Influenza comes every year - and with pigs it is always in season
On 19 September 2017, more than 60 participants gathered in Berlin for the workshop "Virus vom Vogel". The event was organised jointly by the Academy for Public Health Düsseldorf and the National Research Platform for Zoonoses. The spatial capacities were completely exhausted with the number of listeners and speakers. The aim of the workshop was to jointly broaden the horizons of influenza research across disciplines and applications. Lectures from the scientific perspective as well as from the viewpoint of the Public Health Service and the Veterinary Service contributed to creating a picture of the situation that was as complete as possible, on the basis of which joint discussions and questions could be addressed.
Influenza viruses - from A to D
In his lecture on the systematics of influenza viruses, Dr. Dennis Rubbenstroth from the University of Freiburg provided the audience with a comprehensive overview of influenza A, B, C and D viruses. The main focus of the lecture was dedicated to the particularities of influenza A viruses. Mr. Rubbenstroth explained the taxonomic peculiarities (H1-16 and N1-9) as well as the antigenic drift and shift possibilities, the genetic differences between highly and low pathogenic influenza A viruses (polybasic cleavage site) and what makes influenza A viruses potential pandemic pathogens (high mutation rate, wild bird reservoir). In addition, he described the influenza A viruses found for the first time in 2009 and 2010 in South and Central America in bats, for which the taxonomy was extended to include H17 and N10. The new virus raises many new questions, especially regarding a potential reassortment with the known viruses and the zoonotic potential. Influenza B is known as a seasonal influenza virus in humans and also occurs in pigs. Influenza D was found in cattle and pigs. A reassortment between influenza B, C and D viruses is not described.
In the following discussion, the pathogenicity of influenza B viruses was addressed, although the comparatively lower research volume was regretted here. The question of why vaccination against highly pathogenic avian influenza viruses (hp AIV) would not be carried out was justified by the lack of differentiation between vaccinated and infected animals in the available vaccines. Thus, AIV vaccination could encourage the unnoticed spread of the virus in livestock. The development of vaccines that allow differentiation (so-called DIVA vaccines) is still lacking at present. In addition, trade restrictions currently apply to animals with influenza antibodies.
Influenza in birds and pigs
Prof. Dr. Martin Beer from the Friederich-Loeffler-Institute gave a detailed presentation on influenza A viruses in birds - productive and wild birds - and pigs. The reservoir of influenza A viruses is wild water birds (ducks, gulls). Ducks in particular are generally very resistant to influenza A viruses and can therefore carry different variants without symptoms and exchange and spread them over long distances, for example during bird migration. On the other hand, domestic poultry - turkeys, chickens etc. - is very susceptible to some subtypes (H4, H5, H6, H7 and H9). H4, 6 and 9 are never highly pathogenic, but make turkeys sick. There are highly pathogenic variants of H5 and H7, which then cause the so-called avian influenza (AIV)/bird flu. Taking up the vaccination discussion after the previous lecture, Prof. Beer explained that vaccination against AIV would not induce sterile immunity in domestic poultry, but would merely "make ducks out of chickens": that is, the chickens would then carry the virus without symptoms, would not become ill, but would spread it further.
Prof. Beer also described the clinical symptoms (clearly recognisable CNS disorders) of hp AIV infection in wild birds. In domestic poultry, the disease progresses very rapidly, often the animals die peracutely.
The dynamics of avian influenza, hp H5 and hp H7, which are the only subtypes subject to state control due to their economic importance, have changed over the past 20 years. While there were only about 20 avian influenza outbreaks worldwide between 1950 and 1996, more than 20,000 outbreaks have been counted since 1997. This is not due to increased sensitivity on the part of the authorities, but mainly to the occurrence of H5N1. H5N1 was the trigger for the "bird flu" in winter 2005/2006. This virus is still circulating and is being monitored by the authorities in Germany. In 2016/2017 alone, there were over 1200 cases in wild birds, including birds in zoos and 18 dead white-tailed eagles. In 2014, a new subtype, the H5N8 virus, appeared as a new subtype, which was probably spread by long-distance migrants from Siberia to North America and Northern Europe. Influenza A viruses differ significantly in their pandemic potential, as there are some variants that appear to be rather "sedentary" and can only be detected in a certain region for years, whereas other variants are very "mobile" and spread rapidly over long distances. Variants of one and the same subtype also differ in their pathogenicity. For example, H5N8 was generally not fatal for ducks in 2014. In 2016, however, ducks suddenly died of this subtype. The fact that ducks die of influenza is, as mentioned above, an exception. In this case, this made it easier to locate affected farms. Molecularly it could be shown that between 2016 and 2017 numerous changes continued to take place and up to 5 different H5N8 viruses were in circulation. With regard to a pandemic, Prof. Beer concluded that an avian influenza pandemic is definitely spreading among birds in Asia-Europe and North America.
Finally, he discussed swine flu. H1 and H3 are the predominant subtypes in pigs. The pig acts as a "mixing vessel" for avian and human subtypes, which makes pigs relevant for possible emerging pandemic pathogens. Influenza in pigs is not a seasonal disease due to the short life expectancy and the high fattening frequency, but circulates permanently. The detection rate in sampled pigs with respiratory symptoms or fever is constant at an average of 25%. The pandemic strain of the so-called swine fever (from 2009) is, as in humans in seasonal influenza, an integral part of the occurrence in pigs.
After Prof. Beer's lecture, the question was asked whether one should now be afraid of H5. According to Prof. Beer, H5N1 had a long time to adapt without becoming pandemic in humans. He did not estimate the risk of an H5N1 pandemic as high. H7 is more difficult to assess because it causes more fatal infections in humans, although H7 has not been transmitted from person to person so far. The different strains are often very well adapted to birds and do not infect humans effectively. Reassortment is a risk, however, and especially in a country like Germany with such a high density of pigs and a large exchange between humans and pigs (even if only a few people notice this in everyday life), we must always be vigilant in this respect.
Influenza in humans
Dr. Silke Buda from the Robert Koch Institute (RKI) gave an overview of human influenza and how the authorities deal with it - from seasonal influenza in winter to the pandemic plan. She described that influenza in humans takes very different courses, depending on the immune status and also on the age of the persons affected. She explained how the number of flu cases is determined and reported at the RKI. This is done by means of reports of so-called "acute respiratory diseases" (ARE) from doctors. With the help of this tool, the numbers of flu-related doctor visits, sick leave, hospital stays and deaths can be determined and compared over the years. This can also be used to make a statement about the effectiveness of the vaccination. This is around 40-60% - so there is still room for improvement. The RKI produces an influenza weekly report in the winter half-year and provides maps of the current flu situation on the Internet. An epidemiological influenza report is published once a year. The RKI only reports on zoonotic influenza if it is of relevance to human medicine - such as in 2006 and 2009. The WHO provides monthly updates on H7N9, which is of relevance to human medicine. In 2016 and 2017 particularly high numbers were reported, so that the question of a new risk arose. WHO and ECDC have therefore prepared a risk assessment for this. The RKI also has risk assessments on H5N8 that are intended to serve the public health service. In addition, there is a national pandemic plan, which was renewed in 2017.
Following this overview, the composition of the respective seasonal human influenza vaccine was discussed. The composition of the vaccine is always based on the findings of the previous year's influenza season. Due to the great mutability of the virus, however, it can form so-called "escape variants", against which the current vaccine then provides little protection.
Influenza from the perspective of the veterinary office
Dr. Hermann Seelhorst from the district of Cloppenburg reported on the everyday life of the veterinary office. In the beginning he reported to the partly astonished auditorium about the high number of pigs in his district. With this he continued the descriptions of Prof. Beer in the morning, according to which there is a large contact area between humans and pigs in Germany. The district of Cloppenburg is also home to millions of broilers, chickens and turkeys, all of which are susceptible to influenza viruses. It is the task of the official veterinarians to keep the animals healthy in the spirit of the One Health concept, and thus to serve the health of man and the environment, as well as to protect against economic damage threatened by animal disease outbreaks. There are various laws and ordinances to control avian flu, such as the Animal Health Act, the Avian Influenza Ordinance and the Wild Bird Flu Monitoring Ordinance. In the event of an epidemic or suspected case of disease, these ordinances take effect and lead to sometimes bizarre-looking situations. For example, thousands of female chicken chicks are transported from Germany to Poland every day, as cockfattening is practised in Germany and hen fattening in Poland. While in Germany only male chicks grow into broilers, the female chicks only have a future in Poland. If trade in a region is interrupted due to an outbreak of a disease, there is an immediate "jam" of newly hatched female day-old chicks, which may not be transported to Poland. If a solution cannot be found within a few hours, these animals must be killed due to lack of space.
In the following discussion, the cause of the entry of avian flu into modern housing facilities was asked. Often the virus would be brought into a region by migratory birds, but finally carried into the house by humans. Genetic studies of viruses in outbreaks clearly showed that a variety of influenza viruses can be found in wild birds outside ofdoors, but that there is usually only one strain on farms, which slowly undergoes a genetic drift over time and as it spreads from farm to farm. This shows the importance of hygiene in housing. The Animal Disease Fund pays very close attention to the fact that there have been no hygiene deficiencies on farms before it financially compensates for the economic loss of an affected farm. Breaches of regulations mean that, in the worst case, no compensation is paid.
The public health department as key point in an influenza pandemic
Dr. Bernhard Bornhofen of the Public Health Office Apparently, he then described the variety of tasks that a public health office must perform. These tasks are very heterogeneous and extend into many areas of people's lives. Infectious diseases - especially influenza - are only one small area. The 2009 influenza pandemic demanded a great deal from the health authorities. The Infection Protection Act requires that if facts are established that could lead to the occurrence of a communicable disease or it is to be assumed that such facts exist, the competent authority must take the necessary measures to avert the dangers threatening the individual or the general public. In so doing, it may take a variety of protective measures which must be carefully weighed up. Depending on the pandemic stage, various precisely defined tasks must be carried out. The reporting system must function, diagnostics must be carried out, contact-reducing measures must be taken, behavioural measures such as cough labels and hygiene must be instructed and disseminated, protective clothing must be available in sufficient quantities, disinfection measures must be able to be carried out, vaccinations must be organised. All this must be carried out for nursing homes, medical facilities, community facilities, prisons, the private and public environment. The resulting workload has led to an overload of time and personnel in the offices. After the pandemic, the exhaustion and frustration in the offices was therefore very great.
After the presentation, the reasons for the overload were discussed. These were mainly due to the cost-cutting measures of the past years. As a result, neither the personnel resources for such exceptional situations were available, nor were there enough beds in hospitals for patients to be isolated. Finding doctors for the necessary vaccinations and organising additional rooms was also very time-consuming.
New anti-influenza agents
In the final lecture, Prof. Stephan Ludwig (University of Münster) described the current therapeutic options for influenza in humans: M2-channel blockers and neuraminidase inhibitors. Both options are unsatisfactory, as their efficacy is limited and the viruses are also able to build up resistance to them. Scientists around the world are therefore searching for new and better treatment options. Among others, the FluResearchNet, coordinated in Münster, would like to contribute to this. A promising therapeutic option could be an acetylsalicylic acid derivative called LASAG, which targets cellular mechanisms so that the viruses cannot escape it with new mutations. The drug could be inhaled and would act directly in the respiratory tract. The drug is already in your Phase II clinical trial with patients, with first promising results.
Need for new vaccines in humans and animals
After this last presentation, the final discussion was held. There was an intensive discussion whether instead of killing animals in case of an outbreak, one could not switch to vaccination in order to save more animals. Unfortunately, the currently available vaccines would not be able to contain the spread of the virus in poultry. In addition, there are economic barriers to trade in poultry with influenza antibodies. The advantage of killing poultry is therefore that, although it is not pleasant for any of the parties involved and many animals have to die at once, it interrupts the further spread of the virus. Prophylactic vaccination is difficult in broiler flocks - in addition to the lack of differentiation between vaccinated and infected animals - because double vaccination is necessary, but the animals do not reach the age to receive two vaccinations in their short lives. So what innovations are needed? It would be helpful to have a vaccine that could be applied once, which could best be applied in the egg and which would lead to sterile immunity (without virus excretion). In order to keep up with the speed of viral change, the approval process would have to be very short. For humans, a vaccine would be required that is compatible, safe and as universally applicable as possible against all influenza viruses. This is not yet in sight, but should remain the goal of scientific efforts.
The current acceptance of the vaccine in the population was also discussed. Besides the moderately effective vaccine, communication also plays a role. It would be difficult to convince the population of the benefits of a vaccination if even the medical staff found it difficult to protect themselves by vaccination. Here, the role model function and the conviction of the doctors that a vaccination is sensible and right is still missing.
With regard to the already well established wild bird monitoring in Germany, the participants discussed what further research is needed. Prof. Beer explained that too little is still known about flight routes. It would be important to know in real time where new influenza viruses are located and how they change, so that one could better prepare oneself during the bird migration period.
In order to reduce the spread of avian influenza on farms, it was proposed to reduce the density of operations. Although this measure was considered helpful by the participants, it did not appear feasible. In some regions, however, it was still the case that no further farms were approved because the density was already so high there. However, a reduction was not to be expected.
Interdisciplinary approaches for successful influenza control
The interdisciplinary exchange on the topic enabled many new insights. A lot of knowledge, which in some places seemed to be self-evident, was not available in other places, as the working reality was different. In particular, the exchange between veterinary and human medicine is very useful in the fight against influenza. What challenges a pandemic would pose to a public health authority was not conceivable in veterinary medicine due to other regulations. On the other hand, the density of pigs and poultry in Germany, which is known to veterinarians, is interesting for human medicine, as this knowledge enables a new classification of the zoonotic character of a flu infection. The event has thus contributed to a better mutual understanding between veterinary and human medicine on the one hand and between research and ÖGD on the other.
Systematics of influenza viruses
Dr Denis Rubbenstroth, University of Freiburg
Prof. Dr. Martin Beer, Friedrich Loeffler Institute
Management of influenza: from the importance of seasonal frequencies to the pandemic plan
Dr. Silke Buda, Robert Koch Institute
Challenges in the Veterinary Office
Dr. Hermann Seelhorst, County of Cloppenburg
Challenges in the public health department
Dr. Bernhard Bornhofen, Offenbach Health Authority
New ways in influenza therapy
Prof. Dr. Stephan Ludwig, University of Münster
The speakers of the workshop "Virus vom Vogel" provide with their entertaining and detailed lectures a lot of knowledge for the auditorium.