We read with great curiosity the article by Garcia-Arcos et al. (1)
suggesting nicotine as a novel causative factor for the onset and
progression of COPD/emphysema. Chronic nicotine exposure from nebulized e-
liquid (in toxic concentrations) appears to modify inflammation, ion
conductance and mucociliary function in HBECs and induces airway hyper-
reactivity and air space enlargement in A/J...
We read with great curiosity the article by Garcia-Arcos et al. (1)
suggesting nicotine as a novel causative factor for the onset and
progression of COPD/emphysema. Chronic nicotine exposure from nebulized e-
liquid (in toxic concentrations) appears to modify inflammation, ion
conductance and mucociliary function in HBECs and induces airway hyper-
reactivity and air space enlargement in A/J mice.
To reach any meaningful conclusion about toxicity of nicotine, it is
important that the toxic effect has to be compounded with that of an
equivalent dose from cigarette smoking or vaping. Because a 60-kg person
absorbs approximately 1 mg of nicotine (0.017 mg nicotine/kg bodyweight)
from smoking one cigarette (2), the max dose of nicotine equivalent to
smoking 25 cigarettes per day (i.e. the mean level of cigarette
consumption in the US (3)) should be 0.017 x 25 cigarettes = 0.425 ? 0.43
mg nicotine/kg bodyweight in humans. In this study, A/J mice were whole
body exposed daily to 0.4 mL of an e-liquid containing 18 mg/mL nicotine
(i.e. 7.2 mg). If we assume that A/J mice nicotine intake is only 10%
(best case scenario), total daily absorption is 0.72 mg, which nearly
doubles the nicotine/kg bodyweight in humans. Moreover, when we consider
that the average adult A/J mice is about 25 g of weight, then the daily
dose exceed by approx. 80 times that of a 25 cigarette/day smoker. This
has nothing to do with realistic dosing and essentially equates acute
intoxication.
Previous animal studies have shown contradictory results. In
particular, when using different mice strain, it is not possible to
replicate features of COPD in a nicotine-dependent manner. Interestingly,
chronic intraperitoneal injections of much lower concentrations of
nicotine have been shown to induce similar air space enlargement in A/J
mice (4). Therefore, it is likely that the A/J mice has an innate
predisposition at developing emphysematous features when challenged with a
range of noxious stimuli.
Moreover, given that it is well established that the protease:anti
protease ratio is the central component of our understanding of
emphysema.This
hypothesis is also at variance with the epidemiological evidence: for
example biomass fuel combustion is a well known non nicotine-dependent
causative factor for COPD (5,6)
References:
1. Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B,
Cummins N, Eden E, Grosche A, Salathe M, Foronjy R. Chronic electronic
cigarette exposure in mice induces features of COPD in a nicotine-
dependent manner. Thorax. 2016 Aug 24. pii: thoraxjnl-2015-208039. doi:
10.1136/thoraxjnl-2015-208039. [Epub ahead of print]
2. Benowitz NL, Hukkanen J, Jacob P., 3rd Nicotine chemistry,
metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009:29-60.
3. American Lung Association; Trends in Tobacco Use [Internet] 2011
Jul; Available from: http://www.lung.org/finding-cures/our-research/trend
-reports/Tobacco-Trend-Report.pdf.
4. Iskandar AR, Liu C, Smith DE, Hu KQ, Choi SW, Ausman LM, Wang XD.
?-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and
inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice.
Cancer Prev Res (Phila). 2013 Apr;6(4):309-20.
5. Kurmi OP, Semple S, Simkhada P, Smith WC, Ayres JG. COPD and
chronic bronchitis risk of indoor air pollution from solid fuel: a
systematic review and meta-analysis. Thorax. 2010 Mar;65(3):221-8.
6. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-
smokers. Lancet. 2009 Aug 29;374(9691):733-43.
We thank Vanfleteren and colleagues for their comments on our
recently published equivalence trial comparing home-based and centre-based
pulmonary rehabilitation in people with stable chronic obstructive
pulmonary disease (COPD).[1] We agree that there is a compelling need to
increase the implementation, utilization and delivery of pulmonary
rehabilitation.[2] We welcome further discussion regarding the role of new
pulmon...
We thank Vanfleteren and colleagues for their comments on our
recently published equivalence trial comparing home-based and centre-based
pulmonary rehabilitation in people with stable chronic obstructive
pulmonary disease (COPD).[1] We agree that there is a compelling need to
increase the implementation, utilization and delivery of pulmonary
rehabilitation.[2] We welcome further discussion regarding the role of new
pulmonary rehabilitation models, such as our home-based model, in
achieving these aims.
Despite the best efforts of clinicians and the plethora of evidence
supporting its benefits, only a small minority of people with COPD
currently undertake pulmonary rehabilitation.[2] Increasing financial
support for existing programmes and establishing new centre-based
programmes may be important to improve capacity and reduce waiting times.
However these strategies cannot comprehensively address the well
documented barriers of travel, transport, inconvenient location,
inconvenient timing and disruption to routines that prevent debilitated
people with COPD from engaging in centre-based programmes.[3] In
Australia, like many large countries, we must also address health
inequalities related to geography and low population density, with limited
pulmonary rehabilitation options available for those living in remote
areas where the burden of lung disease is high. Our home-based model was
designed to enhance access to pulmonary rehabilitation for patients who
cannot engage in the traditional centre-based model.
As noted by Vanfleteren and colleagues, our study recruited 166
people with COPD who had been referred to pulmonary rehabilitation. We
considered this to be a highly relevant target population. A referral to
pulmonary rehabilitation is no guarantee of programme attendance or
completion; in fact a recent audit in the United Kingdom showed that one
in three of those referred to centre-based pulmonary rehabilitation do not
ever attend an assessment, and 39% of those who attend an assessment do
not complete the programme.[4] In our study, programme completion was
higher in those who underwent home-based pulmonary rehabilitation than in
those who participated in centre-based programmes. Attaining the benefits
of pulmonary rehabilitation is dependent on achieving a sufficient
rehabilitation 'dose'; in our study, patients who completed a programme
(regardless of location) had fewer hospitalisations in the year following
pulmonary rehabilitation.[1] We also found that 54 patients (18% of those
assessed) declined to participate in the trial because they wished to
attend a centre-based programme. It was important to document the
preference of this group who are already motivated to attend centre-based
pulmonary rehabilitation. The home-based model does not remove such an
opportunity for those who wish to engage in centre-based care.
Pulmonary rehabilitation is a core component of integrated and
comprehensive care for people with COPD.[5] We agree with Vanfleteren and
colleagues that this goes beyond exercise and education; it includes (but
is not limited to) problem solving, goal setting, skill acquisition,
decision making and collaboration with health professionals.[5] Our home-
based programme was designed to incorporate these features. Weekly
telephone calls were delivered by highly experienced pulmonary
rehabilitation physiotherapists who were trained in motivational
interviewing. Consistent with a patient-centred approach to care,
participants were encouraged to identify the health problems that were
most relevant to them and to set appropriate health goals. Commonly set
goals related to weight loss, management of chest infections and smoking
cessation. Where relevant, the physiotherapist made a referral to an
appropriate member of the multidisciplinary team. Unexpectedly and
importantly, some patients actively addressed their goals by finding
services that better suited them outside the pulmonary rehabilitation
team, including community based health services that were closer to their
homes. We also note that anxiety and depression decreased in both home-
based and centre-based groups over the trial, with no difference according
to programme location.[1] Our participants were typical of those seen in
many centre-based pulmonary rehabilitation programmes, with a median of
four comorbidities. However, we acknowledge that some patients with
complex co-existing medical conditions may be more suitable for a
supervised, centre-based programme. The severity and impact of
comorbidities should be assessed prior to commencing pulmonary
rehabilitation as part of a comprehensive patient assessment,[6] allowing
patients and clinicians to make sound decisions about the best location of
care.
We support the authors' call to embrace 'P4 medicine' which is
Predictive, Preventive, Personalized and Participatory.[7] This model
places strong emphasis on the participation of the individual, empowering
them to make informed choices about their health care. If participation in
pulmonary rehabilitation is to become a reality for the majority who need
it, more choices are necessary. We look forward to a time when people with
COPD can choose from a suite of evidence-based models of pulmonary
rehabilitation, in order to optimise access to this important treatment
and to ensure its benefits are reaped by all patients with COPD rather
than a few.
References
1. Holland AE, Mahal A, Hill CJ, et al. Home-based rehabilitation for
COPD using minimal resources: a randomised, controlled equivalence trial.
Thorax, published online Sept 26th 2016. doi: 10.1136/thoraxjnl-2016-
208514.
2. Rochester CL, Vogiatzis I, Holland AE, et al. An Official American
Thoracic Society/European Respiratory Society Policy Statement: Enhancing
Implementation, Use, and Delivery of Pulmonary Rehabilitation. Am J Respir
Crit Care Med 2015;192:1373-86.
3. Keating A, Lee A, Holland AE. What prevents people with chronic
obstructive pulmonary disease from attending pulmonary rehabilitation? A
systematic review. Chronic Respiratory Disease 2011;8:89-99.
4. Steiner M, Holzhauer-Barrie J, Lowe D, et al. Pulmonary
Rehabilitation: Steps to breathe better. National Chronic Obstructive
Pulmonary Disease (COPD) Audit Programme: Clinical audit of Pulmonary
Rehabilitation services in England and Wales 2015. National clinical audit
report. London: Royal College of Physicians, 2016.
5. Wagg K. Unravelling self-management for COPD: what next? Chronic
Respiratory Disease 2012;9:5-7.
6. Spruit MA, Singh SJ, Garvey C, et al. An official American
Thoracic Society/European Respiratory Society statement: key concepts and
advances in pulmonary rehabilitation. American Journal of Respiratory and
Critical Care Medicine 2013;188:e13-64.
Based on their findings from a prospective, randomized, controlled
equivalence trial, Holland and colleagues conclude that a 8-week home-
based rehabilitation model produced short-term clinical outcomes that were
equivalent to a center-based pulmonary rehabilitation program.[1]
To their credit, the authors' recruitment and statistical design were of
high quality, as were the outcome measures used. We acknowledge that the...
Based on their findings from a prospective, randomized, controlled
equivalence trial, Holland and colleagues conclude that a 8-week home-
based rehabilitation model produced short-term clinical outcomes that were
equivalent to a center-based pulmonary rehabilitation program.[1]
To their credit, the authors' recruitment and statistical design were of
high quality, as were the outcome measures used. We acknowledge that the
home-based model with exercise training and education on self-management
partially fits with the needs of patients with COPD who are unable and/or
reluctant to attend a formal hospital-based pulmonary rehabilitation
program.[2, 3] Then again, we believe that some issues need additional
discussion. First, the home-based intervention as studied by Holland and
colleagues used only unsupervised exercise training and education; other
core components of pulmonary rehabilitation, like occupational therapy,
nutritional modulation, and psychological counseling were lacking.[4]
Therefore, needs and extra-pulmonary features of individual patients, such
as symptoms of anxiety and depression (present in one-fifth of the current
study sample), an abnormal body composition (in the current study sample
about two-thirds of the patients were overweight or obese) and/or other
medical comorbidities (one-fifth of the current sample had 4 or more
reported comorbidities) cannot adequately be dealt with during a home-
based intervention. Moreover, as patients experience a complex health
behavior change process during pulmonary rehabilitation, we should not
underestimate the major contributing role of skilled healthcare
professionals that are part of the dedicated pulmonary rehabilitation
team.[5] Therefore, the call from ATS/ERS[2] to increase the financial
support of existing comprehensive hospital-based pulmonary rehabilitation
programs is still very valid. This also applies to the call to start new
programs, which will reduce the time and distance to travel from home to
hospital. Moreover, this approach also takes into consideration the desire
to exercise within a peer group together with the possibility for social
interaction.[6] Remarkably, 54 patients (80% of the patients who did not
consent) did not volunteer to participate in this RCT as they wanted to
undertake rehabilitation in a hospital-based program. Indeed, the patients
that volunteered to participate in the study of Holland and colleagues
were all on the waiting list for a hospital-based pulmonary rehabilitation
program.
Whether and to what extent home-based exercise interventions are safe,
feasible and effective in complex patients with COPD remains unanswered.
As the complexity of COPD patients increases, also the complexity of
rehabilitative interventions needs to increase. For example, patients with
chronic respiratory failure may need supervised exercise training with non
-invasive ventilation; in severely underweight patients close supervision
and interaction between physiotherapist and dietician is required to avoid
further weight loss during rehabilitation; smoking cessation programs are
an important integrated part of rehabilitation; subjects with frequent
exacerbations or recovering from a severe exacerbation requiring
hospitalization need close monitoring. Indeed, Greening and colleagues
already showed that an early, unsupervised, home-based exercise training
program is not the right care at the right time at the right place for
patients with chronic respiratory disease recovering from an acute
hospital admission.[7]
Interestingly, patients included in the hospital-based rehabilitation
group only attended 8 of the 16 scheduled sessions (range 0-16). Half of
the patients did not qualify as a program completer, defined as
undertaking 70% of the planned sessions. This may, at least in part,
explain the disappointing mean improvements in exercise capacity and
disease-specific quality of life. The authors reason that the presence of
medical comorbidities may be one of the main reasons for the low
completion rate. Nevertheless, our group[8] and others[9] have shown that
multimorbid COPD patients can complete a multidisciplinary hospital-based
pulmonary rehabilitation program and can achieve clinically relevant
improvements in exercise capacity and health status. The external validity
of the current findings for patients with long-term oxygen therapy (LTOT)
and/or very severe dyspnea is limited, as less than 5% of the patients
were LTOT users and/or scored grade 4 on the modified Medical Research
Council dyspnea scale.
Towards the future, we all recognize the need to increase the
implementation, utilization and delivery of pulmonary rehabilitation.[2]
There are numerous possible solutions, including, but not limited to 1)
formal training of healthcare professionals in the science, process and
benefits of pulmonary rehabilitation; 2) increase payer awareness and
knowledge of pulmonary rehabilitation; 3) increase patient awareness and
knowledge of pulmonary rehabilitation; 4) to improve patients access to
pulmonary rehabilitation by augmenting program commissioning through
increased sustainable payer funding, and creating new programs in
geographical areas where demand exceeds capacity; and 5) developing and
investigating novel program models that will make pulmonary rehabilitation
more accessible to patients.[2] The home-based approach fits with the last
mentioned possible solution. Then again, it seems reasonable to state that
a hospital-based integrated program with a skilled and dedicated
interdisciplinary pulmonary rehabilitation team may be more suitable for
COPD patients who truly need a comprehensive program due to their severely
impaired pulmonary function, numerous extra-pulmonary features and/or
medical comorbidities than a home-based model.
Embracing the principles of P4 medicine (e.g., the right patient, for the
right treatment, for the right dose, for the right outcome), we must
consider that pulmonary rehabilitation programs need to evolve towards
personalized medicine, or precision rehabilitation programs, including the
right setting for the intervention. An integrated assessment of the
patient's physical, psychological, and social complexities, will provide
us with the necessary information about which approach is most feasible
and effective for the individual patient with COPD.
References
1. Holland, A.E., et al., Home-based rehabilitation for COPD using
minimal resources: a randomised, controlled equivalence trial. Thorax,
2016.
2. Rochester, C.L., et al., An Official American Thoracic
Society/European Respiratory Society Policy Statement: Enhancing
Implementation, Use, and Delivery of Pulmonary Rehabilitation. Am J Respir
Crit Care Med, 2015. 192(11): p. 1373-86.
3. Spruit, M.A., et al., Differences in content and organisational
aspects of pulmonary rehabilitation programmes. Eur Respir J, 2014. 43(5):
p. 1326-37.
4. Spruit MA, S.S., Garvey C, et al, American Thoracic
Society/European Respiratory Society statement on pulmonary
rehabilitation. American journal of respiratory and critical care
medicine, 2013. in press.
5. Meis, J.J., et al., A qualitative assessment of COPD patients'
experiences of pulmonary rehabilitation and guidance by healthcare
professionals. Respir Med, 2014. 108(3): p. 500-10.
6. Hogg, L., et al., People with COPD perceive ongoing, structured
and socially supportive exercise opportunities to be important for
maintaining an active lifestyle following pulmonary rehabilitation: a
qualitative study. J Physiother, 2012. 58(3): p. 189-95.
7. Greening, N.J., et al., An early rehabilitation intervention to
enhance recovery during hospital admission for an exacerbation of chronic
respiratory disease: randomised controlled trial. BMJ, 2014. 349: p.
g4315.
8. Mesquita, R., et al., Objectively identified comorbidities in
chronic obstructive pulmonary disease: impact on pulmonary rehabilitation
outcomes. Eur Respir J, 2015.
9. Crisafulli, E., et al., Role of comorbidities in a cohort of
patients with COPD undergoing pulmonary rehabilitation. Thorax, 2008.
63(6): p. 487-92.
In a recent cohort study investigating tuberculin skin test (TST) in
relation to interferon gamma release assay (IGRA) responses in exposed
children and relating responses to previous BCG immunisation the authors
reported a reduced sensitivity of TST using IGRA as a reference standard
at all induration thresholds for young children (less than 5 years old)
who had a previous BCG immunisation compared to those who didn't(1...
In a recent cohort study investigating tuberculin skin test (TST) in
relation to interferon gamma release assay (IGRA) responses in exposed
children and relating responses to previous BCG immunisation the authors
reported a reduced sensitivity of TST using IGRA as a reference standard
at all induration thresholds for young children (less than 5 years old)
who had a previous BCG immunisation compared to those who didn't(1). The
authors did not discuss this finding, which has potentially important
implications for the choice of screening test for latent Mycobacterium
tuberculosis (MTB) infection in young children at high risk of developing
active tuberculosis. The authors findings confirm results of a previous
retrospective analysis of sensitivity of TST induration thresholds for
detection of MTB infection measured against IGRA as reference standard in
2796 children where for all TST thresholds sensitivity was lower in BCG
immunised children with a statistically significantly lower sensitivity
documented for the 10mm induration threshold (2). This finding is
compatible with two hypotheses:
1. BCG immunisation reduces infection (3) but the IGRA is more sensitive
in detection of infection and hence the TST appears less sensitive.
2. BCG induced clonal imprinting (previously termed "original antigenic
sin" phenomenon) where previous exposure to antigens (in this case
contained in BCG) leads to reinforcement of the immune reaction to these
antigens on re-exposure of the immune-system to similar antigens (MTB,
tuberculin) rather than a reaction to new antigens (specific for MTB or
tuberculin) not contained in the antigen mixture of the previous exposure.
This process has been found to be dependent on the action of the cytokine
IL-10 (4). IL-10 is hereby produced by non-antigen specific T-suppressor
cells (5). Future animal studies need to decide whether one of these
hypotheses can be confirmed. In the meantime IGRA needs to be employed to
help rule out MTB infection in young children.
References:
(1)Seddon JA et al. The impact of BCG vaccination on tuberculin skin test
responses in children is age dependent: evidence to be considered when
screening children for tuberculosis infection.Thorax 2016 0:thoraxjnl-2015
-207687v1-thoraxjnl-2015-207687; doi:10.1136/thoraxjnl-2015-207687
(2)Eisenhut M et al. Performance of Tuberculin Skin Test measured against
Interferon Gamma Release Assay as reference standard in
children.Tuberculosis Research and Treatment Volume 2014, Article ID
413459.
(3)Roy A et al. Effect of BCG vaccination against Mycobacterium
tuberculosis infection in children: systematic review and meta-
analysis.BMJ 2014;349:g4643 doi: 10.1136/bmj.g4643 (Published 5 August
2014)
(4)Liu XS, Xu Y, Hardy L, Khammanivong V, Zhao W, Fernando GJP, Leggatt
GR, Frazer IH. IL-10 Mediates Suppression of the CD8 T Cell IFN-response
to a Novel Viral Epitope in a Primed Host. The Journal of Immunology,
2003, 171: 4765-4772.
(5)Filaci G, Fravega M, Fenoglio D, Rizzi M, Negrini S, Viggiani R,
Indiveri F.Non-antigen specific CD8+ T suppressor lymphocytes. Clin Exp
Med. 2004 Oct;4(2):86-92.
with the greatest interest I have read the publication "Lung function
and airway obstruction: associations with circulating markers of cardiac
function and incident heart failure in older men--the British Regional
Heart Study" by Wannamethee et al. (Thorax 2016 71:526-534). Analyzing a
large database with 13 years of prospective follow up the authors conclude
that "reduced FEV1 reflecting airflow ob...
with the greatest interest I have read the publication "Lung function
and airway obstruction: associations with circulating markers of cardiac
function and incident heart failure in older men--the British Regional
Heart Study" by Wannamethee et al. (Thorax 2016 71:526-534). Analyzing a
large database with 13 years of prospective follow up the authors conclude
that "reduced FEV1 reflecting airflow obstruction is associated with
cardiac dysfunction and increased risk of incident HF".
Concerning the underlying pathophysiology the authors discussed "Airway
obstruction decreases expiratory flow rates and causes lung
hyperinflation, which is associated with decreased cardiac function and
may increase NT-proBNP.". While this is certainly appealing and grounded
on previous publications, the concept of neurohumoral activation might
contribute to the observed findings.
With a variety of methods we and others described striking
neurohumoral activation in patients with COPD (1) (2) (3). From patients
with heart failure it is well known, that neurohumoral activation is
central in the pathophysiology of this disease (4). Indeed, ? blocker and
angiotensin receptor blocker reduce mortality and morbidity by their
impact on sympathetic and neurohumoral activation in heart failure (4).
Thus it is intriguing to speculate that airway obstruction in COPD
aggravates heart failure by sympathetic activation.
Yours sincerely
Stefan Andreas
References
1. Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral activation as
a link to systemic manifestation of chronic lung disease. Chest 2005; 128:
3618-3624.
2. Raupach T, Bahr F, Herrmann P, Luethje L, Heusser K, Hasenfuss G,
Bernardi L, Andreas S. Slow breathing reduces sympathoexcitation in COPD.
Eur Respir J 2008; 32: 387-392.
3. Luthje L, Raupach T, Michels H, Unsold B, Hasenfuss G, Kogler H,
Andreas S. Exercise intolerance and systemic manifestations of pulmonary
emphysema in a mouse model. Respiratory research 2009; 10: 7.
4. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. The
New England journal of medicine 1999; 341: 577-585.
F.Guarino and R.Polosa
We read with great curiosity the article by Garcia-Arcos et al. (1) suggesting nicotine as a novel causative factor for the onset and progression of COPD/emphysema. Chronic nicotine exposure from nebulized e- liquid (in toxic concentrations) appears to modify inflammation, ion conductance and mucociliary function in HBECs and induces airway hyper- reactivity and air space enlargement in A/J...
We thank Vanfleteren and colleagues for their comments on our recently published equivalence trial comparing home-based and centre-based pulmonary rehabilitation in people with stable chronic obstructive pulmonary disease (COPD).[1] We agree that there is a compelling need to increase the implementation, utilization and delivery of pulmonary rehabilitation.[2] We welcome further discussion regarding the role of new pulmon...
Based on their findings from a prospective, randomized, controlled equivalence trial, Holland and colleagues conclude that a 8-week home- based rehabilitation model produced short-term clinical outcomes that were equivalent to a center-based pulmonary rehabilitation program.[1] To their credit, the authors' recruitment and statistical design were of high quality, as were the outcome measures used. We acknowledge that the...
In a recent cohort study investigating tuberculin skin test (TST) in relation to interferon gamma release assay (IGRA) responses in exposed children and relating responses to previous BCG immunisation the authors reported a reduced sensitivity of TST using IGRA as a reference standard at all induration thresholds for young children (less than 5 years old) who had a previous BCG immunisation compared to those who didn't(1...
Dear Editor,
with the greatest interest I have read the publication "Lung function and airway obstruction: associations with circulating markers of cardiac function and incident heart failure in older men--the British Regional Heart Study" by Wannamethee et al. (Thorax 2016 71:526-534). Analyzing a large database with 13 years of prospective follow up the authors conclude that "reduced FEV1 reflecting airflow ob...
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