Community-Acquired Pneumonia

299 Pages·2014·9.459 MB·English

by  James D. Chalmers, Mathias W. Pletz, Stefano Aliberti

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NUMBER 63 / MARCH 2014
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EUROPEAN RESPIRATORY monograph eu
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Community-acquired pneumonia remains the leading cause n
i
of hospitalisation for infectious disease in Europe, and a major a
cause of morbidity and mortality. This issue of the European
Respiratory Monograph brings together leading experts in
pulmonology, infectious diseases and critical care from
around the world to present the most recent advances in the
management of community-acquired pneumonia. It provides
a comprehensive overview of the disease, including chapters
on microbiology, pathophysiology, antibiotic therapy and Community-Acquired
prevention, along with hot topics such as viral pneumonias and
pneumonia associated with inhaled corticosteroids.
Pneumonia
Edited by James D. Chalmers,
Mathias W. Pletz and Stefano Aliberti
6
3
Print ISSN 1025-448x
Online ISSN 2075-6674

Print ISBN 978-1-84984-048-4
Online ISBN 978-1-84984-049-1
Number 63 March 2014
€55.00
European Respiratory Monograph 63, March 2014
Community-Acquired
Pneumonia
Published by European Respiratory Edited by
Society ©2014
James D. Chalmers, Mathias W. Pletz and
March 2014
Print ISBN: 978-1-84984-048-4 Stefano Aliberti
Online ISBN: 978-1-84984-049-1
Print ISSN: 1025-448x
Online ISSN: 2075-6674
Printed by Page Bros Ltd, Norwich, UK

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European Respiratory Society
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Tobias Welte
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views of the authors, and not necessarily
those of the European Respiratory
Society, editors or publishers.
Th is book is one in a series of European Respiratory Monographs. Each
individual issue provides a comprehensive overview of one specifi c clini-
cal area of respiratory health, communicating information about the
most advanced techniques and systems required for its investigation.
It provides factual and useful scientifi c detail, drawing on specifi c case
studies and looking into the diagnosis and management of individual
patients. Previously published titles in this series are listed at the back of
this Monograph.
Contents
Number 63 March 2014
Preface v
Guest Editors vii

Introduction ix

1. Epidemiology of CAP in Europe 1
Anika Singanayagam, James D. Chalmers and Tobias Welte
2. The pneumonia triad 13
Santiago Ewig
3. Microbiology of bacterial CAP using traditional and 25
molecular techniques
Mayli Lung and Jordi Rello
4. The pathophysiology of pneumococcal pneumonia 42
Daniel G. Wootton, Stephen J. Aston and Stephen B. Gordon
5. Pneumonia due to Mycoplasma, Chlamydophila and Legionella 64
Francesco Blasi, Paolo Tarsia and Marco Mantero
6. The role of viruses in CAP 74
Gernot G.U. Rohde
7. Severity assessment tools in CAP 88
Helena Sintes, Oriol Sibila, Grant W. Waterer and James D. Chalmers
8. CAP phenotypes 105
Benjamin Klapdor, Santiago Ewig and Antoni Torres
9. Lower respiratory tract infections and adult CAP in primary care 117
Matt P. Wise and Christopher C. Butler
10. CAP in children 130
Susanna Esposito, Maria Francesca Patria, Claudia Tagliabue,
Benedetta Longhi, Simone Sferrazza Papa and Nicola Principi
11. Empirical antibiotic management of adult CAP 140
Mark Woodhead and Muhammad Noor
12. Antibiotic choice, route and duration: minimising the harm 155
associated with antibiotics
Rosario Menendez, Beatriz Montull and Raul Mendez
13. Acute respiratory failure due to CAP 168
Miquel Ferrer
14. Early recognition and treatment of severe sepsis and septic 184
shock in CAP
Anja Kathrin Jaehne, Namita Jayaprakash, Gina Hurst, Steven Moore,
Michael F. Harrison and Emanuel P. Rivers
15. Early outcomes in CAP: clinical stability, clinical failure and 205
nonresolving pneumonia
Stefano Aliberti and Paola Faverio
16. Non-antibiotic therapies for CAP 219
Paola Faverio and Marcos I. Restrepo
17. Inhaled corticosteroids as a cause of CAP 234
Peter M.A. Calverley
18. Macrolides as anti-inflammatory agents in CAP 243
Waleed Salih, Philip M. Short and Stuart Schembri
19. Cardiovascular complications and comorbidities in CAP 256
Stefan Krüger and Dirk Frechen
20. Pneumococcal and influenza vaccination 266
Mathias W. Pletz and Tobias Welte
CME credit application form 285
C O P E COMMITTEE ON PUBLICATION ETHICS
This journal is a member of and subscribes to
the principles of the Committee on Publication
Ethics.
Preface
Community-acquiredpneumonia(CAP)istheleadingcauseofdeathdue
to infectious disease worldwide. As the incidence of CAP increases with
increasing age, the number of cases of pneumonia is increasing steadily, in
parallel with changes in demography. In recent years, we have learned a lot,
primarily from data from large multicentre networks in Spain, the UK,
Germany and the USA, about the course of this disease, its complications,
risk factors for increased mortality and the effectiveness of various
antibiotics. In addition, the understanding of the pathogenic mechanisms
of bacteria and the role of pathogen–host interaction has improved
considerably.
Tobias Welte
Despite the enormous progress in the understanding of CAP, the hospital
Editor in Chief
mortality rate is as high as it was 50 years ago. Unlike hospital-acquired
pneumonia, however, an increasing development of resistance of the most
important respiratory pathogens does not play a significant role. The key
factor for the increased mortality is, along with the rising age and the
increased number of comorbidities of the patients, the virulence of the
pathogens. The introduction of antibiotic therapy in the 1940s has meant
that pathogens are reliably killed, reducing the mortality rate dramatically.
However, the increase of pathogenic factors caused by destroying the
pathogen or late onset of effective therapy has not been successfully tackled
to date.
The future of the treatment of CAP is, therefore, not related to the
improvement of diagnostics or the development of new antibiotics. Instead,
it will focus on two other fields: prevention and immune modulation.
Vaccines as an essential preventive measure are already available for some
pathogens, but their further development, in particular to improve
immunogenicity in the elderly, is a major subject of research. Modulation
of the immune response, both to limit overshooting reactions as well as to
improve lack of immune response, has not been successful despite many
different attempts in the past. Due to the rapid development of sequencing
technology, it will be possible to determine risk profiles of patients quickly
andthiswillallowindividualisedtherapyaccordingtotheimmunestatusof
the patient. This is the music of the future, although a new form of anti-
infective therapy, including pharmacokinetic considerations and a risk
stratification approach, stands out already on the horizon.
I want to thank the three guest editors, James Chalmers, Mathias Pletz and
Stefano Aliberti, for their tremendous work in preparing this issue of the
European Respiratory Monograph (ERM), which summarises the current
knowledgeabouttheprevention,diagnosis,riskstratificationandtherapyof
CAP and gives an outlook to the future. The book represents an ideal basis
for all clinicians, basic scientists and people operating in this field in the
pharmaceutical industry to gain an overview of the state of knowledge. I am
convinced that they will find this ERM useful for further considerations.
EurRespirMonogr2014;63:v.CopyrightERS2014.DOI:10.1183/1025448x.10000714.PrintISBN:978-1-84984-048-4.
OnlineISBN:978-1-84984-049-1.PrintISSN:1025-448x.OnlineISSN:2075-6674.
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Guest Editors
James D. Chalmers is a Wellcome Trust Postdoctoral Fellow and
Lecturer in Respiratory Medicine at the University of Dundee, UK.
He trained in Glasgow and Edinburgh, performing his PhD studies
at the Medical Research Council (MRC) Centre for Inflammation
Research in Edinburgh investigating the role of innate immunity in
non-cystic fibrosis (CF) bronchiectasis. His research and clinical
interests are in respiratory infections, particularly community-
acquired pneumonia (CAP), bronchiectasis and chronic obstructive
pulmonary disease (COPD). He now leads a research group at the
University of Dundee investigating the mechanisms of pulmonary
bacterial infections, supported by grants from the Wellcome Trust,
James D. Chalmers
MRC, Scottish Government and charities.
James Chalmers has been awarded several prestigious young
investigator awards, including from the European Respiratory
Society (ERS) and British Thoracic Society (BTS). He has
published widely on respiratory infections, with over 60 articles in
peer reviewed journals since 2008. He is a member of the
international advisory board of The Lancet Respiratory Medicine.
He is heavily involved in international respiratory societies, being a
current member of the BTS Science and Research Committee, the
ERS Long-Range Planning Committee and the American Thoracic
Society Microbiology, Tuberculosis and Pulmonary Infections
Program Committee.
Mathias W. Pletz, Professor for Infectious Diseases, is a board-
certified physician for internal medicine, pulmonology and
infectious diseases and the head of the Center for Infectious
Diseases and Infection Control of the University Hospital in Jena,
Germany. He also leads a clinical research group focusing on novel
diagnostic and therapeutic strategies against multidrug-resistant
bacterialpathogens,fundedbytheGermanMinistryforScienceand
Education.
Mathias Pletz received his PhD in Virology at the University of
Mathias W. Pletz Leipzig,Germany.Duringhisthesisheworkedasaguestresearcher
at the Food and Drug Administration Laboratory of Parasitic
Pathology and Biochemistry in Bethesda, MD, USA. After his
medical training at the University of Leipzig, Baylor College of
Medicine (Houston, TX, USA) and the University of Basel
(Switzerland), he started his residency at the Chest Hospital in
Berlin, Germany. Subsequently, he spent 2 years as a postdoctoral
researcher at Emory University (Atlanta, GA, USA), working with
EurRespirMonogr2014;63:vii–viii. Keith Klugman’s group on the spread of multi-resistant
CopyrightERS2014.
DOI:10.1183/1025448x.10000614 pneumococci. In addition he served as a guest researcher at the
PrintISBN:978-1-84984-048-4
OnlineISBN:978-1-84984-049-1 Centers for Disease Control and Prevention (CDC) in Atlanta,
PrintISSN:1025-448x
exploring the severe acute respiratory syndrome (SARS) epidemics.
OnlineISSN:2075-6674
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After his return to Germany, he finished his medical training at the
Dept of Respiratory Medicine at the Hannover Medical School.
Mathias Pletz is the deputy director of the German Competence
Network for Community-Acquired Pneumonia (CAPNETZ), a
member of the board of directors of the German-Austrian-Swiss
Paul-Ehrlich-Society for antimicrobial chemotherapy, and scientific
advisor for the German Robert Koch Institute. He has published
more than 100 papers on pneumonia, pneumococcal vaccines,
respiratory infections, antimicrobial resistance and pharmaco-
kinetics of antibiotics in the critically ill. He has also received
numerous scientific awards, e.g. the Honor Award Certificate from
the CDC, the Kass-Award of the Infectious Diseases Society of
America and the Respiratory Infections Awards from the ERS.
StefanoAlibertiisAssistantProfessorinRespiratoryMedicineatthe
University of Milan-Bicocca, Milan, Italy, and consultant at the San
Gerardo Hospital in Monza, Italy. He trained at the Institute of
Respiratory Diseases at the University of Milan, under the
mentorship of Professor Francesco Blasi. During his fellowship, he
received research grants to investigate the epidemiology of non-CF
bronchiectasis and COPD, and he worked as a visiting research
fellow at the Division of Infectious Diseases at the University of
Louisville, KY, USA. He has been an active member of the
Community-Acquired Pneumonia Organization (CAPO)
Stefano Aliberti international study group since 2006, and a member of the
Community-Acquired Pneumonia Inflammatory Study Group
(CAPISG). His research and clinical interests are in both acute
and chronic respiratory infections, including CAP, non-CF
bronchiectasis and atypical mycobacteria. He was awarded the
young researcher award in respiratory infections from the ERS in
2007. During the past 10 years, he has been involved in several
clinicalandtranslationalstudiesonthesetopicsatbothnationaland
internationallevel.StefanoAlibertihaspublishedover60articleson
CAP in peer-reviewed journals since 2006. He is associate editor of
Breathe and the European Journal of Internal Medicine. He has been
heavilyinvolvedintheERS,asSecretaryoftheRespiratoryInfection
Group and Secretary of the Assembly of Respiratory Infections.
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Introduction
James D. Chalmers*, Mathias W. Pletz# and Stefano Aliberti"
*TaysideRespiratoryResearchGroup,UniversityofDundee,Dundee,UK. #CenterforInfectiousDiseasesandInfectionControlandCenterforSepsis
CareandControl,JenaUniversityHospital,Jena,Germany."DeptofHealthScience,UniversityofMilanBicocca,ClinicaPneumologica,AOSan
Gerardo,Monza,Italy.
Correspondence:J.D.Chalmers,TaysideRespiratoryResearchGroup,UniversityofDundee,NinewellsHospitalandMedicalSchool,Dundee,DD19SY,
UK.Email: [email protected]
The morbidity and mortality of respiratory tract infections in Europe throughout history is
incalculable,butwhentheEnglishwriterJohnBunyancoinedthephrase‘‘Captainofallthese
men of death’’ to describe tuberculosis (TB) in 1680, TB was estimated to cause 15–20% of all
deaths in Europe. It was hard to imagine at that time that another infection might one day take
this crown. In 1918, the father of modern medicine, Sir William Osler, observed that pneumonia
hadovertakenTBasoneoftheleadingcausesofdeathinEuropeanddescribedpneumoniaasthe
‘‘Captain of the men of death’’, an appellation it still justifies today.
While improvements in public health and sanitation reduced mortality from many, mostly food-
borne, infections, it was not until the widespread introduction of antibiotics after the Second
WorldWarthatmortalityfrompneumoniainEuropebegantofallsignificantly.Sincethen,there
havebeenfewnewtreatmentsandlimitedprogressinreducingmortalityfrompneumonia.While
mortality rates for cardiovascular diseases and many cancers are falling in Europe, the rates for
hospitalisation and deaths from pneumonia are static or rising. This is a disease of huge clinical
and public health importance.
It is for this reason we are delighted to introduce the 63rd issue of the European Respiratory
Monograph (ERM), dedicated to the epidemiology, pathophysiology, microbiology, investigation,
management and prevention of community-acquired pneumonia (CAP). The 20 chapters of this
ERMserveas acomprehensivetext,describing themodernapproach tothisdisease,eachchapter
written by internationally recognised experts in their field. Major changes in our understanding
and management of pneumonia have been emphasised, including the new microbiology
techniques that are set to change how we detect and diagnose infection, the emerging role of
anti-inflammatorytherapiesandthecurrentcontroversyoverinhaledcorticosteroidsasacauseof
pneumonia in patients with chronic obstructive pulmonary disease. The changing face of
pneumoniareflectstheworldaroundus,withanincreasingimpactofantibioticresistanceandan
ageingpopulationwithcomorbiditiestothefore.Wenowrecognisetheimportantimpactofthis
disease on long-term outcomes. Previously regarded as a purely ‘‘acute’’ condition, new evidence
shows that pneumonia can destabilise the precarious balance in patients with comorbidities and
poor performance status, even after apparent recovery from the acute episode.
Thisisabroadandmultidisciplinarybook,coveringdiversespecialitiesfromepidemiologytothe
basic science of pneumococcal infection, and reviewing CAP in children, in primary care and in
the intensive care unit.
As much as in any other disease, CAP requires improvements in clinical care and to achieve
progressthroughinnovativeresearch.Everyclinicianineveryspecialitywillencounterpneumonia
intheirdailypracticeandwehopethatthisERMwillserveasacompleteandup-to-datereference
for our colleagues.
EurRespirMonogr2014;63:ix.CopyrightERS2014.DOI:10.1183/1025448x.10000514.PrintISBN:978-1-84984-048-4.
OnlineISBN:978-1-84984-048-4.PrintISSN:1025-448x.OnlineISSN:2075-6674.
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Chapter 1
Epidemiology of CAP in
Europe
Anika Singanayagam*, James D. Chalmers# and Tobias Welte"
*InfectiousDiseases,Imperial
SUMMARY: This article describes the epidemiology of
College,London,and
community-acquired pneumonia (CAP) in Europe. Lower #TaysideRespiratoryResearchGroup,
UniversityofDundee,Dundee,UK.
respiratory tract infections are the fifth leading cause of death "DeptofPulmonaryMedicine,
HannoverMedicalSchool,Hannover,
worldwide with the bulk of the mortality attributable to CAP.
Germany.
Pneumonia disproportionately affects elderly populations and
Correspondence:T.Welte,Deptof
demographic changes within Europe are leading to an older,
PulmonaryMedicine,Medizinische
more comorbid population at high risk of pneumonia. HochschuleHannover,
Carl-Neuberg-Str.1,30625
Consequently, recent data suggests a progressive rise in Hannover,Germany.
hospitalisations for pneumonia throughout Europe over the E-mail:[email protected]
past 10 years.
CAP places a substantial burden on healthcare with costs
E
largely attributable to inpatient care. Antibiotic resistance, P
O
particularly Streptococcus pneumoniae resistance to penicillin UR
E
and macrolides, is rapidly increasing in Europe and poses a
N
serious threat to future effective treatment. Prevention of EurRespirMonogr2014;63:1–12. I
P
CopyrightERS2014. A
pneumonia requires an understanding of the population risk DOI:10.1183/1025448x.10003013 C
PrintISBN:978-1-84984-048-4 F
factors, which will be discussed in this chapter. OnlineISBN:978-1-84984-049-1 O
PrintISSN:1025-448x Y
OnlineISSN:2075-6674 G
O
L
In Europe, community-acquired pneumonia (CAP) is the leading infectious cause of death O
MI
andconstitutesaconsiderableeconomicburdenonhealthcaresystems[1].Lowerrespiratory E
D
tract infections (LRTI) were ranked as the fifth most common cause of death across the World PI
E
Health Organization (WHO) European region in the 2010 Global Burden of Disease Study [2]
1:
and accounted for 0.23 million (2.3%) deaths and 2.2 million (1.5%) disability adjusted life
R
years in Europe [3]. CAP disproportionately affects the elderly population’s mortality and E
T
P
morbidity rates, with increased incidence. With the projected proportion of people aged A
H
o65 years increasing to a third of the population over the next decade from a sixth of the C
population in 2004 (based on current trends) [4], the impact of CAP is set to become greater
and more costly.
Incidence of CAP in Europe
The incidence of a disease measures the number or rate of new cases of disease that occurs in a
population over a specified time period. Difficulties arise when evaluating European incidence
rates for CAP, as study populations and calculation methods differ across published studies [1].
Across Europe, only Spain, Finland and the UK have precise epidemiological data on CAP [5].
AmongthedifficultiesindeterminingtheincidenceofCAP,themajorityofcasesaremanagedas
outpatientswherechestradiographconfirmationisnotsought.UseofInternationalClassification
1
of Disease (ICD) codes of hospital discharges are used in many diseases to determine the
incidence, but there is no specific ICD-10 code for CAP and, therefore, population data based
on these codes reflect a mix of CAP and other LRTIs [6]. Microbiological diagnosis is
often unavailable due to lack of sputum for culture or prior use of antibiotics. Therefore,
the burden of CAP may be underestimated because of the differences in CAP definition and
clinical heterogeneity.
Allowing for these limitations the reported annual incidence rate of CAP in adults across Europe
range between 1.07 and 1.2 per 1000 person years and 1.54 and 1.7 per 1000 population [1].
Age, sex and comorbid conditions
The incidence of CAP in Europe varies by age, sex and level of underlying comorbidity. CAP
incidenceincreasewithageandthepresenceofcomorbidity,andishigherinmalesthanfemales[6].
Incidencerateinapopulation-basedcohortstudyof11 241patientsagedo65yearsinSpainwas14
per1000personyears(10.5forhospitalisedand3.5foroutpatientcases)[7].InaFinnishstudy,a
six-foldincreaseinincidencebetweentheagesof30–44 yearsando75 yearswasreported[8].Age-
specificincidenceofhospitalisationfromaUKstudywas7%higherformalesthanfemales[9].The
malepredominanceforhospitalisationwithCAPhasalsobeenshowninaGermanstudy(3.21per
1000peopleperyearsinmalesversus2.52per1000peopleperyearsinfemales)[10],andaDanish
studyof48 551individualsaged50–64 years(4.2per1000personyearsinmalesversus3.4per1000
personyears in females) [11].
CAP incidence rates are also higher in persons with underlying comorbid conditions. Incidence
rates as high as 22.4 (95% CI 21.7–23.2) per 1000 person years were depicted in a cohort of
chronic obstructive pulmonary disease (COPD) patients [12]. Patients with COPD make up
A betweenaquarterandathirdofmosthospitalisedcohortswithCAP,reflectingthehighfrequency
NI
O of the disease in COPD patients [13–15]. High incidence rates have also been reported in the
M
U immuno-compromised (almost three-fold higher than in immunocompetent subjects) [16],
E
N including: Spanish patients with rheumatic diseases treated with tumour necrosis factor
P
antagonists (5.97 (95% CI 4.87–7.25) per 1000 person years) [17]; long-term corticosteroid
D
E therapy(40.1per1000personyears)[16];andaFrenchstudyofpatientswithHIV(12.0(95%CI
R
UI 9.9–14.0) per 1000 person years) [18].
Q
C
A
- Incidence in community settings
Y
T
NI
U Estimates suggest that 50–80% of CAP cases will be managed in the community. In community
M
M settingsinEurope,CAPincidencerangebetween1.7and11.6casesper1000personyearsinadults
O
C [4]. In the European Union (EU), approximately 3 370 000 ambulatory cases are expected
3: annually. Themean numberofhealthcarevisitsper patientin a2-yearpopulation-based studyof
6
H CAP in Spain was 4.5, with 72% in the primary care setting [17]. Whilst most CAP patients are
P
A treated in community settings, the majority of reported CAP studies are on hospitalised patients
R
G andsothetrueburdenofcommunity-baseddiseaseisprobablyunderestimatedduetothelackof
O
N data (table 1). A recent study from the Netherlands that used administrative data suggested that
O
M only 2.3% of cases were referred to hospital, indicating that the vast majority of suspected
pneumonias are treated in the community [19].
Incidence in hospital settings
Hospital admission rates for CAP vary significantly between European countries, ranging from
20% to 50%, with approximately 1 million hospital admissions for CAP per year expected in the
EU (fig. 1) [4].
Hospitalisation is associated with older age, the presence of comorbid conditions and greater
severity of illness [20–22]. Major efforts have been devoted over the past 20 years to increase the
2