archives for chest disease - Fondazione Salvatore Maugeri

Transcript

FSM
September-December 2013
Centro Studi
Fondazione Maugeri
Volume 79 Number 3-4
PULMONARY SERIES
F. Novelli, F. Costa, M. Latorre, L. Malagrinò, A. Celi,
B. Vagaggini, P. Paggiaro
Tiotropium: a new therapeutic option in asthma
VOLUME 79 • NUMBER 3-4. 2 0 1 3 • PULMONARY SERIES
INTERNATIONAL JOURNAL OF CARDIOPULMONARY MEDICINE AND REHABILITATION
ARCHIVES FOR CHEST DISEASE
MONALDI
ISSN 1122-0643
M. Justine, F. Tahirah, V. Mohan
Health-related quality of life, lung function and
dyspnea rating in COPD patients
N. Facciolongo, R. Piro, F. Menzella, M. Lusuardi, M. Salio,
L. Lazzari Agli, M. Patelli
Training and practice in bronchoscopy. A national
survey in Italy
M. Irfan, F. Thiavalappil, J. Nagaraj, T.H. Brown, D. Roberts,
L. Mcknight, N.K. Harrison
Tuberculous pancreatitis complicated by ruptured
splenic artery pseudoaneurysm
S. Katsenos, M. Nikolopoulou
Intramedullary thoracic spinal metastasis from
small-cell lung cancer
SE
A
ISE t:
D
ST eb a
E
CH e w t
h
OR on t
F
e
S
e
e
h
c
r
.a
w
w
VE fr
HI for
Periodico Trimestrale
No. 3-4 Settembre-Dicembre 2013
Poste Italiane s.p.a.
Spedizione in Abbonamento Postale
D.L. 353/2003 (conv. in L. 27/02/2004 n. 46)
articolo 1, comma 1, LO/PV
RC able
A
DI ail
M
AL w av
N
o
O
N
w
/
/
:
p
htt
i
.
m
s
f
st.
MONALDI
An International Scientific Journal for Postgraduate Education in Cardiopulmonary Medicine and Rehabilitation
of the Fondazione Salvatore Maugeri, Care and Research Institute, Pavia, Italy.
Official Journal of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR)
PULMONARY MEDICINE AND REHABILITATION SERIES
CARDIAC REHABILITATION AND PREVENTION SERIES
Editors
Antonio Spanevello
Dept. of Pulmonary Rehab.
Fondazione Salvatore Maugeri
IRCCS
Dept. of Clinical Medicine
University of Insubria
Via Roncaccio 16
I-21049 Tradate (VA)
[email protected]
Editorial Office: [email protected]
Deputy Editors
Mirco Lusuardi
Dept. of Cardio-Pulmonary Rehab.
S. Sebastiano Hospital
AUSL Reggio Emilia
I-42015 Correggio (RE)
[email protected]
Executive Editors
Giuseppe Brunetti
IRCCS
Via Salvatore Maugeri 10
I-27100 Pavia
[email protected]
Associate Editors
R.W. Dal Negro
Bussolengo, Italy
Clinical Pharmacology
R. Trisolini
Bologna, Italy
Case Reports
N. Ambrosino
Pisa, Italy
V. Brusasco
Genova, Italy
G.W. Canonica
Genova, Italy
Bruno Balbi
IRCCS
Via per Revislate 13
I-28010 Veruno (NO)
[email protected]
Maurizio Luisetti
Laboratorio di Biochimica & Genetica
Clinica Malattie Apparato Respiratorio
IRCCS Policlinico San Matteo
Università di Pavia
Via Taramelli 5
I-27100 Pavia
[email protected]
Luca Bianchi
IRCCS
Via Mazzini 129
I-25066 Lumezzane (BS)
[email protected]
R. Dahl
Aarhus, Denmark
R.M. du Bois
London, UK
J.W. Fitting
Lausanne, CH
M.P. Foschino-Barbaro
Foggia, Italy
R.S. Goldstein
Toronto, Canada
P. Howard
Sheffield, UK
F. Meloni
Pavia, Italy
Editorial Board
P. Baiardi, Pavia, Italy
H. Burchardi, Goettingen, Germany
L. Casali, Perugia, Italy
M. Cazzola, Roma, Italy
A. Corsico, Pavia, Italy
I. Cerveri, Pavia, Italy
G. Cremona, Milano, Italy
G. D’Amato, Napoli, Italy
G. Di Maria, Catania, Italy
E.C. Flecther, Louisville, USA
G. Gialdroni Grassi, Pavia, Italy
C. Giuntini, Pisa, Italy
S.B. Gottfried, Montreal, Canada
V. Grassi, Brescia, Italy
R. Keller, Aarau, CH
G.B. Migliori, Tradate, Italy
G. Minuco, Veruno, Italy
Editors
Furio Colivicchi
Clinical Quality Management Unit
Cardiovascular Department
San Filippo Neri Hospital
Via Martinotti 20
I-00135 Roma
[email protected]
J.F. Muir
Rouen, France
S. Nardini
Vittorio Veneto, Italy
E. Pozzi
Pavia, Italy
M. Pistolesi
Firenze, Italy
An. Rossi
Bergamo, Italy
C.M. Sanguinetti
Roma, Italy
R. Sergysels
Bruxelles, Belgium
G. Moscato, Pavia, Italy
M. Neri, Tradate, Italy
D. Olivieri, Parma, Italy
C. Prefaut, Montpellier, France
R. Richmond, Sydney, Australia
J. Roca, Barcelona, Spain
G.A. Rossi, Genova, Italy
C. Roussos, Athens, Greece
M. Saetta, Padova, Italy
G. Scano, Firenze, Italy
G. Semenzato, Padova, Italy
N. Siafakas, Crete, Greece
J. Sorli, Golnik, Slovenia
S. Spinaci, Geneve, CH
C. Tantucci, Brescia, Italy
E. Wouters, Maastricht, NL
J. Zieli ński, Warsaw, Poland
Deputy Editors
Cesare Greco
Cardiac Rehabilitation Unit
S. Giovanni Addolorata Hospital
I-00184 Roma
[email protected]
Executive Editors
Pantaleo Giannuzzi
Dept. of Cardiac Rehabilitation
Institute for Clinical Care
and Research
I-28010 Veruno (NO)
[email protected]
Associate Editors
Maurizio Abrignani (Trapani)
Elisabetta Angelino (Torino)
Samuele Baldasseroni (Firenze)
Pompilio Faggiano (Brescia)
Francesco Giallauria (Napoli)
Scientific Board
M. Ambrosetti (Cunardo)
O. Bettinardi (Ponte dell’Olio)
P. Calisi (Arenzano)
R. Carlon (Cittadella)
V. Ceci (Roma)
S. Celardo (Caserta)
M. Chiatto (Trebisacce)
C. Chieffo (Napoli)
P. Clavario (Genova)
U. Corrà (Veruno)
L. Da Vico (Firenze)
S. De Feo (Peschiera del Garda)
T. Diaco (Crema)
G. Di Pasquale (Bologna)
G. Favretto (Motta di Livenza)
G. Furgi (Telese)
A. Galati (Roma)
M. Gattone (Veruno)
A. Genovesi Ebert (Livorno)
A. Giordano (Gussago)
P. Golino (Caserta)
P. Gremigni (Bologna)
M. Ferratini (Milano)
G.F. Ignone (Brindisi)
Francesco Fattirolli
Dept. Medical and Surgical Critical Care
Azienda Ospedaliero-Universitaria Careggi
Via delle Oblate 4
I-50141 Firenze
[email protected]
Oreste Febo
Institute for Clinical Care and Research
I-27040 Montescano (PV)
[email protected]
Carmine Riccio
Caserta Hospital
I-81100 Caserta
[email protected]
Raffaele Griffo (Genova)
Massimo Piepoli (Piacenza)
Pier Luigi Temporelli (Veruno)
Giovanni Pulignano (Roma)
Paolo Trambaiolo (Roma)
M.T. LaRovere (Montescano)
A. Maggioni (Firenze)
G. Majani (Montescano)
P. Maras (Trieste)
R. Marchioli (S.M. Imbaro)
G. F. Mureddu (Roma)
C. Opasich (Pavia)
S. Pirelli (Cremona)
M. Pistono (Veruno)
F. Rengo (Napoli)
G. Rosato (Avellino)
S. Scardi (Trieste)
M. Scherillo (Benevento)
C. Schweiger (Milano)
D. Scrutinio (Cassano Murge)
P. Stefàno (Firenze)
L. Tavazzi (Cotignola)
D. Temporelli (Veruno)
M. Volterrani (Roma)
M. Uguccioni (Roma)
S. Urbinati (Bologna)
D. Vanuzzo (Udine)
C. Vigorito (Napoli)
Chairman
Ernesto Catena
Inst. of Respiratory Medicine
2nd University of Napoli
V. Monaldi Hospital
I-80131 Camaldoli (NA)
AIMS AND SCOPE: Monaldi Archives for Chest Disease is an international scientific journal of the Fondazione Salvatore Maugeri IRCCS, Scientific Institute, Pavia, Italy, dedicated to the
advancement of knowledge in all fields of cardiopulmonary medicine and rehabilitation. It is published in two series: the “Cardiac Rehabilitation and Prevention Series” (volume, even numbers)
which, since 2002, is the official journal of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR); and the “Pulmonary Medicine and
Rehabilitation Series” (volume, odd numbers). Monaldi Archives for Chest Disease publishes original articles, new methodological approaces, reviews, opinions, editorials, position papers on
all aspects of cardiac and pulmonary medicine and rehabilitation, and, in addition, provides a forum for the inter-exchange of information, experiences and views on all issues of the cardiology
profession, including education. Accordingly, original contributions on nursing, exercise treatment, health psychology, occupational medicine, care of the elderly, health economics and other
fields related to the treatment, management, rehabilitation and prevention of cardiac and respiratory disease are welcome. Monaldi Archives for Chest Disease promotes excellence in the
profession of cardiology and pneumology through its commitment to the publication of research, support to continuous education, and encouragement and dissemination of ‘best practice’.
SUBSCRIPTION: Monaldi Archives for Chest Disease (ISSN 1122-0643) is published in two series: the Pulmonary Series, published quarterly (four issues per year), and the
Cardiology Series, also published quarterly (four issues per year). Monaldi Archives for Chest Disease is distributed by PI-ME Tipografia Editrice s.r.l., Via Vigentina 136A, 1-27100
Pavia, Italy, E-mail: [email protected]. Annual subscription rate: a) Four quarterly issues of the Pulmonary Medicine and Rehabilitation Series: € 96.00 (US $ 124.80); b)
Four quarterly issues of the Cardiac Rehabilitation and Prevention Series: € 63.00 (US $ 81.90); c) Cumulative subscription: € 130.00 (US $ 169.00). Subscriptions should be addressed
to: PI-ME Tipografia Editrice s.r.l., Via Vigentina 136A, 1-27100 Pavia, Italy; Tel: +39 0382 572169; Fax: +39 0382 572102; E-mail: [email protected]. The issues of the
Cardiology Series of Monaldi Archives for Chest Disease are distributed free to all members of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR).
MONALDI ARCHIVES FOR CHEST DISEASE IS PUBLISHED (FULL-TEXT) ON-LINE ON THE WEB-SITE www.archest.fsm.it
Monaldi Archives for Chest Disease is cited in: Index Medicus - Medline, Pubmed and in Excerpta Medica - Embase [Monaldi Arch Chest Dis].
Registered as a journal at the Tribunal of Pavia, Italy, no. 418 July 17,1993 - Registro Stampe Periodiche - ROC 5756 - ISSN 1122-0643 © 1995. AlI rights reserved
Authors submitting manuscripts to the journal do so in the knowledge that copyright passes to Monaldi Archives for Chest Disease.
Monaldi Archives for Chest Disease
Volume 79, Issue 3-4
September-December 2013
CONTENTS
CLINICAL PHARMACOLOGY
F. Novelli, F. Costa, M. Latorre, L. Malagrinò,
A. Celi, B. Vagaggini, P. Paggiaro
109 Tiotropium: a new therapeutic option in asthma
ORIGINAL ARTICLES
116 Health-related quality of life, lung function
and dyspnea rating in COPD patients
N. Barbarito, E. De Mattia
121 Grading the severity of obstruction in patients
with Chronic Obstructive Pulmonary Disease
and morbid obesity
N. Facciolongo, R. Piro, F. Menzella, M. Lusuardi,
M. Salio, L. Lazzari Agli, M. Patelli
128 Training and practice in bronchoscopy.
A national survey in Italy
TB CORNER
M. Irfan, F. Thiavalappil, J. Nagaraj, T.H. Brown,
D. Roberts, L. Mcknight, N.K. Harrison
134 Tuberculous pancreatitis complicated by ruptured
splenic artery pseudoaneurysm
CASE REPORTS
H. Bhardwaj, B. Bhardwaj, P.V. Carlile
136 Recurrent pneumomediastinum in a patient
with rheumatoid arthritis
S. Katsenos, M. Nikolopoulou
140 Intramedullary thoracic spinal metastasis
from small-cell lung cancer
IMAGES OF CHEST DISEASES
A. Andreani, G. Cappiello, M. Valli, M. Giovannini
143 TBNA for the treatment of non complicated
bronchogenic cyst
Monaldi Archives for Chest Disease
BOOKS
146
AUTHOR AND KEYWORD INDEXES
147
MEETING CALENDAR
107
Meeting Calendar
2013
October 17-19
Edinburgh, Scotland, UK
25th Anniversary Scientific Meeting
of the British Sleep Society
Information: www.edinburghsleep2013.co.uk
October 30 - November 3
Paris, France
44th Union World Conference on Lung Health
Information: www.worldlunghealth.org
November 7-9
Alexandroupolis, Greece
Medical Thoracoscopy
(hands-on-course)
Information: [email protected], www.ersnet.org/courses
November 19-22
Marseille, France
Thoracoscopy and Pleural Techniques
(hands-on-course)
November 21-23
Naples, Italy
Primary Ciliary Diskinesia: sharing knowledge
and experience across Europe
2014
January 30 - February 1
Copenhagen, Denmark
Endoscopic Ultrasound in the Diagnosis
and Staging of Lung Cancer
March 6
Barcelona, Spain
European Spirometry Train-the-Trainer Course
107
March 7
Barcelona, Spain
European Spirometry Training Programme Part II
March 17-19
Paris, France
Paediatric Bronchoscopy
March 18-21
Brussels, Belgium
34th International Symposium on Intensive Care and Emergency Medicine
Information: [email protected], www.intensive.org
March 21-23
Landshut, Germany
Joint spring meeting of the Work group of Sleep Medicine and Sleep Research
of the German Society for Sleep Research and Sleep Medicine
Information: [email protected], www.dgsm-paediatrie.de
March 29 - April 1
Mexico City, Mexico
XXII World Congress of Asthma
Information: [email protected], www.wca-2014.com
April 3-5
Heidelberg, Germany
Interstitial Lung Diseases
June 5-7
Lausanne, Switzerland
Pulmonary Hypertension and Pulmonary Vascular Disease
June 6-7
Stresa, Italy
Respiro Stresa
COPD in its severe stage
Information: [email protected], www.collagecongressi.it
108
Monaldi Arch Chest Dis
2013; 79: 3-4, 109-115
CLINICAL PHARMACOLOGY
Tiotropium: a new therapeutic option
in asthma
F. Novelli, F. Costa, M. Latorre, L. Malagrinò, A. Celi, B. Vagaggini P. Paggiaro
ABSTRACT: Tiotropium: a new therapeutic option in
asthma. F. Novelli, F. Costa, M. Latorre, L. Malagrinò,
A. Celi, B. Vagaggini, P. Paggiaro.
Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has
been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that
salbutamol is more effective than ipratropium in treating asthma.
Recently, tiotropium has been studied in asthma,
when added to low-medium dose inhaled corticosteroids
(ICS) in unselected moderate asthmatics or in patients
with uncontrolled asthma, or with COPD and history of
asthma. Later, studies on patients with Arg/Arg beta2-receptor polymorphism demonstrated a similar efficacy of
tiotropium in comparison with salmeterol, when both
were added to ICS.
More recently, pivotal long-term studies have been
performed on severe asthmatics uncontrolled under
ICS/LABA combination, showing the efficacy of tiotropium in improving lung function and in increasing the time
until the first severe asthma exacerbation. These data support the use of tiotropium on top of ICS/LABA combination in moderate-severe asthmatic patients.
New studies are going to be published on the use of
tiotropium in mild and moderate asthmatics, when added
to low or medium dose ICS, in comparison with ICS alone
or with ICS/LABA combination. These data might extend
the indication for using tiotropium in asthma.
Therefore, tiotropium represents now a valid therapeutic option, in addition to the current therapy available
for severe asthmatics, and in alternative to LABA in selected asthma populations. The specific asthma phenotype
which may be appropriate for tiotropium treatment
should still be defined.
Monaldi Arch Chest Dis 2013; 79: 3-4, 109-115.
Keywords: Asthma, Bronchodilator, Tiotropium, Therapy.
Department of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Italy.
Correspondence: Federica Novelli, M.D., Respiratory Pathophysiology Unit, Cardio-Thoracic and Vascular Department,
University Hospital of Cisanello, Via Paradisa 2, 56124 Pisa, Italy; e-mail: [email protected]
Introduction
Asthma is a chronic airway inflammatory disease associated with widespread but variable airway obstruction and an exaggerated bronchoconstrictive response to indirect (e.g. cold air, allergens, dust, exercise) or direct (e.g. inhaled methacoline) stimuli. This hyperreactivity is associated
with abnormal autonomic nervous system control
[1], which may explain the occurrence of symptoms for different triggers. For this reason, the potential usefulness of anticholinergic drugs in the
treatment of asthma has been considered in the last
40 years, but up to now, no studies have clearly
demonstrated the potential contribution of this
treatment in asthma management.
In the last few years some data have been produced on the efficacy of tiotropium in special
groups of asthmatic patients (asthma with persistent
bronchoconstriction, asthma with polymorphism of
beta2-receptor, severe uncontrolled asthma) [2-7],
with positive results. More recently, the first large
randomized controlled clinical trial on the use of
tiotropium as add-on therapy in patients with severe
asthma has been published [8], leading to the submission for the use of tiotropium in asthma.
In this short review, we wish to summarize the
background of the potential usefulness of anticholinergic drugs in the treatment of asthma, and
the results of the more recent data supporting the
use of tiotropium.
Airway cholinergic system in asthma
It is already well known that the parasympathetic system is implicated in the pathogenesis of
asthma. At the level of the peribronchial ganglia,
the pre-ganglionic parasympathetic fibers of the
vagus nerve form cholinergic synapses with postganglionic neurons, which generate postganglionic fibers that innervate the airways. The parasympathetic activity is mediated by muscarinic receptors, in particular the M1 receptors, located on the
parasympathetic ganglia, which are responsible
for cholinergic transmission, while the M2 receptors, located near the postganglionic endings,
have a negative presynaptic feedback in reducing
a further release of acetylcholine. M3 receptors,
located at the airway smooth muscle and submucosal glands, provide the control of both smooth
muscle tone (and thus airway caliber) and mucus
secretion.
F. NOVELLI ET AL.
Cholinergic tone is thought to be increased in
asthma sufferers by several mechanisms: abnormal
muscarinic receptor expression, increased acetylcholine from postganglionic fiber endings, decreased levels of neuromodulators that attenuate
cholinergic neurotransmission. This abnormal
cholinergic hyper-sensitivity of an asthmatic’s airways is highlighted by the bronchoconstrictive response to doses of inhaled cholinergic agents
(acetylcholine and methacholine) that do not affect
normal subjects. Moreover, anticholinergic drugs
such as atropine have demonstrated some protective effects from bronchoconstriction induced by
different non specific stimuli (histamine, cold air,
ultrasonically nebulized distilled water) [9, 10]
and a partial inhibition of immediate airway response to allergen [11]. For all of these reasons,
cholinergic antagonists have been tested as potential drugs for the treatment of obstructive airway
diseases. Systemic administration of atropine is associated with an unacceptably high rate of adverse
events, and inhalation route is ineffective due to
the poor water solubility of atropine. The available
anticholinergic drugs for respiratory disease are inhaled, and combine a potent local anticholinergic
activity with a poor systemic absorption.
Short-acting anticholinergic vs beta2-agonist
drugs in asthma
The first inhaled anticholinergic drug had a
short duration of action, so had to be administered
multiple times per day, and was a nonselective antagonist of M1, M2 and M3 receptors (the antagonism of M2 allows further release of presynaptic
acetylcholine and may antagonize the bronchodilator effect of the M3 antagonism). Ipratropium bromide has been widely studied in the treatment of
asthma, both alone in comparison with SABA as
well as in addiction to SABA. However, in almost
all studies, salbutamol determined a greater bronchodilation than ipratropium bromide in asthmatic
subjects, whereas in normal subjects or in patients
with COPD, both drugs determined a similar bronchodilation [12, 13]. Furthermore, the study comparing ipratropium plus SABA to SABA alone did
not find any significant difference in lung function
and symptoms between two treatments [14, 15].
Some data suggested a possible benefit of anticholinergics in a certain subsets of patients, such
as smokers [16], or in the prevention of the morning dip of peak of expiratory flow (PEF) in nocturnal asthma [17], or in obese patients. In conclusion, the short-acting anticholinergic drugs have
not been used in asthma treatment, except for the
management of acute severe asthma attacks.
Tiotropium in asthma: preliminary studies
The second generation of anticholinergic drugs
started with tiotropium, the first long-acting anticholinergic drug. Tiotropium differs from the other anticholinergics for the more selective antagonism for M1 and M3 muscarinic receptor subtypes
and for a prolonged pharmacologic activity due to
110
the slow dissociation from M1 and M3 receptors.
Tiotropium has largely been studied in COPD,
demonstrating both its efficacy and safety in this
respiratory obstructive disease. However, its role
as a treatment for asthma has only recently been
studied to systematic clinical investigation. The
first trials were conducted on special subgroups of
asthmatic patients (patients with asthma and
COPD, asthma with persistent bronchoconstriction) but more recently some RCTs have been
completed on unselected asthma populations.
Six RCTs and one longitudinal open study included about 2500 patients with asthma, and compared at least 4 weeks tiotropium treatment (range:
4-48 weeks) added to inhaled corticosteroids (ICS)
alone or combined with long-acting β2-agonists
(LABA), with placebo or salmeterol. Apart from
the study carried out by Magnussen which took into account patients affected by COPD and asthma
[3], the other studies excluded COPD patients and
evaluated persistent asthmatics requiring daily
therapy. Three studies were conducted on severe
asthmatics with persistent bronchoconstriction,
symptomatic despite therapy with a high-dose ICS
and LABA [2, 4, 6], while other studies were performed on uncontrolled asthmatics [5, 7]. These
studies are summarized in table 1.
The efficacy of tiotropium has been assessed
primarily through impact on lung function evaluated by spirometry or peak expiratory flow (PEF).
Moreover, other important outcomes, including
exacerbations, symptoms and quality of life, were
taken into account.
In a first pilot randomized crossover study of
Fardon et al [2], 18 non-smoking patients with severe persistent asthma (mean FEV1: 51% of predicted) were treated with HFA-fluticasone propionate 250 mcg BD/salmeterol 50 mcg BD plus
tiotropium bromide 18 mcg OD, or HFA-fluticasone propionate 250 mcg BD/salmeterol 50 mcg
BD plus placebo, for 4 weeks after a run-in period
of 4 weeks with HFA-fluticasone 500 mcg BD. Patients performed spirometry and body plethysmography in order to evaluate the effect of halving the
fluticasone dose with the addition of salmeterol
alone or salmeterol plus tiotropium. Both adding
salmeterol alone and salmeterol/tiotropium to half
the dose of fluticasone led to an improvement vs
baseline in morning PEF (+41.5 L/min (p<0.01)
and +55.3 L/min (p<0.01) respectively) and Raw;
moreover salmeterol/tiotropium also improved
FEV1 (+0.17 L, p<0.05) and FVC (+0.24 L, p<0.05).
There were no significant changes in symptoms or
quality of life compared to baseline in both treatments, which were not significantly different between them.
Following this first study, randomized trials
were conducted, both on patients with moderate
asthma as well as on those with severe asthma, and
also on patients with COPD and a history of asthma.
Peters et al conducted a large randomized,
cross-over, placebo-controlled study that compared the addiction of tiotropium bromide to ICS
versus doubling dose ICS versus ICS/LABA combination, for 14 weeks, on 210 asthmatics with
TIOTROPIUM IN ASTHMA
Table 1. - RCTs on the efficacy of tiotropium on lung function and symptoms in asthmatic patients.
Study
Inclusion
criteria
No. of
patients
Asthma
severity
Trial
design
Lung function
outcome
Clinical
outcome
Fardon
2007 [2]
Severe
persistent
asthma,
FEV1
≤65 %pred.,
no history
of smoking
26
Pre-BD
FEV1:
51 %pred.
on full
dose ICS
Randomised, placebocontrolled, crossover;
4 weeks of half dose
ICS+salmeterol or
half dose ICS+salmeterol
+tiotropium after a run-in
period with ICS alone
Improvement in morning PEF
and RAW in ICS+salmeterol
vs baseline. Improvement
in morning PEF, RAW, FEV1
and FVC in ICS+salmeterol+
tiotropium vs baseline.
No difference between
ICS+salmeterol and ICS+
salmeterol+tiotropium
No difference in
mini-AQLQ score
Magnussen COPD
2008 [3]
and asthma,
FEV1<80%
of pred.
472
Pre-BD
FEV1:
53 %pred.
Randomised, placebocontrolled; 12 weeks
of tiotropium or placebo
in addition to basal therapy
Increase in FEV1 area under
the curve (AUC) from 0 to 6 h
and in morning pre-dose FEV1
in tiotropium vs placebo
Reduction in rescue
medication compared
to baseline in
tiotropium vs placebo
Park
2009 [4]
Severe
persistent
asthma,
PY≤10
138
Pre-BD
FEV1:
58 %pred.
Longitudinal, 8 weeks
of tiotropium in addition
to convention therapy,
to evaluate predictor factors
of response (improvement
in FEV1≥15%)
33,3% of patients responded
to tiotropium. The presence
of Arg16Gly in ADRB2
was associated with response
to tiotropium
Peters
2010 [5]
Asthma,
FEV1>40%
of pred.,
PY≤10
210
Pre-BD
Randomised, placeboFEV1:
controlled, crossover;
71.5 %pred. 14 weeks of tiotropium
or salmeterol + ICS
vs double-dose ICS
Increase in morning and evening
PEF, and pre-BD FEV1, in
tiotropium/ICS vs double-dose ICS.
Increase in morning and evening
PEF in LABA/ICS vs double-dose
ICS. Increase in pre-BD FEV1
and post-BD FEV1 in tiotropium
vs salmeterol
Increase in
asthma-control
days and reduction
in daily-symptom
score and ACQ
in tiotropium
and salmeterol
vs double-dose ICS.
tiotropium
and salmeterol
Kerstjens
2011 [6]
Severe,
persistent
asthma,
FEV1≤80%
of pred.,
PY≤10
107
Pre-BD
FEV1:
58 %pred.
Randomised, placebocontrolled, crossover;
8 weeks of ICS+LABA+
tiotropium 10 mcg
or ICS+LABA+tiotropium
5 mcg or ICS+LABA
+placebo
Increase in peak of FEV1 and
FVC, in trough FEV1 and FVC
at the end of the dosing interval,
in FEV1 and FVC area under
curve from 0 to 3 h, in weekly
mean predose morning PEF,
in both doses of tiotropium
vs placebo
No significant
differences in the
use of rescue
medication,
in the symptom
scores and in
mini-AQLQ
score
Bateman
2011 [7]
Asthma,
388
B16-Arg/
Arg genotype,
pre-BD
FEV1≤80-90%
of pred.,
PY≤10
Pre-BD
FEV1:
75 %pred.
Randomised, placebocontrolled, parallel-group
study; 16 weeks of ICS+
salmeterol or ICS+tiotropium
5 mcg or ICS+placebo after
a run-in period with ICS+
salmeterol
Decrease in morning PEF and
morning pre-dose FEV1 in
ICS+placebo vs ICS+salmeterol
and ICS+tiotropium.
ICS+salmeterol and
ICS+tiotropium
Significant
difference vs
placebo in the use
of rescue
medication,
symptom score,
asthma-control
days and miniAQLQ only
for salmeterol
Kerstjens
2012 [8]
Severe,
persistent
asthma,
FEV1≤80%
of pred.,
Pre-BD
Randomised, placebocontrolled, parallel group;
FEV1:
54.8 %pred. 48 weeks of ICS+LABA+
tiotropium 5 mcg or ICS+
LABA+placebo
At 24 weeks, greater increase
in the peak FEV1 and in trough
FEV1 from baseline with
tiotropium than with placebo
Increase in the
time to the first
severe exacerbation
with tiotropium.
Small improvements
in ACQ and AQLQ
with tiotropium
912
Abbreviations: RCT: Randomised Clinical Trials; ACQ: Asthma Control Questionnaire; AQLQ: Asthma Quality of Life; ICS: inhaled
corticosteroids, LABA: long-acting β2-agonists; FEV1: Forced expired volume in 1 s; FVC: Forced Vital Capacity; Pre-BD: value measured
pre-bronchodilator; PEF: Peak Expiratory Flow; Raw: airway Resistance.
111
F. NOVELLI ET AL.
FEV1 of more than 40% of the predicted value
(mean pre-bronchodilator FEV1: 71.5%) [5]. The
addiction of tiotropium to ICS showed a superiority to the doubling dose ICS for the morning PEF
(mean difference 25.8 L/min, p<0.001), that was
the primary outcome, and for most secondary outcomes including evening PEF (mean difference
35.3 L/min, p<0.001), pre- and post-bronchodilator FEV1 (mean difference 0.10 L, p=0.004 and
0.04 L, p=0.01 respectively), proportion of asthma-control days (with a difference of 0.079,
p=0.01), daily symptoms score, and Asthma Control Questionnaire (with a difference of -0.18
points, p=0.02). Also the addiction of salmeterol to
ICS, compared with doubling dose ICS, showed an
improvement in these outcomes, except in pre- and
post-bronchodilator FEV1 (in particular for the
morning PEF, mean difference was 19.4 L/min,
p<0.001 and for the evening PEF, mean difference
was 24.7 L/min, p<0.001). There were no significant differences between tiotropium and salmeterol treatments with respect to morning PEF
(mean difference in change from baseline for
tiotropium vs salmeterol +6,4 L/min), evening
PEF, number of asthma-control days, daily symptoms score and Asthma Control Questionnaire.
The tiotropium treatment was superior to the salmeterol treatment with respect to the pre- and postbronchodilator FEV1 measured in the morning
(mean difference 0.11 L, p=0.003 and 0.07 L,
p<0.001 respectively).
These results were confirmed in the study by
Bateman, performed on a population of asthmatics
with similar functional findings and uncontrolled
with ICS alone, but with the genetic characteristic
of having the B16-Arg/Arg genotype [7]. The
background for conducting the study only in this
asthmatic population came from the previous observation that the polymorphism in 16 position of
β2-agonist receptor could be associated to a lower
response to the stimulation by β2-agonists, an increased risk of adverse effects by use of β2-agonists, and this might predispose to a higher response rate to tiotropium. In the study by Bateman,
388 asthmatics, after a 4-week run-in period with
50 μg of twice-daily salmeterol, were randomized
to 16 weeks of treatment with 5 μg Respimat
tiotropium once daily, or 50 μg salmeterol twice
daily, or placebo, always maintaining ICS therapy.
The primary endpoint was the change in weekly
PEF from the last week of the run-in period to the
last week of active treatment. Mean weekly morning pre-dose PEF was maintained during the treatment period with tiotropium and salmeterol, but
decreased in patients who switched to placebo
(-3.9 L/min for tiotropium, -3.2 L/min for salmeterol
and -24.6 L/min for placebo, p<0.05). Tiotropium
was not inferior to salmeterol (estimate difference
-0.78 L/min) and both tiotropium and salmeterol
were superior to placebo. Similar results were obtained for mean weekly evening PEF, FEV1 and
FVC (for mean weekly pre-dose FEV1: +0.01 L
for tiotropium, -0.01 L for salmeterol and -0.10 L
for placebo). The aim of this study was to demonstrate the similar efficacy of tiotropium and salme112
terol in a group of asthmatics considered at increased risk of adverse effects through the use of
β2-agonists and possibly better responders to anticholinergics (on the basis of study by Park et al).
Before the publication of this study, extensive
prospective studies have shown the safety of use of
β2-agonists in Arg/Arg asthmatics [18, 19], but the
demonstration of a similar efficacy of LABA and
tiotropium is still important from a clinical point of
view. It is important to note, though, that a similar
improvement in pulmonary function was observed
in the Bateman study in comparison with the Peters study (mean difference in morning PEF: 20.7
L/min vs 25.8 L/min; mean difference in pre-bronchodilator FEV1: 0.113 L vs 0.100 L). However, in
the Bateman study the results on patient-related
aoutcomes were quite disappointing, with no significant improvement in tiotropium vs placebo on
daytime asthma symptoms (change from baseline:
placebo: 0.015, n.s.; salmeterol: -0.221, n.s.;
tiotropium: -0.088, n.s.; significant differences in
placebo vs salmeterol but not in placebo vs
tiotropium), rescue medication use (change from
baseline: placebo: 0.294, n.s.; salmeterol: -0.273,
n.s.; tiotropium: -0.074, n.s.; significant differences in placebo vs salmeterol but not in placebo
vs tiotropium) and quality of life (evaluated by Mini-Asthma Quality of Life Questionnaire, change
from baseline: placebo: 0.039, n.s.; salmeterol:
0.280, n.s.; tiotropium: 0.131, n.s.; significant differences in placebo vs salmeterol but not in placebo vs tiotropium). There was no significant differences between the two active treatments on these
outcomes.
Similar results were also obtained in patients
with severe asthma when it was added to ICS+LABA. Kerstjens et al performed a randomized, double-blind, crossover study on 107 patients with uncontrolled severe asthma (mean pre-bronchodilator FEV1 of 58%) despite treatment with high-dose
ICS plus LABA and evaluated the efficacy and
safety of the addiction of 2 doses of tiotropium (5
mcg and 10 mcg daily), compared with placebo, to
a treatment regimen of glucocorticoids and
LABAs for 8 weeks [6]. The mean peak FEV1 response in the first 3 hours after dosing at the end of
the 8-week treatment period (the primary outcome) was significantly superior to placebo with
both tiotropium doses (5 mcg: difference with
placebo 139 mL, p<0.001, 10 mcg: difference with
placebo 170 mL, p<0.001). Both doses of tiotropium were significantly superior compared with
placebo in all other functional assessments: trough
FEV1 (5 mcg: difference from placebo 86 mL,
p<0.001, 10 mcg: difference with placebo 113 mL,
p<0.001), mean peak FVC in the first 3 hours after
dosing, trough FVC and FVC AUC 0-3h, the
weekly mean predose morning and evening PEF
for weeks 4-8 (for morning PEF, difference with
placebo: 7.9 L/min, p=0.02 with 5 mcg, and 15.3
L/min, p<0.001 with 10 mcg). Despite these impressive results in lung function, it did not demonstrate any significant effects on clinical parameters. In fact there were no significant differences
among the 3 treatments in the rescue medication
use, the mini-AQLQ score (change over the entire
period treatment: placebo: 0.108, tiotropium 5
mcg: 0.205; tiotropium 10 mcg: 0.206) and in the
symptom scores measured with an electronic asthma diary (for asthma symptoms day, change over
the entire period treatment: placebo: -0.121, for
tiotropium 5 mcg: -0.140; for tiotropium 10 mcg:
-0.152).
An important study is that carried out by Magnussen et al [3], and conducted on a subgroup of
patients with COPD and a history of asthma diagnosed before 40 yrs of age. In this randomized,
placebo-controlled study, 472 patients with diagnosis of asthma and COPD were treated with
tiotropium or placebo for 12 weeks in addition to
current therapy. Patients were allowed to continue
treatments with ICS (inhaled steroid use was an inclusion criteria), LABA, theophylline, leukotriene
inhibitors and/or oral corticosteroids. Tiotropium
led to a significant improvement not only in the
primary endpoint, that was the change in FEV1
area under the curve over from 0 to 6 h (difference
= 186±24 mL, p<0.001) after 12 weeks of treatment, but also in all secondary outcomes: morning
pre-dose FEV1, FVC AUC 0-6 h, morning predose FVC, morning and evening PEF and the use
of rescue medications (the mean weekly number of
daily puffs of salbutamol was reduced by
0.05±0.12 puffs/day in the placebo group and by
0.50±0.12 puffs/day in the tiotropium group at
week 12, p<0.05).
Tiotropium in asthma: pivotal studies
Two replicate randomized, double-blind,
cross-over studies were conducted by Kerstjens et
al on patients with severe asthma on treatment
with high dose ICS plus LABA [8]. These studies
included patients with uncontrolled asthma (ACQ
score ≥1.5) and persistent airflow limitations (defined as a post-bronchodilator FEV1 of 80% or less
of the predicted value, after the inhalation of 4
puffs of 100 μg of salbutamol) despite daily therapy with ICS, with at least one exacerbation in the
previous year, nonsmokers or ex smokers with a
smoking history of less than 10 pack-years. These
two studies were conducted on large samples (459
and 453 patients, respectively) and over a long
time period (48 weeks) and had, in addiction to
two lung-function primary endpoints (the peak
FEV1 response in the first 3 hours after dosing and
the trough FEV1 response at week 24), also a third
important co-primary endpoint: the time to the first
severe asthma exacerbation (defined as a deterioration of asthma necessitating initiation or at least
a doubling of systemic glucocorticoids for ≥3
days). The patients had a mean baseline FEV1 of
62% of predicted value. As in previous studies, the
addiction to tiotropium again confirmed the improvement of functional parameters (at week 24,
the mean difference between tiotropium and placebo groups in the change in peak FEV1 from baseline in the first 3 hours was 86±34 ml in trial 1
(p<0.05) and 154±32 ml in trial 2 (p<0.001), and
in the change from baseline in the trough FEV1
was 88±31 ml in trial 1 (p<0.01) and 111±30 ml in
trial 2 (p<0.001), but especially increased the time
to the first severe exacerbation (282 days vs. 226
days, corresponding to a reduction of 21% in risk,
hazard ratio: 0.79, p=0.03) (figure 1). As for the
clinical parameters, once again their improvements (number of symptom-free days, use of res-
Fig. 1. - Effect of tiotropium on reduction of severe exacerbations in patients with severe asthma. Cumulative number of severe exacerbations in
patients with tiotropium therapy in comparison with placebo, with a risk reduction of 21% (hazard ratio, 0.79; P=0.03) (with permission, from
reference # 8).
113
F. NOVELLI ET AL.
cue medications, ACQ and AQLQ scores) were
small and inconsistent and, for ACQ and AQLQ
scores, did not reach the minimal clinically significant difference of 0.5. The safety profile was extremely good, with no difference in the rate of major and minor adverse events between tiotropium
and placebo.
Recent subanalyses of this study have been presented at some major Respiratory International
Meetings, showing that the response to tiotropium is
consistent throughout a large variety of characteristics from asthmatic subjects (atopic vs non atopic,
severe vs non severe airway obstruction, different
asthma durations, different age groups, etc.).
Safety of tiotropium in asthma
Recently, a large debate on the safety of
tiotropium, administered by the Respimat inhaler,
has been developed, with regard to a potential increased risk of cardiovascular events in COPD patients [21]. Therefore, the safety profile of tiotropium in asthma has been assessed. In the preliminary
studies on the relatively low number of patients, no
significant excess of adverse events were observed
in patients treated with tiotropium in comparison
with placebo or other comparators. In the most extensive study, carried out on more than 900 patients [8], half of them treated with tiotropium for
one year, adverse events were reported in 73.5%
from the tiotropium group and in 80.3% from the
placebo group. No major events attributed to
tiotropium were reported; in particular, cardiac adverse events occurred in less than 2% of the patients and all were well balanced throughout the
study groups. Therefore, the safety of tiotropium
in asthma appears to be good.
General considerations
The various studies of tiotropium in asthma
demonstrate that tiotropium is effective in improving lung function. In patients with moderate asthma and not adequately controlled with ICS alone,
tiotropium is non-inferior to salmeterol and superior to both placebo and doubling doses of ICS (with
possible steroid-sparing effects) in improving the
lung function. In patients with severe asthma uncontrolled despite high dose ICS plus LABA, the
addiction of tiotropium still provides significant
improvements in lung function. Surprisingly, almost all studies show only modest and often insignificant benefits regarding symptoms and quality of life.
The regulatory studies also show a significant
reduction in severe exacerbations when tiotropium
is added to ICS plus LABA in severe asthmatics.
Previously, only the studies by Peters and Magnussen had reported data suggesting a possible role
of tiotropium in reducing exacerbation rate (in the
study by Peters an asthma exacerbation occurred
in 7 patients receiving tiotropium, in 13 receiving
double-dose corticosteroids and in 5 receiving salmeterol, and in the study by Magnussen, an exacerbation of COPD and asthma occurred in 11.5%
114
of the patients receiving placebo and 6.6% of the
patients receiving tiotropium).
One aspect which deserves to be investigated
in future studies is the link between tiotropium and
airway inflammation. As regards the possible impact on airway inflammation, there are only few
observations in the studies carried out by Fardon
[2] and Peters [5]. In the first paper there was a little but significant reduction (2.86 ppb) in exhaled
nitric oxide (FENO) during treatment with fluticasone propionate/salmeterol/tiotropium bromide
compared with fluticasone propionate alone, while
in the second study, patients had at baseline a
FENO of 18.8 ppb and a normal sputum
eosinophilia of 0.40 x106 cells, and no treatment
determined a significant change in these biomarkers. As for the possible different responsivenesses
to tiotropium of different inflammatory phenotypes of asthma, Iwamoto et al studied 17 severe
persistent asthmatics and observed a positive correlation between sputum neutrophils and FEV1
improvement after 4 weeks of therapy, and an inverse correlation between sputum eosinophils and
improvement in FEV1 after 4 weeks of therapy
[20], suggesting that tiotropium may be particularly effective in non-eosinophilic asthma.
In summary, the data produced up until now
regarding the efficacy and safety of tiotropium in
asthma have shown:
a) A significant improvement in lung function,
both when tiotropium was added to ICS alone
in patients with moderate asthma, and when it
was added to ICS+LABA in patients with severe asthma and in patients with concomitant
asthma and COPD. The comparison with salmeterol demonstrated similar improvements in
morning PEF and similar or greater improvements in pre-dose FEV1.
b) A significant reduction of the risk of asthma
exacerbations when added to ICS+LABA in
patients with severe asthma and persistent airflow limitation
c) A mild improvement in the control of asthma
symptoms and in quality of life, with a reduction in the use of rescue medications in patients of asthma and COPD, controversial results in patient with moderate asthma (improvement in proportion of asthma-control
days, daily symptoms score and Asthma Control Questionnaire in the study of Peters, and
no change in daytime asthma symptoms, use of
rescue medications and quality of life in the
study of Bateman), and inconsistent change in
asthma control and quality of life scores in patients with severe asthma.
Future perspectives
Asthma management still requires new drugs
and new therapeutic strategies, in order to improve
the level of asthma control in the general practice.
This may be particularly relevant in severe asthmatics who may be still remain symptomatic despite high doses of ICS and LABA. Therefore, the
demonstration of the efficacy of tiotropium along
with the currently available treatment represent a
valid option for the management of more severe
asthmatics. Furthermore, the potential for tiotropium to be an alternative to LABA in the addition to
low-medium doses of ICS might be relevant, taking into account the warning that some regulatory
authorities have issued regarding the risks of using
LABA in asthmatic subjects [22]. Although these
warnings do not seem appropriate according to the
results of the major clinical trials showing the
long-term safety of LABAs when added to ICS in
asthmatics [23], adding tiotropium (instead of
LABA) to ICS may represent a valid alternative.
In more recent years, a program for studying the
efficacy of tiotropium in asthma (TinA project) has
been developed, and in the near future data on the
efficacy of tiotropium in mild and moderate asthmatics are on hold. In particular, studies have been
completed on the addition of tiotropium to low dose
ICS vs ICS alone in mild asthmatics, either with the
addition of tiotropium or salmeterol to medium dose
ICS vs ICS alone in moderate asthmatics. The results will be available in the near future.
If these results prove to be positive, it will remain to be seen which patients may be appropriate
for treatment with either LABA or tiotropium,
leading to a more customized treatment according
to some specific phenotypes.
Therefore, tiotropium is set to become a further yet important resource for the management of
asthmatic patients and improvement in the control
of the disease.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
References
18.
1.
2.
3.
4.
5.
6.
7.
Lewis MJ, Short AL, Lewis KE. Autonomic nervous
system control of the cardiovascular and respiratory
systems in asthma. Respir Med 2006; 100: 1688-1705.
Fardon T, Haggart K, Lee DKC, Lipworth BJ. A proof
of concept study to evaluate stepping down the dose of
fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med 2007; 101:
1218-1228.
Magnussen H, Bugnas B, van Noord J, Schmidt P,
Gerken F, Kesten S. Improvements with tiotropium in
COPD patients with concomitant asthma. Respir Med
2008; 102: 50-56.
Park HW, Yang MS, Park CS, et al. Additive role of
tiotropium in severe asthmatics and Arg16Gly in
ADRB2 as a potential marker to predict response. Allergy 2009; 64: 778-783.
Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium
bromide step-up therapy for adults with uncontrolled
asthma. N Engl J Med 2010; 363: 1715-1726.
Kerstjens HA, Disse B, Schröder-Babo W, et al.
Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128: 308-314.
Bateman ED, Kornmann O, Schmidt P, Pivovarova A,
Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16Arg/Arg patients with asthma. J Allergy Clin Immunol
2011; 128: 315-322.
19.
20.
21.
22.
23.
Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in
asthma poorly controlled with standard combination
therapy. N Engl J Med 2012; 367: 1198-1207.
Fabbri LM, Hendrck DJ, Diem JE. Effect of atropine on
the bronchial response of asthmatic subjects to the inhalation of ultrasonically nebulized distilled water. J
Allergy Clin Immunol 1983; 71: 468-472.
Sheppard D, Epstein J, Holtzman MJ, Nadel JA,
Boushey HA. Dose-dependent inhibition of cold air-induced bronchoconstriction by atropine. J Appl Physiol
1982; 53: 169-174.
Fish JE, Rosenthal RR, Summer WR, Menkes H, Norman SP, Permut S. The effect of atropine on acute antigen-mediater airway constriction in subjects with allergic asthma. Am Rev Respir Dis 1977; 115: 371-379.
Thiessen B, Pedersen OF. Maximal expiratory flows
and forced vital capacity in normal, asthmatic and bronchitic subjects after salbutamol and ipratropium bromide. Respiration 1982; 43: 304-316.
Higgins BG, Powell RM, Cooper S, Tattersfield AE.
Effect of salbutamol and ipratropium bromide on airway caliber and bronchial reactivity in asthma and
chronic bronchitis. Eur Respir J 1991; 4: 415-420.
Jindal SK, Kaur SJ. Relative bronchodilatory responsiveness attributable to sympathetic and parasympathetic activity in bronchial asthma. Respiration 1989; 56:
16-21.
Chhabra SK, Pandey KK. Comparison of acute bronchodilator effects of inhaled ipratropium bromide and
salbutamol in bronchial asthma. J Asthma 2002; 39:
375-381.
Ahmed Z, Singh SK. Relative and additional bronchodilator response of salbutamol and ipratropium in
smoker and nonsmoker asthmatics. J Asthma 2010; 47:
340-343.
Cox ID, Hughes DT, McDonnell KA. Ipratropium bromide in patients with nocturnal asthma. Postgrad Med
J 1984; 60: 526-528.
Bleecker ER, Postma DS, Lawrance RM, Meyers DA,
Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised
studies. Lancet 2007; 370: 2118-2125.
Bleecker ER, Nelson HS, Kraft M, et al. Beta2-receptor
polymorphisms in patients receiving salmeterol with or
without fluticasone propionate. Am J Respir Crit Care
Med 2010; 181: 676-687.
Iwamoto H, Yokoyama A, Shiota N, et al. Tiotropium
bromide is effective for severe asthma with
noneosinophilic phenotype. Eur Resp J 2008; 31: 13791380.
Singh S, Loke YK, Enright PL, Furberg CD. Mortality
associated with tiotropium mist inhaler in patients with
chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.
BMJ 2011; 342: d3215.
Levenson M. Long-acting beta-agonists and adverse
asthma events meta-analysis: statistical briefing package for joint meeting of the Pulmonary - Allergy Drugs
Advisory Committee, Drug Safety and Risk Management Advisory Committee, and Pediatric Advisory
Committee on December 10-11, 2008 (Accessed March
27, 2009, at http:// www.fda.gov/ohrms/dockets/ac/08/
briefing/2008-4398b1-01-FDA.pdf).
Chowdhury BA, Dal Pan G. The FDA and safe use of
long-acting beta-agonists in the treatment of asthma. N
Engl J Med 2010; 362: 1169-1171.
115
2013; 79: 3-4, 116-120
ORIGINAL ARTICLE
Health-related quality of life, lung function
and dyspnea rating in COPD patients
ABSTRACT: Health-related quality of life, lung function
and dyspnea rating in COPD patients. M. Justine, F. Tahirah,
V. Mohan.
Background and Aim. COPD is a progressive and irreversible disease, thus assessing the impact of the disease
on health-related quality of life (HRQOL) is important in
the management of COPD. The aim of this study was to
examine the relationship between HRQOL, lung function
and dyspnea rating in patients with stable COPD.
Methods. One hundred COPD patients (mean age =
64.76±11.43 years) were recruited for this cross-sectional
study. Lung function test was measured using a
FlowScreen portable spirometry. Dyspnea rating was
measured using the baseline dyspnea index (BDI).
HRQOL was assessed using the SF-36v2 which summarized two components; physical health component summary (PHCS) and mental health component summary
(MHCS).
The results. The mean value of lung function (Forced
expiratory volume in 1 second, FEV1% predicted) was
58.19±30.24 and dyspnea rating was 6.85±2.68. The lung
function was significantly correlated with MHCS (r=.294,
p<0.05) but not with the PHCS (p>0.05). The dyspnea rating was significantly correlated with both PHCS (r=.730,
p<0.05) and MHCS (r=.324, p<0.05). Regression analysis
indicated that dyspnea rating emerged as the most significant predictor for PHCS and MHCS accounting for 54%
and 12% of the variances respectively.
Conclusions. The findings show that dyspnea rating is
an important factor in predicting HRQOL of patients with
COPD. This indicates that dyspnea rating influences
HRQOL to a greater extent than the physiological measurement of lung function. Therefore, focusing on such
predictors at an early stage may provide meaningful benefits in the management of COPD.
Keywords: COPD, Dyspnea, Lung function, Quality of life.
Physiotherapy Department, Faculty of Health Sciences, Universiti Teknologi MARA, Puncak Alam Campus, Selangor Malaysia.
Correspondence: Maria Justine, Physiotherapy Department, Faculty of Health Sciences, Universiti Teknologi MARA, Puncak
Alam Campus, 42300 Puncak Alam, Selangor Darul Ehsan, Malaysia; e-mail: [email protected]
Introduction
COPD is one of the principal causes of major
morbidity and mortality that affects the population
worldwide with higher incidence in men than
women [1]. Age and smoking were found to be the
strongest contributors to COPD [2, 3]. Age is considered a non-modifiable factor that accompany the
progression of the disease. In contrast, a study conducted in Abu Dhabi among 40-80 year-old subjects, associations between COPD with cigarette
smoking or with other local inhaled exposures were
not observed [4]. This could be related to the low
prevalence of smoking among this population
(12% current and 12% former smokers) [4].
Asia has been found to be one of the regions
with high prevalence of COPD. A study conducted among populations aged 30 years and older revealed that the number of moderate to severe
COPD cases in the 12 countries of this region is
56.6 million with an overall prevalence rate of
6.3% [5]. In Spain, diagnosed patients with COPD
normally had severe disease and more severely impaired health-related quality of life (HRQOL)
while patients with undiagnosed COPD stage 1+
also showed impairment in HRQOL and in some
aspect of ADL [3]. Various outcome measures had
been used to measure the quality of life of COPD
patients and mostly showed consistent findings in
the reduction of HRQOL [6-9].
At present, there are no epidemiological sound
longitudinal follow-up of populations that can provide an accurate picture of the success or failure,
of the efforts that over the past few decades have
been made to prevent and treat COPD [10]. The
current methods for assessing the clinical outcomes in COPD mainly rely on physiological tests
(FEV1 measurements) combined with the use of
questionnaires [11]. While it is well understood
that COPD is a progressive and irreversible disease, thus assessing the impact of the disease on
HRQOL is rather an important aim in the management of COPD. Furthermore, continuous efforts
on identifying the optimal methods for assessing
the outcomes of COPD on HRQOL may provide a
meaningful clinical outcome especially in maintaining the daily function of patients with COPD
despite the presence of a breathing difficulty.
Therefore, the purpose of this study was to examine the relationships between HRQOL (physical health and mental health component summaries) with lung function and dyspnea rating.
This study also sought to answer whether lung
function and/or dyspnea rating significantly pre-
QUALITY OF LIFE, LUNG FUNCTION AND DYSPNEA IN COPD
dict the HRQOL. The findings of this study may
be significant for healthcare providers in deciding
which factor could be the target for COPD management.
Materials and Methods
Sample
A group of 100 stable COPD patients, who attended outpatient medical treatment, was recruited
for this cross-sectional correlational study. The criteria for subject inclusion in the study were as follows: a diagnosis of COPD; FEV1/FVC less than
70 percent, age 40 years and above, Malaysian citizens, and has less than 5 co-morbidities. Criteria
for exclusion were as follows: disabled (wheelchair dependent), diagnosed with cancer, uncontrolled diabetes, uncontrolled hypertension, psychiatric illness, exertional chest pain, musculoskeletal or neurologic disease with functional
limitation, liver or renal failure, unstable gastrointestinal condition, current substance abuse problem, and legally blind or deaf. Each subject was required to sign a written consent form. The protocol
for this study was approved by the ethics committee of the local university.
Data Collection
HRQOL, lung function and dyspnea rating were
assessed in each patient on the same day of their visit to the outpatient clinic. The sequence of data collection was selected so that scores of dyspnea rating
and HRQOL would be obtained prior to the results
of the physiological tests. Subjects’ demographic
and health characteristics which include gender,
age, duration of illness, body weight, height, body
mass index, comorbidities, smoking history and
type of medication taken were recorded.
The HRQOL was measured using the SF36v2, a questionnaire that covers two summary
measures; physical health component summary
(PHCS) and mental health component summary
(MHCS). The questionnaire is easy to use, and has
been validated in several languages, including
Malay [11]. The questionnaire was found to be a
valid instrument to measure the impact of COPD
on HRQOL [12], and shown to be discriminative
as well as responsive to long-term disease progression [11]. The total score for each component
ranges from 0 to 100. The higher the score the better the HRQOL is.
Lung function was measured in a seated position using a portable Spirometry (Model:
Flowscreen: VIASYS, SN 38201743, 240Hz,
50/60 Hz, 60Watt). The system sets met the criteria for standardization and were calibrated prior to
testing. FEV1 predicted normal values were taken
from the asian population percentage by calculating the height and weight of the subject [13]. A
minimum of three efforts was performed until a reproducible maximal value were obtained.
Dyspnea rating was measured using the baseline dyspnea index (BDI), a multidimensional in-
strument for measuring breathlessness based on
three components that may evoke dyspnea: functional impairment, magnitude of the task and magnitude of the effort. A previous study has demonstrated a good validity and reliability of the BDI in
patients with COPD [14]. Patients may select from
one of five grades of dyspnea based on a brief history of each of the three components of the BDI.
This process took about 5 minutes to complete.
The grading of the indexes was such that the lower the score reflecting the more severe the breathlessness perceived [14].
Statistical Analysis
Descriptive analysis was conducted to present
the means, standard deviations, and ranges for
each variable of interests. Examination of the frequencies and analysis of the data indicated that all
variables were normally distributed without any
outliers.
Correlational analyses using the Pearson’s correlation coefficient (r) were conducted to determine the degree of association between i) physical
health component summary (PHCS) with lung
function and dyspnea rating; and ii) mental health
component summary (MHCS) with lung function
and dyspnea rating. A p-value of less than 0.05
was considered significant. A regression analysis
was conducted to further investigate whether variables that were significantly correlated reliably
predict the score for PHCS and MHCS. Examination on the bivariates correlation matrices, variance inflation factor (VIF) values, and tolerance
criteria indicated no multicollineriaty among the
independent variables.
Results
The mean age of the participants for this study
was 63.76±11.43 yr (±SD) (range, 40-84 years),
84% of the respondents were male and 16% were
female, mean height was 166.66±7.51cm (range,
142-179 cm), and mean weight was 60.87±16.24
kg (range, 26.2-131.85 kg). With regards to the respondents’ health history, 64% of the subjects
were ex-smokers, 22% were current smokers and
14% were non-smokers. Most of the respondents
presented with 2 to 4 co-morbidities and none of
the respondents had more than 5 co-morbidities
with a mean of 4.076±4.396 years of duration of
illness.
Values for the PHCS, MHCS, lung function
and dyspnea rating are shown in Table 1.
Table 2 shows the results of the correlational
analysis. There were significant positive strong relationships between dyspnea rating with PHCS
(r=.736, p<0.05), and significant positive moderate relationship with MHCS (r=.346, p<0.05).
There was a statistically significant low correlation
between lung function with PHCS (r=0.267,
p<0.05) but no significant correlation with MHCS
(r=0.095, p>0.05). These results indicate patients
who perceived higher breathing capacity (dyspnea
rating) were also likely to obtain a higher quality
117
M. JUSTINE ET AL
explained that patients with
COPD frequently decrease
their activity in order to
Variables
Mean ± SD
Range
avoid the unpleasant sensation of breathlessness which
Dyspnea rating
6.85 ± 2.68
0 - 12
in turn impact their quality
Health-related quality of life (HRQOL)
of life. Another possible explanation for this may be
PHCS
41.69 ± 7.99
20.21 - 56.68
that dyspnea significantly
MHCS
46.47 ± 13.14
11.74 - 74.66
influences HRQOL as both
Lung function (FEV1% predicted)
58.19 ± 30.24
30.7 - 100
dyspnea and HRQOL are assessments of a patient’s perspectives [19]. Dyspnea provides information about the impact of respiratory
of life. While patients who have higher lung funcimpairment on the patient’s HRQOL which can be
tion were also likely to present with higher PHCS
considered to be the most important aspect of
but not MHCS.
COPD from a patient’s perspective [20]. While
A stepwise multiple regression was conducted
Jones et al [21], who have found a significant corto determine whether dyspnea rating and/or lung
relation between dyspnea rating and PHCS, exfunction significantly predict PHCS. The overall
plained that dyspnea is the predominant symptom
model was found to be statistically significant
of most of the COPD patients which is the main
(R2=.543, F=58.209, p=0.001). However, the dystarget for medical management. Thus, it may be
pnea rating alone explained about 53.7% of the
concluded that by encountering dyspnea, one may
variance in PHCS (R2=.537, F=114.83, p=0.001).
improve their quality of life.
A bivariate regression was conducted to determine the predictor for mental health. Since the
Lung function and HRQOL
lung function was not significantly correlated with
MHCS, then the MHCS was regressed only on the
There is a statistically significant low correladyspnea rating. The model was statistically signiftion between lung function and PHCS, whereas no
icant (R2=0.115, F=12.527, beta=1.615, p<0.05)
significant correlation was found between lung
which indicated that dyspnea rating explained
function with MHCS. Therefore, it can be conabout 11.5% of the variance in MHCS.
cluded that changes in the lung function may or
may just slightly affect the health-related quality
of life among COPD sufferers.
Discussion
The results of this research are consistent with
a number of previous studies, who reported low
Dyspnea rating and HRQOL
correlation between lung function and quality of
life [12, 16, 22-24]. In contrast, a few studies reThere was a statistically significant positive
ported no significant correlation between lung
strong relationship between dyspnea rating with
function and quality of life [15, 25].
PHCS and statistically significant positive moderLung function, as measured by the FEV1, may
ate relationship with MHCS. Therefore it can be
not be influenced by the quality of life which can
concluded that differences in the clinical rating of
be due to several factors. According to Glaab [11],
dyspnea may influence the quality of life in pathis could be attributed to the FEV1 measurements
tients with COPD. This finding is consistent with
that is based on an artificial maneuver that may not
a previous study which stated that the severity of
really represent the functional adaptation of padyspnea was a significant predictor for HRQOL
tients with COPD. It was also highlighted that the
[12]. Similar conclusions were drawn from various
change in patient’s symptoms may occur against a
other studies [15-17].
relatively modest change in lung function, thus the
The possible reason for the finding may be due
reduction in FEV1 may not correlate well with pato the problem whereby dyspnea exerts a major eftient’s HRQOL [19, 20]. While Jones et al [21]
fect on COPD patient’s ability to perform various
discussed that there may be improvements in qualdaily activities, thus it interferes with the patient’s
ity of life with only minimal changes in FEV1. This
HRQOL. This is supported by Siafakas [18] who
is because although FEV1 measures reflect direct
changes in airflow limitation, the measure of the
symptom is much more important in revealing the
Table 2. - Results of the analyses of Pearson’s correlation
burden of the disease in the patient’s everyday life.
Thus the FEV1 measure alone does not really reComponents
Dyspnea rating
Lung function
of HRQOL
r
r
flect the nature and the burden associated with
COPD.
PHCS
.736*
.267*
Other than that, confounding factors such as
age, smoking history and other comorbidities may
MHCS
.344*
.095
affect the findings on quality of life without any real changes in lung function and vice versa. For ex* significant at p < 0.05.
ample, at a younger age one may have a better
Table 1. - Dyspnea rating, health-related QOL and lung function of study participants
118
QUALITY OF LIFE, LUNG FUNCTION AND DYSPNEA IN COPD
quality of life although with poor FEV1. The presence of other comorbidities may also impact on the
quality of life without deteriorations in FEV1.
While smoking habits may definitely influence
FEV1 results, most smokers feel that their days are
incomplete without smoking [26]. Thus people
who are satisfied with their everyday lives are the
ones that perceive a good quality of life.
Another argument is that the selection of the
instrument which is a generic measure for
HRQOL. According to Chen et al [27], SF-36 include most of the essential concepts of HRQOL
and have been shown to be suitable for cross-cultural applications irrespective of their type or number of illness. However, they may be not sensitive
to some problems unique to particular disease
[27]. Thus, it may be more accurate to use a disease specific measure such as the St George’s Respiratory Questionnaire (SGRQ). A recent study
has shown that the SGRQ demonstrated greater reliability in discriminating among different levels
of severity stages of COPD than generic measures
of health, which suggests that the SGRQ may provide COPD studies with greater statistical power
than the SF-36 summary in capturing meaningful
differences in clinical severity [28].
According to our data, dyspnea level influences the quality of life to a greater extent than
physiologic measurements do in patients with
COPD. Thus, it is imperative that clinicians treat
not only the medical illness itself but also the concomitant physical symptoms in order to optimize
the quality of life of people with COPD. A shift of
focus from the pathophysiology of disease to assessment and relief of symptoms may provide
meaningful benefits for COPD patients in terms of
enhancement of quality of life.
For the health care professionals, the selection
of measurement tools in clinical practice to quantify symptoms as well as the overall health status
are essential. Thus, the implementation of the BDI
and SF-36 outcome measures in the assessment of
COPD patients’ physical function should be put
forward. However, the limitation of using the SF36 is that as a generic measure, it is considered less
responsive than disease-specific instruments in
COPD and is not consistently responsive to therapeutic effects [11]. As suggested by Chen et al [27]
a combination of generic and disease specific measure of HRQOL may be more appropriate for monitoring changes in a patient’s health status due to
an intervention. Thus, it is recommended that future studies involving similar population background may need to be undertaken in order to
more accurately measure the quality of life over
time along with the progression of the disease using a disease-specific outcome measure such as the
SGRQ.
Acknowledgements: The authors are indebted to the
staff at Lung Function Laboratory at the Institute of Pulmonary Rehabilitation, Kuala Lumpur and all of the subjects
for their assistance and cooperation for the successful completion of the study.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Afonso ASM, Verhamme KMC, Sturkenboom MCJM,
Brusselles GGO. COPD in the general population:
Prevalence, incidence and survival. Respir Med 2011;
105: 1872-84.
Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (The BOLD
Study): A population-based prevalence study. Lancet
2007; 370: 741-50.
Miravitlles M, Soriano JB, Garcia-Rio F, et al. Prevalence of COPD in Spain: Impact of undiagnosed COPD
on quality of life and daily life activities. Thorax 2009;
64: 863-8.
Al Zaabi A, Asad F, Abdou J, et al. Prevalence of
COPD in Abu Dhabi, United Arab Emirates. Respir
Med 2011; 105: 566-70.
Tan WC, Seale JP, Charaoenratanakul S, et al. COPD
prevalence in 12 Asia- Pacific countries and regions:
Projections based on the COPD prevalence estimation
model. Respirology 2003; 8: 192-8.
Berry CE, Drummond MB, Han MLK, et al. Relationship between lung function impairment and health-related quality of life in COPD and interstitial lung disease. Chest 2012; 142: 704-11.
Han MLK, Curran-Everett D, Dransfield MT, et al.
Racial differences in quality of life in patients with
COPD. Chest 2011; 140:1169-76
Sundh J, Ställberg B, Lisspers K, Montgomery SM,
Janson C. Co-morbidity, body mass index and quality
of life in COPD using the clinical COPD Qqestionnaire.
Chest 2011; 8: 173-81.
Xu W, Collet JP, Shapiro S, et al. Negative impacts of
unreported COPD exacerbations on health-related quality of life at 1 year. Eur Respir J 2010; 35:1022-30.
Celli BR. The light at the end of the tunnel: is COPD
prevalence changing. Eur Respir J 2010; 36: 718-19.
Glaab T, Vogelmeier C, Buhl R. Outcome measures in
chronic obstructive pulmonary (COPD); strength and
limitations. Respir Res 2010; 11: 79.
Mahler DA, Mackowiak JI. Evaluation of the ShortForm 36-Item questionnaire to measure health-related
quality of life in patients with COPD. Chest 1995; 107:
1585-9.
Singh R, Singh HJ, Sirisinghe RG. Sprometric studies
in Malaysians between 13 and 69 years of age. Med J
Malaysia 1993; 48: 175-184.
Mahler DA, Weinberg DH, Wells CK, Feinstein AR.
The measurement of dyspnea: contents, interobserver
agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85: 751-758.
Hu J, Meek P. Health-related quality of life in individuals with chronic obstructive pulmonary disease. Heart
Lung 2005; 34: 415-22.
Mahler DA, Faryniarz K, Tomlinson D, et al. Impact of
dyspnea and physiologic function on general health status in patients with chronic obstructive pulmonary disease. Chest 1992; 102: 395-401.
Viramontes JL, O’Brien B. Relationship between
symptoms and health related quality of life in chronic
lung disease. J Gen Intern Med 1994; 9: 46-8.
Siafakas NM, Anthonisen NR, Georgopoulos D. Acute
exacerbations of chronic obstructive pulmonary disease. Marcel Dekker Inc. New York, 2004.
Linus H, Tomas S, Varkey B. Improving health-related
quality of life in chronic obsructive pulmonary disease.
Curr Opin Pulm Med 2004; 10: 120-7.
Ries AL. Impact of chronic obstructive pulmonary disease on quality of life: The role of dyspnea. Am J Med
2006; 119: S12-S20.
Jones P, Lareau S, Mahler DA. Measuring the effects of
COPD on the patient. Respir Med 2005; 99: S1-S18.
119
M. JUSTINE ET AL
22.
23.
24.
25.
120
Hajiro T, Nishimura K, Tsukino M, Ikeda A, Koyama
H, Izumi T. Analysis of clinical methods used to evaluate dyspnea in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:
1185-9.
Stahl E, Lindberg A, Jansson S, et al. Health-related
quality of life is related to COPD disease severity.
Health Qual Life Outcomes 2005; 3: 56.
Terence AR, Gavin C, Elizabeth A, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 1998; 157: 1418-22.
Seung Kim HS, Kunik ME, Molinari VA, et al. Func-
26.
27.
28.
tional impairments in COPD patients: The impact of
anxiety and depression. Psychosomatics 2000; 41: 6.
Spiter J. You Smoke Because You’re a smoke-a-holic!
Joel’s Reinforcement Library, 2000. Retrieved April
22, 2009 from www.yahoo.com
Chen TH, Li L, Kochen MM. A systematic review:
How to choose appropriate health-related quality of life
(HRQOL) measures in routine general practice? J Zhejiang Univ SCI 2005; 6B (9): 936-940.
Pickard AS, Yang Y, Lee TA. Comparison of healthrelated quality of life measures in chronic obstructive
pulmonary disease. Health Qual Life Outcomes 2011;
9: 26.
2013; 79: 3-4, 121-127
ORIGINAL ARTICLE
Grading the severity of obstruction
in patients with Chronic Obstructive
Pulmonary Disease and morbid obesity
N. Barbarito1, E. De Mattia2
ABSTRACT: Grading the severity of obstruction in patients
with Chronic Obstructive Pulmonary Disease and morbid
obesity. N. Barbarito, E. De Mattia.
Aim. To evaluate the severity of airway obstruction in
patients affected by chronic obstructive pulmonary disease (COPD) in the presence of concomitant restriction
due to morbid obesity.
Methods. Lung function test, six-minute walking distance
(6MWD) test, body mass index measurement (BMI), and determination of dyspnoea using the Modified Medical Research Council Dyspnoea Scale (MMRC) were performed on
each patient referred to our department according to their individual respiratory diagnosis or symptoms. Analysis was
performed on smokers or ex-smokers patients, with both dyspnoea and chronic productive cough, showing non fully reversible airflow obstruction, with normal-weight (NW: BMI
22 to 24 kg/m2) or morbid-obesity (MO: BMI * 40 kg/m2).
Results. In 33 COPD patients, spirometric data differ between NW and MO only in fixed FEV1/FVC ratio
(50±9 and 62±7, respectively; p = 0.0001) and FEV1/SVC
% of predicted (57±15 and 71±11, respectively; p =
0.005). Furthermore, SVC was found to exceed FVC only in NW (2.82±0.7 L and 2.08±0.9 L, respectively; p =
0.03). NW and MO differ significantly also in MMRC
(3.4±0.9 vs 2.4±1, respectively; p = 0.004), 6MWD in metres (226±100 and 331±110, respectively, p = 0.007),
6MWD as % predicted (49±22 and 81±23, respectively;
p = 0.0003), and BODE index (5.8±2 and 3.6±2, respectively; p = 0.003).
Conclusions. There is a significant overgrading of obstruction in morbidly obese patients affected by COPD.
Therefore, we suggest that an alternative grading system
be used for patients with mixed ventilatory dysfunction.
Keywords: Chronic Obstructive Pulmonary Disease (COPD), Morbid Obesity, Forced Expiratory Volume in the First Second
(FEV1), Body Mass Index (BMI).
1
2
Emergency Department, Medicina 4, AO Salvini, Rho (Milan);
Pulmonary Rehabilitation, Centro Clinico NEMO, Fondazione Serena Onlus, Milan, Italy.
Correspondence: Nicola Barbarito, Pronto Soccorso, Medicina 4, AO Salvini, Corso Europa 250, 20017 Rho (MI), Italy;
e-mail: [email protected]
Introduction
Chronic obstructive pulmonary disease
(COPD) and obesity are major causes of morbidity and mortality worldwide and, according to current estimates, the global burden of these conditions is set to increase even further [1]. A potential link between obesity and COPD is also increasingly recognised [2], although very little is
known about the mechanisms underlying this association. The risk of developing obesity is increased in patients with COPD as a result of a reduced level of physical activities in daily life in
these patients compared with healthy agematched controls [3]. In addition, patients with
COPD who receive repeated courses of systemic
glucocorticosteroids could be at an increased risk
of truncal obesity as a result of glucocorticoid mediated redistribution of stored energy and the
stimulatory effect on intake [4].
While classification of obesity is based on
one’s body mass index (BMI), an index of weight
to height ratio, as defined by the World Health Organization [5], spirometry is required for diagnosis
and used for the graduation of COPD severity, according to the Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines [6].
Obesity, which is defined as BMI of at least 30
kg/m2, is considered as severe (or morbid) when
BMI is * 40 kg/m2 [7]. It was found an inverse relationship between BMI and lung volumes assessed by spirometry [8, 9], with changes in lung
function better demonstrated when BMI results
greater than 45 kg/m2 [10].
Current recommendations for COPD, which is
defined as airflow obstruction that is not fully reversible, are that the severity of airflow obstruction
should be based on the percentage predicted of the
measured forced expiratory volume in the first second (FEV1%pred) [11, 6].
To date no recommendations from the guidelines exist for the grading of obstruction in the
presence of an additional restriction. Using forced
expiratory volume in the first second (FEV1) to
gauge the degree of obstruction in mixed pulmonary disorders would be expected to overestimate the degree of obstruction as FEV1 is reduced
from both the obstructive and the restrictive com-
N. BARBARITO, E. DE MATTIA
ponents of the underlying disease [12]. Obesity
could cause a restrictive ventilatory defect, since
lung volumes decrease as body mass index (BMI)
increases [8, 9]. To address the grading obstruction
in the presence of concurrent pure extrapulmonary
restrictive process, we embarked on a restrospective analysis of spirometries in patients affected by
COPD of normal weight and morbid obesity.
Each patient referred to the Pulmonary Rehabilitation department at Villa Esperia Hospital
(Salice T., Pavia, Italy) and depending on their respiratory diagnosis or symptoms, clinical history,
spirometry, exercise capacity, dyspnoea and nutritional status were thoroughly assessed.
Smoking habits, respiratory history and symptoms were collected during an assisted interview.
Spirometry was performed by using a computerized pneumotachograph (MasterScreen Pneumo,
Jager, Germany). The test procedures were performed by experienced and specially trained technicians, following the ATS recommendations [13],
with each patient placed in a relaxed upright sitting
position and provided with a nose-clip. Short acting
and long acting bronchodilator medications were
withheld six and twelve hours prior to testing, respectively. Vital capacity, defined as the difference
between total lung capacity (TLC) and residual volume (RV), was measured as both a slow (slow vital
capacity, SVC) and a forced (forced vital capacity,
FVC) maximal expiration from TLC to RV. In patients showing airflow obstruction according to the
current guidelines (i.e., FEV1/FVC less than 70%),
we assessed a reversibility test, performing on the
same day a second spirometry approx. 15 minutes
after the inhalation of four puffs of salbutamol,
each containing 100 mcg (total dose administered
was 400 mcg), using a spacer mouthpiece. For
analysis, we used only post-bronchodilator lung
function values, in order to exclude from the study
the patients showing fully reversible airflow obstruction (i.e., without any airflow obstruction after
bronchodilator).
Exercise capacity was measured during a sixminute walking test, consistent with the ATS protocol [14]. The six-minute walk distance (6MWD)
was measured considering the best out of two
walk tests separated by > 60 min [14, 15]. The
6MWD was expressed in absolute values and as a
percentage of predicted using published reference
values [16].
Perception of dyspnoea was evaluated by the
Modified Medical Research Council (MMRC) dyspnoea scale. The MMRC is a 0-4 point category
scale which selects the best expression to define the
dyspnoea levels among five expressions related to
dyspnoea (grade 0 meaning breathlessness only
with strenuous exercise, and grade 4 representing
the most severe category, indicating that the patient
is too breathless to leave the house or becomes
breathless when dressing or undressing) [17].
Nutritional status was assessed by body mass
index (BMI), that was computed as the ratio of
122
body weight in kilograms to height in meters
squared; height and weight were measured in a
standing position without shoes, with patients
wearing only light clothing [5].
In each patient included in the study, we also
calculated the BODE index, a 11-point composite
score (0 through 10) system that incorporates an
assessment of airflow obstruction as FEV1%pred,
6MWD in metres, MMRC, and BMI: higher
scores indicate poorer outcomes [18].
For inclusion in the study, patients had to satisfy all of the following criteria: over 45 yrs of age,
current or ex-smoker for * 10 pack-yrs,
FEV1/FVC post-bronchodilator < 70%, BMI > 21
kg/m2, with both dyspnoea and chronic productive
cough, absence of diagnosis relating to any type of
lung disease other than COPD. Patients were clinically stable for at least 6 weeks and were receiving optimal medical therapy according to the current guidelines. Exclusion criteria were: uncontrolled cardiovascular diseases, BMI 25 to 39.9
kg/m2, and inability to perform the lung function
and 6-min walk tests.
Our data were collected while both authors
worked at Villa Esperia Hospital in Salice Terme
(Pavia, Italy): the study period amounted to 28
months (January 1 2008 to April 30 2010).
All patients gave written informed consent to
treatment of all data collected during their hospital
stay.
Data are presented as mean ± SD (unless otherwise stated), and were analysed by two-sample
independent t tests. Differences were regarded as
significant with p values < 0.05.
Results
Analysis was performed on a group of 33 subjects (age range = 48-87 years, male/female ratio =
1/0.9, BMI range = 21.1-61.6 kg/m2, FEV1%pred
range = 19-93%pred), smokers or ex-smokers,
both with dyspnoea and with chronic productive
cough, showing FEV1/FVC ratio of < 70%, with
normal weight or morbid obesity.
Anthropometric and spirometric characteristics of the analysed patients are showed in table 1.
Both absolute values and percent of predicted of
FEV1 (figure 1), FVC and SVC did not differ significantly in the two groups. On the contrary, patients without obesity showed significantly lower
mean values of both fixed FEV1/FVC ratios and
FEV1/SVC % of predicted. Furthermore, SVC was
found to exceed FVC in patients with normalweight (2.82±0.7 L and 2.08±0.9 L, respectively; p
= 0.03), but not in patients with morbid-obesity
(2.61±0.9 L and 2.16±0.8 L, respectively; p = 0.15),
as figure 2 shows.
Normal-weight COPD patients showed significantly higher dyspnoea (assessed with MMRC)
than morbid-obese COPD patients: 3.4±0.9 vs 2.4±1,
respectively (p = 0.004), as figure 3 shows.
Normal-weight COPD patients showed significantly lower exercise performance (assessed by
6MWD) than morbid-obese COPD patients, expressed both in absolute values (226±100 metres
GRADING THE SEVERITY OF OBSTRUCTION IN COPD AND MORBID OBESITY
structive component alone on the basis of FEV1 would be expected to
over-estimate the degree of obstruction because the reduction in FEV1
would reflect the combined effects of
both the obstructive and the restrictive components [12].
A restrictive ventilatory defect
could be caused by obesity [8, 9]. In
fact, an obese individual’s accumulation of fat around the ribs, the diaphragm and the abdomen causes a
decrease in chest wall compliance.
The reduction in chest wall compliance is the primary reason for a decrease in expiratory reserve volume
(ERV) and, consequently, in vital capacity (VC) observed in morbid obesity without any changes in residual
volume (RV) due to lung parenchimal disease [22].
Normative predictive equations
for spirometric measurements,
plethysmographic lung volumes and
TLCO are generally not corrected
for weight. This could have implications for the clinical interpretation
of pulmonary function tests in the
obese [1].
We also found that normalweight and morbid-obese COPD patients did not differ in mean values of
FEV1%pred, whereas patients without obesity showed lower mean values in both fixed FEV1/FVC ratios
and FEV1/SVC % of predicted.
In order to address the issue of grading obstruction in the presence of restriction, Balfe and
colleagues [23] analyzed 147 patient pulmonary
function tests with both restriction and obstruction,
Table 1. - Demographic and lung function characteristics of the study
patients
vs 331±110 metres, respectively p = 0.007) and as
% of predicted (49.1±22%pred vs 81.5±23%pred,
respectively p = 0.0003), as figures 4 shows.
The BODE index was found to be significantly lower (i.e., better) in morbid-obese than in normal-weight cases, as figure 5 shows: 3.6±2 and
5.8±2, respectively (p = 0.003).
Discussion
Our study on patients with COPD shows that
functional capacity, for the same grading of airflow obstruction, is better in the presence of a restrictive ventilatory defect due to morbid obesity.
Overgrading airflow obstruction
Using the FEV1%pred is recommended by
means of the ATS/ERS guidelines to grade the
severity of lung disease in the presence of obstruction and/or restriction [11] and by the GOLD
guidelines to grade the severity of airflow obstruction in COPD patients without any recommendations in the presence of an additional restriction
[6]. FEV1 is a strong and independent predictor of
health status and has been found to be an independent predictor of both all-cause and respiratory
mortality [19-21]. However, in the presence of
mixed disorders, assessing the severity of the ob-
Fig. 1. - Gradation of COPD severity by spirometry.
123
Fig. 2. - Vital capacity measured as both a slow and a forced maximal
expiration from Total Lung Capacity to Residual Volume.
Fig. 3. - Dyspnoea.
without specifying the subtended lung diseases.
They determined the grading of airway obstruction by comparing the ATS recommendations
(based on FEV1%pred) with the Intermountain
Thoracic Society (ITS) recommendations (based
on the FEV1/FVC ratio) [24]. The authors found
that patients categorized as having severe or very
severe obstruction were 90% using the ATS grading criteria (i.e., FEV1 < 50%pred), and 3% using
the ITS grading system (i.e., FEV1/FVC < 4 CIs).
In order to correct the complete reversal in the
distribution of severity grades, which perhaps underestimated the true degree of obstruction, Balfe
and colleagues recommended using the ITS grading in these patients but with modified CIs so as
to normalize severity grade distribution: by using
the proposed system, patients with mixed dysfunction resulted in 38% of cases as having severe obstruction (i.e., FEV1/FVC < 2 CIs), therefore leading to a more balanced severity difference distribution [23].
More recently, Gardner and colleagues [25]
studied 199 patients with mixed dysfunction, affected by a variety of obstructive, interstitial and
extrapulmonary lung diseases. They found that adjusting the FEV1 for the degree of restriction results in a more appropriate distribution of the
severity of obstruction: patients categorized as
having severe or very severe obstruction amounted
to 76% with the ATS grading (i.e., FEV1%pred),
and 33% with the adjusted data (by dividing
FEV1%pred by TLC % of predicted). In support of
this, the authors demonstrate that the adjusted
FEV1%pred correlates better than the unadjusted
value with the RV/TLC ratio, another index of airflow obstruction, suggesting that the adjusted value more accurately reflects the degree of obstruction [25].
Furthermore, we found that both SVC and FVC,
as well as FEV1, did not differ between normalweight and morbid-obese COPD patients, both in
terms of absolute values and as % of predicted.
However, SVC was found to exceed FVC in patients with normal-weight, but not in patients with
morbid-obesity. We believe that this finding is consistent with a recent paper by O’Donnell and colleagues stated that, with increasing BMI, subjects
with airway obstruction (greatly in patients with the
most severe airway obstruction) had consistent reductions in lung hyperinflation [26]. Indeed, the
pathological hallmark of COPD are inflammation
of the small airways (bronchilolitis) and destruction
of lung parenchyma (emphysema). Bronchiolitis
narrows and obliterates the airways lumen and actively constricts the airways; emphysema reduces
the elastic recoil of the lung and the elastic load applied to the small airways [27]. The functional consequence of both these abnormalities is the non-fully reversible airflow obstruction characteristic of
COPD. In such patients with small-airway collapse,
FVC can be lower than SVC. Vital capacity reflects
parenchimal properties in normal individuals [28,
29], but also airway properties in obstructed patients
[30, 29]. It was hypothesized that an increase in airflow may increase viscous pressure losses within
narrowed peripheral airways, thus causing the transmural pressure to be less and airway closure to occur at somewhat higher lung volumes: the greater
the bronchoconstriction, the lower the vital capacity
after forced expiration [31].
124
Inability in patients with both COPD and obesity:
Dyspnoea and Walk distance
Both COPD and obesity are independently
linked to dyspnoea on exertion and poor function-
Fig. 4. - Exercise capacity.
al capacity. The main symptoms of COPD are dyspnoea and limitation of physical activity, resulting
in a complex integrated manner by several independent negative effects of dynamic hyperinflation
(DH). Furthermore, DH leads to an increase in
elastic and threshold loads on the inspiratory muscles (thus increasing the oxygen cost of breathing),
maximal shortening the muscle fibers in the diaphragm and other inspiratory muscles (causing
functional inspiratory muscle weakness), increasing the physiological dead space (leading to CO2
retention and arterial oxygen desaturation during
exercise), and adversely affecting dynamic cardiac
function [32]. On the other hand, obesity increases
the work of breathing due to a reduction in chest
wall compliance (attributed to the mechanical effects of fat on the chest wall) [33, 34] and a weakness of respiratory muscles (attributed to reduced
chest wall compliance and/or lower operating lung
volumes) [35, 34]. Furthermore, obese individuals
have a higher metabolic demand at any given power output (as a result of the high oxygen cost of lifting heavy limbs) [36-38] and may have expiratory
flow limitation at rest which, when compounded
by high ventilatory requirements, leads to significant air trapping and dynamic increase in end-expiratory lung volume during exercise [36-38].
The 6-min walking distance (6MWD) test has
gained importance in the assessment of functional
exercise capacity in several kinds of diseases, including COPD [18, 39] and obesity [40, 41].
This test evaluates the global and integrated responses of the pulmonary, cardiovascular and muscular component and also reflects the functional exercise level for daily physical activities [14].
6MWD was found to reduce both COPD and obesi-
ty. Casanova and colleagues determined the 6MWD in 294 patients
with COPD: its median value at
baseline was 380 m, and its annual
rate of decline was 19% (16 m/yr)
over 5 yrs [42]. Zutler and colleagues determined 6MWD in 369
adults without established COPD:
the mean 6MWD was 522±90 m,
and in multiple linear regression
analysis, adjusting for age and sex,
the presence of obesity was associated with a 67±9 m decrement in
6MWD (p < 0.001) [43].
In the present study, we found
that normal-weight COPD patients
showed higher dyspnoea (assessed
with MMRC) and lower exercise
performance (assessed by 6MWD)
than morbid-obese COPD patients,
for the same grading of airflow
obstruction. Evidently, in normalweight patients the cause of
breathlessness and functional exercise capacity are the abnormalities
of dynamic ventilatory mechanics
and ventilatory demand that characterise COPD, whereas in morbid
obese patients there appeared to be
an overgrading of the respiratory disease.
In each of our patients, we also assessed their
BODE index, a multidimensional grading system,
which proved to be better than FEV1 in predicting
the risk of hospitalization [44] and death [18]
among patients with COPD. This multistage scoring system incorporates an assessment of symptoms (i.e., MMRC), nutritional state (i.e., BMI),
and exercise capacity (i.e., 6MWD) together with
spirometric measure of airflow (i.e., FEV1%pred)
[18]. We excluded from our study the COPD pa-
Fig. 5. - Gradation of COPD severity by multistage scoring system.
125
tients with BMI ) 21 kg/m2, as low BMI is associated with increased all-cause and COPD-related
mortality unrelated to disease severity [45], and
this inverse relation between BMI and survival is
not linear but has an inflection point, which is just
21 kg/m2 [18, 45]. Regarding BODE index (ranging from 0 to 10 points) the patient receives points
ranging from 0 to 3 for all variables but BMI, for
which the value is either 0 or 1, because of the
unique relation between BMI and survival described above [18]. Using such knowledge, we
found that the BODE index was significantly lower (i.e., better) in the morbid-obese than in normalweight cases, in confirmation that dyspnoea and
exercise limitation are lower in COPD patients
with a likely overgraded airflow obstruction.
In conclusion, our results show that there is a
significant overgrading of obstruction in morbid
obese patients affected by COPD. Therefore, we
suggest that an alternative grading system be used
in patients with mixed ventilatory dysfunction
such as obesity. We believe that any substantial
downgrading of the severity of obstruction in morbid obese patients with COPD is clinically significant as such a change would inevitably lead to different treatment recommendations. Medications
used to treat more severe obstructive lung diseases
are expensive and can expose patients to unwanted
or adverse side effects. If we are able to better diagnose the severity of obstruction, we could ultimately avoid using medications that are not suitable and incurring the costs and risks associated
with their use [25].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
126
Franssen FME, O’Donnell DE, Goossens GH, Blaak
EE, Schols AMWJ. Obesity and the lung: 5. Obesity
and COPD. Thorax 2008; 63: 1110-1117.
Poulain M, Doucet M, Major GC, et al. The effect of
obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies. CMAJ 2006; 174: 1293-9.
Pitta F, Troosters T, Spruit MA, Probst VS, Decramer
M, Gosselink R. Characteristics of physical activities in
daily life in chronic obstructive pulmonary disease. Am
J Respir Crit Care Med 2005; 171: 972-7.
Dallman MF, la Fleur SE, Pecoraro NC, Gomez
F, Houshyar H, Akana SF. Minireview: glucocorticoids-food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology 2004; 145: 2633-8.
World Health Organization. Overweight and obesity: a
new nutrition emergency? Monitoring the rapidly
emerging public health problem of overweight and obesity: the WHO global database on body mass index.
SCN News 2004: 5-12.
Vestbo J, Hurd SS, Agusti AG, et al. Global Initiative
for Chronic Obstructive Lung Disease. Global strategy
for the diagnosis, management and prevention of
COPD. 2010. Available from: http://www.goldcopd.org/
uploads/users/files/GOLDReport_Aprile112011.pdf.
Yanovski SZ, Yanovski JA. Obesity. N Engl J Med
2002; 346: 591-602.
Jones RL, Nzekwu MMU. The effects of body mass index on lung volumes. Chest 2006; 130: 827-833.
Cotes JE, Gilson JC, John C. Effects of inactivity and
gain in weight upon lung function and indices of submaximal exercise. J Physiol 1967; 188: 36P-38P.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
D’Ávila Melo SM, De Melo VA, Meneze Filho RS,
Santos FA. Effects of progressive increase in body
weight on lung function in six groups of body mass index. Rev Assoc Med Bras 2011; 57: 499-505.
Pellegrino R, Viegi G, et al. Interpretative strategies for
lung function tests. Eur Respir J 2005; 26: 948-968.
Culver BH. Obstructive? Restrictive? Or a ventilatory
impairement? Chest 2011; 140: 568-569.
Standardization of Spirometry, 1994 Update. American
Thoracic Society. Am J Respir Crit Care Med 1995;
152: 1107-1036.
ATS Committee on Proficiency Standards for Clinical
Pulmonary Function Laboratories. ATS Statement:
guidelines for the six-minute walk test. Am J Respir
Crit Care Med 2002; 166: 111-117.
Sciurba FC, Slivka WA. Six-minute walktesting. Semin Respir Crit Care Med 1998; 9: 383-391.
Enright PL, Sherrill DL. Reference equations for the
six-minute walk in healthy adults. Am J Respir Crit
Care Med 1998; 158 (5 Pt 1): 1384-7.
Bestall J, Paul E, Garrod R, Garnham R, Jones
PW, Wedzicha JA. Usefulness of the Medical Research
Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 581-6.
Celli BR, Cote C, Marin JM, et al. The body-mass index, airflow obstruction, dyspnoea and exercise capacity index in chronic obstructive pulmonary disease. N
Engl J Med 2004; 350: 1005-1012.
Foxman B, Higgins ITT, Oh MS. The effects of occupation and smoking on respiratory disease mortality.
Am Rev Respir Dis 1986; 134: 649-652.
Annesi I, Kauffmann F. Is respiratory mucus hypersecretion really an innocent disorder? Am Rev Respir
Dis 1986; 134: 688-693.
Ortmeyer CE, Costello J, Morgan WKC, Swecker S,
Peterson M. The mortality of Appalachian coal miners
1963 to 1971. Arch Environ Health 1974; 29: 67-72.
Salome CM, King GG and Berend N. Physiology of
obesity and effects on lung function. J Appl Physiol
108: 206-211, 2010.
Balfe DL, Lewis M, and Mohsenifar Z. Grading the
Severity of Obstruction in the Presence of a Restrictive
Ventilatory Defect. Chest 2002; 122: 1365-1369.
Morris AH, Kanner RE, Crapo RO, Gardner RM. Clinical pulmonary function testing: a manual of uniform
laboratory procedures. Salt Lake City, UT: Intermountain Thoracic Society, 1984.
Gardner ZS, Ruppel GL, and Kaminsky DA. Grading
the Severity of Obstruction in Mixed Obstructive-Restrictive Lung Disease. Chest 2011; 140: 598-603.
O’Donnell DE, Deesomchok A, Lam YM, et al. Effects
of BMI on Static Lung Volumes in Patients With Airway Obstruction. Chest 2011; 140: 461-468.
Cosio Piqueras MG, Cosio MG. Disease of the airways
in chronic obstructive pulmonary disease. Eur Respir J
2001; 18: Suppl 34, 41s-49s.
Anthonisen NR. Tests of mechanical function. In:
Macklem PT, Mead J, eds. Handbook of Physiology.
Section 3, Vol. III, Part 2. The Respiratory System: Mechanics of Breathing. Bethesda, MD, American Physiological Society, 1986; pp. 753-784.
Sutherland PW, Katsura T, Milic-Emili J. Previous volume history of the lung and regional distribution of gas.
J Appl Physiol 1968; 25: 566-574.
Leith DE, Mead J. Mechanisms determining residual
volume of the lungs in normal subjects. J Appl Physiol
1967; 23: 221-227.
Brusasco V, Pellegrino R, Rodarte JR. Vital capacities
in acute and chronic airway obstruction: dependence on
flow and volume histories. Eur Respir J 1997; 10:
1316-1320.
32.
33.
34.
35.
36.
37.
38.
39.
O’Donnell DE, Banzett RB, Carrieri-Kohlman V, et al.
Pathophysiology of dyspnoea in chronic obstructive
pulmonary disease: a roundtable. Proc Am Thorac
Soc 2007; 4: 145-68.
Chlif M, Keochkerian D, Mourlhon C, Choquet D, Ahmaidi S. Noninvasive assessment of the tension-time
index of inspiratory muscles at rest in obese male subjects. Int J Obes (Lond) 2005; 29: 1478-83.
Sharp JT, Henry JP, Sweany SK, Meadows WR, Pietras
RJ. The total work of breathing in normal and obese
men. J Appl Physiol 1964; 43: 728-39.
Weiner P,Waizman J, Weiner M, Rabner M, Magadle
R, Zamir D. Influence of excessive weight after gastroplasty for morbid obesity on respiratory muscle performance. Thorax 1998; 53: 39-42.
Ofir D, Laveneziana P, Webb KA, O’Donnell DE. Ventilatory and perceptual responses to cycle exercise in
obese women. J Appl Physiol 2007; 102: 2217-26.
Whipp BJ, Davis JA. The ventilatory stress of exercise
in obesity. Am Rev Respir Dis 1984; 129: S90-2.
Babb TG, Buskirk ER, Hodgson JL. Exercise end-expiratory lung volumes in lean and moderately obese
women. Int J Obes 1989; 13: 11-9.
Celli BR, MacNee W, ATS/ERS Task Force, Standards
for the diagnosis and treatment of patients with COPD:
40.
41.
42.
43.
44.
45.
a summary of the ATS/ERS position paper. Eur Respir
J 2004; 23: 932-946.
Imai K, Gregg EW, Chen YJ, Zhang P, de Rekeneire N,
Williamson D. The association of BMI with functional
status and self-rated health in US adults. Obesity (Silver
Spring) 2008; 16: 402-08.
Jensen GL, Hsiao PY. Obesity in older adults: relationship to functional limitation. Curr Opin Clin Nutr
Metab Care 2010; 13: 46-51.
Casanova C, Cote CG, Marin JM, et al. The 6-min
walking distance: long-term follow up in patients with
COPD. Eur Respir J 2007; 29: 535-540.
Zutler M, Singer JP, Omachi TA, Eisnerc M, Iribarren
C, Katz P, Blanc PD. Relationship of obesity with respiratory symptoms and decreased functional capacity in
adults without established COPD. Prim Care Respir J
2012; 21: 194-201.
Kian-Chung Ong KC, Earnest A, Lu SJ. A Multidimensional Grading System (BODE Index) as Predictor
of Hospitalization for COPD. Chest 2005; 128: 38103816.
Landbo C, Prescott E, Lange P, Vwatbo J, Almdal TP.
Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 1999; 160: 1856-1861.
127
2013; 79: 3-4, 128-133
ORIGINAL ARTICLE
Training and practice in bronchoscopy
A national survey in Italy
N. Facciolongo1, R. Piro1, F. Menzella1, M. Lusuardi2,
M. Salio3, L. Lazzari Agli4, M. Patelli5
ABSTRACT: Training and practice in bronchoscopy.
A national survey in Italy. N. Facciolongo, R. Piro, F. Menzella,
M. Lusuardi, M. Salio, L. Lazzari Agli, M. Patelli.
Background and Aim. Bronchoscopy is performed in a
variety of different settings in Italy. The surveys conducted so far have highlighted the heterogeneity of the procedures and the frequent inability to adhere to the guidelines. The aim of this survey was to analyse procedures,
training, and opinions of Italian respiratory physicians
performing interventional bronchology in the clinical
practice.
Methods. The study was conducted retrospectively on
300 pulmonologists. From January to June 2008, these
were invited to participate in an email survey to be sent
out monthly to each participant for four consecutive
months.
Results. Two hundred and one respiratory physicians
took part in the study, most of whom (83.5%) work in ei-
ther Pulmonology or Interventional Pulmonology Units.
The year before the survey, 21.2% of the participants had
performed fewer than 100 examinations, 42.3% 100 to
300, and 36.6% more than 300 bronchoscopies; 53.9%
were familiar with the international guidelines on the topic. Among the responders, 34.1% had received less than 6
months training, 55.3% considered further training in
rigid bronchoscopy, laser procedures and thoracoscopy,
invaluable for their professional activity. Adequate training for transbronchial needle aspirates, was reported by
49.6% of respondents.
Conclusions. Our data show that interventional bronchoscopy procedures are regularly performed according
to current recommendations by over half of the Italian
Pulmonologists participating in our survey. The need for
more comprehensive basic education and training was put
forward by the majority of physicians.
Keywords: Bronchoscopy, Guidelines, Interventional pulmonology, Training, Survey.
1
2
3
4
5
Department of Cardiac-Thoracic-Vascular and Intensive Care Medicine, Pneumology Unit, Santa Maria Nuova Hospital
- IRCCS, Reggio Emilia;
S. Sebastiano Hospital, Respiratory Rehabilitation, Azienda Unità Sanitaria Locale Reggio Emilia, Correggio;
Department of Pneumology, San Martino Hospital, Genova;
Department of Pneumology, City Hospital, Via Frosinone, Riccione;
Unit of Thoracic Endoscopy and Pulmonology, Maggiore Hospital, Bologna, Italy.
Correspondence: Nicola Facciolongo, MD. Department of Cardiac-Thoracic-Vascular and Intensive Care Medicine, Pneumology
Unit, Santa Maria Nuova Hospital - IRCCS, Viale Risorgimento 56, 42123, Reggio Emilia, Italy; e-mail: [email protected]
Introduction
Interventional pulmonology (IP) is an area of
pulmonary medicine that focuses on the use of advanced minimally invasive diagnostic and therapeutic techniques for the treatment of patients with
airway and pleural disorders.
Bronchoscopy, introduced in 1887 by Killian,
has seen its applications modified over the last
forty years thanks to the use of the flexible bronchoscope [1]. The introduction of additional advanced methods has considerably extended its potential, providing pulmonologists with fundamental support in both diagnosis and therapy. Different
scientific societies have published guidelines for
bronchoscopy, focusing in particular on methodology and safety issues [2-4].
The surveys on bronchoscopy conducted so far
have highlighted the heterogeneity of the procedures
implemented by individual operators [5, 6] and the
frequent failure to adhere to guidelines [7, 8].
In Italy, apart from Pulmonology Units, bronchoscopies are performed in a variety of different
settings, as well as for referral or secondary care
centres. The practices for IP in Italy have never
been studied systematically, nor have they been
compared with the reference guidelines.
The aim of our survey was to analyse training,
procedures and expert opinions from the respiratory physicians performing interventional bronchoscopy throughout Italian hospitals.
Participants
The study was conducted retrospectively on
300 pulmonologists enrolled in the “Interventional
Pulmonology” study group of the Italian Association of Hospital Pulmonologists (AIPO), that represent a significant group of Italian respiratory endoscopists from all the country. Through the peri-
SURVEY ON BRONCHOSCOPY
Throughout the year prior to the study period,
21.2% had performed fewer than 100 bronchoscopy examinations; 42.3% had performed 100
to 300, and 36.6% more than 300 examinations.
Familiarity with the national AIPO guidelines was
reported by the 68.8% of participants, while 53.9%
were also familiar with international (ATS/ERS,
ACCP) guidelines. Guidelines were rated as definitely useful by 72.3% of the responders, while
27.7% agreed only in part.
od January-June 2008, an e-mail was sent out to
each pulmonologist inviting them to participate in
an e-mail survey.
Design and methods
The study was approved by the Scientific
Rewiew Board of AIPO. The survey consisted of
an anonymous questionnaire, written in Italian,
with 64 multiple-choice questions to be completed
online at a dedicated website (www.surveymonkey.com). The questions were drafted by a board
of experts consisting of three pulmonologists nominated by the Interventional Pulmonology AIPO
study group and who were then approved by the
members of the same group. The survey was divided into five sections: general information, training, organization, flexible bronchoscopy, and rigid
bronchoscopy.
The data collected were stored in the website
database and then exported to Microsoft Excel
Worksheets for analysis of the percentages relative
to the replies given for each question.
Training
Out of those taking part in the survey, 34.1%
had received at most 6 months training, 32.6% had
received between 6 and 12 months training, and
33.3% had received more than a year’s training.
Table 2 illustrates the specific training that participants received in interventional pulmonology
techniques. For flexible bronchoscopy, only a minority had attended a post-graduate course and/or
trained during their residency period. The same
was true for rigid bronchoscopy, for which 30.5%
had received on-the-job training, 46.1% were
trained at a referral centre, and only 11.3% attended a specific training course during residency.
Among the global group of responders, 55.3%
considered a formal training program necessary
for rigid bronchoscopy, laser procedures and thoracoscopy. Further training was considered useful
for electrocautery (43.3%), biopsy and bronchoalveolar lavage (17.7%), and flexible bronchoscopy (9.2%). The remaining 9.2% did not report any need for further training.
Training in performing transbronchial biopsies
(TBB) was considered as sufficient by 52.8% of
participants, while 24.4% and 22.8% of responders
reported training as insufficient or incomplete, respectively. Comparable data were obtained for
transbronchial needle aspirates, since 49.6% of the
participants reported that they had received sufficient training, while 29.3% believed it was insufficient and 21.1% incomplete.
Of the 59 pulmonologists performing rigid
bronchoscopy, 65.4% stated that their post-graduate training did not actually include rigid bronchoscopy and, as a consequence, they had not received sufficient training for stent positioning, and
laser procedures.
Results
General data
Of the 300 respiratory endoscopists invited,
201 (67.0%) participated in the study. Of these,
91.5% were male, 34.1% aged between 35-50
years and 62.5% over 50 years of age. The regional distribution is shown in tab. 1.
The majority of the participating physicians
(83.5%) work in Pulmonology Units, the remainder in Internal Medicine or other departments.
Seventy-four percent of the doctors participating
in the study had been performing bronchoscopy
for at least 10 years.
Table 1. - Regional distribution of participants
North Italy
59.1%
Center Italy
15.9%
South Italy
25%
Table 2. - Modalities of training for interventional pulmonology techniques (data presented as percentage of physicians)
During
Internship
Post-graduate
Attendance
Course
at a referral centre
On-the-job
Training
None
Flexible bronchoscopy
36.2
36.2
58.2
74.5
0.
Rigid bronchoscopy
11.3
14.9
46.1
30.5
30.5
Stent positioning
5.0
8.5
37.6
30.5
44.0
Laser electrocoagulation
6.4
7.8
34.8
34.0
45.4
Thoracoscopy
9.2
18.4
32.6
37.6
36.9
129
N. FACCIOLONGO ET AL.
Flexible bronchoscopy
Opinions regarding the minimum quantitative
criteria for acquiring adequate skills for performing a bronchoscopy, both flexible and rigid, and
the minimum criteria necessary for maintaining
competence are summarised in table 3, which
compares data with the guidelines standard.
Monitoring, premedication, and sedation
A venous access is always prepared before the
examination by 71.5% of responders, 98.4% of
which monitor the oxyhaemoglobin saturation,
32.5% monitor the arterial blood pressure, and
35.0% monitor the electrocardiographic tracing.
Among the partecipating bronchoscopists,
13.8% always sedate the patients, 24.4% administer sedation frequently (over 80% of cases), and
60% only occasionally (less than 20% of cases).
Midazolam or diazepam are the drugs of choice by
70.7% and 23.6% of operators, respectively, 82%
preferring the intravenous and 13.8% the intramuscular route of administration.
Fifty-two percent of the pulmonologists do
not premedicate with Atropine, while 28.5% premedicate in less than 20% of patients. Lidocaine
as a local anaesthetic is used by 94% of participants.
Oxygen supplementation is administered to all
patients by 28.5% of the bronchoscopists; 23.6%
administer O2 to 80% of the patients, while 39.8%
administer oxygen only if the oxyhaemoglobin saturation falls below 90%.
Before the procedure, bronchoscopists request
the evaluations shown in table 4.
Organizational framework
29.3% of participants work at Centers that perform over 1000 bronchoscopies per annum,
26.8%, 22.8% and 21.1% work at Centers that perform between 500-1000, 250-500 and < 250 bronchoscopies per annum, respectively. 57.4% of the
responders involved in the survey had a reference
population between 50,000 and 300,000.
According to 50.4% of participants, diagnostic
flexible bronchoscopy should be performed in all
hospitals, while 45.4% consider it necessary only
in referral centres. Only 2.1% consider therapeutic
bronchoscopy necessary to be carried out in all
hospitals, while the vast majority believed it
should only be available in district (41.1%) or referral centers (46.7%).
88.6% of responders performed flexible bronchoscopy in a dedicated endoscopy suite; the remaining 8.9% in multiple procedure rooms (endoscopic suite). Fifty-nine percent of operating
doctors were assisted by two nurses during the
endoscopy procedure and 38.2% by only one
nurse; only 1.6% have had the assistance of three
nurses. In 67.5% of cases, staff nurses have acquired specific experience working in the Interventional Pulmonology departments only, while
29.3% of nurses work in other endoscopy services too.
Video-bronchoscope is routinely (i.e., in
more than 80% of the procedures) used to perform the examination by 60.2% of the respiratory
specialists.
Transbronchial Biopsies
During the 12 months prior to the survey,
28.5% of responders had performed fewer than 10
TBB, 43.9% 10 to 50, and 27.6% more than 50.
Thirty percent of respiratory physicians never
use fluoroscopic guide when performing TBB,
12.8% use it occasionally, 22.0% always, while
15.4% use it only when localised peripheral lesions are present.
Table 3. - Opinion about minimum training quantitative criteria (number of procedures) for performing
bronchoscopy (data presented as percentage of physicians) - comparison with international and national guidelines
Flexible Bronchoscopies
to acquire competence
Flexible Bronchoscopies
to maintain competence
< 10
1.6
0.0
4.4
14.9
10 to 20
1.6
1.6
17.7
23.8
21 to 50
22.8
23.6
42.7
40.3
51 to 100
39.0
41.5
29.4
11.9
> 100
35.0
33.3
–
–
5.9
9.0
ACCP 100
ACCP 25
ACCP 20
ATS/ERS 20
AIPO 100
AIPO 100
ACCP 10
ATS/ERS 15
AIPO 30
No of procedures
Do not know
Guidelines’ standard
Rigid bronchoscopies
Rigid bronchoscopies
to acquire competence to maintain competence
Abbreviations: ACCP = American College of Chest Physicians, ATS = American Thoracic Society, ERS = European Respiratory
Society, AIPO = Associazione Italiana Pneumologi Ospedalieri.
130
Table 4. - Patients’ evaluations requested before
performing bronchoscopy (data presented as percentage
of physicians)
Evaluations
Chest X-ray
66.7
Platelet count
69.1
Prothrombin time
70.7
Total blood count
62.6
ECG
67.5
Blood gas analysis
22.0
Laboratory tests
(nitrogen, creatinine, electrolytes, etc.)
31.7
Spirometry
8.9
Chest CT
52.0
All above
15.4
According to clinical history
and programmed procedures
43.9
Forty-four percent of physicians routinely request a chest X-ray after performing TBB, and
71.6% keep the patient under observation outside
the endoscopy room for 1 to 3 hours.
The percentage of endoscopists reporting adequate expertise in the performance of diagnostic
and therapeutic procedures during endoscopy is
shown in table 5.
Rigid bronchoscopy
Rigid bronchoscopy is performed by 49.6% of
endoscopists, 67.8% of whom have been performing it for more than 5 years. Sixty-five percent perform these examinations in the operating room and
31.6% in endoscopy suites.
General anaesthesia with controlled ventilation
is used by 53.4% of responders and 43.1% use profound sedation in spontaneous breathing.
In the 12 months preceding this survey 79.6%
had performed therapeutic procedures during rigid
bronchoscopy, 75.5% using a laser technique.
Eighty-four percent of the study participants
hospitalised patients for therapeutic bronchoscopy.
Table 6 shows performance data for rigid bronchoscopy procedures.
Discussion
This survey, aimed at studying the behaviour
and orientation of Italian respiratory specialists
performing interventional bronchoscopy, made it
possible to evaluate the situation in Italy for the
first time. We conducted this study interviewing
only the pulmonologists registered at AIPO, bear-
ing in mind that this group may not be representative of all the physicians that perform bronchoscopies in Italy. Our data show that Italian pulmonologists in our series have acquired expertise in
bronchoscopy mainly through a long period of
practice in the field for at least 10 years, since 2
out of 3 are aged 50 years and older this would
lead to suggest some difficulties in generation
turnover. The main reason may be due to an access difficulty to residency programs; a reduction
has been observed in more recent years in the
number of those attending pulmonology postgraduate schools, and regrettably, only a small
part of these residents are trained in bronchoscopy.
The majority of Italian pulmonologists are satisfied with the national (68.8%) and international
(53.9%) guidelines and they firmly believe in their
usefulness. However, that which is published does
not not always reflect that which is applied in clinical practice, according to our survey.
The data about training show serious gaps.
Most responders declared that they had received
their background “on the job” and not during their
post-graduate education course. In Italy, postgraduate schools did not have a core curriculum until a
formal decision made by the Ministry of Education, Universities and Research for its introduction
in 2005. It is for this reason that training on respiratory endoscopy was very heterogeneous over the
past thirty years as highlighted by our study.
Nowadays, every new pulmonologist has to have
performed at least thirty broncoscopies. This standard may be insufficient as the number indicated is
lower than that suggested by scientific societies
and that considered necessary by the physicians
participating in our study. As a matter of fact 30
procedures is deemed insufficient to acquire adequate competence, 100 being considered as an appropriate target, a number similar to that proposed
by the scientific societies [9-11].
In addition, it is possibly considered more important the introduction of quantitative criteria.
Two articles published in 2010 [12, 13] showed
how difficult it is to certify the skills in IP, thus
highlighting that the minimum number of proce-
Table 5. - Endoscopic advanced procedures during
fiberoptic bronchoscopy (data presented as percentage
of physicians with specific expertise)
Bronchoscopy with aspirate and brushing
100.0
Bronchial biopsy
97.6
Transbronchial biopsy
86.2
Transbronchial needle aspirate
84.6
Broncho-alveolar lavage
96.7
Bronchoscopy with autoflorescence
31.7
Echoendoscopy with radial and linear probes
8.9
131
N. FACCIOLONGO ET AL.
Table 6. - Rigid bronchoscopy: percentage of physicians performing a definite number of procedures per year
< 5 procedures
5-30 procedures
> 30 procedures
Rigid broncoscopy
26.8
44.6
28.6
Therapeutic bronchoscopy
18.8
45.9
25.0
Stent positioning
56.3 () 20 procedures)
dures cannot be reliable as a quality standard. The
article by Lamb [13] provides important indications on the evaluation methods useful for the certification of an IP curriculum. In their large
prospective study, Wahidi et al [12] focused their
attention on the training methodology on IP with
simulators that would allow a more rapid and complete education as compared to conventional training [14-15]. Other authors have agreed on the
same conclusions, suggesting the use of simulators
on much larger cohorts to confirm these results
[16-19].
Our data underline the need for additional
training in the manoeuvres that are more complex
to perform. As an example, rigid bronchoscopy is
almost completely absent in institutional postgraduate education and the vast majority of the responders expressed the need for more complete
training. As a consequence, only 49% of responders were able to perform procedures with the
rigid bronchoscope. A prospective study on safety
in IP showed an increase in complication incidence with advanced methods such as TBB in centres performing few examinations, with operators
presumably unable to maintain adequate skills
[20]. Therefore, it would be necessary to define
which level of competence and expertise is appropriate for an interventional pulmonologist, with
the aim of updating university and post-university
training criteria.
Recent clinical practice guidelines form the
Thoracic Society of Australia and New Zealand
underline that training for advanced IP procedures
should not be simply based on theoretical case
numbers, but should also take into account the type
of hospital where the physician will operate (e.g.
major city versus provincial hospital) with regard
to probability of performing definite procedures
according to the actual prevalence of conditions
and the organization of the centre, in order to update one’s skills and maintain adequate efficacy
and safety standards [21].
To date there is no unanimous agreement regarding training courses [22]; we believe that the
scientific societies must play a more prominent
role in stimulating and proposing appropriate curricula within universities.
The organisational framework described is for
the most part satisfactory. Approximately 70% of
centres carry out more than 250 bronchoscopies
per year and 30% perform more than one thousand procedures. This reasonably ensures that operators are highly skilled and experienced. Fur132
16.7 (> 20 procedures)
thermore, they work in dedicated endoscopy
suites with the assistance of trained staff. As regards pre-endoscopic tests, in absence of literature
evidence about their ability to predict complications, 70% of study participants nevertheless request a coagulation test, total blood and platelet
counts. Of those interviewed, 50% request a Computed Tomography of the Chest (CT) before performing a bronchoscopy, and only 22% and 9%
ask for a blood gas analysis and a spirometry, respectively. This is quite a negative point, given the
high percentage of patients undergoing bronchoscopy affected by COPD, who may pose a significant risk of complications when FEV1 < 40%
predicted or < 1.0 L, such as acute hypercapnia in
case of oxygen administration [23].
Several studies suggest that sedation should always be proposed as it improves the performance
of procedures and acceptance by the patient [24-26].
According to our survey, midazolam is most commonly used but only 40% of endoscopists routinely administer it. Since this survey was conducted
in 2008, no data are reported about new technologies (such as EBUS - Bronchial thermoplastyElectromagnetic navigation, etc.), not yet largely
available back then.
Fifty-one percent of participants believe that
bronchoscopy must be performed in all hospitals,
while 45% consider that it should be a prerogative
only of provincial referral centres. In our opinion,
the most appropriate model should be a close network where the basic procedures can be carried
out in secondary care hospitals, while the more
complex manoeuvres must be performed only in
regional referral centres. This type of organisational model would improve the efficiency in the utilisation of the human and technological resources,
assuring patients adequate efficacy and safety. It
would also allow institutions to improve their
strategic planning of investment in technology implementation and training.
In conclusion, the data we collected from a cohort representing a large number of Italian respiratory physicians performing bronchoscopy, show
that, despite a certain non-uniformity of behaviour,
the results are in line with the standards of the major international guidelines in over half of participants. A strong demand appears for more comprehensive training that would stimulate a greater
commitment for scientific and academic institutions. For this purpose, an ad hoc international scientific board could ensure greater uniformity and
quality of training criteria for IP.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Ikeda S, Yanai N, Ishikawa S. Flexible bronchofiberscope. Keio J Med 1968; 17: 1-16.
Harrison BD. Guidelines for care during bronchoscopy.
British Thoracic Society. Thorax 1993; 48: 584.
British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax 2001; 56: 1-21.
Casalini A, Cavaliere S, Consigli GF, et al. Standard
operativi e linee guida in endoscopia toracica. Rassegna di Patologia dell’Apparato Respiratorio 1997; 12:
293-355.
Niwa H, Tanahashi M, Kondo T, et al. Bronchoscopy in
Japan: a survey by the Japan Society for Respiratory
Endoscopy in 2006. Respirology 2009; 14: 282-9.
Smyth CM, Stead RJ. Survey of flexible fibreoptic
bronchoscopy in the United Kingdom. Eur Respir J
2002; 19: 458-63.
Honeybourne D, Neumann CS. An audit of bronchoscopy
practice in the United Kingdom: a survey of adherence
to national guidelines. Thorax 1997; 52: 709-13.
Wahidi MM, Rocha AT, Hollingsworth JW, et al. Contraindications and safety of transbronchial lung biopsy via
flexible bronchoscopy. A survey of pulmonologists and
review of the literature. Respiration 2005; 72: 285-95.
Ernst A, Silvestri GA, Johnstone D, American College
of Chest Physicians. Interventional pulmonary procedures: Guidelines from the American College of Chest
Physicians. Chest 2003; 123: 1693-717.
Bolliger CT, Mathur PN, Beamis JF, et al. ERS/ATS
statement on interventional pulmonology. European
Respiratory Society/American Thoracic Society. Eur
Respir J 2002; 19: 356-73.
Ost D, Eapen GA, Jimenez CA et al. Improving procedural training and certification in pulmonary medicine.
Chest 2010; 137: 6-8.
Wahidi MM, Silvestri GA, Coakley RD, et al. A
prospective multicenter study of competency metrics
and educational interventions in the learning of bronchoscopy among new pulmonary fellows. Chest 2010;
137: 1040-9.
Lamb CR, Feller-Kopman D, Ernst A, et al. An approach to interventional pulmonary fellowship training.
Chest 2010; 137: 195-9.
American Board of Internal Medicine. Internal Medicine
Policies. Available at: http://www.abim.org/certification/
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
policies/imss/im.aspx#procedures. Accessed 24 February 2013.
Cooper JB, Taqueti VR. A brief history of the development of mannequin simulators for clinical education
and training. Postgrad Med J 2008; 84 (997): 563-70.
Dong Y, Suri HS, Cook DA, et al. Simulation-based
objective assessment discerns clinical proficiency in
central line placement: a construct validation. Chest
2010; 137: 1050-6.
Davoudi M, Colt HG. Bronchoscopy simulation: a brief
review. Adv Health Sci Educ Theory Pract 2009; 14:
287-96.
Issenberg SB, McGaghie WC, Petrusa ER. Features and
uses of high-fidelity medical simulations that lead to effective learning: a BEME systematic review. Med
Teach 2005; 27: 10-28.
Colt HG, Crawford SW, Galbraith O 3rd. Virtual reality bronchoscopy simulation: a revolution in procedural
training. Chest 2001; 120: 1333-9.
Facciolongo N, Patelli M, Gasparini S, et al. Incidence
of complications in bronchoscopy. Multicentre
prospective study of 20,986 bronchoscopies. Monaldi
Arch Chest Dis 2009; 71: 8-14.
Fielding D, Phillips M, Robinson P, et al. Advanced interventional pulmonology procedures: training guidelines form the Thoracic Society of Australia and new
Zealand. Respirology 2012; 17: 1176-1189.
Haponik EF, Russell GB, Beamis JF Jr, et al. Bronchoscopy training: current fellows’ experiences
and some concerns for the future. Chest 2000; 118:
625-30.
Hattotuwa K, Gamble EA, O’Shaughnessy T, et al.
Safety of bronchoscopy, biopsy, and BAL in research
patients with COPD. Chest 2002; 122: 1909-12.
Putinati S, Ballerin L, Corbetta L, et al. Patient satisfaction with conscious sedation for bronchoscopy.
Chest 1999; 115: 1437-40.
Silvestri GA, Vincent BD, Wahidi MM, et al. A phase
3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium injection for
moderate sedation in patients undergoing flexible bronchoscopy. Chest 2009; 135: 41-7.
Cases Viedma E, Pérez Pallarés J, Martínez García MA,
et al. A randomised study of midazolam for sedation in
flexible bronchoscopy. Arch Bronconeumol 2010; 46:
302-9.
133
2013; 79: 3-4, 134-135
TB CORNER
Tuberculous pancreatitis complicated by
ruptured splenic artery pseudoaneurysm
M. Irfan1, F. Thiavalappil1, J. Nagaraj1, T.H. Brown2,4,
D. Roberts3, L. Mcknight3,4, N.K. Harrison1,4
ABSTRACT: Tuberculous pancreatitis complicated by
ruptured splenic artery pseudoaneurysm. M. Irfan,
F. Thiavalappil, J. Nagaraj, T.H. Brown, D. Roberts,
L. Mcknight, N.K. Harrison.
Tuberculosis involving the pancreas is rare. We report a patient with pancreatic tuberculosis complicated by
haemorrhage from a splenic artery pseudoaneurysm. As
far as we are aware, the development of a splenic artery
pseudoaneurysm in association with a large caseating
mass of tuberculous pancreatic lymph nodes has not been
reported previously. We review the literature and discuss
the varied presentations of tuberculosis involving the pancreas or the pancreatic bed and its draining lymph nodes.
Keywords: Tuberculosis, Pancreatitis, Splenic artery pseudoaneurysm.
1
2
3
4
Respiratory Unit, Morriston Hospital, Swansea;
Department of Surgery, Morriston Hospital, Swansea;
Department of Radiology, Morriston Hospital, Swansea;
College of Medicine, Swansea University, Singleton Park, Swansea, UK.
Correspondence: Dr M. Irfan, Specialty training registrar, Dept of Respiratory Medicine, Room 1021, First floor, Glan Clwyd
Hospital, Rhyl, Wales, UK, LL18 5UJ; e-mail: [email protected]
Tuberculosis involving the pancreas is rare.
We report a patient with pancreatic tuberculosis
complicated by haemorrhage from a splenic artery
pseudoaneurysm.
A 33-yr-old Eritrean man was admitted with
abdominal pain and fever. He gave a six month history of anorexia, weight loss of 37 kg, vomiting and
drenching night sweats. Three days before admission he had developed unsteadiness of gait. He had
lived in the UK for six years. He was an ex-smoker of five cigarettes per day and worked in a warehouse. His past medical history included malaria
aged 25. Three months before admission he had
been investigated at another hospital for similar
symptoms. A computed tomography (CT) scan at
that time revealed mediastinal and intra-abdominal
lymphadenopathy (figure 1a). Whilst it was suspected he might have a lymphoma, microscopic examination of a bone marrow aspirate and a CT scan
guided core biopsy of an intra-abdominal node
showed caseating granulomata and in the latter,
acid fast bacilli (AFB) were demonstrated by ZielNielsen stain although samples had not been cultured for mycobacteria. He was referred to a chest
clinic but defaulted and was lost to follow-up.
At the time he re-presented, physical examination revealed an emaciated man with a temperature
of 38.5°C. He had palpable, non tender posterior
cervical lymphadenopathy and mild epigastric tenderness on palpation of the abdomen but physical
examination was otherwise unremarkable.
Investigations revealed a haemoglobin of 11.9
g/dl and white cell count of 8.2x 103 /μl. His renal
function was normal. Liver function tests showed
alkaline phosphatase of 245 U/l (normal range 40129 U/l) and alanine aminotransferase of 16 U/l
(<41 U/l). His serum amylase was102 U/l (<100
U/l) and a human immunodeficiency virus (HIV)
screen was negative. A CT scan of the brain
showed a ring enhancing lesion in the mid-brain
and possible meningeal enhancement. These findings were later confirmed by magnetic resonance
imaging. An upper gastrointestinal endoscopy revealed normal gastric and duodenal mucosa but
there was evidence of extrinsic compression of the
pylorus.
As the earlier biopsies strongly suggested a diagnosis of mycobacterial infection a needle aspirate of a cervical lymph node was performed and
cultured for AFB. He was then treated with
quadruple therapy using appropriate doses of rifampicin, isoniazid, ethambutol and pyrazinamide
together with and pyridoxine 10 mg daily and dexamethasone 4mg twice daily.
He continued to complain of severe abdominal
pain. Repeat serum amylase was elevated at
620 U/l and alkaline phosphatase at 303 U/l. A CT
scan revealed the abdominal lymph nodes had increased in size and in close proximity there was a
large mass. The latter had the appearance of a
retroperitoneal haematoma with intense central enhancement suggestive of a splenic artery pseudoaneurysm (figure 1b).
This pseudoaneurysm was embolised with
coils but it was only possible to occlude the
aneurysm and not the artery beyond it.
TUBERCULOUS PANCREATITIS
A
B
Fig. 1. - A) A large haematoma lies between the aorta and left lobe of
liver extending to the spleen (arrow) with central enhancement of the
pseudaneurysm (arrow head). B) A coeliac axis angiogram showing
normal flow in the hepatic artery and coils in the aneurysm (arrow).
His abdominal pain initially improved but recurred 20 days into treatment. Repeat abdominal
CT scan confirmed further bleeding into the
pseudoaneurysm. An emergency laparotomy
showed a large haematoma pushing the stomach
forward. The lesser sac was opened with careful
dissection onto the tail of pancreas and splenic
hilum. The feeding vessels were ligated by passing
sutures just distal to the tail of pancreas to surround the splenic artery and vein at the splenic
hilum. The proximal coeliac vessels were not explored as the coeliac axis was impossible to access
without entering the haematoma.
Thereafter, the patient made a steady recovery
regaining his appetite and weight. Culture of the
lymph node aspirate subsequently grew mycobacterium tuberculosis which was fully sensitive to all
first line drugs.
virus [1]. There are several ways in which the pancreas may be affected by tuberculosis [2]. These
are; haematogenous spread following primary infection; physical encroachment by adjacent caseating pancreatic lymph nodes and a toxic allergic reaction of the pancreas to generalised TB – so
called ‘concomitant pancreatitis’. Furthermore,
isoniazid – induced pancreatitis has also been described during treatment of TB [3].
Pancreatic and peri-pancreatic nodal TB can
present with a wide spectrum of symptoms including upper abdominal pain with elevated serum amylase, obstructive jaundice mimicking pancreatic carcinoma, pancreatic abscess refractory to conventional antibiotic therapy, massive gastrointestinal
hemorrhage due to duodenal wall erosion, splenic
vein thrombosis and chronic pancreatitis [4-6].
As far as we are aware, the development of a
splenic artery pseudoaneurysm in association with
a large caseating mass of tuberculous pancreatic
lymph nodes has not been reported previously. Indeed, there has been only one reported case of
splenic artery pseudoaneurysm caused by tuberculosis and this was associated with tuberculous gastritis [7].
Tuberculous involvement of blood vessels
may manifest as miliary TB of the intima, tubercular polyps attached to the intima, infiltration of all
layers of the arterial wall, aneurysm formation,
and arterial stenosis [8]. Tubercular aneurysms are
mostly pseudoaneurysms (87%) and only rarely,
true (9%) or dissecting (4%) aneurysms [8]. Unlike the aorta or peripheral arteries, aneurysms and
pseudoaneurysms of the splanchnic arteries are
very rare and when caused by infection, arise as a
result of septic emboli or infiltration from an adjacent infectious organ or lymph node mass as in the
case here described.
References
1.
2.
3.
4.
5.
6.
7.
Discussion
Tuberculosis (TB) involving the pancreas or
the pancreatic bed and its draining lymph nodes is
rare and the majority of cases have been described
in patients infected with human immunodeficiency
8.
Meesiri S. Pancreatic tuberculosis with acquired immunodeficiency syndrome: a case report and systematic review. World J Gastroenterol 2012; 18: 720-6.
Stock KP, Riemann JF, Stadler W, Rösch W. Tuberculosis of the pancreas. Endoscopy 1981; 13: 178-80.
Mattioni S, Zamy M, Mechai F, et al. Isoniazid-induced
recurrent pancreatitis. JOP 2012; 13: 314-6.
Woodfield JC, Windsor JA, Godfrey CC, Orr DA, Officer NM. Diagnosis and management of isolated pancreatic tuberculosis: recent experience and literature review. ANZ J Surg 2004; 74: 368-371.
Raghavan P, Rajan D. Isolated pancreatic tuberculosis
mimicking malignancy in an immunocompetent host.
Case Rep Med 2012; 2012: 501246.
Xia F, Poon RT, Wang SG, Bie P, Huang XQ, Dong
JH. Tuberculosis of pancreas and peripancreatic lymph
nodes in immunocompetent patients: experience from
China. World J Gastroenterol 2003; 9: 1361-4.
Jae Kyu Kim, Seok Kyun Chung, Woong Yoon, Yong
Yeon Jeong, Heoung Keun Kang. Hematemesis due to
a Pseudoaneurysm of the Splenic Artery Secondary to
Gastric Tuberculosis. Cardiovasc Intervent Radiol
2005; 28: 506-508.
Choudhary SK, Bhan A, Talwar S, Goyal M, Sharma S,
Venugopal P. Tubercular pseudoaneurysm of aorta.
Ann Thorac Surg 2001; 72: 1239-1244.
135
2013; 79: 3-4, 136-139
CASE REPORT
Recurrent pneumomediastinum
in a patient with rheumatoid arthritis
H. Bhardwaj1, B. Bhardwaj2, P.V. Carlile1
ABSTRACT: Recurrent pneumomediastinum in a patient
with rheumatoid arthritis. H. Bhardwaj, B. Bhardwaj,
P.V. Carlile.
Spontaneous pneumomediastinum (SPM); also
known as mediastinal emphysema, is a rare and usually
benign self-resolving appearance of extraluminal air in the
mediastinum without any underlying trigger. This is an
uncommon disorder mostly seen in the young males and
classic clinical presentation is with chest pain, dyspnea,
cough and appearance of subcutaneous emphysema. Al-
though several connective tissue disorders have been reported in association with SPM, it is a rare occurrence in
rheumatoid arthritis (RA) with only small number of cases reported in literature. We report a 69 years old male
with RA who developed recurrent asymptomatic episodes
of SPM detected over a period of one year. The recurrent
but benign episodes of SPM in this patient reestablish the
usual uncomplicated course of this unusual clinical entity
even in the rare recurrent cases.
Keywords: Spontaneous pneumomediastinum, Rheumatoid Arthritis, Interstitial Lung Diseases.
1
2
Pulmonary Medicine & Critical Care, Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City,
USA.
Pulmonary Medicine and Tuberculosis, Internal Medicine, Indira Gandhi Medical College Shimla, India.
Correspondence: Himanshu Bhardwaj MD, Pulmonary and Critical Care Medicine, Department of Medicine/OUHSC, PO Box
26901, WP1310, Oklahoma City, OK 73190, U.S.A.; e-mail: [email protected]
Spontaneous pneumomediastinum (SPM) is
defined as the appearance of extraluminal air within the mediastinum without any underlying trigger
or cause. It is rare disorder, mostly seen in young
males and it usually has a benign self-limiting clinical course. SPM has been described in association
with different connective tissue diseases with most
of the cases reported in dermatomyositis patients.
SPM secondary to rheumatoid arthritis (RA) related interstitial lung disease (ILD) is very rare and
only handful of cases have been reported in the literature. We report a patient of RA related ILD who
presented with recurrent episodes of SPM; each of
these episodes was managed conservatively without any complication. Besides the rarity of SPM
reported in RA, another unusual aspect in our presented case here is the recurrent nature of SPM. An
overview of SPM with different proposed pathophysiological mechanisms and management considerations are discussed.
Case Report
A 69 years old Native American male with
known history of rheumatoid arthritis (rheumatoid
factor positive and anti-CCP antibody positive)
and interstitial lung disease (ILD) related to
rheumatoid arthritis was evaluated in our chest
medicine clinic with 2 weeks history of worsening
dyspnea and worsening cough of the same duration. He denied any fever, chills or night sweats. At
baseline patient’s pulmonary function tests were
consistent with moderate restriction with FVC
measured at 57%, FEV1 of 66%, FEV1/FVC ratio
of 89% and DLCO of 29%. His medications for
rheumatoid arthritis included prednisone 5
mg/day, sulphasalazine and infliximab. In the clinic, patient was in mild respiratory distress due to
dyspnea; his vital signs included blood pressure
110/70, respiratory rate 20, pulse 92 and temperature 99 degree Fahrenheit. He was saturating 93%
on his home oxygen through nasal cannula at 3
liters/minute. Significant physical examination
findings were consistent with bibasal velcro-type
crackles on lung auscultation. Hamman’s crunch
was not heard on cardiac auscultation. There was
no neck vein distention or subcutaneous emphysema. A plain chest radiograph was done which
showed bilateral extensive generalized fibrosis,
most pronounced in the lung bases consistent with
his established diagnosis of RA related ILD (figure 1).
No mediastinal extraluminal air was seen on the
plain chest radiograph. Due to worsening dyspnea
and cough in past 2 weeks and history of significant ILD, we obtained a computed tomographic
scan of the chest which showed large amount of
pneumomediastinum which extended from the level of the aortic arch inferiorly, to below the level of
the carina (figure 2 Panel A). Patient was admitted
to the hospital for observation and was started on
cough suppressant medications. Basic laboratory
tests including complete blood count and chemistry panel did not show any abnormality. A barium swallow was done to rule out esophageal per-
RECURRENT PNEUMOMEDIASTINUM IN A PATIENT WITH RHEUMATOID ARTHRITIS
Discussion
Fig. 1. - Chest Radiograph PA and Lateral view, showing extensive
bibasilar fibrosis with relative sparing of the apices consistent with
RA associated ILD.
foration which did not show any leak. Over next
three days in the hospital, patient’s cough as well
as dyspnea improved significantly and he was discharged home in stable condition. A follow up CTScan of the chest 3 months later showed resolution
of SPM (figure 2 Panel B).
Patient was followed in our pulmonary medicine clinic and over next one year he got one more
CT-Scan of the chest for unrelated reason (for follow up of the lung nodules) which surprisingly,
again showed new onset SPM, although in lesser
amount compared to previous one (figure 2 Panel
C). Since patient was completely asymptomatic,
we decided not to pursue any intervention and only follow patient in the clinic with close observation. Patient has remained asymptomatic till date.
Pneumomediastinum, also known as mediastinal emphysema is defined as the presence of extraluminal air within the mediastinum. First ever
description of this clinical entity in the medical literature was by Laennec [1] in 1827. Pneumomediastinum can be classified into two major forms
based on etiology: traumatic and spontaneous.
Traumatic forms of pneumomediastinum are much
more encountered and usually result from thoracic
trauma and iatrogenic injuries to respiratory & digestive tracts. Spontaneous pneumomediastinum
(SPM) is defined as that occurring without any apparent triggering event. SPM was first described
by Louis Hamman [2] in 1939 with the description
of classic physical examination sign named after
his name ‘Hamman’s crunch’ described as
‘crunching rasping sound which can be heard in
synchrony with heart beats’ during auscultation in
some pneumomediastinum patients. SPM is an uncommon disorder with overall incidence ranging
from 0.003% to 0.0095% in all hospitalized patients based on 3 major case series reported so far
[3-5]. Most commonly it is seen in young male
adults with age distribution between 18 years to 25
years. In the largest review published so far, Takada et al [6] described total 414 patients of SPM described in various major case series, 303 (73.1%)
patients in this review were males.
Fig. 2. - Panel A: CT-Scan chest at the time of diagnosis, showing significant pneumomediastinum with air tracking along the bronchovascular
bundles (Arrow). Panel B: CT-Scan chest 3 months after the diagnosis, showing complete resolution of the pneumomediastinum. Panel C:
CT-Scan chest at 1 year after the diagnosis, showing recurrent pneumomediastinum with air around the aorta (Arrow).
137
H. BHARDWAJ ET AL.
The pathophysiological mechanisms underlying the development of SPM are based on ‘pressure gradient’ theory described by Macklin &
Macklin in 1939 with animal model experiments,
this theory is also known as ‘Macklin Effect’ [7].
The theory explains the development of SPM
based on the index event of an acutely raised intraalveolar pressure causing increase in the pressure gradient between the air-filled alveoli and
their surrounding interstitial space and eventually
resulting in alveolar rupture. Some of the precipitating events known to increase the intraalveolar
pressure and possibly predispose to the development of SPM include the factors that provoke Valsalva maneuver: coughing, sneezing, vomiting,
child birth and inhalation of drugs (speed, cocaine,
amphetamine-derived drugs). After the alveolar
rupture, the free gas dissect along the peribroncho
- vascular fascial sheaths into the hilum and then
into the mediastinum resulting in SPM. Off note,
once in the mediastinal space, the air can extend
further through the fascial planes connecting the
cervical soft tissues with the mediastinal, retroperitoneal spaces and may even extend upward to
the prevertebral space.
Various connective tissue diseases related interstitial lung diseases (ILD) have been reported to
be associated with SPM. Most commonly it is seen
in polymyositis/dermatomyositis patients with
overall prevalence of around 8.3% in this patient
population [8]. Others have reported SPM in lupus
[9-11], systemic sclerosis [12-14], and also
rheumatoid arthritis [15-17]. In one recent large review, Goff et al [18] reported total 62 patients of
connective tissue diseases associated SPM described in literature so far and 49 (79%) of these
patients had dermatomyositis. There were three
patients each of polymyositis, lupus, systemic
sclerosis and rheumatoid arthritis (4.8% each). For
rheumatoid arthritis related SPM, besides our presented case, one other case reported had persistent
SPM like our patient [15].
Clinical symptoms in SPM can be diverse and
vary depending on the amount of trapped air and
the inflammation in adjacent mediastinal tissues.
Significant numbers of patients remain asymptomatic but chest pain, cough and dyspnea are the
most commonly seen symptoms. Iyer et al [19] reported a 63% prevalence of chest pain, 45% of
dyspnea and 44% of cough in a retrospective review of total 62 patients with SPM. The typical
chest pain in SPM patients is known to radiate towards back & neck and it gets exacerbated with
swallowing, inspiration or leaning forward. Some
other reported symptoms include neck pain, dysphagia, dysphonia and dizziness. Like clinical
symptoms, physical examination findings in SPM
patients are diverse too. The most remarkable
physical examination finding is subcutaneous emphysema which was reported in 62% cases of the
total 414 SPM patients reviewed by Takada et al
[6]. Most popular auscultative finding in SPM remains ‘Hamman’s crunch’ described as loud bubbling crunchy sound heard with each heart beat.
Although popular, prevalence of Hamman’s
138
crunch in SPM patients is only around 30% [6].
Other less commonly reported signs include the
presence of pulsus paradoxus, cyanosis, and muffled heart sounds [3].
The diagnosis of SPM is made based on the
different radiographic findings. Chest radiographs
are the initial diagnostic tests of choice and for definitive diagnosis computed (CT) scan of the chest
is the preferred test. On chest radiographs, some of
the common suggestive findings include the presence of lucent streaks of gas outlining mediastinal
structures, demonstration of subcutaneous emphysema and prominence of the cardiac silhouette.
Some of the other infrequently seen chest radiographic signs are the double-bronchial-wall sign,
continuous diaphragm sign, Naclerio’s V sign and
the-ring-around-the-artery sign. Although, chest
radiographs remain useful diagnostic tests in the
diagnosis of SPM, some of the cases may be
missed with plain chest radiographs. Hence, chest
CT scan is thought to be the most reliable diagnostic modality in diagnosing SPM. Furthermore,
chest CT may reveal undiagnosed pre-existing pulmonary disease. Some of the additional diagnostic
tests performed in SPM patients to investigate the
cause of air leakage after the initial diagnosis is
made include esophagoscopy, esophagram or flexible bronchoscopy.
Most of the uncomplicated cases of SPM are
self-limiting and resolve on its own; only watchful observation with adjunctive analgesic treatments is needed. Multiple reports in the literature
recommend hospital admission for observation.
Other treatment approach reported in several other reports involves the breathing of 100% of oxygen which is thought to promote rapid reabsorption of the mediastinal air by so called ‘nitrogen
washout’ method [15]. Although a proven treatment in the management of pneumothorax, the efficacy of this therapeutic intervention in cases of
SPM is not conclusive and routine use is not recommended [4].
Overall clinical course in SPM patients is usually benign with very low rate of complications.
Most of the symptomatic patients show improvement in the symptoms within 2 days and resolution
of the radiographic findings within one week [6].
The recurrence of SPM after initial resolution is also rare; in the review by Takada [6], only five
(1.2%) out of total 414 SPM patients were found to
have recurrence. Natale et al [21] also described
12 cases of recurrent pneumothoraces described in
various case series but they were able to demonstrate a precipitating cause for recurrent SPM in
most of the patients. Persistent and prolonged
SPM of weeks to month’s duration like in our presented case is also very rare and it is usually seen
in patients with pre-existing underlying lung diseases. One such case of RA associated SPM of 2
months duration was reported by Patel et al [15].
Normally the management of the recurrent episode
is similar to that of the first episode, i.e. rest, cough
suppressants and analgesia.
We conclude that SPM is a rare and unusual
complication of connective tissue related lung dis-
RECURRENT PNEUMOMEDIASTINUM IN A PATIENT WITH RHEUMATOID ARTHRITIS
eases. Most of the cases have been reported in association with dermatomyositis, although scattered
reports have shown development of SPM in some
other connective tissue diseases too. To our knowledge, our presented case represents the fourth such
case of SPM seen in association with RA. Recurrent course seen in our patient makes it more unusual and probably represents persistent air leak in
terminal alveoli. Regardless of the underlying
cause, the benign course and self-resolution of the
SPM with only watchful observation in our patient
reestablishes the usual uncomplicated nature of
this clinical entity even in the rare recurrent cases.
9.
10.
11.
12.
13.
References
14.
1.
2.
3.
4.
5.
6.
7.
8.
Laennec RT. A treatise on the diseases of the chest and
on mediate auscultation. 3rd ed. London: Thomas &
George Underwood; 1829. p. 152-78.
Hamman L. Spontaneous mediastinal emphysema. Bull
Johns Hopkins Hosp 1939; 64: 1-21.
Abolnik I, Lossos IS, Breuer R. Spontaneous pneumomediastinum: a report of 25 cases. Chest 1991; 100:
93-5.
Takada K, Matsumoto S, Hiramatsu T, et al. Management of spontaneous pneumomediastinum based on
clinical experience of 25 cases. Respir Med 2008; 102:
1329-34.
Kim DH, Park JH, Chei CS, et al. Spontaneous pneumomediastinum: clinical investigation. Korean J Thorac Cardiovasc Surg 2006; 39: 220-5.
Takada K, Matsumoto S, Hiramatsu T, et al. Spontaneous pneumomediastinum: an algorithm for diagnosis
and management. Ther Adv Respir Dis 2009; 3: 301-7.
Macklin MT, Macklin CC. Malignant interstitial emphysema of the lungs and mediastinum as an important
occult complication in many respiratory diseases and
other conditions: an interpretation of the clinical literature in the light of laboratory experiment. Medicine
1944; 23: 281-358.
Kono H, Inokuma S, Nakayama H, Suzuki M. Pneumomediastinum dermatomyositis: association with cutaneous vasculopathy. Ann Rheum Dis 2000; 59: 372-6.
15.
16.
17.
18.
19.
20.
21.
Richards AJ, Talbot IC, Swinson DR, Hamilton EB.
Diffuse pulmonary fibrosis and bilateral pneumothoraces in systemic lupus erythematosus. Postgrad Med J
1975; 51: 851-5.
Masuda A, Tsushima T, Shizume K, et al. Recurrent
pneumothoraces and mediastinal emphysema in systemic
lupus erythematosus. J Rheumatol 1990; 17: 544-8.
Paira SO, Roverano S. Bilateral pneumothorax and mediastinal emphysema in systemic lupus erythematosus:
Clin Rheumatol 1992; 11: 571-3.
Mohammad A, Boon Low T, O’Dwyer D, et al. Spontaneous pneumo-mediastinum in systemic sclerosis: a
case report. Rheumatology (Oxford) 2007; 46: 1376-7.
Teixeira Moreira Almeida Mdo S, Dias LT, Fernandes
SJ, et al. Spontaneous pneumomediastinum and subcutaneousemphysema in systemic sclerosis. Rheumatol
Int 2007; 27: 675-7.
Jun JB, Song SY. The development of pneumomediastinum after pulmonary function testing in a patient
with systemic sclerosis [letter]. Rheumatol Int 2007; 27:
1097-8.
Patel A, Kesler B, Wise RA. Persistent pneumomediastinum in interstitial fibrosis associated with rheumatoid arthritis: treatment with high-concentration oxygen. Chest 2000; 117: 1809-13.
Dikensoy O, Bayram N, Bingol, et al. Bronchiolitis
obliterans in a case of juvenile rheumatoid arthritis presented with pneumomediastinum. Respiration 2002;
69: 100-2.
Kobayashi T, Satoh K, Ohkawa M, et al. Multiple
rheumatoid nodules with rapid thin-walled cavity formation producingpneumothorax. J Thorac Imaging
2005; 20: 47-9.
Le Goff B, Chérin P, Cantagrel A, et al. Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis. Arthritis Rheum 2009
15; 61: 108-18.
Iyer VN, Joshi AY, Ryu JH. Spontaneous pneumomediastinum: analysis of 62 consecutive adult patients.
Mayo Clin Proc 2009; 84: 417-21.
Bejvan SM, Godwin JD. Pneumomediastinum: old signs
and new signs. AJR Am J Roentgenol 1996; 166: 1041-8.
Natale C, D’Journo XB, Duconseil P, et al. Recurrent
spontaneous pneumomediastinum in an adult. Eur J
Cardiothorac Surg 2012; 41: 1199-201.
139
2013; 79: 3-4, 140-142
CASE REPORT
Intramedullary thoracic spinal
metastasis from small-cell lung cancer
S. Katsenos1, M. Nikolopoulou2
ABSTRACT: Intramedullary thoracic spinal metastasis
from small-cell lung cancer. S. Katsenos, M. Nikolopoulou.
Lung cancer with intramedullary spinal cord metastasis (ISCM) is a rare event exhibiting dismal prognosis.
In the present paper, we describe a 74-year-old male who
developed bilateral leg weakness with associated backache
and non-productive cough. Chest imaging evaluation
demonstrated pronounced bilateral mediastinal lymphadenopathy and a nodular opacity in the right lower
lobe. The patient was diagnosed with small cell lung can-
cer through bronchoscopic procedures. Magnetic resonance imaging of the spinal cord with contrast-enhancement revealed an intramedullary lesion consistent with
metastasis at the T5-T6 level. Despite chemotherapy and
thoracic spine radiotherapy, he eventually succumbed to
the disease 3 months after diagnosis. A brief overview of
the current literature is also provided laying emphasis on
the therapeutic strategies of this unusual extrathoracic
metastatic disease.
Keywords: Lung cancer, Intramedullary Spinal cord metastasis.
1
2
Department of Pneumonology, Arny General Hospital of Athens, Athens;
First Department of Pneumonology, General Hospital of Chest Diseases “Sotiria”, Athens, Greece.
Correspondence: Stamatis Katsenos, MD, PhD, Department of Pneumonology, Army General Hospital of Athens, 158
Mesogion&Katehaki Avenue, 115 25 Athens, Greece; e-mail: [email protected]
Intramedullary spinal cord metastasis (ISCM)
is a well-known but rare complication of systemic
malignant tumors [1]. Its presence indicates a
widespread systemic disease which progresses
rapidly. Herein, we report a well-documented case
of a small cell lung cancer with solitary thoracic
spinal cord metastasis and include a short review
of the recent literature regarding the clinical and
therapeutic aspects of this unusual entity.
Case Report
A 74-year-old male, ex-smoker (40 pack/
years-smoking cessation 25 years ago), wasreferred to our department due to a weakness in his
lower limbs accompanied by backache and nonproductive cough, gradually progressive over the
last three months. His past medical history included total laryngectomy with permanent tracheostomy for squamous cell laryngeal cancer which he
had undergone in 1982.
Chest physical examination revealed diminished
breath sounds in the right middle and lower lung
fields. Furthermore, proximal paresis of the legs was
noted and muscle strength graded 2-3/5 based on
Medical Research Council (MRC) scale. Sensory
function testing and especially pain sensation was
slightly impaired below the L2 level in both legs.
Admission chest radiograph and contrast-enhanced computed tomography showed a right perihilar tumor mass accompanied by a nodular opacity
in the right lower lobe (figure 1). Transbronchial
needle aspiration from enlarged mediastinal lymph
nodes as well as transbronchial biopsies using fluoroscopy all resulted positive for small cell lung cancer. Additional work-up using abdominal and brain
CT and bone scan did not detect any extrathoracic
metastases. However, gadolinium-based contrast
magnetic resonance imaging of the spine demonstrated a spindle-like enhancing intramedullary lesion at the T5-T6 levels measuring 2.1 cm in diameter with surrounding edema (figure 2). These findings were compatible with metastatic disease.
The patient was recommended surgical resection of the intramedullary lesion because of its
solitary location and his relatively good general
condition (ECOG performance status: 2). Nevertheless, he refused any surgical intervention and
consequently received palliative thoracic spine radiotherapy (30 Gy in 10 fractions) as well as systemic corticosteroids. After radiotherapy, he reported partial improvement in motor function of
the lower extremities and back pain relief. Moreover, he was given combination chemotherapy
regimen including cisplatin and etoposide. After
just two cycles, he developed acute respiratory
failure and CT imaging showed findings compatible with lymphangitis carcinomatosa thus reflecting a rapidly growing tumor burden. He eventually succumbed to the disease approximately three
months after his initial diagnosis.
Discussion
Intramedullary spinal cord metastasis is a rare
and tantalizing complication of malignancy. It has
INTRAMEDULLARY THORACIC SPINAL METASTASIS FROM SMALL-CELL LUNG CANCER
Fig. 1. - Contrast-enhanced chest computed tomography showing a right
perihilar tumor mass accompanied by a nodular opacity in the right lower
lobe.
been reported in 0.9-2.1% of all neoplasm autopsies and usually coexists with brain or leptomeningeal metastases in cancer patients [1, 2].
Additionally, ISCMs commonly present as solitary
lesions. Multiple metastases are even rarer, with
two lesions found in only 10% of patients [3].
Lung and breast carcinomas comprise the most
common primary tumor sites in ISCM [2, 4].
ISCM usually occurs in patients with advanced
stage diseases, thus suggesting rapidly progressing
systemic malignancy. Occasionally, ISCM may
occur as initial presentation of malignancy [1, 5].
At diagnosis, the majority of patients with ISCM
have a known primary cancer often associated
with cerebral and other systemic metastases. The
duration of symptoms before diagnosis ranges
from 2 days to 8 months (median, 7 days) [4].
Common presenting symptoms are pain, motor
weakness, sensory loss, and incontinence. Another
manifestation is Brown-Sequard syndrome or
complete spinal cord transaction which is observed
in almost half of patients with ISCM [1].
With the advent of MRI diagnosis of ISCM
has been greatly simplified. Moreover, contrastenhanced MRI may easily depict intramedullary
spinal metastatic lesions with their associated edema, thus delineating the extent of lesions as well
as regions of spinal cord compression [1]. Prior to
the era of MRI, only 5% of ISCMs were detected
antemortem. Nowadays, positron emission tomography scanning combined with computed tomography (PET/CT) is gaining ground in the assessment of secondary malignant involvement of
the spinal column resulting in increased sensitivity (98%) [6].
Optimal management of ISCM is cumbersome
due to its rarity, the wide variety of clinical aspects
and a lack of controlled studies comparing the different therapeutic modalities involved. Currently,
the surgical approach is less invasive by virtue of
the ability of new imaging techniques (MRI,
PET/CT) in precisely localizing the lesion level,
Fig. 2. - Contrast sagittal T1-weighted magnetic resonance
imaging (MRI) of the thoracic spine showing a spindle-like
enhancing intramedullary lesion at the T5-T6 levels.
thus allowing spinal cord tumor excision with an
acceptable morbidity rate [7]. The primary goal of
surgery is decompression of the functional neural
tissue followed by histological confirmation in
case of isolated revealing tumor. Surgical resection
is inappropriate in most patients, as some often
suffer from other debilitating comorbidities. A recently published study reported prolonged median
survival in selected patients who had undergone
surgery and showed an improvement in their neurological status [5].
Radiotherapy has been employed either as a
supplementary postoperative treatment or as a
mainstay of treatment for ISCM, particularly for
radiosensitive carcinomas. According to a current
retrospective study, a 6-month survival rate was
36% with a median survival period of 4 months,
when patients with ISCM received only radiotherapy at a total dose of 20-40 Gy. The majority of patients (56%) had showed either neurological improvement or pain alleviation [8]. The risk of radiation myelitis is not negligible after a considerable
amount of radiation exposure. Currently, much
more targeted radiotherapy such as stereotactic radiotherapy is recommended. Anecdotal case reports have highlighted the role of fractionated
stereotactic radiosurgery when other treatment options are unfeasible [9].
Overall prognosis of ISCM is generally sinister. Particularly, the mortality rate is 80% during
the first three to four months after the manifestation of the first symptom [1, 2]. The median survival rate is contingent on several factors such as
the preoperative neurological status, nature of the
primary cancer, and presence of systemic and/or
central nervous system metastases [5, 7]. Furthermore, patients with breast cancer were found to
have a favorable outcome compared to those with
lung cancer or any other poorly differentiated primary tumors [1, 10].
In conclusion, ISCM is relatively uncommon
and portends poor prognosis. Early recognition of
141
S. KATSENOS, M. NIKOLOPOULOU
this rare entity by means of MRI is of the utmost
importance in promptly initiating therapeutic
modalities, for preventing paraplegia and improving quality of life. Radiotherapy remains the main
therapeutic approach albeit surgical resection
should be considered as the primary treatment
whenever feasible, particularly in the case of
rapidly progressive neurological deficits and when
a clear cleavage plane exists.
4.
References
7.
1.
2.
3.
142
Kalayci M, Cağavi F, Gül S, Yenidünya S, Açikgöz B.
Intramedullary spinal cord metastases: diagnosis and
treatment-an illustrated review. Acta Neurochirurgica
2004; 146: 1347-1354.
Sung WS, Sung MJ, Chan JH, et al. Intramedullary
spinal cord metastases: A 20-year institutional experience with a comprehensive literature review. World J
Neurosurg 2013; 79: 576-84.
Koutsis G, Spengos K, Potagas C, Dimitrakopoulos A,
Sfagos K, Zakopoulos N. Intramedullary spinal cord
metastases in a patient with small-cell lung cancer. Eur
J Intern Med 2006; 17: 372-374.
5.
6.
8.
9.
10.
Lee SS, Kim MK, Sym SJ, et al. Intramedullary spinal
cord metastases: a single-institution experience. J Neurooncol 2007; 84: 85-89.
Dam-Hieu P, Seizeur R, Mineo JF, Metges JP, Meriot
P, Simon H. Retrospective study of 19 patients with intramedullary spinal cord metastasis. Clin Neurol Neurosurg 2009; 111: 10-17.
Metser U, Lerman H, Blank A, Lievshitz G, Bokstein F,
Even-Sapir E. Malignant involvement of the spine: assessment by 18F-FDG PET/CT. J Nucl Med 2004; 45:
279-284.
Kalita O. Current insights into surgery for intramedullary spinal cord metastases: a literature review.
Int J Surg Oncol 2011; 2011: 989506.
Hashii H, Mizumoto M, Kanemoto A, et al. Radiotherapy for patients with symptomatic intramedullary spinal
cord metastases. J Radiat Res 2011; 52: 641-645.
Parikh S, Heron D. Fractionated radiosurgical management of intramedullary spinal cord metastases: A case
report and review of the literature. Clin Neurol Neurosurg 2009; 111: 858-861.
Zebrowski A, Wilson L, Lim A, Stebbing J, Krell J. Intramedullary spinal cord metastases in breast cancer are
associated with improved longer term systemic control.
Future Oncol 2010; 6: 1517-1519.
Images of Chest Diseases
TBNA for the treatment of non complicated
bronchogenic cyst
A. Andreani, G. Cappiello, M. Valli, M. Giovannini
A 65-year old male ex smoker came to our
attention, coming from a department of General Medicine where he was admitted for a transitory ischemic attack, for the accidental detection during thoracic CT (performed as a routine
chest radiograph had showed a suspect enlargement of the right pulmonary hilum) of a mediastinal round, well-circumscribed and fluid
density mass adjacent to the posterior wall of
the right main bronchus (fig. 1a). The patient
was completely asymptomatic denying in particular fewer, cough, weight loss, retrosternal
pain or dyspnea.
We, therefore, performed bronchoscopy
during which we noticed an extrinsic compression of the posterior wall of the proximal part
of the right main bronchus; in this site the mucosa appeared bluish and hyperemic (fig. 1b).
Observing this lesion, we decided to perform a
transbronchial needle aspiration (TBNA) with
a collection of 35 millilitres of a viscous,
brownish and turbid-type fluid (fig. 2). After
the TBNA the compression of the posterior
wall of the right main bronchus disappeared
and the mucosa faded in colour (fig. 1c).
According to literature the patient received
an antibiotic prophilaxis before and after TBNA. Cytological examination of the fluid
showed a nonspecific inflammatory pattern
with numerous macrophages while microbiology analysis was negative for specific pathogenic forms: these findings, supported by the radiological (CT in particular) results, were consistent with benign bronchogenic cyst.
Another thoracic CT, performed the day after, the procedure showed macroscopic reduction of the mediastinal mass (fig. 1d). Follow
up examination after 3 months was almost unchanged; subsequent thoracic CT, scheduled after 4 months, will give us an indication of the
evolution.
Bronchogenic cysts are lesions of congenital origin deriving from the primitive foregut
and are the most common primary cysts of the
mediastinum. Generally they contain clear fluid or, less commonly, hemorrhagic secretions
or air. They are lined by columnar ciliated epithelium, and their walls often contain cartilage
and bronchial mucous glands [1]. Although
some bronchogenic cysts are asymptomatic and
are incidental findings upon thoracic CT, most
cysts, causing compression or irritation to the
adjacent structure, could be symptomatic with
cough, fever, pain, and dyspnea. Tracheobronchial compression and pulmonary infections may occur due to the relatively soft tracheobronchial tree [2]. Infection is a common
complication, especially in cysts with bronchial
communications.
The treatment of choice in cases presenting
with complications is surgical resection with
complete removal of the secreting mucosal lining. The role of surgery is however controversial in asymptomatic patients where an endoscopic aspiration could be attempted. The simple transbronchial needle aspiration (TBNA) is
sometimes associated with a high recurrence
rate as the lining of the cyst cannot be removed
[2]. Endobronchial ultrasound transbronchial
needle aspiration (EBUS-TBNA) instead, allowing visualisation during aspiration, could
enable complete aspiration of the cyst causing
the collapse of the cystic space with the consequent adhesion of the mucosal surfaces of the
cavity; in this way one reduces the likelihood of
recurrence [3].
We indeed agree with the literature regarding limiting the therapeutical use of simple TBNA only in cases of acute compression or in
compromised or nonoperative patients [4],
however, being a relatively simple and readily
available technique for every bronchoscopist,
in contrast to the lengthy preparation involved
necessary to organize a session with EBUS, and
as also suggested by some past works demonstrating a low recurrence rate [5], we think that
2013; 79: 3-4, 143-145
Department
of Respiratory Diseases,
St Maria Bianca
Hospital, Mirandola
(Modena), Italy.
Corrispondence:
Alessandro Andreani
MD, Department
of Respiratory Diseases,
Hospital St Maria Bianca,
Mirandola (Modena),
Italy; e-mail:
[email protected];
[email protected]
A. ANDREANI, ET AL.
Fig. 1. - Anticlockwise: 1a
CT scan showing the presence of a mediastinal round
and fluid mass leaning
against the posterior wall
of the right main bronchus
(white arrow): the well-defined margins, the absence
of irregular wall, the homogeneous CT attenuation,
the typical homogeneous
water density (20 Hounsfield
Units) and its position
could already suggest a diagnosis of benign bronchogenic cyst; 1b image
acquired during bronchoscopy showing the posterior wall of the beginning
of the right main bronchus
been tense and hyperemic
for extrabronchial compression; 1c the same image as before acquired immediately after TBNA: the
bronchial mucosa now appears smooth and whiter
(in the white oval we can
see the precise point of entry of the needle); 1d CT
scan, performed after
TBNA, showing a clear reduction of the size of the
bronchogenic cyst.
a simple TBNA could still be the most suitable
technique (especially if EBUS is not readily
available) as an initial approach in the management of suspected bronchogenic cysts, especially when the radiological appearance leaves
no doubt regarding the benign nature of the lesion. If in fact the future follow up shows no
evidence of recurrence we would avoid having
the patient undergo a thoracotomy and may
achieve both the diagnostic and therapeutic
goal with a simpler, faster and safer technique
in a single bronchoscopic session.
Clearly, if we decide to adopt a simple TBNA as the first approach treatment for suspected bronchogenic cysts, it will be necessary to
program a careful clinical and radiological follow up and, therefore we must be prepared to
perform safer therapeutic interventions in the
event of complications or recurrence.
144
Fig. 2. - Image showing the
container where we collected the brownish and torbid,
but surprisingly odorless
fluid taken during TBNA.
As it is a very viscous fluid,
we had to apply a considerable amount of suction force
through the syringe connected to the needle during
TBNA in order to collect as
much of it as possible.
TBNA FOR THE TREATMENT OF NON COMPLICATED BRONCHOGENIC CYST
References
1.
2.
3.
Twehues AR, et al. Management of mediastinal
bronchogenic cust with transbronchial needle aspiration. Chest 2009; 136: 23s-24s.
Dhand S, Krimsky W. Bronchogenic cyst treated by
endobronchial ultrasound drainage. Thorax 2008;
63: 4.
Galluccio G, Lucantoni G. Mediastinal bronchogenic
4.
5.
cyst’s recurrence treated with EBUS-FNA with a
long-term follow-up. European J of Cardio-thoracic
Surgery 2006; 29: 627-629.
Ribet E, Copin MC, Gosselin B. Bronchogenic cyst
of the mediastinum. J Thorac Cardiovasc Surg
1995; 109: 1003-10.
Kuhlman JE, Fishman EK, Wang KP, Zerhouni
EA, et al. Mediastinal cyst: diagnosis by CT and
needle aspiration. Am J Roentgenol 1988; 150:
75-8.
145
Books
Non-invasive Respiratory Support
A Pratical Handbook
3rd edition
Edited by Anita K. Simonds
Hodder Education
The Washington Manual® Pulmonary Subspecialty Consult
Edited by Lippincott Williams & Wilkins
ACCP Critical Care Medicine Board Review
20th Edition
Karger, 556 pp.
Respiratory Physiology: A Clinical Approach
Edited by R.M. Schwartzstein, M.J. Parker
Lippincott Williams & Wilkins
ACCP Pulmonary Medicine Board Review
25th Edition
Karger, 738 pp.
Respiratory Physiology
The essentials
Edition: Seventh
Edited by: J.B. West
Cystic Fibrosis in the 21st Century
Priftis KN, Anthracopoulos MB, Eber E, Koumbourlis AC,
Wood RE eds.
Progress in Respiratory Research, Vol. 38
Karger, 212 pp. and online supplementary material
Clinical Epidemiology - The essentials
Edition: Fourth
Edited by: R.H. Fletcher, S.W. Fletcher
New Drugs and Targets for Asthma and COPD
Hansel TT, Barnes PJ eds.
Progress in Respiratory research, Vol. 39
Karger, 310 pp.
Oxford Handbook of Respiratory Medicine
First Edition
Stephen Chapman, Grace Robinson, John Stradling,
Sophie West eds.
Oxford University Press
Respiratory Infections
Sanjay Sethi ed.
Informa Healthcare Respiratory Medicine Books, 384 pp.
Controversies in the Treatment of Lung Cancer
Heide J, Schmittel A, Kaiser D, Hinkelbein V eds.
Frontiers of radiation Therapy and Oncology, Vol. 42
Karger, 214 pp.
Clinical Chest Ultrasound
From the ICU to the Broncoscopy Suite
Bolliger CT, Herth FJF, Mayo PH, Miyazawa T, Beamis JF eds.
Karger, 222 pp. and online supplementary material
Pediatric Bronchoscopy
Priftis KN, Anthracopoulos MB, Eber E, Koumbourlis AC,
Wood RE eds.
Karger, 212 pp.
New Drugs and Targets for Asthma and COPD
Hansel TT and Barnes PJ eds.
Karger, 310 pp.
History of Telemedicine
Evolution, Context and Transformation
Bashshur RL, Shannon GW eds.
Mary Ann Liebert Inc., 432 pp.
Antituberculosis Therapy
PR Donald, PD Helden eds.
Karger, 252 pp.
Pulmonary Vascular Disorders
M Humbert, R Souza, G Simmoneau eds.
Karger, 29 pp.
Principles and Practice of Lung Cancer
Pass HI, Carbone DP, Johnson DH,
Minna JD, Scagliotti GV, Turrisi AT eds.
Specialty Imaging: HRCT of the Lung
Gurney JW, Abbott GF, Winer-Muram HT,
Rosado de Christenson M, Mohammed T-LH eds.
Chronic Obstructive Pulmonary Disease
Graeme P. Currie ed.
Oxford University Press, UK, 102 pp.
146
ACCP-SEEK
Assessment in Critical Care and Pulmonology
- Self-Education and Evaluation of Knowledge Vol. 19:
Pulmonary Medicine Karger, 330 pp.
Lung transplantation
Wickii Vingneswaran ed.
Atlas of Flexible Bronchoscopy
Pallav Shah ed.
Hodder Arnold, UK, 224 pp.
Tuberculosis: the Essentials
Mario C. Raviglione ed., 4th Edition
Interventional Pulmonary Medicine
John F Beamis Jr, Praveen Mathur, Atul C Metha eds.,
2nd Edition
Obstructive Sleep Apnea in Adults
Alain Lurie ed.
Advances in Cardiology, Vol. 46
Karger, 272 pp.
Antituberculosis Chemotherapy
Donald PR, van Helden P eds.
Progress in Respiratory Research Vol. 40
Karger 252 pp.
Pulmonary Vascular Disorders
Umbert M, Souza R, Simonneau G eds.
Progress in Respiratory Research Vol. 41
Karger, 290 pp.
Allergy and the Nervous System
Bienenstock J ed.
Chemical Immunology and Allergy Vol. 98
Karger, 272 pp.
Pleural Diseases
Demosthenes Bouros ed.
Non-invasive Ventilation and Weaning:
Principles and Practice
Mark Elliott, Stefano Nava and Bernd Schonhofer eds.
Hodder Arnold Publisher, UK, 621 pp.
Pediatric Airway Surgery
Cristopher J Hartnick, Maynard C Hansen
Thomas Q Gallagher eds., Karger, 158 pp.
The Chemical Componentes of Tobacco and Tobacco Smoke
Alan Rodgman, Thomas A. Perfetti eds.
CRC Press, Taylor and Francis Group
MONALDI
INTERNATIONAL JOURNAL FOR CARDIOPULMONARY MEDICINE AND REHABILITATION
Volume 79, 3-4 Issues
AUTHOR AND KEYWORDS INDEXES
Author Index
Accorsi P.
Airoldi A.
Alamo A.
Amaradio M.D.
Ambrosino N.
Andreani A.
Apollonatou V.
Artioli D.
Attinà D.
Balbi B.
Barbarito N.
Bassi L.
Bektemur G.
Bettinzoli M.
Bhardwaj B.
Bhardwaj H.
Boffi R.
Bolzon M.
Bonini L.
Braghini A.
Brown T.H.
Bruno C.M.
Burunsuzoglu B.
Caponnetto P.
Cappiello G.
Caramori G.
Carlile P.V.
Castiglioni M.
Cazzuffi R.
Celi A.
Cesario A.
Chatzivassiloglou F.
Cibella F.
Ciccarese F.
Contini C.
Contini P.
Contoli M.
Corda L.
Corsello G.
Costa F.
De Marco C.
De Mattia E.
Demir M.
Di Paco A.
Dominioni L.
Ekinci G.H.
93
20
12
12
8
143
96
44
49
5
121
20
90
93
136
136
8
93
93
93
134
12
90
12
143
44
136
67
44
109
73
87
38
49
44
49
44
93
38
109
8
121
90
8
67
90
Facciolongo N.
Fagerström K.O.
Ferrante G.
Ferrara F.
Ferrara G.
Freixinet Gilart J.L.
Geraneo K.
Giannopoulos A.
Giordano L.
Giovannelli F.
Giovannini M.
Gkermpesi M.
Guardigni V.
Guzzinati I.
Haciomeroglu O.
Harrison N.K.
Iliopoulou M.
Imperatori A.
Irfan M.
Jiménez-Ruiz C.A.
Joachim Meyer F.
Justine M.
Karkoulias K.
Katsenos S.
Kavas M.
Kojicic M.
Kovačević P.
Kraniotis P.
La Grutta S.
Latorre M.
Lazzari Agli L.
Libanore M.
Liotta G.
Lococo F.
Lusuardi M.
Lykouras D.
Malagrinò L.
Malizia V.
Mangini M.
Mantovani W.
Mcknight L.
Menzella F.
Mohan V.
Mughetti M.
Nagaraj J.
Nardi I.
128
27, 33
38
38
44
81
73
96
93
20
143
96
44
44
90
134
96
67
134
27, 33
61
116
96
140
90
61
61
96
38
109
128
44
38
73
128
96
109
38
67
67
134
128
116
49
134
73
Nardini S.
Nicosia F.
Nikolopoulou M.
Novelli F.
Ongel E.A.
Pacifici R.
Paddeu A.
Paggiaro P.
Paolucci M.
Papi A.
Pasqua F.
Pasquini C.
Patelli M.
Piro R.
Poli A.
Polosa R.
Prokakis C.
Psathakis K.
Radovanovic D.
Rajkovača Z.
Rinaldi R.
Roberts D.
Rocca A.
Rodríguez Suárez P.M.
Rossi R.
Rotolo N.
Russo C.
Salio M.
Santus P.
Simoni M.
Skouras V.
Spagnoletti M.
Spanevello A.
Spiropoulos K.
Stanetić M.
Tantucci C.
Tahirah F.
Thiavalappil F.
Tsintiris K.
Vagaggini B.
Valli M.
Veljković S.
Viegi G.
Voulgaridis A.
Yilmaz A.
Zanini A.
Zompatori M.
6
93
140
109
90
6
67
109
67
44
73
44
128
128
67
12
96
87
20
61
44
134
49
81
44
67
12
128
20
38
87
67
5
96
61
93
116
134
87
109
143
61
38
96
90
67
49
147
Keyword Index
Adult
90
Apnea
93
Asbestos
96
Asthma
38, 109
Bacilllus Calmette-Guérin (BCG)
immunotherapy
44
Birth-Hogg-Dubè syndrome
49
Bladder carcinoma
44
Body Mass Index (BMI) 121
Bronchodilator
109
Bronchoscopy
128
Bupropion
27
CAP
44
Chest radiography
67
Chest x-ray
67
Children
38
Chronic Obstructive Pulmonary Disease
(COPD)
121
Cognitive-behavioral interventions
33
COPD smokers
27
COPD
33, 116
Cost-effectiveness
67
CT thorax
49
Dyspnea
116
E-cigarettes
6
Economic evaluation
67
Electronic cigarettes
12
Endothelin-1
61
Environmental tobacco smoke
38
Extralobar
90
148
Forced Expiratory Volume in the First
121
Second (FEV1)
Guidelines
128
Health education
8
Health
6
High doses of nicotine replacement
therapy
27
Hypocapnia
93
Indoor environment
38
Interstitial Lung Diseases 136
Interventional pulmonology 128
Intramedullary Spinal cord metastasis
140
Kidney neoplasm
49
Lung cancer screening
67
Lung cancer
73, 96, 140
Lung cysts
49
Lung development
38
Lung function
116
Malignancy
96
Malignant effusion
81
Medical thoracoscopy
87
Morbid Obesity
121
Nicotine addiction
12
Nicotine replacement therapy
27
Osteophytes
87
Outcomes
20
Pancreatitis
134
Pharmacological treatment
27, 33
Pleural abrasion
81
Pleural effusions
87
Pleural mesothelioma
96
Pleurodesis
81
Pneumonia
44
Pneumothorax
49, 81
Population-based
67
Prevention
8
Psychiatric disorder
93
Pulmonary rehabilitation 73
Pulmonary sequestration 90
Quality of life
116
Rheumatoid Arthritis
136
Smoking cessation
12, 20
Smoking habit
8
Smoking reduction
12
Smoking
6, 20, 27, 33
Spirometry
61
Splenic artery pseudoaneurysm
134
Spontaneous pneumomediastinum
136
Surgery
73
Survey
128
Talc
81
Therapy
109
Third-hand smoke
38
Thoracoscopy
81
Tiotropium
109
Tobacco control
38
Tobacco harm reduction 12
Tobacco
20
Training
128
Treatment
33
Tuberculosis
134
Uremia
61
20, 27
Varenicline
LE PUBBLICAZIONI DELLA FONDAZIONE SALVATORE MAUGERI
1. I “Quaderni di Medicina del Lavoro e Medicina Riabilitativa”
con i quali si propone di rendere disponibile in forma organica argomenti e problemi attuali in Medicina del Lavoro e Riabilitazione, di presentare elaborazioni di materiale informativo e didattico riguardante i
vari settori di attività della Fondazione.
Volumi pubblicati:
1. G. Pezzagno: Rischio da Benzene. 1989
2. G. Franco: Attività umane e rischio per la salute. 1990
3. M. Imbriani, S. Ghittori, G. Pezzagno, E. Capodaglio: Esposizione professionale ad anestetici per inalazione. 1990
4 F. Franchignoni: Aggiornamenti in Riabilitazione 2. 1990
5. E. Capodaglio, L. Manzo: Esposizione a Stirene. 1990
6. G. Pezzagno, E. Capodaglio: Criteri di valutazione energetica
delle attività fisiche. 1991
7. G. Franco: Acidi biliari e xenobiotici. 1991
8. S. Cerutti, G. Minuco: Spectral Analysis of Heart Rate Variability
Signal. Methodological and Clinical Aspects. 1991
9. F. Franchignoni: Aggiornamenti in Riabilitazione 3. 1991
10. M. Imbriani, A. Di Nucci: Effetti della interazione tra etanolo e solventi. 1991
11. F. Cupella, R. Turpini: La riabilitazione in gastroenterologia. 1991
12. L. Manzo, M. Imbriani, L.G. Costa: Current Issues in Alcoholism.
1992
13. C. Rampulla, N. Ambrosino: Muscoli respiratori e patologia: valutazione e trattamento. 1992
14. S. Della Sala, M. Laiacona: Laboratorio di Neuropsicologia. 1992
15. F. Franchignoni: Aggiornamenti in Riabilitazione 4. 1992
16. E. De Rosa, G.B. Bartolucci, V. Cocheo: Atti 11° Congresso Nazionale A.I.D.I.I. 1992
17. B. Carù, R. Tramarin: New trends in cardiac rehabilitation. 1992
18. L. Manzo, D.F. Weetman: Toxicology of combustion products. 1992
19. C. Minoia, E. Sabbioni, P. Apostoli, A. Cavalleri: Valori di riferimento di elementi in traccia in tessuti umani. 1992
20. D. Cottica, G.F. Peruzzo: Atti 12° Congresso Nazionale A.I.D.I.I. 1993
21. G. Pezzagno: Strategie di campionamento ambientale. Alcune
applicazioni statistiche per lo studio degli inquinanti ambientali.
1993
22. M. Casacchia, R. Casale, E. Ferrari, C. Setacci: Stress. Riunione
operativa sottoprogetto stress - Progetto finalizzato CNR - FATMA.
1993
23. G. Moscato: Asma professionale. 1993
24. A. Cavalleri, G. Catenacci: Obbligo di referto e malattie professionali. 1993
25. G. Bazzini: Nuovi approcci alla riabilitazione industriale. 1993
26. P. Pinelli, G. Minuco: Il controllo motorio della mano e della parola: teoria e applicazioni. 1993
27. F. Candura, G. Sardo: L’Ispettorato Medico Centrale del Lavoro
in Italia: storia e prospettive. 1994
28. G. Bertolotti, E. Sanavio, G. Vidotto, A.M. Zotti: Un modello di
valutazione psicologica in Medicina Riabilitativa. 1994
29. D. Cottica, M. Imbriani: Atti 13° Congresso Nazionale A.I.D.I.I 1994
30. S. Della Sala, A.M. Zotti: Psicologia dell’invecchiamento ed
epidemiologia della demenza: uno studio di popolazione. 1994
31. A. Cavalleri: Lavanderie a secco: rivalutazione del rischio da solventi. 1994
32. G.D. Pinna, R. Maestri: Spectral analysis of cardiovascular variability signals. 1995
33. R. Casale, A. Tango: Le algodistrofie. Dalla diagnosi alla prevenzione. 1995
34. D. Cottica, V. Prodi, M. Imbriani: Atti 14° Congresso Nazionale
A.I.D.I.I. 1995
35. C. Rampulla, A. Patessio, A. Rizzo, F. Iodice: Valutazione funzionale del danno respiratorio. 1995
36. R.F.E. Pedretti, P. Della Bella: Le Tachiaritmie Ventricolari Maligne dopo Infarto Miocardico. 1995
37. K. Foglio: La ventiloterapia domiciliare nei pazienti broncopneumatici con insufficienza respiratoria cronica. 1996
38. L. Riboldi, C. Ravalli: Lo stress nel mondo del lavoro: quali soluzioni per un problema in espansione. 1996
39. A. Molfese: Piattaforme Petrolifere. Igiene, Sanità e Sicurezza a
bordo. 1996
40. R. Gibellini, A. Ferrari Bardile, M. Zambelli, M. Fanello: La riabilitazione in angiologia. 1996
41. S. Binaschi: Medicina del Lavoro. 1997
2. I “Documenti” della Fondazione Salvatore Maugeri, nei quali vengono pubblicati gli Atti di Convegni di particolare interesse organizzati
dagli Istituti della Fondazione.
Volumi pubblicati:
1. C. Passerino: La nuova riforma sanitaria. 1995
2. Serials with an Institute for Scientific Information (ISI). Impact
Factor. 1995
3. F. Candura: Atti del Convegno: Metodologia di indagine sul
danno ambientale. Inquinamento atmosferico e acustico nel territorio di Pavia. 1995
4. N. Ambrosino, G. Bazzini, F. Cobelli, F. Franchignoni, P. Giannuzzi, C. Rampulla, M. Vitacca: Percorsi valutativi e terapeutici in
Medicina Riabilitativa. 1995
5. G. Franco: Rischi lavorativi in ambiente sanitario: patologia da
guanti. 1996
6. G.B. Bartolucci, D. Cottica, M. Imbriani: Atti 15° Congresso Nazionale A.I.D.I.I. 1996
7. E. Capodaglio, C. Passerino: Atti del Convegno: Sistemi classificativi dei pazienti in degenza riabilitativa. 1996
8. A. Borgo: L’analisi in componenti principali come studio di correlazioni. 1996
9. F. Pisano: Valutazione e trattamento delle compromissioni motorie centrali: stato dell’arte e recenti acquisizioni. 1996
10. G. Vittadini, I. Giorgi: Dalla cibernetica dell’io all’approccio ecologico: alcolismo e servizi nell’ottica sistemica. 1996
11. N. Ambrosino, G. Bazzini, F. Cobelli, F. Franchignoni, P. Giannuzzi, C. Rampulla, M. Vitacca: Percorsi valutativi e terapeutici in
Medicina Riabilitativa. 1997
12. C. Minoia, G. Scansetti, G. Piolatto, A. Massola: L’amianto: dall’ambiente di lavoro all’ambiente di vita. Nuovi indicatori per futuri
effetti. 1997
13. A.M. Cirla, G. Catenacci: Organizzazione dell’emergenza sanitaria e del primo soccorso nei luoghi di lavoro. 1997
14. G.B. Bartolucci, D. Cottica, M. Imbriani, D. Sordelli: Atti 16° Congresso Nazionale A.I.D.I.I. 1997
15. G. Catenacci, G.B. Bartolucci, P. Apostoli: III Congresso Nazionale di Medicina Preventiva dei Lavoratori della Sanità. 1998
16. D. Cottica, G.B. Bartolucci, M. Imbriani, E. Grignani, D. Sordelli:
Atti 17° Congresso Nazionale A.I.D.I.I. 1998
3. “Advances in Occupational Medicine & Rehabilitation” “Aggiornamenti in Medicina Occupazionale e Riabilitazione”, rivista quadrimestrale.
Volumi pubblicati:
1. G. Bazzini: Efficacia e qualità in riabilitazione motoria. 1995
2. M. Imbriani, S. Ghittori, G. Pezzagno E. Capodaglio: Update on
Benzene. 1995
3. M.R. Strada, G. Bernardo: Interventi riabilitativi in Oncologia.
1996
4. J. Nilsson, M. Panizza, F. Grandori: Advances in Magnetic Stimulation. 1996
5. S. Della Sala, C. Marchetti, O.H. Turnbull: An interdisciplinary approach to the rehabilitation of the neurological patient: A cognitive perspective. 1996
6. P. Capodaglio, G. Bazzini: L’attività motoria degli arti superiori:
aspetti in medicina occupazionale e riabilitativa. 1997
7. G. Pezzagno, M. Imbriani: Cinetica e Monitoraggio Biologico dei
Solventi Industriali. 1997
8. L. Manzo, J. Descotes, J. Hoskins: Volatile Organic Compounds
in the Environment. Risk Assessment and Neurotoxicity. 1997
9. P. Capodaglio, M.V. Narici: Muscle Atrophy: Disuse and Disease. 1998
10. G. Moscato: Allergia respiratoria. 1998
11. G. Miscio, P. Pinelli: Prefrontal cortex, Working memory and Delayed reactions: from the theory to the clinical application. 1998
4. “Advances in Rehabilitation” “Aggiornamenti in Medicina Riabilitativa”.
Volumi pubblicati:
1. F.M. Cossa, L. Mazzini: Assistenza clinica e ricerca scientifica: validità dell’approccio multidisciplinare al traumatizzato cranico. 1999
2. P. Capodaglio, M.V. Narici: Physical Activity in the Elderly. 1999
3. G. Miscio, F. Pisano: Spasticity: mechanisms, treatment and
rehabilitation. 1999
4. M. Buonocore, C. Bonezzi: Il dolore neurogeno: dalla definizione
alla terapia. 1999
5. A. Salvadeo: Insufficienza renale acuta. 1999
6. P. Pinelli, R. Colombo, S. Onorato: Analisi dell’attenzione protratta nelle reazioni verbali. Sistema prefrontale e Processi riverberanti. Le reazioni dilazionate in Neuropsichiatria (with an English Outline). 1999
7. N. Ambrosino, C.F. Donner, C. Rampulla: Topics in Pulmonary
Rehabilitation. 1999
8. A.M. Zotti, G. Bertolotti, P. Michielin, E. Sanavio, G. Vidotto:
Linee guida per lo screening di tratti di personalità, cognizioni e
comportamenti avversi alla salute. Manuale d’uso per il CBA
Forma Hospital. 2000
9. P. Capodaglio, M.V. Narici: The ageing motor system and its
adaptations to training. 2000
10. F. Rengo, R. O. Bonow, M. Gheorghiade: Heart Failure in the Elderly. Implication for Rehabilitation. 2000
11. G. Megna, S. Calabrese: Riabilitazione neuromotoria 2000. 2000
12. P. Pinelli & Coll.: Freud in a Psychophysiological Framework or
About Unconscious and Soul. 2001
13. F. Rengo, R.O. Bonow, M. Gheorghiade: Chronic Heart Failure
In The Elderly. The Evolution Of Chronic Heart Failure. 2002
14. G. Bazzini: ll Day-Hospital Riabilitativo. 2003
15. M. Buonocore, C. Bonezzi: Il dolore nelle neuropatie periferiche
post-traumatiche. 2003
16. M. Barat, F. Franchignoni: Assessment in Physical Medicine and
Rehabilitation Views and Perspectives. 2004
17. P. Giannuzzi, F. Rengo: Dall’Eccellenza all’Alta Specializzazione
in Cardiologia Riabilitativa. 2005
18. M. Monticone. L’evoluzione della Riabilitazione per le Malattie
Neurodegenerative. 2010
19. F. Franchignoni. Research issues in Physical & Rehabilitation
Medicine. 2010
5. “Advances in Occupational Medicine” “Aggiornamenti in
Medicina Occupazionale”.
Volumi pubblicati:
1. L. Alessio, P.A. Bertazzi, A. Forni, G. Gallus, M. Imbriani: Il monitoraggio biologico dei lavoratori esposti a tossici industriali. Aggiornamenti e sviluppi. 2000
2. L. Ambrosi, L. Soleo, S. Ghittori, L. Maestri, M. Imbriani: Mercapturic Acids as Biomarkers of Exposure to Industrial Chemicals.
2000
3. C. Meloni, M.T. Querciolli, S. Verdirosi, M. Imbriani: Aggiornamenti in Scienze Infermieristiche. 2002
6. “Symposia” “I Congressi della Fondazione Maugeri”.
Volumi pubblicati:
1. D. Cottica, F. Benvenuti, E. Grignani, M. Casciani, M. Imbriani: Il
rischio microbiologico negli ambienti di lavoro: approccio, valutazione, interventi. Convegno AIDII - ISPESL, Centro Congressi
Fondazione Salvatore Maugeri. Pavia, 29 ottobre 1998. 1999
2. L. Soleo, P. Apostoli, D. Cavallo, D. Cottica, G. Nano, L. Ambrosi: II Congresso Europeo di Igiene Industriale - I Congresso
Mediterraneo di Igiene Industriale - Convegno AIDII, Centro Internazionale Congressi. Bari, 30 giugno - 3 luglio 1999. 2000
3. M. Buonocore, C. Bonezzi: La gestione del paziente con dolore
neuropatico: indicazioni diagnostiche e terapeutiche. II incontro
sul dolore neurogeno. Pavia, 12 maggio 2000. 2000
4. D. Cottica, G.B. Bartolucci, G. Nano, M. Imbriani: Atti 18° Congresso Nazionale AIDII. Trento, 21-24 giugno 2000. 2000
5. C. Minoia, R. Turci, G.B. Bartolucci, S. Signorini, P. Apostoli:
Progressi nella valutazione del rischio espositivo da chemioterapici antiblastici. Convegno Nazionale, Centro Congressi Fondazione Salvatore Maugeri. Pavia, 14-15 ottobre 1999. 2000
6. C. Bonezzi, M. Buonocore: Dolori radicolari e pseudoradicolari:
indicazioni diagnostiche e terapeutiche. Centro Congressi Fondazione Salvatore Maugeri. Pavia, 4 maggio 2001. 2001
7. M. Buonocore, C. Bonezzi: Sindromi algodistrofiche: dall’inquadramento diagnostico al trattamento riabilitativo. Centro Congressi
Fondazione Salvatore Maugeri. Pavia, 17 maggio 2002. 2002
8. Simposio in occasione dell’80° compleanno del Prof. Paolo Pinelli: Funzioni nervose e processi mentali. Centro Congressi
Fondazione Salvatore Maugeri. Pavia, 16 dicembre 2001. 2003
9. A. Estraneo, L. Manzo, L. Santoro: Gestione e recupero del traumatizzato cranico. Sala Convegni dell’Ospedale G. Vietri - Larino
(CB), 24-26 ottobre 2002. 2003
7. “I Manuali della Fondazione Maugeri”.
Volumi pubblicati:
1. L. Bianchi, S. Nava, E. Zampogna: Manuale dei Metodi e delle
Procedure Fisioterapiche in Riabilitazione Respiratoria. 2002
2. E. Banco, B. Cattani, G. Fugazza: I disturbi di deglutizione. Opuscolo informativo per pazienti e familiari. 2002
3. M. Schmid, S. Compiano: Degenerazione maculare: nuove strategie. Informazioni utili a persone anziane con degenerazione
maculare. 2002
4. E. Zanotti, C. Bizzarri con la collaborazione di R. Grasso, L. Govoni, P. Mombaruzzo, M. Piran, L. Zocchi: Le malattie polmonari
croniche ostruttive: conoscere, curare, convivere. Manuale pratico per il paziente. 2004
5. Maugeri - Ricerca. I Laboratori di Ricerca della Fondazione Maugeri IRCCS. 2005
6. P. Pinelli, M. Gianesella: Introduzione alla NeuroPsicoCronometria di Veruno e Training della VOLONTÀ in Neuroriabilitazione.
With an Outline of Prefrontal processes in normal and pathological conditions. 2006
7. P. Pinelli, A. Giordano, M. Gianesella, N. Maffini - con prefazione
di R. Anchisi e un capitolo di L. Marchese: Training della Working
Memory. Processi binari e processi fuzzy nella logica e nel funzionamento cerebrale. 2006
8. G. Fizzotti, I. Giorgi, M. Manera, M. Marchioni, R. Mauri, A. Meneghini, O. Nervi, G. Olivieri, A. Saade, M. Secone - Presentazione di C. Pistarini: La mielolesione: conoscerla e viverla. 2007
9. G. Majani, A. Pierobon, A. Giardini, S. Callegari: Valutare e favorire l’aderenza alle prescrizioni in riabilitazione cardiologica e
pneumologica. 2007
10. P. Ceriana, I. Springhetti: La cannula tracheotomica. Istruzioni
per l’uso. 2007
11. P. Pinelli - con prefazione di G. Berlucchi: Training della Working
Memory. Analisi dei fattori influenti su vari tipi di sequenze. 2007
12. P. Pinelli: Neurosequenze. L’Io, il suo ruolo, i suoi recuperi. 2007
13. A. Mezzani, F. Cacciatore, P. Giannuzzi. Manuale delle metodiche
e delle procedure di Riabilitazione Fisica in Cardiologia. 2007
14. P. Preti & D. Miotti. Le Cure Palliative nel paziente oncologico.
Manuale Pratico. 2008
15. E. Galante, A. Petrolati, A. Tralli, C. Forlani, G. Grioni: Il progressivo deterioramento cognitivo nella demenza. Semplici suggerimenti per la stimolazione cognitiva a domicilio. 2010
16. P. Pinelli, R. Colombo, M. Gianesella, I. Napolitano, A. Mazzone,
A. Patriarca. Diagnostica funzionale in neuroriabilitazione. La
prova di 100 reazione Self-rated e l’inibizione della risposta. 2010
17. Maugeri - Ricerca. I Laboratori di Ricerca Sperimentale della
Fondazione Maugeri IRCCS. 2010
18. Manuale per il paziente operato di protesi d’anca. A cura della Divisione di Recupero e Rieducazione Funzionale. 2010
19. C. Opasich e M. Zambelli: Arteriopatia arti inferiori. AOCP. Manuale pratico per il paziente. 2011
20. E. Zanotti, C. Bizzarri, con il contributo di G. Majani e con la collaborazione di S. Bagliani, M. Biglieri, L. Govoni, R. Grasso, P.
Mombaruzzo, L. Zocchi. Ossigenoterapia. Compendio di conoscenza e curiosità. 2011
21. “Il Viaggio”. Formazione per il caregiver del paziente con Grave
Cerebrolesione Acquisita. Equipe Riabilitativa Istituto Scientifico
di Montescano. 2011
22. Veronica Bruno, Diego Sparpaglione: I disturbi di deglutizione.
Come aiutare i pazienti: note per familiari ed assistenti. 2012
23. AA.VV. Dedicato ai familiari che assistono un malato in cure palliative. Suggerimenti, informazioni, supporto. Aspetti tecnico-pratici. 2013
8. “Monaldi Archives for Chest Disease”, Pulmonary Medicine and
Rehabilitation Series (Rivista scientifica internazionale di Riabilitazione respiratoria) e Cardiac Rehabilitation and Prevention Series
(Rivista scientifica internazionale di Cardiologia riabilitativa).
9. “Giornale Italiano di Medicina del Lavoro ed Ergonomia”,
Rivista trimestrale di Prevenzione, Patologia, Ergonomia e Riabilitazione e Supplemento di Psicologia Applicata alla Medicina del Lavoro
e della Riabilitazione.
Instructions to Authors
Monaldi Archives for Chest Disease is a scientific journal of the Fondazione Salvatore Maugeri IRCCS, Scientific Institute, Pavia, Italy, and its Cardiac Rehabilitation and Prevention
Series is the official journal of the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR - Associazione Italiana di Cardiologia
Riabilitativa e Preventiva). It publishes in English and Italian original papers on clinical research and health management related to cardiopulmonary medicine and rehabilitation. The
journal will also accept well written articles of current opinion, reviews, controversy, educational papers and letters to the editor in pertinent areas of interest. All manuscripts must be
written in accordance with the following Instructions to authors, and will be evaluated by expert Reviewers, selected by the Editors, and eventually accepted on the basis of priority
and consensus criteria established by the Reviewers and the Editors.
Cardiology manuscripts should be mailed to the Editorial Office of Monaldi Archives for Chest Disease - Cardiac Series: [email protected]
Pulmonary manuscripts should be mailed to:
Centro Studi, IRCCS Fondazione Salvatore Maugeri, Via Salvatore Maugeri 4, I-27100 Pavia, Italia, E-mail: [email protected]
Journal Sections
l.
2.
3.
4.
5.
6.
Editorials: invited articles or brief editorial comment that represent the opinion of recognized leaders in cardiopulmonary medicine and rehabilitation.
Reviews: invited articles by recognized authorities on special topics of general interest. Independent submissions will be considered.
Original Articles: original experimental and clinical studies are included in this category.
Case Reports: presentation of a clinical case which may suggest novel working hypotheses, with a short discussion of the pertinent literature.
Study Protocols: novel study protocols or working hypotheses supported or suggested by recent observations or by a critical review of the literature.
Letters to the Editor: these should deal with topics of immediate scientific interest or discuss previously published articles.
Special Instructions only for the Pulmonary Section
l. Case Reports: Abstract (unstructured): max. 200 words, Main manuscript (introduction, case report and discussion): max. 800 words. Figures and Tables: max. 3. References: max. 20.
Keywords: 3-5.
2. Images of Chest Diseases: These succint submissions couple a interesting, novel, or highly educational images with text designed to briefly highlight the clinical context and to
highlight the pertinent information displayed by the visual. Text (unstructured): max 300 word. Figures and Tables: max. 3. References: max. 3. Keywords: 3-5.
General Instructions
Manuscripts must be typed double-spaced on paper of A4 format, on one side only, with 3 cm margins on all sides. Manuscripts may be sent by e-mail.
Manuscripts must be accompanied by a covering letter addressed to the Editor, in which the corresponding author must indicate the section in which the paper should be published and
state that the paper is not under consideration by any other journal contemporaneously and that it has not been accepted for publication elsewhere, in any language, except as an abstract.
The author may suggest the names of Reviewers.
The manuscript must be arranged as follows: a) title page, b) abstract and keywords (in English and Italian language, on separate pages), c) text, d) acknowledgments, e) references, f)
tables, g) figure legends, h) figures. Pages should be numbered consecutively, beginning with the title page.
Upon notification of the article’s acceptance for publication, all authors will be required to sign a conflict of interest statement (form provided by the Editorial Office) and a copyright
declaration transferring all rights to PI-ME Tipografia s.r.l. No part of the published material can be reproduced without written permission from the Publisher.
In order to maintain uniformity of style the Editorial Office reserves the right to make, where necessary, linguistic alterations to the manuscript; these will be sent to the authors for
approval on revision of proofs.
Title Page
The title, authors’ names (full names) and a short running title less than 45 characters (including spaces) should be typed on the title page. The name and address of the institution from
which the work originated, plus information about grants should also be specified. The full name, postal address with zip code, telephone, fax number and e-mail of the author to whom
communications, proofs, and requests for reprints should be sent must be typed at the bottom.
Abstract
Reviews, original articles, study protocols and case reports should be accompanied by an abstract (in English and Italian) of no more than 300 words. Abbreviations (except for standard
units of measurement and chemical symbols) should not be used. A list of 3 to 6 keywords should be typed at the end of abstract.
For original articles, a structured abstract should be provided presenting essential data in four paragraphs as follows: Background and Aims, Methods, Results, Conclusions. Complete
sentences should be used. All data provided in the abstract must also appear in the manuscript text or tables.
Text
A list of abbreviations or acronyms such as ECG, LVH, CAD, AMI and their definition must be provided on a separate page. Abbreviations of measurements (e.g. mm, kcal) and
chemical symbols should be according to the Uniform Requirements for Manuscripts Submitted to Biomedical Journal Editors published in Ann Intern Med 1982; 96: 766-71 and BMJ
1982; 284: 1766-70.
All references, figures and tables must be cited in the text in numerical order using arabic numerals.
The text of original articles should be subdivided into the following sections: Introduction, Methods, Results and Discussion.
References
References should be typed double spaced, should begin on a separate sheet and be numbered in the order of appearance in the text. List all authors if 6 or fewer, otherwise list the first
3 and add et al. Abbreviations of journals should conform to those used in Index Medicus, National Library of Medicine. The style and punctuation of references should follow the
examples below:
Journal article:
Fornai E, Desideri M, Pistelli F, et al. Smoking reduction in smokers compliant to a smoking cessation trial with nicotine patch. Monaldi Arch Chest Dis 2001; 56: 5-10.
Chapter in a Book:
Lown B. Cardiovascular collapse and sudden death. In: Braunwald E, ed. Heart disease. A textbook of cardiovascular medicine. Philadelphia, FA: WB Saunders, 1980: 778-817.
Book:
Pujadas G. Coronary angiography. New York, NY: McGraw-Hill, 1980: l0.
Abstract:
Ferrari R, Nayler WG. The protective effect of nifedipine on ischemic and reperfused heart muscle. (abstr) In Abstracts of the International Congress of Pharmacology. Tokyo, 1981:
285.
Figures
Figures should be in electronic format (.jpg, .tif, .gif) and the name of the file must contain the figure number (e.g. Figure1.jpg). Figures should not be larger than 22x28 cm (8.5 x 11
inches). The lettering on the figures should be of sufficient sizes to withstand reduction. Most graphs will be reduced to the width of one column. All line drawings should be in black.
Figure title and caption material must appear in the legend, not on the figure, on pages separate from the text. All abbreviations should be explained in the legend in alphabetical order.
Tables
Tables should be typed on separate pages with the table number and title indicated at the top of the table (aligned to left). Abbreviations should be listed and explained in a footnote in
alphabetical order.
Reprints
Articles will be printed free of charge. Reprints may be ordered from PI-ME Tipografia Editrice s.r.l., Via Vigentina 136A, I-27100 Pavia, Italy; Tel.: +39 0382 572169; Fax: +39 0382
572102; E-mail: [email protected]. The Journal is available for free on the web at: http://archest.fsm.it
MONALDI
INTERNATIONAL JOURNAL FOR CARDIOPULMONARY MEDICINE AND REHABILITATION
Volume 79, Number 3-4
2013
Meeting Calendar
...........................................................................................................................
107
Clinical
Pharmacology
F. Novelli, F. Costa, M. Latorre, L. Malagrinò, A. Celi, B. Vagaggini P. Paggiaro:
Tiotropium: a new therapeutic option in asthma ....................................................
109
Original articles
M. Justine, F. Tahirah, V. Mohan: Health-related quality of life, lung function
and dyspnea rating in COPD patients ......................................................................
116
N. Barbarito, E. De Mattia: Grading the severity of obstruction in patients
with Chronic Obstructive Pulmonary Disease and morbid obesity ......................
121
N. Facciolongo, R. Piro, F. Menzella, M. Lusuardi, M. Salio, L. Lazzari Agli,
M. Patelli: Training and practice in bronchoscopy. A national survey in Italy ....
128
M. Irfan, F. Thiavalappil, J. Nagaraj, T.H. Brown, D. Roberts, L. Mcknight,
N.K. Harrison: Tuberculous pancreatitis complicated by ruptured splenic
artery pseudoaneurysm ..............................................................................................
134
H. Bhardwaj, B. Bhardwaj, P.V. Carlile: Recurrent pneumomediastinum
in a patient with rheumatoid arthritis ......................................................................
136
S. Katsenos, M. Nikolopoulou: Intramedullary thoracic spinal metastasis
from small-cell lung cancer ........................................................................................
140
Images of Chest
Diseases
A. Andreani, G. Cappiello, M. Valli, M. Giovannini: TBNA for the treatment
of non complicated bronchogenic cyst ......................................................................
143
Books
...........................................................................................................................
146
Author and
keyword indexes
...........................................................................................................................
147
TB Corner
Case reports
ISSN 1122-0643
PI-ME PRESS, PAVIA (ITALY)

archives for chest disease - Fondazione Salvatore Maugeri

Transcript

Documenti analoghi

Assessment of Community care services appropriateness using the

REAL SOCIEDAD CANINA DE ESPAÑA

Summary of all agents

selected reports - erbeofficinali.org

Practice parameters for sublingual immunotherapy

Read PDF

Pulmonary Rehabilitation in Chronic (Obstructive) Pulmonary Disease

A. Dovio

parte1