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Influenza A Viren (IAVs) sind eine große Bedrohung für das Gesundheitssystem. Neben den saisonalen, auch „humanen“, IAVs, die jährlich Hundertausende Tote fordern, befeuert die Möglichkeit einer Reassortierung mit aviären IAVs die Sorge einer zukünftigen Pandemie. Momentan zugelassene Impfstoffe zielen darauf ab, Antikörper gegen die Kopfdomäne des Oberflächenproteins Hämagglutinin (HA) zu bilden, die das Virus effektiv neutralisieren können. Die stetige Veränderung des HAAntigens von Saison zu Saison macht es jedoch unverzichtbar, dass die vorhandenen Impfstoffe jedes Jahr neu angepasst werden. Zusätzlich ist gegen möglichweise auftretende, zoonotische IAVs dadurch auch kein Schutz gewährleistet. Es ist demzufolge dringend notwendig, dass subtyp-unspezifische Ansätze gegen IAVs entwickelt werden, sei es als Impfstoff, um die initiale Ausbreitung zu stoppen und die Bevölkerung zu schützen, oder als antivirales Medikament, um schwere Krankheitsverläufe abzumildern. In dieser Doktorarbeit wurden zwei unterschiedliche Projekte bearbeitet. Im ersten Projekt geht es darum, den Schutz gegen eine heterologe IAV Infektion nach einer vektor-basierten Immunisierung mit unterschiedlichen IAV Proteinen zu untersuchen und die zugrundeliegende Immunantwort zu charakterisieren. Das zweite Projekt zielt darauf ab den Effekt des zellulären Proteins ADAR1 (adenosine deaminase acting on RNA 1) auf die Replikation von IAV zu erforschen. Im ersten Projekt wurden die internen Proteine NP und M1 bezüglich ihres Schutzpotentials gegen heterologe IAV Infektionen untersucht und mit den momentan weit verbreiteten Ansätzen einer Immunisierung gegen die Stammdomäne des HA (HAstem) oder dem M2 Protein verglichen. Wir konnten zeigen, dass die Immunisierung mit NP und M2, aber auch H3stem mittels eines viralen Vektors die Schwere der Erkrankung einer heterologen IAV Infektion in Mäusen maßgeblich reduzieren kann und dass dies unabhängig von nachweisbaren T-Zell Antworten war. Eine Analyse der humoralen Immunantwort zeigt hohe IgG Titer, unterscheidbare IgG Subklassen-Profile gegen verschiedene IAVs und vor allem eine Aktivierung des murinen FcγRIV. Dieser ist dafür bekannt Antikörpervermittelte zellbasierte Zytotoxizität und –Phagozytose durch alveoläre Makrophagen auszulösen. Außerdem konnte keine Schutzwirkung durch eine Immunisierung mit M1 beobachtet werden, was mit der Abwesenheit von Antikörpern korreliert. Dieser Aspekt verdeutlicht erneut, dass die verabreichten Antigene keine T-Zell vermittelte Schutzfunktion ausübten, die in unseren Experimenten fälschlicherweise nicht detektiert worden wäre. Obwohl Antikörper gegen interne Proteine schon vor Jahrzenten beschrieben wurden, wurde ihnen bislang wenig Beachtung geschenkt. Der Hauptgrund dafür ist die Lokalisation der internen Proteine, da diese Fragen über den Schutzmechanismus durch humorale Immunantworten aufwerfen. Sie wurden daher in der Vergangenheit häufig vernachlässigt oder ignoriert. Obwohl keine Neutralisation der Viruspartikel stattfinden kann, können diese Antikörper jedoch Fc-vermittelten Schutz gegen homologe und auch heterologe Viren hervorrufen und so vor einem schweren Krankheitsverlauf schützen. Unsere Resultate bieten tiefere Einblicke in diese Mechanismen und korrelieren mit dem beschriebenen Potential von NP und M2 schützende Antikörperantworten auszulösen. Die vorliegenden Daten verdeutlicht daher, dass die beschriebenen Immunantworten bei der Entwicklung von zukünftigen IAV Impfstoffen nicht ignoriert werden sollten. Im zweiten Projekt dieser Dissertation wurden zwei verschiedene Zellkultur-Systeme genutzt, um den Effekt von ADAR1 auf die virale Replikation des IAV zu untersuchen. Wir konnten einen proviralen Effekt der Isoform ADAR1p150 in HeLa Zellen nachweisen, was mit bereits publizierten Daten aus anderen Zellkultursystemen übereinstimmt und das Konzept des proviralen ADAR1p150 bezüglich IAV festigt. Außerdem haben wir den Effekt von verschiedenen ADAR1 Isoformen in IAV infizierten MDCK Zellen charakterisiert, die mittels CRISPR/Cas9n gentechnisch verändert wurden. Dabei haben wir eine signifikante Hemmung der viralen Replikation in Abwesenheit von ADAR1p150 gezeigt. Des Weiteren führte eine IAV-Infektion in ADAR1-defizienten MDCK Zellen zu einem reduzierten Zelltod, was ebenfalls für ADAR1 als ein vielversprechendes Ziel eines Medikaments spricht. Patienten, die an einer IAV Infektion versterben weisen eine starke Schädigung des Lungengewebes durch eine überschießende Immun- und Entzündungsreaktion auf, die zum Zusammenbruch der epithelialen Barrierefunktion der Lunge führt. Unsere Ergebnisse, dass eine Inhibition von ADAR1 nicht notwendigerweise zu einer angeborenen Immunaktivierung führt, in Kombination mit Hinweisen auf einen verringerten Zelltod, bilden eine vielversprechende Basis für die weiteren Untersuchungen von ADAR1 als Ziel antiviraler Therapeutika.

In December 2019 a novel coronavirus was firstly encountered in Wuhan/China with a massive outbreak of fatal pneumonia leading to a pandemic declared by the World Health Organization in March 2020 (WHO Dashboard COVID-19. [WHO web site]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019), affecting mainly elderly adults with underlying co-morbidities. Clinical course in children below the age of 10 years is considered to be mild or even with subclinical signs (Sinha IP, Ha et al. The Lancet Respiratory medicine 2020;27;S2213–2600(20) 30152-1). We describe a 4 month old infant with co-infection of SARS CoV-2 and influenza A virus.

There is little evidence on the clinical characteristics and the course of complicated infections with respiratory syncytial virus (RSV) compared to influenza A in adults. Therefore, the present monocenter study aims to compare infections with RSV and influenza A with regard to potential predisposing factors, clinical profile, course and outcome in hospitalized patient. the study was performed between Jan 1th and March 31 this year and included all hospitalized patients with a Polymerase chain-reaction-(PCR) confirmed infection of influenza A and RSV. Patients were characterized by clinical symptoms at the time of diagnosis, laboratory parameters of inflammation and potential predisposing factors like chronical diseases of heart, lung, kidney, metabolism and tumors. Data on the length of hospital stay, origin of infection (nosocomial), rate of pneumonia, antimicrobial use, need of mechanical ventilation and hospital mortality were obtained to evaluate clinical severity and outcome. A total of 190 patients with Influenza A and 98 patients with RSV were included. Both patient groups did not differ with regard to anthropometric data and clinical symptoms: it was surprising to see that only 2/3 oft all patients exert symptoms of a respiratory infection. 15.3 % of influenza A and 13.3 % RSV infections were defined as being nosocomial. Comparing the clinical course and outcome, patients with RSV infections and chronical disease of the lung had an increased rate of mechanical ventilations (odds ratio 10.55 [95 % CI 1.18 - 507.1] p = 0.014). The present data clearly show that RSV is a frequent pathogen in hospitalized adults with complicated infections in the winter season. RSV infections seems to be more severe compared to influenza A particular in patients with chronic lung disease, but were as frequent as influenza A of nosocomial origin. In this context, an early diagnosis seems to be helpful for a successful infections prevention management under hospital conditions. Zum klinischen Profil und Verlauf von komplizierten Infektionen mit RSV bei Erwachsenen im Vergleich zur Influenza A ist wenig bekannt. Die vorliegende Untersuchung hatte deshalb zum Ziel. prädisponierende Grunderkrankungen, klinisches Profil, Verlauf und Prognose bei hospitalisierten Patienten mit RSV- und Influenza-A-Infektionen miteinander zu vergleichen. Eingeschlossen wurden Patienten mit RSV- und Influenza-A-Infektionen, die zwischen 1.1.2017 und 31.3.2017 hospitalisiert wurden. Die Diagnostik erfolgte mittels molekularbiologischer Verfahren. Zur Charakterisierung wurden klinische Symptome, Laborparameter sowie disponierende chronische Grunderkrankungen erfasst. Darüber hinaus wurde Verlauf und Schwere der Infektion anhand verschiedener klinischer Parameter einschließlich Beatmungspflichtigkeit und Letalität abgeschätzt. Insgesamt wurden 190 Patienten mit Influenza-A- und 98 Patienten mit RSV-Infektion ausgewertet. Sowohl das mittlere Alter als auch die klinische Symptomatologie bei Diagnosestellung waren in beiden Patientengruppen vergleichbar. Nur 2/3 der Patienten zeigten Influenza-typische respiratorische Symptome. Zwischen 13 und 16 % der Infektionen waren nosokomialen Ursprungs. Bezüglich des klinischen Verlaufs mussten insbesondere Patienten mit RSV-Infektion und einer chronischen Lungenerkrankung signifikant häufiger invasiv beatmet werden (odds ratio 10,55 [95 % CI 1,18 – 507,1] p = 0,014). RSV-Infektionen kommen als häufige Ursache von komplizierten Influenza-ähnlichen Erkrankungen bei älteren, hospitalisierten Patienten in Frage. Im Vergleich zur Influenza A verlaufen RSV-Infektionen insbesondere bei einer chronischen Lungenerkrankung schwerer. Bei beiden Entitäten ist ein nicht unerheblicher Teil der Infektionen nosokomialen Ursprungs, was im Hinblick auf ein erfolgreiches Hygienemanagement eine möglichst rasche Diagnosestellung impliziert.

In a closed farrow-to-finish piglet producing farm 80% of 7-week-old piglets displayed respiratory disease with a 5% mortality rate. In addition to purulent bronchopneumonia in combination with interstitial pneumonia predominantly in the apical and middle lobes, fibrinous serositis was present in the thoracic and abdominal cavities. Further investigations succeeded in confirming the non-pandemic strain of porcine influenza A virus (FLUAVsw) subtype H1avN1. The molecular genetic studies on Mycoplasma (M.) hyopneumoniae and porcine reproductive and respiratory syndrome virus were negative, whereas M. hyorhinis and Haemophilus parasuis were isolated from serous membranes. The possible importance of the underrated M. hyorhinis as a cofactor for viral infections should be emphasized and we demonstrated that the cause of apical lobe pneumonia is not restricted to M. hyopneumoniae. Mother pigs had been vaccinated with an influenza vaccine covering the subtype H1avN1. Only 33% of the examined piglets had maternal antibodies in the 7th week of life. The difficulty of prophylaxis of infections by FLUAVsw in weaners due to lack of vaccine authorization for piglets before their 56th day is reflected by this observation.

The aim of this study was to investigate the role of the poultry red mite (Dermanyssus [D.] gallinae) in the horizontal transmission of avian influenza A virus (AIV) to chickens. This mite is the most common ectoparasite in poultry worldwide, and may play a role in the spread of infectious agents including AIV. Currently, the control of mites is difficult due to frequently developed resistance to many acaricides, their nocturnality and their ability to survive hidden without feeding for months.D. gallinae were collected in a commercial layer farm and housed in self-made fibreboard boxes. SPF chickens were intravenously infected with AIV strain A/turkey/Ontario/7732/1966 (H5N9). The viraemia in chickens was monitored and at an appropriate time point about 1000 mites were allowed to suck on the AIV infected chickens. Re-isolation of the virus from blood-filled mites was tried daily for 14 days using chicken embryo fibroblast cultures and embryonated chicken eggs. Subsequently, the virus containing mites were placed into boxes that contained naïve SPF chickens to enable virus transmission from mites to chickens. Possible transmission to the chickens was examined using clinical signs, serology, gross lesions, histopathology and immunohistochemistry.Chickens developed a dose-dependent viraemia one day after infection, therefore this day was chosen for the bloodmeal of the mites. AIV was detected in mites after bloodsucking on AIV-infected chickens over a 10-day period. Naïve SPF chickens were infected during bloodsucking of AIV carrying mites. AIV isolates in mites and in chickens were undistinguishable from the original AIV inoculum by RT-PCR.D. gallinae ingested AIV during bloodmeals on AIV infected chickens and are able to transmit AIV to SPF chickens. Therefore, mites serve as mechanical vector of AIV and may play a major role in the circulation of AIV within a facility or area although the life span of infectious virus in the mite is limited.The proven transmission requires more than ever a systematic control of this ectoparasite in order to maintain poultry health and productivity. The demonstrated vector function of this mite is of great significance for poultry flocks all over the world.

The causes of the notifiable fowl plague are high and low pathogenic avian influenza A viruses of the haemagglutinin subtypes H5 and H7 but also other haemagglutinin subtypes If the intravenous pathogenicity index is greater than 1.2. The German fowl plague order (Geflügelpest-Verordnung) differentiates between highly pathogenic influenza A viruses of the subtypes H5 and H7, if multiple basic amino acids at the cleavage site of the haemagglutinin molecules are detected by virus isolation, antigen or genome determination and low pathogenic avian influenza A viruses of the subtypes H5 and H7 if either the intravenous pathogenicity index is lower than 1.2 or no basic amino acids are present at the cleavage site of the haemagglutinin molecule. Aspects of diagnosis, control including culling, therapy and vaccination are reviewed. The currently available means and their limitations of a therapy of fowl plague by oral administration of neuraminidase inhibitors (e. g. oseltamivir) are described. Following granted permission, individually marked valuable zoo and pet birds may be vaccinated using licensed inactivated vaccines. Vector vaccines have not been used in Germany so far. Avian influenza A viruses of other haemagglutinin subtypes (H1-H4, H6, H8-H18) may also cause infections and severe disease. These subtypes are not subject to governmental interventions and disease can be prevented by timely use of inactivated vaccines.

Virale Vektoren stellen eine vielversprechende Plattformtechnologie zur Herstellung rekombinanter Impfstoffe dar, die neben der klassischen Prävention von Infektionskrankheiten zunehmend auch zur Entwicklung neuer, innovativer Therapiekonzepte, wie beispielsweise als therapeutische Tumorimpfstoffe, eingesetzt werden. Die vorgelegte Dissertation basiert auf Arbeiten mit dem Orf-Virusvektor D1701-V und lässt sich in zwei Schwerpunktthemen, rekombinante Impfstoffentwicklung und Vektormodifikation, untergliedern. So konnten erfolgreich Impfstoffe gegen Tollwut und Influenza A Viruserkrankungen hergestellt und die Wirksamkeit im Tiermodell erfolgreich untersucht werden. Zusätzlich konnten Grundlagen zur Generierung polyvalenter Orf Virusvektoren konzipiert und eine neue, hocheffiziente Selektionsmethode entwickelt werden.

Yearly epidemics and occasional pandemics with Influenza have been observed for several hundred years. During the last pandemic the reported deaths due to confirmed influenza was lower than expected. New epidemiologic analyses demonstrate that the severity has probably been underestimated. In addition, cohort data from severely ill patients support the use of neuraminidase inhibitors in complicated influenza infections. Due to the increasing divergence of the two circulation Influenza B strains, WHO has recommended a quadrivalent vaccine. Several quadrivalent vaccines have been successfully developed. The association of adjuvanted 2009 pandemic vaccine and narcolepsy is still debated, new data from several countries contribute to this discussion. Avian viruses have fuelled all pandemics since 1918. Surveillance of avian influenza viruses is thus regarded essential for pandemic preparedness. In 2013 a new avian influenza virus, H7N9 has cause human infections and deaths. This new strain has low pathogenicity in birds and thus surveillance is especially challenging.

Wild aquatic birds are natural hosts for a large variety of influenza A viruses. Occasionally, viruses are transmitted from this reservoir to other species, such as chickens, pigs, and man, and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The H5N1-, H7N7-, H9N2-, and H2N2-viruses are considered to have high pandemic potential, because of their pathogenicity in humans and because of the lack of immune protection in the human population. However, the unexpected outbreak of the H1N1 pandemic in 2009 demonstrates that the reliability of such predictions is limited. Host specificity, pathogenicity, and transmissibility are polygenic traits that depend on the interactions of viral proteins with host factors, among which receptor specificity and fusion activity of the hemagglutinin, nuclear transport of the polymerase, and interferon antagonism of the NS1 protein are of particular importance.

Die vorliegende Arbeit befasst sich mit der Untersuchung einer neu identifizierten Spleißvariante des humanen Guanylat-bindenden Proteins 3 (hGBP-3), einer Interferon-induzierten großen GTPase. Dieser hGBP-3deltaC benannten Spleißvariante von hGBP-3 fehlt das komplette C-terminale Exon 11 und 81 Nukleotide des Exons 7. Die Analyse einer potentiellen antiviralen Wirkung von GBPs ergab, dass die Überexpression der hGBP-3 Varianten die Influenza A Virusreplikation signifikant reduziert, wobei die hGBP-3deltaC-vermittelte Reduktion der Virustiter am effizientesten war. hGBP-3deltaC interferiert dabei sowohl mit der viralen Transkription, als auch der Synthese von viralen Proteinen und RNA-Spezies (vRNA, mRNA, cRNA), was eine Reduktion der viralen Polymeraseaktivität einschließt. Eine funktionelle Charakterisierung der hGBP-3 Domänen ergab, dass die antivirale Aktivität von der N-terminalen globulären Domäne der GTPase vermittelt wird und von einer effizienten GTP-Bindung abhängig ist.

The influenza virus isolation in embryonated chicken eggs was possible early in 1930er years and allowed the influenza vaccine production. Most influenza vaccines were derived from this, but actually new virus cell culture methods are established. For better tolerability, influenza vaccines include only antigen proportions (split- and subunit vaccines) but with the disadvantage of minor vaccine efficacy. This was compared with the addition of adjuvants. Aluminium salts are used for many decades and still in use to enhance the effect of vaccines. New formulations are MF59, AS03, AS04 or toll- like receptor-agonists. Also virosomal formulations and "ISCOMs"(Immune Stimulating Complexes) are newly designed and compromises enhanced immune reactions. Actually a broad range of various influenza vaccines exist and are available for a very different group of patients (which depends on physical conditions, age, immune status or allergies).

The propagation of multi-resistant bacteria, especially methicilline-resistant Staphylococcus aureus strains (MRSA), in hospitals and nursing homes is a well-known sanitary and therapeutic problem (Healthcare-associated MRSA, HA-MRSA). For some years, an increasing incidence of MRSA outside the hospital environment (Community-acquired or Community-Associated MRSA, CA-MRSA) has been observed all over the world, which, contrary to the hospital strains, produces the leukocytotoxic toxin PVL and causes purulent inflammations of the skin and necrotizing pneumonia. In previously healthy children and adolescents these pneumonias are fatal in most cases. The authors report a case of fatal necrotizing S. aureus pneumonia in a 16-year-old girl observed in 2001. The suspicion that the infection had been caused by a CA-MRSA strain following an influenza A infection was confirmed by the bacteriological investigation of a heart blood specimen stored for more than 2 years at 4 degrees C. In view of the bad prognosis and the fulminat course of these special pneumonias the attending physician could not be accused of having caused the death of the girl by omitting the indicated antibiotic treatment. This case of pneumonia caused by CA-MRSA was one of the first seen in Germany. The epidemiological situation suggests that a higher incidence has to be expected in the future.

A monitoring programme has been initiated in Bavaria to continuously control wild birds for the presence of avian Influenza A virus (AIV) and to monitor the possible occurrence and accumulation of notifiable AIV subtypes as an early-warning system. In addition information about the regional, seasonal and species-specific distribution of AIV could be obtained. Between July 2007 and December 2008 samples from 5864 wild birds of twelve different zoological orders had been collected (cloacal- and tracheal swab samples, droppings, and organs) and analysed. AIV genomes were detected in 3.7% of the 5864 wild birds by RT real time PCR. The subtype component H5 was identified in 52 samples (0.9%) and the N1 subtype component in 13 samples (0.2%), but never in combination with each other. The hemagglutinine subtype component H7 could not be detected. Most of the positive AIV genome results originated from samples in the district Swabia, which is situated in the central area of the south-west bird migration route across southern Germany and harbours favourable resting areas for migrating birds. Mallards (Anas platyrhynchos) were the most frequently sampled bird species and had the highest AIV infection rate of 6.4%, followed by Tufted ducks (Aythya fuligula) (AIV prevalence of 5.4%), Mute Swans (Cygnus olor) (1.6%), Coots (Fulica atra) (0.3%) and Greylag Goose (Anser anser) (0.1%). The detection rate of AIV in Bavarian wild birds showed a seasonal peak in autumn/winter. Ten virus isolates could be obtained after sample inoculation in embryonated hen's eggs.

The evolution of influenza viruses is increasingly pursued by molecular analyses that complement classical methods. The analyses focus on the two surface proteins hemagglutinin (HA) and neuraminidase (NA) which determine the viral antigenic profile. Influenza A(H3N2) viruses are exceptionally variable, so that usually at least two virus variants cocirculate at the same time. Together with influenza B viruses they caused approximately 90% of influenza virus infections in Germany during the last 12 seasons, while influenza A(H1N1) viruses only played a subordinate part. Unexpectedly, reassorted viruses of subtype A(H1N2) appeared during the seasons 2001/02 and 2002/03, but were isolated only rarely and gained no epidemiological significance. Furthermore, during the season 2001/02 influenza B viruses of the Victoria-lineage reappeared in Germany and other countries of the northern hemisphere after 10 years of absence. These viruses reassorted with the cocirculating Yamagata-like influenza B viruses, as could be seen by the appearance of viruses with a Victoria-like HA and a Yamagata-like NA.

Antiviral agents are the most effective treatment option for influenza. Two classes of drugs are available, the adamantanes and the neuraminidase inhibitors. Neuraminidase inhibitors were a major breakthrough in the treatment options for influenza and were licensed in the year 2000. They have an excellent safety profile and effectively reduce viral shedding, symptoms, duration of illness, secondary complications, hospitalizations and consumption of antibiotics. Patients have also shown a more rapid return to everyday activities. The therapeutic efficacy is highly dependent on the time between the onset of symptoms and the starting of therapy. Very early initiation is primordial to have a maximal effect. Neuraminidase inhibitors are also effective in primary and secondary prophylaxis during epidemic influenza. They are a key point in the pandemic preparedness. Resistance to neuraminidase inhibitors does occur but has not become an extensive problem so far.

An outbreak of avian influenza in August 2007 resulted in the culling of hundreds of thousands of Peking ducks. An earlier tutorial had shown that whole house gassing with carbon dioxide to kill waterfowl has to be refused because of interference with animal welfare. Culling by electrocution is a reliable method that fulfils animal welfare requirements. Stationary electrocution lines for slaughtering should be preferred if suitable for the killing of the birds. Mobile electrocution lines (MET) are a good alternative or supplementation with a capacity of circa 2,500 animals per hour. MET are suitable for killing Peking ducks with a weight of approximately 500 g. At least two veterinarians are required per MET for the supervision of animal welfare during culling. When following German animal welfare laws, killing in mobile gas containers filled with carbon dioxide is an alternative with a capacity comparable to that of MET. The problem of looking into the containers for controlled stunning and killing can be solved by installing observation windows. Manpower requirements are comparable to those of MET, while requirements for material and transportation are unlikely higher. This method is suitable for birds which are too small to be killed by electrocution.

The transmission of PRDC-pathogens (PRRSV, influenza virus A, PCV2, M. hyopneumoniae, A. pleuropneumoniae) between swine herds, which was summarized in the first part of the review, mainly occurs via pig movement. The risk of pathogen transmission by insemination with contaminated semen plays only a relevant role in the infection with PRRSV and PCV2. A risk of the aerogen transmission of pathogens between herds within a distance of 2 to 3 km is described for M. hyopneumoniae and PRRSV. Evidence for the other pathogens is not investigated. The PRDC-pathogens are frequently detected in wild boar populations. Therefore, the transmission between wild boars and domestic pigs seems possible by close contacts. PRRSV and M. hyopneumoniae can be transmitted by contaminated clothes and boots, but the use of sanitation protocols appears to limit their spread. Live vectors like rodents or birds seemed to have no special importance for the transmission of PRDC-pathogens.

Knowledge on the different ways of transmitting PRDC pathogens (PRRSV, influenza virus A, PCV 2, M. hyopneumoniae, A. pleuropneumoniae) between swine herds is of special interest for the development of biosecurity measures or the retrospective risk analysis in the framework of activities of the consulting veterinarian. In this literature review the current knowledge of the transmission of PRDC-pathogens is summarized. Since the assessment of investigations into pathogen detection in detail is influenced considerably by the chosen test for the diagnosis, the standard methods of routine diagnostic procedures are described. In this context the limits of the interpretation of the diagnostic findings are especially described in detail. Finally, the transmission caused by pig movement is summarized in this first part of the review.

Federal and regional authorities are currently preparing for a possible influenza pandemic caused by a new human influenza virus subtype. Ethical discussions in the context of such a pandemic were not systematically held within the Public Health scientific community in Germany as yet. This deficit is being approached by the authors. They plea for a systematic conception of a Public Health Ethics framework. Normative benchmarks can be set within such a framework that are more adequate for the discussion than the traditional ethical principles used within medical ethics. Public Health Ethics is an applied ethics that can be utilised for Public Health scientists and policy makers to give them advice and counsel them for a morally acceptable public health practice. The authors present a concise set of ethical principles that are applied in this article to the challenges of an influenza pandemic.

Antiviral drug therapy has rapidly evolved in recent years. A large number of specific inhibitors against newly detected viral targets has been developed. Viral infections except HIV and viral hepatitis infections are clinically relevant mostly in severely immunocompromised patients. Especially respiratory viral infections and herpes virus infections are associated with high morbidity and mortality in these patients. Therapeutic and preventive strategies have been developed for a number of these infections. There is high priority for the development of new substances for a number of viruses not yet treatable and substances active against resistant viral strains.

To help in the control of fowl plague caused by highly pathogenic avian influenza A viruses of hemagglutinin (HA) subtypes H5 and H7 several vaccines have been developed. A prophylactic immunization of poultry with inactivated influenza viruses in non-endemic situations is questionable, however, due to the impairment of serological identification of field virus-infected animals which hinders elimination of the infectious agent from the population. This problem might be overcome by the use of genetically engineered marker vaccines which contain only the protective influenza virus hemagglutinin. Infected animals could then be unambiguously identified by their serum antibodies against other influenza virus proteins, e.g. neuraminidase or nucleoprotein. For such a use, purified HA or HA-expressing DNA vaccines are conceivable. Economically advantageous and easier to apply are modified live virus vaccines in use against other poultry diseases, which have been modified to express influenza virus HA. So far, recombinant HA-expressing fowlpox virus (FPV) as well as infectious laryngotracheitis and Newcastle disease viruses have been asssessed in animal experiments. An H5-expressing FPV recombinant is already in use in Central America and Southeast Asia but without accompanying marker diagnostics. Advantages and disadvantages of the different viral vectors are discussed.

In order to determine the actual prevalence of avian influenza viruses (AIV) in wild birds in Germany, extensive surveillance studies were carried out between March 2003 and January 2005. More than 3.000 samples of 79 different species of wild birds (migratory and resident birds) were taken and 1.151 established pools investigated. Samples came from 80 different regions of Germany. Forty AIV isolates representing 14 combinations of eight different hemagglutinin and eight neuraminidase subtypes, among them H5 and H7, were identified. All H5 and H7 isolates were found to be of low pathogenicity. The overall incidence of the investigated pools based on virus isolation was 3,5 % for AIV, with considerable variability noted among species, season and location. All AIV were isolated from birds sampled in autumn. Most of the AIV isolates came from the resting or wintering areas of mallards breeding far north. This study adds to the understanding of the ecology of influenza viruses in wild birds and empahsizes the constant need for surveillance in times of an ongoing and expanding epidemic of highly pathogenic AI.

In this article the most important properties of influenza A viruses are described to understand influenza pandemics. There are at least three possibilities: (1) By reassortment between an avian and the prevailing human influenza A virus viruses with a new surface are created, against which no neutralizing antibodies are present in the human population. Such a virus can spread immediately worldwide. (2) Viruses, which have been present in the human population some time ago, reappear and infect the new generation, which has not been in contact with this virus before. (3) An avian influenza virus crosses the species barrier to humans and forms there a new stable lineage. In relation to pandemic planning, the first possibility can be more or less excluded, since the now-a-days human influenza A viruses have evolved so far away from their original source, the avian influenza viruses, that the formation of a well-growing and well-spreading reassortant is practically not possible anymore. Point two is a dangerous possibility, in that, e.g., a human H2N2 virus could reappear, which had disappeared in 1968 from the human population. The third possibility is at the moment the most dangerous situation, if, e.g., a highly neurotropic H5N1 virus from Southeast Asia crosses the species barrier to humans. An infection with such a pandemic virus presumably cannot be treated efficiently by antivirals. In such a situation only a rapid vaccination would be successful. In this respect in the last year important results have been obtained by using the reverse genetics. Meanwhile in about 50 countries there have been drawn up pandemic-preparedness plans.

The huge potential economic impact of highly pathogenic avian influenza (HPAI) substantiates specific and rigorous legal regulations worldwide. According to the O.I.E. Terrestrial Animal Health Code fowl plague is a notifiable disease. International trading activities concerning poultry and poultry products originating from countries with active HPAI are rigorously restricted. In EU member states directive 92/40/EEC subsumes measures against fowl plague and has been transferred into German legislation by the "Geflügelpest-Verordnung". These acts specify that vaccination against HPAI is principally prohibited. The aim of all sanctions is the extinction of disease and the eradication of the causative agent. However, HPAI viruses, exclusively belonging to subtypes H5 and H7, can re-emerge de novo from progenitor viruses of low pathogenicity which are perpetuated in the wild bird population. An outbreak of HPAI requires prompt action by a stamping out strategy. Fast and accurate diagnosis, a strict stand-still and the culling of affected flocks are at the basis of success. In areas with a high density of poultry holdings preemptive culling and creation of buffer zones, devoid of susceptible poultry, may be neccessary. In these cases emergency vaccinations can be considered as a supportive measure in order to limit mass culling. Vaccinations on merely prophylactic grounds, not being connected to acute outbreaks, should be avoided beware of selective pressures on the virus leading to antigenic drift and escape of vaccine-induced immunity. Instead, high standard biosecurity measures, particularly limiting direct and indirect contacts with wild birds, should be maintained.

Highly pathogenic avian influenza (HPAI) represents a severe form of generalized avian influenza which is characterized by a rapid and severe course of disease and a very high mortality. All poultry species are susceptible. Turkeys and chickens are most vulnerable. There are no pathognomonic symptoms or specific pathological alterations. The disease is caused by avian influenza virus strains of the subtypes H5 or H7. These viruses arise spontaneously from apathogenic progenitors by insertional mutation in the HA gene. Until recently, outbreaks of HPAI were rare events, however, they have been found to cause increasing losses over the past few years. Since 2003, a widespread occurrence of HPAI has been registered in southeast Asia, and some countries are endemically infected with HPAIV strain H5N1. In six countries this virus has also caused fatal human infections. This has sparked fears that this agent may be the progenitor of a new pandemic influenza virus. During summer 2005 the disease has slowly spread westward. Isolated outbreaks have been reported from Kazakhstan, Russia, Romania, Turkey, Croatia and Ukraine. Migratory birds have been tentatively accused for spreading the infection along their flyways.

RT-PCR assays which amplify conserved regions of the influenza A virus gene are useful tools for the rapid and specific detection of infections of poultry with avian influenza virus (AIV) and for the investigation of large numbers of samples, e.g. within the framework of surveillance programs. Here, we present findings on the efficiency and on the limits of an RT-PCR assay which amplifies a part of the matrix protein gene. Sensitivity and specificity of the method were increased by the additional use of nested PCR. Parameters which may have an essential influence on the detection limit are outlined and discussed. A major focus of the study is the detection of AIV RNA from organ samples and swabs.

An influenza pandemic is not merely a theoretical threat, but an historical fact. Reliable predictions of the timing of a new pandemic or its extent are, however, impossible. A pandemic poses a threat to society at large, which can be effectively prepared for by appropriate planning and investment in supplies of vaccine doses, antiviral medication and effective monitoring systems. During the interpandemic phase, general practitioners have an important role in raising the level of immunization and providing medical care to those contracting the disease when a pandemic does break out.

Influenza A is one type of influenza virus that commonly causes acute respiratory illness. Outbreaks of influenza occur every year. Major antigenic variations preclude permanent immunity in the population. Often signs of conjunctivitis or photophobia are common during acute infection. Posterior uveitis is very rare.A young lady with a diagnosed anterior uveitis was sent for further evaluation to the eye department with a known history of flu.This patient had a severe ocular manifestation of influenza A infection. There was bilateral panuveitis with keratic precipitates, cells and flare, and an impressive retinopathy in both eyes. Serology was positive for influenza A.The course of an influenza A infection is usually uncomplicated. Severe affection of the choriocapillaris results in a complicated post-influenza retinal pigmentary degeneration. Treatment with amantadine and therapy with hyperimmunoglobulins seem to be useful.

This brief review summarises some structural and biological properties of the highly pathogenic avian influenza virus and its biological significance for animal and man. Sources of actual information in case of an acute disease outbreak are also given.