Influenza

From Ganfyd

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, H1N1) is first in the 21st century.^[2][3]

UK 2005-6 reports

Contents 1 Aetiology 2 Clinical 2.1 Complications of influenza 2.2 Death from influenza 3 Epidemiology 3.1 Surveillance of influenza 3.2 Mutation of the influenza virus 3.2.1 "Drift" 3.2.2 "Shift" 3.3 Pandemic 3.4 Seasonal influenza 4 Investigations 4.1 Radiology 5 Treatment 5.1 Medical 5.1.1 NICE guidance 5.1.2 HPA guidance 5.2 Surgical 6 Prevention 6.1 Vaccination against influenza 6.1.1 Who should receive the influenza vaccination? 6.1.1.1 Vaccination of pregnant women 6.1.1.2 Concerns about vaccinating women in pregnancy 6.1.1.3 Vaccination of social and health care staff 6.1.2 Why is a different vaccine required each year? 6.1.2.1 Misplaced concerns about "swine flu" vaccine in the 2010-11 seasonal vaccine 6.1.3 Supply of Influenza Vaccine 6.1.3.1 In the UK 6.1.4 Payment and Reimbursement 7 External links 7.1 General influenza references 7.1.1 Previous year's recommendations 7.2 Pandemic references 8 References

Aetiology

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.

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^[4].

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. Morbidity also reflects secondary infection and individual characteristics.

Detection probability of 2009 A/H1N1 in second wave^[5]

	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.^[7]) 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.

"Drift"

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^[8] , 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^[4]. 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. 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

• Flu treatment - zanamivir (review), amantadine and oseltamivir (No. 58)
• Full Guidance on the the use of zanamivir, oseltamivir and amantadine for the treatment of influenza
• Flu prevention - amantadine and oseltamivir (No. 67)

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

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.^[9][10]

Vaccination against influenza

Who should receive the influenza vaccination?

The Chief Medical Officer's recommendations for 2011 can be found at this DH page.^[11] There is also revised guidance from the JCVI here.^[12] The Green Book chapter on influenza vaccination was updated on 29 July 2011, and is available here.^[13] 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.^[14] 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."^[15]

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.^[16]

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.^[17][18][19]
• Reducing the risk of harm to the fetus caused by the mother’s influenza illness.^[20]

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.^[21][22] 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.

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".

The Chief Medical Officer letter recommends that social and health care staff should be vaccinated against flu,^[23] 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%^[24]. Similar guidance applies in other countries, such as the USA.^[25]

A high level of immunisation in workers in care homes is associated with fewer deaths during winter in residents.^[26] 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.^[27].

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.^[28]

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.^[29]

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.^[30] 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),^[31][32] 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.

External links

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

General influenza references

• Influenza Gateway from BioMed Central
• CMO letter with advice on influenza vaccination for the 2006-2007 season.
• Information on diagnosis of influenza from CDC here.
• Information on influenza from Health Protection Agency is available here.
• There's good information on the influenza virus at Wikipedia here.
• A re-usable online textbook Influenza 2006
• Medscape Influenza Resource Center (sponsored by GlaxoSmithKline).

Previous year's recommendations

• CMO letter PL/CMO/2005/2, PL/CNO/2005/2,PL/CPHO/2005/2 from 2005.

Pandemic references

• A good starting point for comprehensive references is the FLUwiki , (or the UK page at that site).
• Information on avian and pandemic influenza from World Health Organisation here.
• Information on pandemic influenza from UK Department of Health here. The guide to pandemic flu is particularly good.
• Information on influenza from Health Protection Agency, including HPA pandemic plan, is available here.
• Financial Times "Ask the Expert" interview with Bruce Mann from the Cabinet Office on how organisations can prepare for Avian or pandemic Influenza
• Draft guidance on the operation of the coroner system in the event of pandemic influenza - for consultation

References