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Renate Walthes Betreuerin: Prof. Inhaltsverzeichnis I Inhaltsverzeichnis 0 Danksagung Mein Dank gilt zuallererst Frau Prof.

Des Weiteren verdanke ich Frau Prof. Die Strategien der Kinder sind daher bis heute weitgehend unbekannt, zumal sich nur wenige Forschungen zu diesem Bereich finden lassen.

Foley, Gordon ; Foley ; Lambert et al. Sadato et al. Die Handlungen der Kinder werden in Videoaufzeichnungen festgehalten und mit Hilfe eines standardisierten Beobachtungsbogens dokumentiert.

In diesem Zusammenhang soll ebenfalls diskutiert werden, inwiefern Verbesserungen notwendig bzw. So lagen bereits Ende des Jahrhunderts und zu Beginn des Broca , S.

Damit wurde die Grundlage der zerebralen Lokalisation des Kortex gelegt und die Forscher begannen verschiedene kortikale Areale mit unterschiedlichen Funktionen zu differenzieren vgl.

Zihl , S. Fishman , S. Die Pathophysiologie des Sehvorganges erforschten vor allem Gratiolet und Meynert Es war also bereits Ende des Huguenin , Haab , Hun McAuley, Russell ; Reivich et al.

Zihl, Cramon , S. Die Forscher gingen nun davon aus, dass beim Sehvorgang Objekte vom visuellen System analysiert werden.

Food held before his eyes leaves him unmoved so long as he does not smell it The sight of the whip which used to drive him regularly into the corner does not frighten him any more in the least.

He was trained to give the paw of the same side if one moved the hand past his eye. Such obersavations can be multiplied. There can be no doubt about their interpretation.

One can say that the dog through our operation Jahrhunderts bzw. Anfang des Das Facetten- oder Komplexauge der Hausfliege bildet z.

Man geht davon aus, dass die Erregungen an der innersten Schicht der Netzhaut Retina in neuroelektrische Signale umgewandelt werden.

Dieser Vorgang wird als periphere Codierung bezeichnet. Roth , S. Die Retina wird in vier Segmente unterteilt: den nasalen und temporalen, oberen und unteren Bereich s.

Zeki , S. Regionen, die um diesen zentralen Bereich liegen, werden als periphere Bereiche der Retina bezeichnet. Hier finden teilweise Faserkreuzungen statt, so dass jeweils nur noch die Nervenfasern aus korrespondierenden Netzhautarealen zusammen verlaufen.

Leydhecker, Grehn , S. Roth ; Milz ; s. Fischer ; s. Die Informationen verteilen sich dabei in zwei Hauptrichtungen: durch die ventralen Verbindungen nach unten zum unteren Teil des Temporallappens und durch die dorsalen Verbindungen nach oben zum Parietallappen.

Das Areal das er untersucht hat war der visuelle Kortex. Besondere Bedeutung kommt ihnen daher wohl bei der Verarbeitung und Speicherung des visuellen Inputs auf der Ebene des Erkennens bei.

Die bedeutungshafte Wahrnehmung soll dagegen in den assoziativen Arealen stattfinden. Bestimmte Regionen und Teilregionen des assoziativen Kortex sind dementsprechend auf diese einzelnen visuellen Funktionen spezialisiert s.

Zeki, Meadows ; Pearlman et al. Hollins ; s. Kapitel 2. Aufgrund der Ergebnisse bei Menschen mit Blindsight geht man davon aus, dass das bewusste Sehen von Bewegungen sowohl ein intaktes Areal V1 als auch ein intaktes Areal V5 voraussetzt.

Alternatively, whatever operations V5 may undertake, the results of that operation must be re- entered into V1. Im Bereich der Sehnervkreuzung zweigen vielmehr einige Fasern vom Sehnerv ab.

Eine noch kleinere Anzahl von Nervenbahnen soll ebenfalls subkortikal zu einer anderen Struktur des Stammhirns verlaufen, der pretektalen Region.

Beide subkortikalen Bahnen werden auch als tectopulvinare Verbindungen bezeichnet vgl. Milz ; Hollins ; s. Singer , S.

Obwohl die Hirnforschung schon seit ca. Fragen wann, wie und wo wir uns bewusst werden ein Objekt zu sehen, wie sensorische Impulse z.

Milz Lauber ; Hoyt, Kommerell ; Savino et al. Zihl, Cramon Lediglich hochgradiger Visusverlust, zerebrale Achromatopsien oder Verluste des Tiefensehens bilden hier die Ausnahme vgl.

Cramon, Zihl , S. Schnabel, Sentker Lissauer unterscheidet zwei Formen der visuellen Objektagnosie: a apperzeptive visuelle Agnosie vgl.

Mawatari et al. Nach Zihl und Cramon , S. Auf der rechten Seite zeigen sich Schwierigkeiten selbst einfache Formen nachzuzeichnen.

Quelle: Zeki , S. Kawahata et al. Die Schwierigkeiten manifestieren sich vielmehr bei der Interpretation der Bedeutung von Formen.

Ein Patient, von dem Zeki , S. Pratesi et al. Zuvor wurde es entweder der Objektagnosie oder der Seelenblindheit zugeordnet Wilbrand ; Heidenhain bzw.

Gerard et al. Manchmal kann ein Patient auch verschiedene Gesichter unterschieden. Ein Patient konnte z. Quelle Zeki , S. Es gibt kein einheitliches Erscheinungsbild von Patienten mit Farbagnosie.

Brown Sie wurden zuerst von Poppelreuter systematisch untersucht. Lenz , Gelb und H. Lenz beschrieben.

Marx et al ; Barbizet et al. Die Schwierigkeiten zeigen sich vor allem beim Kopieren von einfachen geometrischen Figuren oder beim freien Zeichnen.

Critchley Heilman, van den Abell bzw. DeRenzi , negelect of one half of external space oder Hemineglect vgl. Crick , um das Syndrom zu beschreiben.

So kann es z. Befindet sich jedoch gleichzeitig irgendetwas Bemerkenswertes auf der anderen Seite, kann es sein, dass das Objekt auf der linken Seite nicht mehr gesehen wird.

Nach Crick kann Hemineglekt nicht nur bei der visuellen Wahrnehmung, sondern auch bei der visuellen Vorstellung auftreten.

Cogan, Adams bezeichnet. Hartmann Allerdings merken Zihl und Cramon , S. Babinsky ; Poetzl ; Barkman McDaniel, McDaniel Es wurde nach Anton benannt, der eine Frau beschrieb, die ihre Blindheit nicht bemerkte.

Beck et al. Hartmann et al. Walsh, Hoyt Sie lassen sich je nach Schweregrad, ihrer Lage, Form und Ausdehnung einteilen.

Tabelle 1. Jan, Groenveld ; s. Foley, Gordon ; Merrill, Kewman ; Ronen et al. Gloning, Tschabitscher ; Ritter et al.

Alexandridis et al. Unterschiedliche Begrifflichkeiten entstehen jedoch, indem einige vgl. Baillet et al. Pschyrembel , S. Foley, Gordon ; Merrill, Kewman ; Celesia et al.

Auch Ronen et al. Barnet et al. Weiskrantz et al. Ter Braak et al. Denny- Brown, Chambers ; Keating Obwohl sie behaupteten, dass ein solcher Versuch aussichtslos sei, stellte sich heraus, dass sie mit einer erstaunlich hohen Trefferquote die verschiedenen Richtungen der Stimuli auseinander halten konnten.

Auch dieser Patient versicherte ihm, ebenso wie die anderen Betroffenen, nichts zu sehen, sondern lediglich zu raten, obwohl er eine Vielzahl visueller Reize auseinander halten konnte vgl.

Campion et al. Nach Stoerig und Cowey , S. Stoerig et al. Weiskrantz ; Morland et al. Blythe et al. Barbur et al.

Stoerig ; Stoerig, Cowey ; Brent et al. Perenin et al. Obwohl auch Perenin et al. Jan et al. Aufgrund dieser weiter gefassten Definition kann nach Jan et al.

Henrich in der Literatur finden. Hertz et al. Porro et al. Tabelle 2. Snelling et al. Aldrich et al.

Casanova et al. Whiting et al. Hochstetler, Beals ; Gospe bis hin zu einem bzw. Thomas, Troost ; Parry et al. Gjerris, Mellemgaard ; Prakash et al.

Truwit et al. Antonellis et al. Grimes et al. Ichikawa et al. Levavi et al. Lambert et al. Eldridge, Punt ; Singh bzw.

Felber et al. Memon et al. Merimsky et al. Nakajo et al. Chew bzw. Coughlin et al. Chew ; van Nieuwenhuizen, Willemse ; Wong ; Chen et al.

Ceccaldi et al. Sadeh et al. Ronen et al. Auch Good et al. Balzar et al. Kraus et al. Akute Kortikale Blindheit kann in kritischen Situationen, wie z.

Garty et al. Ein Hydrozephalus kann sowohl akute als auch chronische CVI verursachen vgl. Lorber ; Arroyo et al.

Tabelle 3. Anton ; Gerlach et al. Henrich Obwohl der Begriff der Blindheit auch heute noch von verschiedenen Autorinnen und Autoren verwendet wird, ist er aufgrund der verschiedenen Beobachtungen und Tests vgl.

Kapitel 3. Cytowic et al. Nieuwenhuys et al. Cytowic , S. Groenveld et al. In den Studien von Huo et al.

Von insgesamt 76 untersuchten Kindern, diagostizierten Lanners et al. Quelle: nach Lanners et al. Van Hof- van Duin et al. Sie setzen stattdessen korrektive Augenbewegungen ein, um ein Objekt zu fixieren.

Dieses Verhalten kann ebenfalls bei angeborener homonymer Hemianopsie beobachtet werden. Nystagmus Lanners et al. Es ist daher wahrscheinlich, dass bei den Kindern, die einen Nystagmus aufweisen, zumindest kleine Teile des striaten Kortex erhalten geblieben sind.

Huo et al. Jan, Groenveld , S. Bei Huo et al. Kolobome im Zusammenhang mit CVI auftreten. Infolge koexistierender Verletzungen der Augen bzw.

Good et al. So konnten Lanners et al. Wong , S. Bei Groenveld et al. Lanners et al. Castano et al. Quelle: Lanners et al.

In der Studie von Huo et al. Wieser , S. Ahmed und Dutton berichten z. Es wird vermutet, dass das Ziel von Stimulationen immer darauf ausgerichtet ist, den visuellen Kortex zu stimulieren vgl.

Wenn Licht die Retina erreicht, entsteht eine photochemische Reaktion, welche die Nervenbahnen vom Auge erregt.

Diese Aktionspotentiale werden zum visuellen Kortex transportiert. Nach Jan et al. Daher vermuten Jan et al.

Light gazing Jan et al. Tso, La Piana ; Guerry et al. Desmond et al. Da alle drei Verhaltensweisen der Stimulation des visuellen Kortex dienen sollen vgl.

Auch bei Kindern mit Photophobien kann light gazing auftreten vgl. Bei Kindern mit starken Photophobien empfehlen Lanners et al. Dadurch kann sich eine Art zentraler Photophobie entwickeln, die als "thalamic glare" bezeichnet wird.

Der Thalamus spielt u. Wiesel ; Groenveld ; Dutton et al. Porro et a. Nach Porro et al. Overlooking Jan et al. Bei Lanners et al. Taylor et al.

Nach Good et al. Jedem Kind sollte daher 18 Benton et al. Devinsky und Good et al. Auch in der Studie von Jan et al. Die 2 Kinder von den 16 untersuchten Personen mit kortikaler Blindheit, die Dutton et al.

Einige Autoren vgl. Segrares et al. Rizzo, Hurtig Identifikation von Objekten Jan et al. Diese Kinder konnten z.

Auch Kivlin , S. Morse , S. Identifikation von Gesichtern Verschiedene Autoren vgl. Kivlin ; Whiting et al.

Bei der Studie von Whiting et al. Kivlin , S. Entfernungs- und Tiefenwahrnehmung Die Ergebnisse verschiedener Studien vgl.

Abschnitt Identifikation von Objekten. Kosslyn et al. Die Autorinnen und Autoren konnten dementsprechend bei mentalen visuellen Bildern keine Aktivierung des visuellen Kortex nachweisen vgl.

Rowe, Kahn nach Chatterjee, Southwood Chatterjee, Southwood , S. Chatterjee und Southwood , S.

Auch Devinsky , S. Devinsky , S. Goldenberg et al. Goldenberg ; Redlich, Bonvicini nach Goldenberg et al.

Die Autoren gehen daher davon aus, dass die Verneinung der Blindheit dadurch entsteht, dass die betroffenen Personen ihre mentalen visuellen Bilder mit der realen Wahrnehmung verwechseln.

Die Ergebnisse von Goldenberg et al. In der Diskussion geht es vor allem um autistische Symptome wie z. Humphries , S.

Diagnostiziert wird Autismus jedoch aufgrund des Verhaltens und nach speziellen Kriterien. Ek et al.

Jordan Internet Adresse; Garreau et al. Fraiberg ; Gense, Gense Jordan Internet Adresse. Dzikowski , S. Solche Empfindungen werden durch Bewegungen im visuellen Feld und bei schnellen Bewegungen im peripheren Bereich hervorgerufen Flickering vgl.

Auch schauen sie Objekte oder Personen selten direkt an, auch wenn sie versuchen diese zu erreichen und schenken einem einzelnen Spielzeug mehr Aufmerksamkeit als einer breiten Auswahl von Spielzeugen vgl.

Frith ; Grandin ; Jordan, Riding Tabelle 5. Dutton et al. Ogden Munk unterscheidet die Seelenblindheit als Verlust der visuellen Vorstellung von der Rindenblindheit als Verlust der visuellen Wahrnehmung.

Stoerig und Cowey , S. Stoerig , S. WHO Die vorhandenen Registrierungen orientieren sich zudem an unterschiedlichen Definitionen von Blindheit bzw.

Pfau et al. Hochrechnungen angewiesen vgl. Die wichtigsten vorhandenen Angaben sollen im Folgenden kurz dargestellt werden.

Steinkuller , S. Foster, Gilbert ; Gilbert et al. Mai und dem Uganda In Uganda wurden zwischen und in Schulen und zwischen und in communities 44 Regionen insgesamt Kinder unter 15 Jahren untersucht.

Waddell Im Zeitraum zwischen Februar und Dezember konnten so 45 Kinder, die zwischen einem und sechs Jahren alt waren, beobachtet werden.

Olurin , S. Bei drei anderen Kindern manifestierte sich die kortikale Blindheit als Folge einer Enzephalitis und bei drei weiteren Kindern aufgrund von schweren Kopfverletzungen.

Das Alter der Betroffenen reichte von einem Monat bis zu 76 Jahren. Foster, Gilbert ; Eckstein et al. Tirosh et al.

Texas Williamson et al. Tielsch et al. Steinkuller et al. Jan, Robinson ; Jan et al. Nach der nordamerikanischen Definition wird partially seeing Sehbehinderung von Blindheit legally blind unterschieden.

Legally blind beschreibt dabei Kinder von einem Visus von 0,1 bis zum Fehlen von Lichtscheinwahrnehmung und umfasst damit einen wesentlich breiteren Bereich als der deutsche Begriff der Blindheit vgl.

Hudelmayer Mets , S. Schweden Am Dezember geboren wurden. Bei sechzehn Kindern wurde cortical blindness, bei neun Kindern cortical visual impairment, diagnostiziert vgl.

Ducrey et al. Estimation of visual function is difficult owing to communication problems: A Infants and young children deemed by refering clinicians to have poor vision.

B Multiply handicapped children. Bei Kindern bis zum Rath, Hudelmayer , S. In einer Studie von Hansen et al. Hansen et al. Waddell ; Dandona et al.

Meremikwu et al. Rosenberg et al. Kommt es im Zusammenhang mit CVI z. Da CVI meist mit mehrfachen Behinderungen s.

Einige Autorinnen und Autoren erfassen sowohl Kinder als auch Erwachsene vgl. Doch auch bei diesen Studien variiert das Altersspektrum deutlich.

So gibt es Autorinnen und Autoren vgl. Bayce, Alemayece , andere Kinder bis 9 Jahren vgl. Arnaud et al.

Williamson et al. Trosh et al. Dandona et al. Bohme, Tonnquvist Wesentlich geringer fallen die Populationen in der Untersuchung von Meremikwu et al.

Im VIP werden z. Trotz der differierenden Erhebungs- bzw. Foster, Gilbert ; Thylefors ; Eckstein et al. Ferrell , Whiting et al.

Seit ca. Robertson et al. Nach Wieser , S. Shibata et al. Yuen ; Kasahata et al. Psatta, Matei ; Lambert et al. DeVolder et al.

Price et al. Patronas, Argyopoulou , Embolien vgl. Heeney, Koo ; Acolovschi et al. Lebedeva, Kanevskaia ; Howard et al.

Tsutsui et al. Murayama et al. Sanin, Mathew ; Ogden ; Milandre et al. Man nimmt an, dass der zugrunde liegende Mechanismus Infarkte an den arteriellen Grenzzonen der Wasserscheidengebiete, den sogenannten parietookkipital und parasagittalen Regionen, sind vgl.

Volpe et al. Hoyt, Walsh ; Benton et al. Das Erscheinungsbild bzw. In den Untersuchungen von Flodmark et al.

Pape, Wigglesworth Casteels ; s. Shuman, Selednik ; Roland et al. Uggetti et al. Flodmark et al. So war auch in den Untersuchungen von Groenveld et al.

Hoyt, Walsh ; Weinberger et al. Casteels et al. Haas, Souner Griffith, Dodge ; Drymalski Auch Palinopsien 26 konnten beobachtet werden vgl.

Singh Der Sehverlust nach weniger schweren Traumata kann sich ca. Han, Wilkinson Tabelle 7. Hier manifestiert sich die Blindheit sofort oder innerhalb einiger Minuten nach dem Unfall.

Das adoleszente Muster, bei dem die Betroffenen zwischen 8 bis zu 14 Jahren alt sind, wird von Greenblatt als das Paradigma des Syndroms verstanden.

Gjerris und Mellemgaard betonen, dass Erwachsene wesentlich mehr verschiedene und schwerere Symptome haben. Es kann sich dabei iktal Zung, Margalith ; Joseph, Louis oder postiktal vgl.

Skolik et al. Kosnik et al. Barry et al. Verdile, Verdile ; Chew ; Lau et al. Die Mehrheit der Betroffenen war zehn oder zwanzig Jahre alt, und der Sehverlust dauerte einige Minuten bis zu einer halben Stunde.

Der Sehverlust manifestierte sich entweder iktal oder postikatal. Postiktale Blindheit kann u.

Olurin ; Fiume Aldrich, Vanderzant Daher ist nach Good et al. Helmchen et al. Kinn, Breisblatt ; Kermode et al. Horwitz, Wener ; Good et al.

Wesentlich seltener wird es nach Aortographie vgl. Johnson, Moss 32 und nach Myelographie vgl. Smirniotopoulos et al. Kinn, Breisblatt ; Rama et al.

Studdard et al. Manifestation Der Sehverlust als Folge der Infusion von Kontrastmitteln manifestiert sich innerhalb von ein paar Minuten bis zu 12 Stunden nach einer Angiographie.

Fast alle Betroffenen regenerieren sich nach und nach innerhalb von zwei bis zu sieben Tagen vgl.

Brewster et al. Lawrence et al. Kabra et al. Waldron, Stallworth 36 oder als Komplikation einer Nephritis vgl.

Devathasan et al. Drymalski Ackroyd Tepperberg et al. Gado et al. Katafuchi et al. Es lassen sich auch Berichte von Neurotoxikosen nach einem Kobrabiss vgl.

Berger, Brook , einer Quecksilbervergiftung vgl. Davis et al. Gospe oder einer Toxoplasmose vgl.

Wilson et al. Cyclosporin-A, Interleukin 2 vgl. Cisplatin berichtet vgl. Higley et al. Das Kokain diffundiert sehr schnell durch die Plazentaschranke.

Dixon , S. Kupferschmidt et al. Craigen et al. Brown et al. Amano et al. Servidei et al. Kormguth et al.

Connolly et al. Hagerty et al. Mathe et al. Durand et al. Tsutsumi et al. Burke et al. Marsh, Hurst ; Hayashi et al.

Goldberg, Custis 52, Leigh-Syndrom vgl. Morris, Harbord ; Donovan ; Oldfors et al. MacDonald ; Markowitz et al. Schonlein-Henoch Syndrom vgl.

Benhamou et al. Schimmelpfennig-Feuerstein-Mims-Syndrom vgl. Hager 56, Creutzfeld-Jakob Krankheit Pinto et al.

Carney, Anderson a,b 58, Mumps vgl. Ohama et al. Hahn et al. Fanton et al. Payton, Jones 61, Multiple Sclerose vgl.

Castaigne et al. Constantinou et al. Assadi et al. Opitz et al. Ikeda et al. Elner et al. Sahota et al. Es kann aber auch verschiedene neurodegenerative Erkrankungen z.

Estbe ; Jin et al. Krimmel, Reinert ; Okamoto et al. Hydrozephalus kann akute, aber auch chronische CVI bedingen.

Corbett Sekhar et al. Hochwald, Sahar ; Saher Osher et al. Keane ; Drymalski , aber auch schwerer bilateraler Sehverlust kann beobachtet werden vgl.

Keen ; Wybar ; Jan et al. Der Sehverlust kann abrupt auftreten und von einer Reihe visueller Symptome begleitet werden vgl.

Hayreh und Okkipitalinfarkte aufgrund der Kompression der hinteren Zerebralarterie vgl. Arroyo et al. Moore, Sterm Erstmals von zerebraler Blindheit in Folge einer Bestrahlung haben Pomeranz et al.

In dieser haben sie drei Kinder untersucht. Das Absterben eines Zwillings geschieht teilweise unbemerkt, so dass Good et al. Angeborene Hirnfehlbildungen s.

Bei 14 Kindern waren die zerebralen Anomalien unspezifisch. Barkovich, Norman a und der Abwesenheit des Septum Pellukidum vgl. Barkovich, Norman b verbunden.

Barkovich et al. Fantz Teller et al. Birch und Bane , S. McDonald et al. Good ; Jan et al.

Allen et al. Meienberg et al. Das Suchmuster kann dann als grobes Muster benutzt werden, um das visuelle Feld zu messen vgl.

Van Hof-van Duin, Mohn Manchmal erlaubt auch ein Goldmann Perimeter ein genaues Messen des Gesichtsfeldes s. Akiyama et al.

Danach werden differente Elektroden, die in Kontaktlinsen eingearbeitet sind, auf die Hornhaut gesetzt. Nickel, Hoyt Bei dieser Methode werden an der Kopfhaut der Patientinnen und Patienten Kontaktelektroden angebracht, die die Potentialschwankungen des Gehirns registrieren.

Der Alpharhythmus entwickelt sich im Alter von drei Monaten und stabilisiert sich mit dem ersten Lebensjahr. Er wird durch psychosensorische Reizung z.

Jan, Wong Ackroyd , Tepperberg et al. Bodis- Wollner et al. Reim , S. Kupersmith, Nelson Jan, Wong ; Whiting et al.

So stellten auch Whiting et al. Bowerman et al. Mohn et al. Von pathologischen Strukturen wie z. Weindling et al. PVL ist daher in der subakuten Phase mit Sonographie nur schwer zu diagnostizieren.

Bosley et al. Gottlob , S. Die visuellen Funktionen sollen sich bei diesen Kindern erst zwischen dem zweiten und vierten Lebensjahr verbessern.

Innerhalb der ersten zwei Jahre soll es bei dieser Gruppe zu einer Verbesserung des Visus kommen, selbst wenn die zugrundeliegende Augenkrankheit nicht behandelt werden kann.

Sie zeigen keine visuelle Aufmerksamkeit und fixieren oder folgen auch keinen hellen Objekten vgl.

Lancet Fielder, Mayer ; Wieser Vielmehr konnten auch visuelle Antworten bei Kindern ohne visuellen Kortex beobachtet werden vgl.

Aylward et al. So beschreiben Aykward et al. Lambert Nach Flodmark et al. Smythies , S. Griffith, Dodge Drymalski ; Ramani ; Beck et al.

Faust Viele Kinder haben Schwierigkeiten mit ganz spezifischen visuellen Stimuli vgl. Morse , die sich z.

Daher kann nach Groenveld et al. Diese Faktoren werden daher mit bestimmten Prognoseaussichten verbunden.

Dabei gehen Flodmark et al. Auch Lambert et al. Wong ; Foley, Gordon ; Hoyt ; Wunderlich et al. Erwachsene mit erworbenem CVI vgl.

Wong, ; Foley, Gordon , Wong ; Casteels et al. For all the rubbished drafts, the yellow highlights and the disagreements about clinical data I am so grateful, like the gratitude one feels towards ones parents for denying them chocolate and forcing the vegetables as a child.

I also thank Kate Templeton, my co-supervisor, whose keen eye for publishable data and optimistic attitude have promoted belief in my work at the most challenging of times.

You have given me unprecedented access to resources both reagents and staff without which I simply could not have undertaken the bulk of this research.

Contamination, negative results and no controls! You are queen of the laboratory and it was such a priviledge to be shown the skills by the best in the business.

Also for all the phylogenetic advice I am truly indebted. Jill Douglas , the whole research group would will?!

Thank you for your organization, patience, and leadership. David Taylor. The man who single-handedly saved my career.

You were an absolute rock during the most difficult time; a world of David Taylors would be a noble one indeed.

You welcome when I arrived at Summerhall i. To my collaborators and those I have sought advice from externally, many thanks for your enthusiasm and willingness to discuss ideas.

To my partner, Mr Richard Selby, you were really there when I needed you and not there when I needed you not to be!

Thank you for giving me perspective, for keeping me grounded, for keeping me sane even if by driving me insane. To my parents. Thank you for always believing in me and giving me the values and strength to follow my dream.

This is, of course, dedicated to you. The recent discovery of several novel respiratory viruses, such as human metapneumovirus HMPV , human bocavirus and human coronaviruses HCoVs NL63 and HKU1 has nevertheless created significant challenges in respiratory diagnostics, as identification of which pathogens should be tested for is increasingly difficult.

Clinically, coronaviruses were similar to viruses currently included in routine diagnostics, with the exception of HCoVE which was identified as an opportunistic pathogen in immunocompromised hosts.

The low detection frequencies of HCoVs, comparable to those of parainfluenza viruses 1 and 2 which are included in the routine diagnostic screening panel indicate a borderline case for inclusion of these pathogens in routine respiratory diagnostics.

To investigate the epidemiology and clinical correlates of HMPV in Edinburgh, large scale retrospective screening of over respiratory samples collected over two years was conducted.

Comparisons of the clinical presentations of the two genotypes revealed little difference, with only the observation that sub-genotype B2 was more frequently associated with infection of immunocompromised patients.

Detection - iii - frequencies and symptomatology associated with HMPV infections were comparable to respiratory viruses currently included in the routine diagnostic panel, mandating its inclusion in future diagnostic screening.

A switch of the predominantly circulating genotype of HMPV was observed between respiratory seasons. This is a phenomenon more widely reported for the closely related respiratory syncytial virus HRSV , which also comprises two circulating groups.

The fusion and attachment G genes were targeted, as these encode major surface proteins and are immunogenic.

Switching of the predominantly circulating lineage does not arise for either virus due to emergence of novel strains, but through fluctuating circulation frequencies of pre-existing lineages which have been circulating for several decades, indicated by the time since the most recent common ancestor.

Positively selected sites identified within the HRSV G gene were incongruent with those identified in a previous study, generating the hypothesis that immune evasion occurs within linear epitopes rather than at specific sites.

A great deal of clinical and epidemiologic data was generated through this work, parallel studies of other respiratory viruses and through diagnostic screening results.

To provide a robust indication of where resources should be diverted in terms of diagnostics, therapeutics and vaccine development, and to inform infection control measures and public health policy planning, quantification of the relative disease burden attributable to the most commonly detected respiratory viruses was calculated using the World Health - iv - Organization- endorsed Disability Adjusted Life Year DALY model.

Relative disease burden was calculated in an age stratified manner to reflect the differences in sampling in different age groups.

HRSV and influenza A were consistently one of the greatest causes of disease regardless of sampled population, although HRSV caused more disease in children under 5 than influenza A and B combined.

Rhinoviruses and PIV-3 were significant pathogens in all groups except those aged years; rhinoviruses were the leading cause of disease in the immunocompromised patient group.

The potential for patient-specific diagnostic screening and guidance of interventions such as patient cohorting were clear.

General Introduction A brief history of respiratory microbiology Respiratory virus classification Clinical outcomes of infections with respiratory viruses Upper respiratory tract infections URTIs Lower respiratory tract infections Miscellaneous presentations during respiratory virus infections Sequelae of respiratory infections Respiratory sequelae Neurologic sequelae Systemic sequelae Respiratory virus diagnostics in the clinical setting Epidemiology and evolution of respiratory viruses Recombinant and zoonotic respiratory viruses The paramyxoviruses Epidemiologic relationships between respiratory viruses Analyses of virus evolution at the genomic level Disease burden of respiratory viruses Materials and Methods Materials: respiratory sample archive, Edinburgh Sample collection and storage Archive parameters Diagnostic testing Clinical data Methods: Laboratory based techniques Nucleic acid extraction Pooling of respiratory RNA Reverse transcription Primer design Nested PCR Synthesis of high copy number coronavirus RNA and multiplex assay sensitivity Agarose gel electrophoresis Sequencing reaction Methods: Computational analyses Statistical analyses Sequence alignment Phylogenetic analyses Bootstrap values Detection of residues under positive selection Sampled population Clinical outcomes and estimates of morbidity scores Immunocompromised patients Estimating DALYs Results I.

The clinical presentations of human coronaviruses Respiratory coronavirus epidemiology Coronavirus infected patients Coronavirus circulation trends Clinical correlates of coronavirus infections Coronaviruses in mixed infections Assay sensitivity and specificity Epidemiologic observations of coronaviruses Clinical aspects of coronavirus infections Coronavirus recombination Results II.

Clinical outcomes of respiratory virus infection Molecular epidemiology of HMPV Patient parameters in HMPV infection Results III. HRSV-G phylogenetic analyses and epidemiologic inferences HRSV G protein evolution HMPV G protein evolution Results IV.

The relative disease burden of ten respiratory viruses, quantified using the disability adjusted life year DALY model Prevention from respiratory virus infections Treatment of respiratory virus infections Allocating resources in the field of acute respiratory infections Results and discussion Study parameters Disease burden of ten respiratory viruses Concluding remarks Study limitations Future directions General discussion Critique of the design of the studies undertaken for this thesis Clinical correlates of respiratory virus infection Epidemiologic trends of respiratory viruses Quatification of disease burden Respiratory virus diagnostics Forthcoming observations on clinical aspects of respiratory virus infections Pneumovirus evolution Fluorescent probe hybridization to amplification product and release from sequestration by Taq polymerase Distribution of age of patients from whom samples were collected Origin of all samples collected between July and June Breakdown of sample types by physiological origin in the respiratory tract.

Frequency of clinical symptoms and their associated virus detection frequencies. The algorithmic process of PCR protocol design Ct values for serially diluted coronavirus transcripts Detection of the four coronaviruses by age group Detection frequencies of the four coronaviruses over three years in Edinburgh compared with influenza A detection frequency in clinical specimens.

A Comparison of the respiratory presentations of study subjects singly infected with coronaviruses and those infected with respiratory viruses included in diagnostic screening.

B Proportion of samples testing singly positive for each respiratory viruses that were taken from patients with immunosuppression.

Boxplots detailing the Ct values obtained for different coronaviruses in single s and mixed m infections. Monthly HMPV detection frequency Clinical correlates of HMPV by genotype Clinical presentations associated with the most commonly detected respiratory viruses Relative proportion of disease burden caused by ten respiratory viruses Relative disease burden caused by ten respiratory viruses in males compared with females.

Taxonomic breakdown of the main viral agents of acute respiratory tract infections Aetiologic agents of the common cold Detection frequencies of the aetiologic agents of community acquired pneumonia Detection frequencies of the aetiologic agents of LRTI in children Biochemical and genetic properties of viruses which cause symptomatic acute respiratory tract infection Respiratory viruses and their associated sequelae Outline of the classic longitudinal prospective community based epidemiologic studies Reagents for four-way multiplex real-time RT-PCR for detection of the four known human respiratory coronaviruses.

Virus specific nested PCR cycle numbers and anneal temperatures Summary of models commonly cited for phylogenetic tree construction Definitions of disability weighting Ct values obtained on triplicate runs of serially diluted coronavirus transcripts of known copy number using the novel four-way real-time RT-PCR multiplex assay Calculation of the theoretical detection threshold of the four coronaviruses Detection frequencies of respiratory viruses over 3 years Rates of admission of coronavirus infected patients into intensive therapy units ITU Breakdown of symptoms associated with coronavirus infections which were categorized as other.

Mean Ct values for samples testing singly positive for coronaviruses from patients with different clinical presentations Summary of published longitudinal studies of the molecular epidemiology of HMPV.

Detection rates of respiratory viruses from samples over 2 years Fishers exact test for association of HMPV infecting strain with immunological status Summary of the evolutionary analyses undertaken by taxomonic group Sequence datasets for phylogenetic and for positive selection analyses Detection frequency of respiratory viruses Intensive therapy unit ITU admission rate, and pairwise comparison p values 3 d.

Relative disease burden attributable to the most commonly detected respiratory viruses Relative disease burden of ten respiratory viruses in males and females standardised to the same denominator for direct comparison General Introduction 1.

A brief history of respiratory microbiology Respiratory illnesses have plagued mankind for millennia, acquiring a reputation among the most feared diseases.

These affections are commonly of short duration, but if neglected may last for a long while. This set the precedent for the discoveries of two major causative agents of pneumonia, Streptococcus pneumoniae and Klebsiella pneumoniae in General Introduction and by Carl Friedlander, a German pathologist and microbiologist, and Albert Fraenkel, a German physician, respectively Fraenkel, ; Friedlaender, The NIMR founders prioritised research into viral diseases, perhaps influenced by the undetermined aetiology of the very recent influenza pandemic Porterfield, , and this was rewarded by the seminal discovery at the NIMR of the first respiratory virus, influenza A virus in Smith, The purpose of the CCRU was to identify the aetiology of colds, how they were transmitted, and what their effects were.

Transmission studies of common cold viruses were conducted on human volunteers, who were recruited through advertisements in newspapers to holiday in the south of England for a period of ten days, at the price of risking catching a cold Figure 1.

Not one, but many different viruses were isolated during the studies conducted at the CCRU, including many strains of rhinoviruses of both species A and B Andrewes, ; Parsons, ; Tyrrell, Various exposures were tested to elucidate the mechanisms of virus spread, including sharing sleeping quarters, playing cards and dining with infected individuals.

In this way, the respiratory and fomite routes of transmission were identified for common cold viruses, and incubation periods were determined.

Having achieved the mission statement originally declared, the CCRU closed in General Introduction Figure 1. Left clipping, January 21, ; centre clipping, November 17, ; right clipping, January 3, Other research groups investigating the aetiologies of respiratory tract illnesses concurrently with the work undertaken at the CCRU reported several significant discoveries in the s and s.

A subsequent community outbreak of disease in the same population was determined to be of the same aetiology, as was a previous community epidemic through retrospective testing.

The novel influenza-like virus was in accordance with the contemporary taxonomy called influenza B Francis Jr, The virus was pneumotropic in animal models, and seroconversion was demonstrated in two sets of paired sera of General Introduction humans Hirst, A new species was tentatively identified as probably an influenza virus; this virus has since been classified as influenza C.

An outbreak of acute respiratory tract infection ARTI in chimpanzees in an American laboratory which transmitted to the laboratory staff led to the discovery of respiratory syncytial virus HRSV in Chanock, then called chimpanzee coryzal agent CCA.

HRSV is unquestionably the leading cause of lower respiratory tract disease in infants and young children. A quarter to a third of primary HRSV infections result in development of lower respiratory tract disease Glezen, ; Sterner, , and the rate of infant hospitalisation during the annual HRSV epidemics is 0.

Lack of a good cell culture system for PIV-4 has meant that clinical and epidemiological studies undertaken prior to the development of molecular methods such as the polymerase chain reaction PCR have infrequently included the virus.

Nevertheless, an excellent longitudinal study of the four parainfluenza viruses between and in England and Wales provided some key insights into the clinical and epidemiologic correlates of these viruses Laurichesse, Pneumonia and bronchiolitis were diagnosed during PIV-4 infections as frequently as during other parainfluenza infections, lending support to the suggestion that this virus has been overlooked due to its infrequent detection rather than mild clinical correlates.

It quickly became apparent that adenoviruses are not principally agents of acute respiratory infections, but rather are transmitted primarily by the faecal-oral route and cause a wider range of clinical outcomes including epidemic conjunctivitis Jawetz, and infantile gastroenteritis Flewett, ; Yolken, Most seminal was the discovery that adenovirus induced malignant tumours in newborn hamsters Trentin, ; this was the first time a virus was shown to be oncogenic.

Currently there are seven human adenovirus species, A-G comprising over 50 serotypes, most of which were originally detected in man.

The principal serotypes associated with respiratory presentations are 3, 4, 7, 14 and 21; with the exception of serotype 4 species E , these are all assigned to species B.

LRTI caused by adenovirus occurs through inhalation of aerosolized virus into the lungs, whereas application of virus to the mouth, nasal mucosa or intestine does not produce infection of the lower respiratory tract Couch, An impressive array of enteroviruses belonging to all four species A-D are associated with respiratory outcomes Jacques, Hereon, new echovirus serotypes were frequently identified.

A recent study in a General Introduction hospitalized patient cohort detected parechoviruses as frequently in patients with lower respiratory tract infections as in patients with no respiratory symptoms Harvala H, , and suggested that in the future, parechovirus diagnoses should only be sought in patients presenting with neonatal sepsis or meningitis.

An intermission in the discovery of novel respiratory viruses followed the characterisation of the coronaviruses in the s, denoting an end to the era of virus discovery by cell culture.

New serotypes and strains of a range of species were discovered, and reclassifications including the division of the myxoviruses into orthoand paramyxoviruses and the creation of the Parechovirus genus took place, but it was not until the development of molecular detection techniques that further truly novel discoveries were made.

In , a previously uncharacterized virus was isolated from respiratory samples collected from children with lower respiratory tract disease.

The virus grew poorly in monkey kidney cells; cytopathic effects were observed, but only after a longer duration than seen on infection of cell culture with HRSV van den Hoogen, 1.

To determine the identity of this HRSV-like virus, electron microscopy, chloroform treatment, and randomly amplified PCR and nucleotide sequence analyses were undertaken.

A pneumovirus distinct from HRSV was identified and called human metapneumovirus HMPV , maintaining taxonomic congruity with the virus to which it was most closely related, avian metapneumovirus.

Since this time, a multitude of studies to determine the biochemical, clinical and epidemiologic characteristics of this recently discovered respiratory virus have been undertaken.

This was the first truly novel respiratory virus to be discovered since the s, which is perhaps one of the reasons for the inordinate research interest.

Of course, this suggestion is mere speculation, but it is a pleasing thought nonetheless. General Introduction may indeed cause significant respiratory disease McIntosh, , ; Wenzel, The severity of illness observed on infection with the severe acute respiratory syndrome associated coronavirus SARS-CoV conveyed a wider role of coronaviruses in respiratory tract disease than previously thought; a notion strengthened by the subsequent discovery of a further two coronaviruses, HCoV-NL63 in van der Hoek, and HCoV-HKU1 in Woo, a in patients with lower respiratory tract infections.

Human bocavirus HBoV was discovered in by random amplification of nucleic acids in respiratory samples, cloning of products into E.

HBoV detection frequencies in the range of 1. The conclusion of this study that disease caused by HBoV arises through the exacerbation of symptoms during primary infection with other respiratory agents is supported by further studies Martin, HBoV has been identified in gastrointestinal samples at a similar frequency to the detection rate in respiratory specimens Lau, ; Vicente, General Introduction The recent discovery of a novel rhinovirus species has been laid claim to by several research groups.

The first publications came to press in , when a high incidence of influenza like illness in in New York, which was not due to any of the pathogens usually associated with this disease presentation, was further investigated amid concerns that a novel agent might be involved.

Amplification, nucleotide sequencing and phylogenetic analyses of isolates revealed a previously unidentified lineage of rhinoviruses, now classified as species C HRV-C; Lamson, Additionally, an investigation into the causes of asthma exacerbation using DNA microarray identified five divergent rhinovirus isolates which formed a distinct genetic group Kistler, Also of note, the recently identified WU and KI polyomaviruses identified in respiratory samples taken from patients with presentations of acute infection Allander, a; Gaynor, are identified as frequently in samples from control groups as in samples from respiratory patients Norja, It is likely that new viral agents of respiratory disease will be discovered in the future.

Not all cases of acute respiratory illness are diagnosed, and novel molecular techniques such as deep sequencing provide almost unlimited potential for exploratory investigations of the agents residing in respiratory secretions.

Further, changes in human demography and virus evolution will together pave the way for emergence of novel respiratory viruses.

Globally, increasing population densities, ageing populations, increasing survival of immunocompromised persons, and higher rates of allergy, COPD and asthma all increase population susceptibility to respiratory virus infections.

Respiratory virus classification The main viral agents of acute respiratory infections are taxonomically diverse, representing five families Table 1.

The human adenoviruses are assigned to the Mastadenovirus genus of the Adenoviridae, which currently comprises over twenty species Fauquet, Seven of these species are human adenoviruses A-G, which is somewhat of a misnomer, as these species frequently include simian serotypes and human adenovirus C even includes a feline strain.

Well over a hundred adenovirus serotypes have been identified, with over 50 of these infecting humans, and zoonotic transfer events between species are observed Afshar, ; Phan, ; Xiang, Influenza, parainfluenza and HRSV viruses were originally classified together as myxoviruses, but were subsequently recognised as representatives of two distinct virus families.

The parainfluenza viruses were assigned to the alternate subfamily - the Paramyxovirinae, which comprises several genera.

Also of the Paramyxovirinae, measles virus is identified within the Morbillivius genus. Concurrent with the reclassification of the Paramyxoviridae, the influenza viruses were reassigned as orthomyxoviruses.

Each influenza virus species A-C is assigned within a different genus in the Orthomyxoviridae family. The Coronaviridae divide into two subfamilies; the Coronavirinae, to which human coronaviruses belong, and the Torovirinae.

The Coronavirinae comprises three genera. SARSCoV phylogenetically branches early from the group 2 coronaviruses, and is accordingly subdivided in group 2b, with the remainder of the group 2 coronaviruses are components of group 2a.

Only avian strains of the Gammacoronavirus genus group 3 have been identified. General Introduction Table 1. Taxonomic breakdown of the main viral agents of acute respiratory tract infections.

The viruses of particular relevance to this thesis are indicated in boldface. Among these, the rhinoviruses and enteroviruses of the Enterovirus genus are divided into seven distinct species rhinovirus species A-C and enterovirus species A-D.

Despite this bipartite nomenclature, these seven species are equidistantly related genetically; their clinical differences arise through different replication sites at least in part governed by differences in receptor use.

The General Introduction - 10 - parechoviruses are classified within a distinct Parechovirus genus, with currently ten human serotypes grouped within the human parechovirus species.

Clinical outcomes of infections with respiratory viruses Acute respiratory tract infection ARTI is the most common type of acute infection in children and adults.

Infection of the upper respiratory tract is indicated by any or a combination of presentations including coryza, tonsillitis, sore throat, laryngitis, sinusitis, pharyngitis, and rhinitis.

Rhinoviruses were detected during In the later study, the recently discovered coronaviruses, influenza C and human metapneumovirus were tested for.

Lower respiratory tract infections Lower respiratory tract infections LRTIs were in identified as the 8 th leading cause of disability adjusted life years DALYs; a combined assessment of morbidity and mortality; refer to 1.

In the African region, 8. General Introduction - 12 - Table 3. Detection frequencies of the aetiologic agents of community acquired pneumonia Aetiologic agent Study of community acquired CAP Lieberman, 1 Lauderdale, Jokinen, Luna, Diagnosis of community acquired pneumonia CAP is based on clinical presentations, which should include cough and at least one other symptom of acute LRTI Scottish Intercollegiate Guidelines Network, , and identification of pulmonary infiltrate on a chest radiograph.

Young children and the elderly are the most commonly afflicted with pneumonia. Streptococcus pneumoniae is almost invariably the most frequently detected pathogen in aetiologic studies of CAP.

Differentiating viral and bacterial pneumonias is difficult based on presentation alone, one inevitable ramification being over-prescription of antibiotics.

Bronchitis, predominantly a condition of older adults - particularly males Ball, - is characterized by a cough of one to three weeks duration associated with URTI, where pneumonia has been excluded.

Bronchiolitis is characterized by wheezing, hypoxia and tachypnoea caused by obstruction of the small airways, and is predominantly seen in infants and young children.

Additional to symptoms of LRTI and URTI, infections with respiratory viruses may further be specifically associated with other clinical presentations and sequelae.

General Introduction - 15 - These sometimes involve the respiratory tract but may also be of neurological, systemic, gastrointestinal, ocular or other consequence.

Miscellaneous presentations during respiratory virus infections Pyrexia is frequently observed during acute respiratory tract illness Putto, Fever is incorporated in the case definition of influenza, and is exacerbated in children, in whom it may cause convulsions Brocklebank, ; Glezen, ; Price, Tissue tropism in virus infection is dictated by the receptor specificity of the infecting virus, and respiratory and gastrointestinal epithelia express many of the same cell surface molecules.

For example, abundant expression of sialic acids on the epithelia of both respiratory and gastrointestinal tracts would theoretically allow infection of both tissues by sialic acid binding respiratory viruses e.

Infection with influenza is sometimes associated with vomiting and diarrhoea, and the virus has been detected in stool samples from patients with concurrent gastrointestinal and respiratory symptoms Chan, Children have a higher incidence of gastrointestinal manifestations than adults Dingle, The degree of sequence similarity between these two viruses is sufficient for bi-directional serologic cross-reactivity Gerna, It is perhaps surprising, then, that evidence of GI General Introduction - 16 - presentations during respiratory coronavirus infections is sparse.

Clinical studies of SARS-CoV provided the strongest association of gastrointestinal presentations with respiratory coronavirus infection; diarrhoea and vomiting were reported in a quarter of cases Booth, ; Hsu, ; Lee, ; Tsang, In a longitudinal epidemiologic study of the four respiratory coronaviruses, four of 32 single coronavirus infections were associated with gastrointestinal symptoms Kuypers, In clinical studies of HCoVNL63, two of seven and four of twelve infections involved gastrointestinal presentations Leung, ; Wu, Adenoviruses are often associated with outbreaks of gastroenteritis, and a high incidence of gastrointestinal presentations during adenoviral RTI are reported Sterner, Summarily, that adenoviruses cause both respiratory and diarrhoeal presentations is established, but how extensively these conditions overlap is altogether unclear.

Cardiac involvement on HRSV infection has presented in a range of ways, including myocarditis, tachycardia, and arrhythmias Eisenhut, HRSV associated cardiac presentations have proven fatal in previously healthy patients.

Some enteroviruses which cause respiratory illness have been identified in patients with myocarditis, and death due to myocarditis preceded by upper respiratory tract infection in which the only pathogen detected was enterovirus has been documented Panagiotopoulos, During the course of influenza virus infection, onset of acute myopericarditis as respiratory symptoms wane has been described Adams, Additional to cardiac presentations, a generalized role for acute respiratory infection in the exacerbation of nephritic syndrome is suggested MacDonald, General Introduction - 17 - Table 5.

Similarly, apnoeas have been identified in PIV-3 infections have also been linked with apnoeas in infants under the age of six months Karron, The presentation of acute otitis media AOM is frequently attributed to acute respiratory virus infections, and reciprocally, acute respiratory virus infections are frequently accompanied by otitis media.

Case fatalities in immunocompromised populations have been observed on infection with most respiratory viruses, including but not limited to influenza Ljungman, ; Milne, ; Schnell, ; Simonsen, , adenovirus Halstead, ; Klinger, ; Murtagh, ; Wenman, , parainfluenza viruses Lewis, b , HRSV Englund, ; Whimbey, , HMPV Englund, ; Sivaprakasam, , and rhinoviruses Longtin, ; Nicholson, General Introduction - 19 - 1.

Respiratory sequelae Sequelae of respiratory virus infections are summarized Table 6. Perhaps the most widely studied sequela of ARTI is asthma, the most common chronic disease of childhood, characterized by recurrent attacks of wheezing and breathlessness.

There is strong epidemiologic evidence that early HRSV infection predisposes to asthma Sigurs, , but several studies of the association of other respiratory viruses with asthma onset provide less compelling results Martinez, In children under two years of age, asthma exacerbation is most often due to HRSV infection, whereas rhinoviruses are the predominant cause in older children and adults Johnston, ; Nicholson, ; Rakes, HRSV induces upregulation of the intracellular adhesion molecule ICAM-1, which supports adhesion and retention of infiltrating neutrophils and activated eosinophils, thereby contributing to inflammation Stark, Table 6.

Adenoviruses were first associated with CNS disease in the s Lelong, Reports of adeno-associated neuropathy intermittently since this time have been of sufficient rarity to prevent evaluation of epidemiologic trends or refined clinical definitions.

Coronavirus infections cause demyelination in primate models Murray, and virions have been isolated from and visualized in the brain of multiple sclerosis patients Burks, ; Tanaka, Detection of other coronaviruses in the nervous system of neurologically afflicted patients has not been reported; nevertheless, General Introduction - 21 - much speculation surrounds the association of coronaviruses with neurologic manifestations Dessau, ; Gilden, ; Lau, ; Severance, Despite extensive vaccination campaigns, poliovirus still causes epidemics of acute flaccid paralysis, and enterovirus 71 has been associated with poliovirus-like paralysis Chonmaitree, However, the cross-over between enterovirus types causing respiratory illness and the neurologic manifestations described is currently poorly defined.

Systemic sequelae In , Ernest Goodpasture published his observations on the histopathologic findings from post-mortem examinations of individuals who had died during the influenza pandemic Goodpasture, He rebuked suggestions that a bacterial pathogen was the cause of the pandemic, and inferred the disease was of an as yet unknown aetiology influenza A virus was discovered in Smith, The condition arises through an autoimmune response to Goodpasture antigen, expressed in the lung and kidney, and is extremely rare.

Adenovirus serotypes of species A 12, 18 and 31 are highly oncogenic Kuwano, The link between adenoviruses and oncogenesis was first suggested in the s Trentin, , when it was proposed that for malignancy due to adenovirus, integration of viral DNA into the host genome precedes transcription and translation of viral polyprotein with loss of infectious virus.

Studies conducted to detect adenovirus DNA, RNA and proteins in cancer patients have nevertheless yielded negative results Green, , and a report of adenoviral nucleic acid detection in neurogenic tumours General Introduction - 22 - Ibelgaufts, remains unconfirmed.

The mechanism by which adenoviruses cause cancer is therefore yet to be resolved. Adenoviruses have also long been associated with hepatitis Hartwell, , particularly in liver transplant patients Cames, Nevertheless, as for enteroviruses, the overlap of respiratory presentations due to adenovirus infection with the sequelae described is unclear.

Sudden unexplained death in infancy SUDI formerly sudden infant death syndrome SIDS is a poorly understood phenomenon, most likely caused in some cases by an immunodeficient response to respiratory infection.

Respiratory virus diagnostics in the clinical setting A lack of available therapeutics and influence of the diagnostic test result on patient management raises the question of the value of diagnosing respiratory infections.

Bonner et al Bonner, determined the differences in management of patients with influenza whose clinicians were aware of the diagnosis compared with patients whose clinicians were blinded to the diagnostic testing results.

For influenza patients managed by clinicians aware of the aetiology of illness, fewer tests were performed thereby saving money and resources , fewer antibiotics were prescribed, the length of stay in the accident and emergency department was shorter, and the number of influenza positive patients receiving antiviral therapy was significantly higher.

It is suggested that rhinovirus infections may be responsive to corticosteroid therapy, whereas this is not recommended for treatment of HRSV infection Templeton, General Introduction - 23 - and so in a child admitted to hospital with bronchiolitis a viral diagnosis can guide patient management.

Gonzalez et al Gonzales, b used bacterial prevalence rates in clinical presentations of otitis media, sinusitis, pharyngitis, bronchitis and URTI to determine the number of antibiotic prescriptions that should have been made for these diagnoses in the USA in Of 41 million prescriptions, The prognosis during mixed infections with viruses, and dual infections with viruses and bacteria is worse Hament, ; Richard, McCullers showed that treatment of influenza infection with neuraminidase inhibitors improved survival during secondary bacterial infections in mice McCullers, ; secondary bacterial pneumonia is widely acknowledged as a cause of influenza associated death Scadding, In the last few years there has been a shift in respiratory virus diagnostics from use of traditional cell culture methods to an overwhelming preference for molecular detection techniques, most commonly real-time polymerase chain reaction PCR.

Together with the near-patient test, these are now currently used exclusively for respiratory virus detection in Scottish diagnostic laboratories.

To prevent spread of respiratory infections in hospitals, patients with the same infection can be admitted to a designated cohort area.

However, laboratory testing for respiratory viruses by real-time PCR has a turnaround time of hours, which is too General Introduction - 24 - inefficient to guide cohorting procedures.

Patients admitted with respiratory symptoms may be allocated to an isolation unit if one is available until virus testing results are returned.

To improve the turnaround time for a diagnosis of viruses for which cohorting strategies are implemented, near patient NPT or point of care testing for respiratory viruses, with a turnaround time of just fifteen minutes, offers a sufficiently rapid diagnostic result to inform cohorting decisions at the time of admission.

NPTs have been successful in reducing nosocomial transmission events of HRSV Mackie, , although rapid tests are of reduced sensitivity and specificity compared with diagnostic PCR.

Commercially produced NPTs are available for most of the respiratory pathogens listed in Table 3 and Table 4, sometimes in multiplex form.

The sample swab is dipped into a vial of solution and rotated, then pressed against the side of the vial to release the HRSV into the solution.

The solution containing virus is then pipetted into the test well and incubated for fifteen minutes, during which time the HRSV fusion antigen binds to anti-fusion antibody adsorbed on the test strip.

Adhesion of the fusion antigen to the test strip induces a colour change to pink-purple. The suitability of near-patient testing for influenza virus infection is also established, though as for near-patient testing for HRSV infection, a negative result should be treated with caution due to the potential for false-negative results Harnden, ; Ruest, Regardless of the results of the near patient test, respiratory samples are always taken in parallel for routine diagnostics.

The first stage of routine diagnostic testing is extraction of nucleic acids from respiratory samples, prior to amplification by PCR for virus detection.

This can be undertaken using an automated or manual procedure, though increasingly in the diagnostic setting automated extraction is undertaken.

Studies General Introduction - 25 - comparing manual and automated extraction found no difference in sensitivity between the two methods Espy, ; Gobbers, ; Knepp, The automated machines used for extraction are large and so space is also a consideration.

Commercially available automated nucleic acid extraction machines are reviewed elsewhere Espy, The BioRobot MDx Qiagen used for extraction of nucleic acids throughout this work captures nucleic acids from diagnostic specimens by vacuum pull-through onto magnetic silica particles.

The throughput time for extraction of 96 samples quoted by the manufacturer is 2. Nevertheless, for large scale epidemiologic study, automated extraction is the fastest, easiest, and most highly sensitive, standardised, and most reliable method of extraction currently available.

Real-time PCR operates in a closed system to give semi-quantified results without the need for an additional step for detection of amplified product such as gel electrophoresis , improving turnaround time and reducing the risk of contamination compared with conventional PCR.

Several manufacturers produce thermocycling instruments for multiplex real-time PCR reviewed in Espy, Some of the most advanced technology on the open market manufactured by General Introduction - 26 - Cepheid, USA is a fully integrated system GeneXpert Infinity, which allows detection of up to 50 pathogens directly from diagnostic samples with the first results produced in under an hour, and boasts a theoretical throughput of over samples in 24 hours.

Such technology probably gives an indication of what the future holds for diagnostic laboratories. Nucleic acid amplified during a real-time PCR reaction is detected by a fluorescent signal produced when fluorophores are released during polymerization.

ABI machines support TaqMan probes and molecular beacons for nucleic acid detection. Multiplex PCR exploits this by use of probes which absorb different wavelengths for specific detection of multiple target sequences.

Theoretically, the yield of target sequence doubles each PCR cycle, and the strength of the fluorescence emitted by the reporter probe is semi-quantitative of the amount of target sequence in the sample.

The cycle threshold Ct value is the number of PCR cycles after which the sample is identified as positive.

A lower Ct value reflects a greater the concentration of target nucleic acid in the sample.

As an alternative to real-time PCR for multiplex detection of respiratory pathogens, sophisticated microarray assays are now under development.

Arrays have been used for the simultaneous detection of nine pathogens with a turnaround time comparable to that for results produced by PCR detection, although they have the potential to detect all pathogens that are known to be causative of a specific clinical outcome simultaneously reviewed in Raoult, A clinical sample can be tested directly using microarray, which enables combination of purification, amplification and detection of pathogen into one step, reducing time, cost and risk of contamination.

General Introduction - 27 - Figure 2. Fluorescent probe hybridization to amplification product and release from sequestration by Taq polymerase As the polymerase progresses down the DNA strand, it displaces the TaqMan probe through its endonuclease activity.

This number varies substantially between different viruses, determined by a range of factors such as duration of infectivity, degree of immunity from re-infection, viral persistence, and so forth.

Low density populations can support some viruses; in primitive indigenous tribes still in existence in the most isolated parts of the world, hepatitis B, Epstein-Barr, and cytomegalovirus circulate, having survived through inter-generational transmission probably over millennia Black, General Introduction - 28 - No modelling has been undertaken to determine the threshold population size needed to maintain viruses associated with respiratory presentations.

The most relevant analogy can be drawn from comparison with measles virus, which probably emerged at least two thousand years ago Sharp, To sustain itself, measles virus requires a population size of which supports a maintained susceptible pool of Black, Critically, measles is transmitted by the respiratory route, causes non-persistent infections and does not survive for any length of time in the environment.

Measles infection induces life long immunity, which is likely the result of the systemic nature of MV infections and its antigenically monotypic nature, contrasting with the plethora of respiratory virus strains generated through antigenic drift.

It follows that the population size required for maintenance of respiratory viruses such as HRSV may be smaller than that needed for measles, and so other respiratory viruses may have been circulating for substantially longer.

Recombination events create new viruses by capturing genes or gene segments from other viruses or from the host cell genome , can occur in both segmented and non-segmented viruses, and can be homologous or heterologous.

Homologous recombination occurs between parental RNAs of the same virus species with crossovers occurring at homologous sites in the genome, and does not necessarily occur during virus replication.

Coronavirus progeny of the same infection have been demonstrated to undergo homologous recombination Keck, Heterologous recombination may occur between different virus species via the copy choice mechanism first proposed for polio virus Cooper, , wherein during replication the viral RNA-dependent RNA polymerase switches templates to create a hybrid virus.

Heterologous recombination occurs between strains of the same species General Introduction - 29 - e. Reassortment involves the mixing of virus genome segments between strains of multipartite viruses during virion assembly to yield a novel virus, and is most widely associated with influenza virus discussed in more detail subsequently.

Independent circulation in humans To illustrate, rabies reaches stage two, causing sporadic human cases; ebola virus causes limited outbreaks in people, attaining stage three; dengue causes long outbreaks in humans before returning to the sylvatic host, thereby reaching stage four; and HIV-1 clade M has successfully established itself in humans to attain stage five.

The ability of respiratory viruses to re-infect hosts is widely thought to be a product of immune-driven adaptive evolution, facilitated by the RNA-dependent RNA polymerase which does not, unlike DNA-dependent RNA polymerase, have proofreading activity.

Frequent errors during RNA replication result inevitably in the production of some progeny viruses with deleterious mutations, which are removed from the population by purifying selection.

Recombinant and zoonotic respiratory viruses Historically, rhinoviruses and coronaviruses have been considered separately from other respiratory viruses, conceptually segregated as common cold viruses, which is in part attributable to the excellent epidemiologic studies of respiratory viruses conducted in the mid twentieth century Table 7.

Much of the understanding of respiratory virus epidemiology today is drawn from the results of these classic studies. Rhinoviruses are the most common cause of acute infectious illness in humans.

The mean infection rate in the Seattle study was 0. Young adult females experience more rhinovirus infections and illnesses than their male peers, due to their increased contact with young children, though this is redressed in later years when illness rates are higher among males Gwaltney Jr, General Introduction - 31 - Table 7.

Nasopharyngeal swabs on respiratory and COPD in later life presentation General Introduction May - Jun Families observed for one year - 32 - Rhinovirus immunogenicity is poor, and varies greatly with serotype Fox, ; an increasing number of serotypes are being reported, with over of species A and B, and 61 of species C to date.

It is this diversity which permits re-infection with rhinoviruses year after year, and on which the presumption that there will never be a vaccine for the common cold is based.

Rhinovirus and enterovirus species group within the Enterovirus genus of the Picornaviridae, and undertake recombination as a mechanism to produce novel strains McIntyre, ; McWilliam Leitch, , ; Santti, ; Savolainen, Enteroviruses undergo periodical turnover and replacement of contemporary clades by a rapidly disseminating recombinant form with striking regularity.

This remarkably high frequency of recombination provides some insight into the tremendous success of rhinoviruses to circumvent population immunity and re-infect individuals frequently throughout life.

Coronaviruses have a longer incubation period than rhinoviruses, though the duration of illness is generally shorter and symptoms are indistinguishable.

The classic epidemiologic studies of coronaviruses were of course limited to HCoVE and HCoV-OC43, though recent studies of the four coronaviruses together including the results presented here do not imply any deviating trends for the newly discovered coronaviruses2.

Antibody to coronaviruses appears in early childhood and increases in prevalence rapidly with age McIntosh, , with seroconversion in most occurring for HCoVE and HCoV-NL63 by the age of 3 and a half Dijkman, The development of a cell culture system for HCoV-HKU1 is only very recently reported Pyrc and serosurveillance was undertaken using a baculovirus expression system incorporating nucleocapsid gene.

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