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Viral Respiratory Infections in Adults Focus on RSV and Rapid Molecular Diagnostic Testing

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Viral Respiratory Infections in Adults Focus on RSV and Rapid Molecular Diagnostic Testing Viral respiratory infections in adults Focus on RSV and rapid molecular diagnostic testing Laura Marion Vos Colophon Cover design by: Joep Deiman Layout and design by: David de Groot, Persoonlijkproefschrift.nl Printed by: Ridderprint BV, Ridderprint.nl ISBN: 978-94-6375-439-2 © L.M. Vos, Utrecht, the Netherlands, 2019. All rights reserved. No part of this dissertation may be reproduced or transmitted, in any form or by any means, without prior permission of the author. ϐ Longfonds, Mediphos and the Utrecht RSV Research Group. Viral respiratory infections in adults Focus on RSV and rapid molecular diagnostic testing ðī­ăÐăķÆìĴœÐæðĊåÐÆĴðÐĮÅūŒďăœ­ĮĮÐĊÐĊ Met een focus op RS virus en moleculaire sneldiagnostiek met een samenvatting in het Nederlands Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht ϐ ǡ prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 7 november 2019 des middags te 12.45 uur door Laura Marion Vos geboren op 15 juli 1989 te Gouda Promotor: Prof. dr. A.I.M. Hoepelman Copromotoren: Dr. J.J. Oosterheert Dr. F.E.J. Coenjaerts Contents CHAPTER 1 9 General introduction PART I - VIRAL RESPIRATORY INFECTIONS: FROM INFLUENZA VIRUS TO RSV CHAPTER 2 25 Lower respiratory tract infection in the general adult community: associations between viral aetiology and illness course. Manuscript submitted. CHAPTER 3 47 Use of the moving epidemic method (MEM) to assess national surveillance data for respiratory syncytial virus (RSV) in the Netherlands, 2005 to 2017. Euro Surveill. 2019 May;24(20):34-44. CHAPTER 4 73 High epidemic burden of RSV disease coinciding with genetic alterations causing amino acid substitutions in the RSV G-protein during the 2016/2017 season in the Netherlands. J Clin Virol. 2019 Mar;112:20-26. CHAPTER 5 95 External validation and update of prognostic models to predict poor outcomes in hospitalized adults with RSV: a retrospective Dutch cohort study. J Med Virol. 2019 Aug [Epub ahead of print]. PART II - RAPID DETECTION OF RESPIRATORY VIRUSES CHAPTER 6 123 ϐǡ ǡ and other respiratory viruses: a systematic review of diagnostic accuracy and clinical impact studies. Clin Infect Dis. 2019 Jan [Epub ahead of print]. CHAPTER 7 159 Syndromic sample-to-result PCR testing for respiratory infections in adult patients. Neth J Med. 2018 Aug;76(6):286-293. CHAPTER 8 177 More targeted use of oseltamivir and in-hospital isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients. J Clin Virol. 2019 Apr;116:11-17. PART III - SUMMARY & GENERAL DISCUSSION CHAPTER 9 203 Summary & general discussion CHAPTER 10 219 Nederlandse samenvatting APPENDICES CHAPTER 11 229 List of publications CHAPTER 12 233 Dankwoord CHAPTER 13 239 Curriculum vitae CHAPTER 1 GENERAL INTRODUCTION Chapter 1 GENERAL INTRODUCTION Globally, respiratory tract infections are the most common type of disease in both adults and children (1). Although the number of deaths resulting from respiratory tract infections has decreased over the last decades, respiratory infections still account for 3-4 million deaths per year worldwide (2–5). Although, on a global ǡ ϐ ȋʹǡ͸Ȍǡ ϐ ǡ annual death rate of 1.3 million people (4,5). Especially adults aged 50 and over, accounting for 84% of these deaths, should be noted (5). Respiratory tract infections can be divided in upper and lower respiratory tract infections. Upper respiratory tract infections, including the common cold, sinusitis, pharyngitis, but also conjunctivitis and otitis media, are mostly considered as mild, self-limiting infections with a viral cause and low morbidity and mortality (7). Lower respiratory tract infections, including bronchitis, bronchiolitis and pneumonia, on the other hand, are associated with more severe clinical symptoms as well as high morbidity and mortality rates (7). Historically, the overriding clinical approach to the management of lower respiratory tract infections has been to focus on bacterial aetiologies, with Streptococcus pneumoniae as the dominant pathogen (8). However, over the last decades, evidence has increased for a role of respiratory viruses in severe lower Ǥϐ acute respiratory tract infections, the most frequently detected pathogens are ǡϐǡ ȋȌǡ ȋȌǡ ȋȌǡϐȋȌȋͻȌǤ overview of the viral, epidemiological and clinical characteristics of these six most common respiratory viral pathogens is shown in Table 1. 10 General introduction Table 1. Viral, epidemiologic and clinical characteristics of common respiratory viruses. Viral Epidemiology in Common Clinical outcomes characteristics adult patients symptoms Rhinovirus Family 20.1% of adults with cough, sore throat, 19.5% of CAP Picornaviridae ARI consulting the GP rhinorrhoea, patients has severe 4.2% of hospitalized myalgia CAPa; 19.5% with 1 RNA virus adults with ARI η͵Ǣ >100 serotypes 4.5-8.5% of ~10.0% mortality hospitalized adults among adults with with CAP severe ARI ϐ Family 9.9% of adults with fever, cough, sore 19.2% of CAP Orthomyxoviridae ARI consulting the GP throat, headache, patients has severe 11.8% of hospitalized myalgia, malaise, CAPa; 20.0% with Enveloped RNA adults with ARI gastrointestinal η͵Ǣ͸ǤͲǦ virus 5.6-5.8% of symptoms. 8.5% mortality Subtype A, B, C hospitalized adults among adults with with CAP severe ARI Coronavirus (CoV) Family 7.4% of adults with fever, chills, rigors, 20.2% of CAP Coronaviridae ARI consulting the GP cough, chest pain, patients has severe 2.4% of hospitalized gastrointestinal CAPa; 0.0% with Enveloped RNA adults with ARI symptoms. η͵Ǣ virus 1.2-2.3% of ~14.3% mortality Subtype 229E, hospitalized adults among adults with NL63, OC43, with CAP severe ARI. HKU1, SARS, MERS Respiratory syncytial virus (RSV) Family 4.6% of adults with cough, coryza, 27.1% of CAP Paramyxoviridae ARI consulting the GP rhinorrhoea, patients has severe 2.0% of hospitalized conjunctivitis CAPa; 11.1% with Enveloped RNA adults with ARI η͵Ǣ virus 2.4-3.0% of severe disease in Subtype A, B hospitalized adults infants and elderly; with CAP ~8.0% mortality among hospitalized adults. 11 Chapter 1 Viral Epidemiology in Common Clinical outcomes characteristics adult patients symptoms Human metapneumovirus (hMPV) Family 4.4% of adults with cough, nasal 20.0% of CAP Paramyxoviridae ARI consulting the GP congestion, patients has severe 3.8% of hospitalized rhinorrhoea, CAPa; 17.6% with Enveloped RNA adults with ARI dyspnoea, η͵Ǣ virus 1.7-3.9% of hoarseness, ~10.0% mortality Subtype A, B hospitalized adults wheezing. among adults with with CAP severe ARI. ϐȋȌ Family 2.6% of adults with fever, rhinorrhoea, 25.9% of CAP Paramyxoviridae ARI consulting the GP cough, sore throat, patients has severe 2.8% of hospitalized myalgia. CAPa; 7.1% with Enveloped RNA adults with ARI η͵Ǣ̱͹Ǥ͹Ψ virus 1.4-2.9% of mortality among Subtype 1, 2, 3, 4 hospitalized adults adults with severe with CAP ARI. ARI, acute respiratory infection; CAP, community acquired pneumonia; GP, general practitioner; MERS, Middle East Respiratory Syndrome; PSI, pneumonia severity index; SARS, Severe Acute Respiratory Syn- Ǣǡ ǤǤϐ ηͳ the following: impaired consciousness, a respiratory rate >30 per minute, PaO2 <60 mmHg, PaO2/FiO2 δ͵ͲͲǡ ǡ δͻͲ ǡ ǡϐ ηͳϐ ͷͲΨͶͺǡδʹͲ millilitre per hour or acute renal failure needing dialysis. ðī­ăīÐĮĨðī­ĴďīřðĊåÐÆĴðďĊĮȚåīďĉðĊŦķÐĊš­ŒðīķĮĴďtw ǡϐ ǡ ϐ ȋͳͲȌǤǡ ϐǡ Ǧ ȋͳͳȌǦǤ ǡϐ is still the viral pathogen associated with the highest mortality and morbidity in adults (12-14), there is increasing evidence that other viral pathogens - especially RSV - also form an important burden of disease in the adult population (15,16). ϐϐȋͳ͹ȌǤ ǡ clinicians and researchers has been on RSV infections in children. In young children, RSV is the most common cause of lower respiratory tract infections globally (18) and has been associated with 12-63% of all acute respiratory infections causing 12 General introduction hospitalization (19). In adults, RSV has traditionally been considered to cause only mild illness (20,21). However, over the last years, RSV has been increasingly recognized as an important cause of illness in adults, especially in vulnerable elderly people (22). In prospective cohort studies among elderly patients, RSV infection developed annually in 3-7% of healthy elderly patients and in 4-10% percent of adults with chronic heart or lung diseases (22). Among hospitalized elderly, RSV has an 8% mortality rate (22). 1 ϐ Ǧϐ viruses, like RSV, there are many promising new therapeutics currently being evaluated in clinical trials. These drugs (pimodivir, S033188, favipiravir, MHAA45449A, VIS4 and nitazoxanide) might reduce the immune response Ȁǡϐǡȋʹ͵ǦʹͷȌǤ clinically advanced drug candidates for RSV infection are ALS-8176 (lumicitabine) and GS-5806 (presatovir) (24-27). Lumicitabine is a nucleoside analogue which inhibits the L-protein, the RNA-polymerase of RSV, allowing it to both inhibit RSV replication within infected cells and protect uninfected cells from infection (25). Presatovir is a fusion (F) glycoprotein inhibitor that blocks viral-envelope fusion with the host-cell membrane (25). In studies among healthy adults infected with clinical RSV strains, both therapeutics have been associated with a reduction in viral load and reduced severity of symptoms (26-28). The results of phase 2 trials in adults on both therapeutics are forthcoming (29,30). Additionally, there are Ǧϐ development, such as Novovax and MEDI-559 for RSV (31,32). Given the poor clinical outcomes of adult patients with viral respiratory tract Ǧ ϐ (22,33,34) -, the development and evaluation of these new therapeutics and vaccines is a current research priority. However, to improve individual patient management, epidemiological and prognostic studies are also required to evaluate ϐ Ǥ In the interest of public health, we should thereby not only focus on hospital ϐ ǡ and disease burden of different respiratory viruses in the general population (35,36,37).
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