and clinical reports of influenza-like-illness (ILI), and thus identify when influenza is circulating in the community. (This is a form of public health surveillance.)

Decisions about when influenza levels exceed the level at which antiviral treatments may be used in the NHS for the prevention or treatment of influenza are made by government ministers, based - at least in part - on advice from the HPA.

WHO monitors human swine and avian influenza.

Mutation of the influenza virus

The influenza virus changes and evolves through two main mechanisms: "drift", and "shift". (New research has recently challenged previous understanding of this.[8]) Influenza B has neuraminidase but not haemagglutinin, therefore fewer antigen changes occur than with 'Flu A and most adults are fully or partially immune each year.

Info bulb.png

B is more stable than A: no pigs
Pigs host three different Influenza As:- avian, swine and human.
Theoretically 2 viruses circulating in 1 host cell might churn out 256 different viruses.
Influenza B is more particular and has only one host - humans.
B alters by mutation and natural selection, new strains arising by drift, and surviving in the face of antibodies from immune and partially immune population-antigenic, but not by shift.
Since infection gives rise to long-lasting cross-reacting antibodies, adults, especially mature ones tend to get fewer clinical episodes, leaving a pool of children to go down with B infections, and if they survive, become immune for perhaps life.
Dr Basab Kumar Barua

"Drift"

Haemagglutinin genetic drift from data submitted up to 26th May with Swine flu outbreak 2009
RNA lacks the parity-checking second strand of DNA and has less control of where transcription starts and how it continues, so it mutates more rapidly. This form of mutation tends to produce gradual changes in the virus, which mean that the precise antigens expressed change gradually over time.

As a consequence of this antigenic "drift", different vaccines are recommended by the World Health Organisation each year.

"Shift"

Influenza viruses can infect a wide range of animal hosts. For the most part, viruses only infect a single species (or group of closely related species). Occasionally, however, viruses can cross from one species to another.

In some cases viruses will cause disease in one species, but can infect another without causing any symptoms.

Poultry, pigs, and horses have all been associated with strains of influenza virus that have infected humans.

If an animal is infected with two different strains of influenza virus simultaneously, it is possible for the viral nucleic acids to produce proteins for both strains in the same cell, and for the proteins to reassemble, creating a novel influenza virus with features of both the parent strains. This may be quite dramatically different from previous viruses, with different antigenicity, virulence, and pathogenicity in humans.

Sometimes a third host is thought the most likely context for reassortment - for example, it is thought that strains of influenza virus that usually infect poultry and humans might undergo reassortment in pigs.

Reassortment of this kind is thought to be most likely to happen when different species live in very close contact with each other.

Pandemic

When a pandemic emerges, the pattern of disease in the population is quite different from that of seasonal 'flu. Because of the lack of immunity, it will tend to attack all population groups equally. It may not begin in winter time. A pandemic typically occurs in waves, with a 15 week interval[9] , achieving a cumulative attack rate of 25%. There are, however, great variations in age affected, and in severity. Clinically there can be variation eg Asian 'flu was characterized by a high incidence of diarrhoea, beginning up to a week before respiratory symptoms appeared. It also had a longer than average incubation period. 1 in 200 hospitalized is a reasonable estimate. See also pandemic references and pandemic influenza articles.

Seasonal influenza

This can be very accurately modelled in terms of epidemiological ascertainment and resulting disease burden[6]. Most of the rest of this article refers to seasonal 'flu as selective vaccination has proved to be a very effective public health measure in reducing the impact on population mortality and health services.

Investigations

  • Virus can be found by culture or PCR in the upper airway.
  • Retrospective serological diagnosis is possible.

Radiology

Not routinely applicable. Appropriate on occasion if clinically indicated (for example if viral pneumonia suspected).

Treatment

Medical

Various antiviral drugs with efficacy against influenza are available. There are the Neuraminidase inhibitors such as zanamivir and oseltamivir; and amantadine (targets M2 protein).

Note that the lower age limit for the use of oseltamivir was reduced to 1 year in 2006.

The use of neuraminidase inhibitors is strictly regulated in the UK, under Schedule 2 of the National Health Service (General Medical Services Contracts) (Prescription of Drugs etc.) (Amendment) Regulations 2004, which came into force on 3rd January 2005. In England, prescribing of these drugs in primary care is now formally restricted to those circumstances and those at-risk patient groups specified by NICE (chronic lung/cardiac/renal disease, immunodeficiency). Treatment should be initiated within 48 hours of onset. It has been shown in pregnant women during the 2009 pandemic that treatment upon symptoms without awaiting serology reduced mortality[10]. Schedule 2 also enables GPs in England to write private prescriptions for prophylactic oseltamivir for their patients who have been in close contact with an influenza sufferer when influenza is circulating at sufficiently high levels, even though they are not in the ‘at-risk’ groups specified by NICE, in accordance with the product licence. Post-exposure prophylaxis is for 10 days. Amantadine is not recommended for this purpose.

NICE guidance

HPA guidance

HPA page on the use of anvirals in the treatment of seasonal influenza, which has links to detailed guidance and flowcharts.

Surgical

Not routinely applicable.

Prevention

Advance recommendations for vaccination

These are made about 8 months in advance so can not be perfect due to the time lag in vaccine production. The last time there was a significant miss was 2015, and this resulted in morbidity and mortality that emphasised how important vaccination is as a public health measure most of the time. WHO recommends that influenza vaccines for use in the 2017-2018 northern hemisphere influenza season contain the following viruses [11]:

  • an A/Michigan/45/2015 (H1N1)pdm09-like virus
  • an A/Hong Kong/4801/2014 (H3N2)-like virus
  • a B/Brisbane/60/2008-like virus.


Preventing influenza is worth-while if it prevents hospitalisation, deaths, and illness - especially complications of pneumonia, which may be responsible for much of the seasonal mortality. Vaccination against influenza can be effective in preventing illness and complications, and is offered to people at higher risk, including old people - although there is some evidence that the vaccine may be less effective in older people, and that alternative strategies such as immunising their contacts and carers might be more effective.[12][13]

Vaccination against influenza

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About influenza vaccines

Flu strains covered by the vaccine

Because there is constant change to the circulating influenza strains, the flu vaccine has to be changed each year, to ensure the best possible "match" between the vaccine and circulating strains.

Flu vaccines generally contain antigens from three ("trivalent") or (four "tetra-" or "quadrivalent") strains of the flu virus: each has two influenza A strains; with one or two B strains in the tri- and quadrivalent vaccines.

The WHO makes recommendations for the composition if the vaccines each year, based on surveillance of strains circulating (and remember that influenza is seasonal, with most cases happening in winter; and that the Southern Hemisphere winter happens in the May to September, in contrast to the Northern Hemisphere winter). For example the WHO states: It is recommended that trivalent vaccines for use in the 2017-2018 northern hemisphere influenza season contain the following:

  • "an A/Michigan/45/2015 (H1N1)pdm09-like virus;
  • "an A/Hong Kong/4801/2014 (H3N2)-like virus; and a B/Brisbane/60/2008-like virus.

"It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Phuket/3073/2013-like virus."

Types of influenza vaccine

Apart from the strains covered, there are several ways that influenza vaccines can be subcategorised, including:

There are tri- and quadrivalent versions of each.

If a vaccine is to be effective, it needs to generate immunity to antigens present on flu in a way which prevents illness (and, ideally, infection and infectiousness). Immunity to these antigens can be generated by presenting the antibodies to the immune system with more or less other parts of the virus, or in other ways.

Inactivated influenza vaccines

A virus can be simply killed - e.g. with formaldehyde - and injected. This often involves injecting many other proteins and other molecules, which can increase the stimulation of the immune system, enhancing the immune response; but which are also responsible for increased "reactogenicity" - including fever and other adverse events. Whole virus, subunit, or very pure "just the necessary antigens" vaccines can be created via genetic engineering, with the antigens being expressed by different organisms).

In the UK at present we use a range of inactivated vaccines.

In August 2017 an adjuvanted inactivated influenza vaccine was licensed in the UK and Europe. The manufacturers claim that this vaccine is more effective in older people (who are at increased risk of complications associated with influenza, and in whom influenza vaccines are generally less effective).[14] This vaccine will be available for the 2018-9 Northern hemisphere influenza season (and presumably for the 2018 Southern hemisphere season).

Live organism influenza vaccines

Live organism vaccines ("Live attenuated influenza vaccines", LAIV) currently in use for influenza comprise influenza viruses that have been attenuated so that they do not cause illness.

Data from the USA appeared to show reduced efficacy for LAIV, compared to inactivated flu vaccines, so their use was curtailed. In the UK and Europe, however, LAIV has continued to be used. The reasons for these differences are still being explored.[15]

Hybrid organisms - other live viruses or bacteria that have been genetically engineered to express antigens; and it may be that in future influenza vaccines may use such methods.

Genetically engineered vaccines may combine antigens with proteins which enhance the immune response, as adjvuants or like conjugated vaccines.

Route/method of administration

Live attenuated influenza vaccines currently available in the UK are administered as nasal drops. These vaccines are only licensed for use in under-18s in the UK and Europe, because of reduced efficacy at older ages. They may, however, be used "off-label" for people with needle phobia: better this than no vaccine. (See page 16 of the PHE guidance.[16])

Currently inactivated vaccines are all administered by injection - usually intramuscular - injection.

One novel route of administration was a vaccine (Intanza Ⓒ) used a special syringe to facilitate intradermal injection. This was also said - due to the increased immune cells in this layer of the dermis - to be more effective in older people, but it seems not to have gained market traction.

As with many other vaccines, the future of influenza vaccination may be administration via a microneedle patch.

Who should receive the influenza vaccination?

The Chief Medical Officer's recommendations for 2011 can be found at this DH page.[17] There is also revised guidance from the JCVI here.[18] The Green Book chapter on influenza vaccination was updated on 29 July 2011, and is available here.[19] There is also this DH leaflet for 2011.

Each year, the WHO direct formulation of an influenza vaccine based on circulating strains. This is offered between September and mid-November to at risk groups e.g. elderly, or chronic disease eg asthma, cystic fibrosis, congenital heart disease. It is an inactivated vaccine, and some products are contraindicated in egg anaphylaxis - see the Green Book Influenza chapter (as above) for details.

Since a proportion of influenza vaccine doses are given opportunistically, when patients attend for whatever reason, following that recommendation absolutely would generate additional work and congestion in general medical practices, however it can be reflected in the operation of recall systems.

It is worth noting that the Cochrane Collaboration has published a number of reviews that are far less enthusiastic about influenza vaccination than are the JCVI and Department of Health. The minutes of the JCVI's meeting in February 2011 state:

"The committee noted that there is some evidence that frontline healthcare workers may not consider influenza vaccination to be effective in preventing influenza and that this view may have may have stemmed in part from the findings of a Cochrane review of influenza vaccination of healthcare workers.[20] The committee considered this review to be based on a highly flawed interpretation of the evidence and did not support the findings of the report."[21]

Regrettably, If they have explained this opinion, they did not do so in the text of the minutes.

Vaccination of pregnant women

During the H1N1 flu pandemic it became clear that pregnant women infected with that strain of flu were at increased risk of complications. During a pandemic, and even during the flu season, a large proportion of the population gets flu. If even a small proportion of those infected experience severe complications, the number who do so can be large. As pregnant women are at increased risk of complications, it is worthwhile vaccinating them, to prevent complications.[22]

Flu vaccination in pregnancy has the additional benefits including:

  • Providing some protection to the baby in the first year of life, through passive immunity (maternal antibodies passed through the placenta) and possibly a reduced risk of catching flu from their mother.[23][24][25]
  • Reducing the risk of harm to the fetus caused by the mother’s influenza illness.[26]
Concerns about vaccinating women in pregnancy

The harm caused by thalidomide last century has left a legacy of concern about giving pregnant women any medicine that can be avoided during pregnancy, including vaccines. Midwifes, rightly, tend to discourage women from taking any medicine that isn’t known to be safe and worthwhile.

Influenza vaccination has, however, been shown to be valuable in pregnancy (see above); and also to be safe, with no risk of teratogenicity.[27][28] The benefits to the fetus far exceed any risks from the vaccine.

Vaccination of social and health care staff

See also Vaccination of social and health care staff for more general discussion not specific to Influenza.

Flag of the United Kingdom.png

Healthcare workers with direct patient contact should be vaccinated against flu annually, as early as possible in the season - to reduce the chance of infecting their patients as well as to protect their only health. Mark Crislip has described those who refuse to be vaccinated as "dumb-asses" (or longer 2012 version).

The Chief Medical Officer letter recommends that social and health care staff should be vaccinated against flu,[29][30][31][32][33] citing benefits in terms of improved patient outcomes (it stops the staff from infecting their patients) and reduction of staff illness and absenteeism. Uptake rates as part of the 2009 H1N1 (A) pandemic strategy in England were only 40%[34]. Similar guidance applies in other countries, such as the USA.[35]

A high level of immunisation in workers in care homes is associated with fewer deaths during winter in residents.[36] Clearly the contribution of immunisation can be confounded by various other factors, such as greater care and organisation but it seems likely it is beneficial to patients to immunise their attendants. A recent review article, however, found that the evidence to support this is, as yet, poor.[37].

Why is a different vaccine required each year?

Vaccination with influenza vaccine is thought to give long-term protection: revaccination is not because the vaccines given previously are unlikely to continue to work.

Rather, annual revaccination is necessary because of the rapid viral mutation, which means that the viruses circulating each year are sufficiently different from viruses circulating in previous years for antibodies induced by previous years' vaccines to have low activity against them.

New vaccines are in development that may not have this problem.[38]

Misplaced concerns about "swine flu" vaccine in the 2010-11 seasonal vaccine

Some patients (and even some doctors who should know better) have expressed concerns about the fact that the seasonal vaccine for the 2010-11 (Northern hemisphere) season contains H1N1 strains.

Every year there is a new vaccine, containing vaccines to prevent the 'flu viruses which have been circulating most widely up until as recently as possible. Since H1N1 has largely displaced most other strains of flu, it would have been bizarre - and a cause for concern - not to include it in the seasonal vaccine.

Most of the concerns about the 2009 vaccine when it was released last year to try to prevent/curtail further spread of pandemic influenza:

  1. the speed of introduction;
  2. the adjuvant used or
  3. the tenuous historical links between H1N1 vaccine and Guillain-Barré Syndrome (GBS).

The first can be discussed and, one would hope, dismissed.

The second can be dismissed as the seasonal flu vaccine is unadjuvanted.

The third can be discussed and, one would hope, dismissed - the latest version of the Green Book (download it from the DH web site) contains information about research showing that while influenza does considerably increase the risk of GBS, vaccination doesn't appear to do so.[39]

Supply of Influenza Vaccine

In the UK

Vaccine is produced by several companies. The process takes several months, and therefore the companies must plan production starting in the preceding winter. Ordering of vaccine commences shortly after giving the previous year's order finishes.

Most doses are bought by General Practices. Some are ordered by occupational health departments and groups, and some by Pharmacies and wholesalers. Each of these buyers will consider how many doses they used the previous year, whether there is a secular trend, and whether any new events have occurred - government offering to pay for a separate group it wants immunised for instance, and then calculate how many they expect to use.

It must be assumed that the Department of Health expresses an opinion of how demand is changing and what its policy for the following year might be, but this does not amount to a promise to buy or compensate for losses arising from over-production, nor therefore is it an order to produce.

Payment and Reimbursement

In 2006-7 GPs in England can expect a fee for each immunisation given to members of several published groups, as described in the CMO letter.[40] Most of the groups described in categories 1 and 2 of the letter (see table above are covered by a "directly enhanced service (DES)". Recommendations concerning chronic liver disease sufferers and carers were introduced in the 2005 CMO letter, and were not covered by a DES - this has not changed in the 2006-7 season.

GP practices are small businesses. As such, they purchase vaccine from manufacturers using their own money. Orders have to be placed months in advance (I think by early July); and any vaccine left over at the end of the season cannot be used the following year, and has to be destroyed.

GPs therefore own the vaccine they are delivered. It is their property, to do with what they will. They can give it to whomsoever they see fit. If they choose to provide it for pregnant women, as recommended by the JCVI (for the 2007-8 season and onwards),[41][42] for example, they can do so. However they get paid – and make a profit – from giving the vaccine to people in the target groups for whom there is a "directly enhanced service (DES)", and for any groups for whom a LES has been agreed. They receive a small reimbursement for vaccinating people for whom they feel that influenza vaccine is clinically indicated, but who are outside these groups; but the amount is very small relative to the amount received for vaccinating people in the target groups.

In addition for each dose bought in and personally dispensed, generic arrangements provide reimbursement of the notional wholesale cost plus an agreed on-cost and profit percentage. This last is however offset by efforts by Primary Care Trusts to reduce overall expenditure on drugs, which include payments for Practices which show smaller year on year increases in drug costs than some.

Consequently, practices have a considerable financial incentive to ensure that their vaccine is targeted on people in the target groups.

The amount ordered has to be calculated carefully. Any shortages will mean that they fail to maximise their profits, and may experience complaints from people in the target groups who cannot be vaccinated. On the other hand, any money spent on unused vaccine will not be reimbursed to them. Practices can “lay off” some of this risk by ordering a certain amount of vaccine, and arranging to have a certain extra amount of vaccine held back for them to order if they need it – but manufacturers will only be prepared to hold back a limited amount of vaccine in this way.

In practice, most practices order vaccine based on the number of people in the practice who, at the time of ordering, can be predicted to be in the target groups, and many will order a certain amount extra.

The system is complex, and may well be adaptive, however in 2005-6 a gap between supply and demand became manifest in October and was declared by the DoH in November.

Effectiveness

Vaccination is only about 60% effective. Efficacy varies from year to year as a result of prior immunity (from natural exposure and to vaccines), and the quality of the "match" between the vaccine strain and circulating strains of influenza.

This means that standard treatment must be offered in high risk groups such as pregnant women on first clinical suspicion, whatever their immunisation status[43].


External links

See also NICE guidance and HPA guidance on the use of antivirals above.

General influenza references

Pandemic references


References

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  3. Morens DM, Taubenberger JK, Fauci AS. The persistent legacy of the 1918 influenza virus. The New England journal of medicine. 2009 Jul 16; 361(3):225-9.(Link to article – subscription may be required.)
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