We use cookies to improve our service and to tailor our content and advertising to you.More infoYou can manage your cookie settings via your browser at any time. To learn more about how we use cookies, please see our cookies policy.
Dear Editor, We thank Dr Mansell for her comments regarding our
recently published trial. [1] We agree that there are different phenotypic
variations within the obesity hypoventilation syndrome (OHS), although it
remains to be determined whether OHS with co-existent obstructive sleep
apnoea (OSA) responds differently to treatment in comparison to OHS
without OSA. [2] Acknowledging that the presence and severity of OSA in...
Dear Editor, We thank Dr Mansell for her comments regarding our
recently published trial. [1] We agree that there are different phenotypic
variations within the obesity hypoventilation syndrome (OHS), although it
remains to be determined whether OHS with co-existent obstructive sleep
apnoea (OSA) responds differently to treatment in comparison to OHS
without OSA. [2] Acknowledging that the presence and severity of OSA in
OHS may impact on the response to CPAP or non-invasive ventilation (NIV),
clinical definitions and clinical trials in OHS have defined OHS as
obesity (BMI > 30 kg/m2) with chronic hypercapnia, irrespective of the
degree of co-existent OSA. [3] The degree of OSA in our study is in
keeping with the severity of OSA in previous clinical trial of OHS, [4,
5], although the degree of obesity, severity of baseline hypercapnia and
degree of pulmonary function impairment was substantially greater. All
three randomised controlled trials have found similar outcomes for CPAP
and NIV, and so do not support the routine use of NIV for all patients
with OHS. The predominant phenotype appears to be OHS in conjunction with
severe OSA, which comprised more than 70% of participants in the recent
manuscript from the Spanish Sleep Network. [6] In this subgroup they found
NIV provided greater improvement in respiratory failure and symptoms than
life style measure in OHS without OSA, however further results are awaited
to determine whether CPAP and NIV have different impacts in this subgroup.
We chose clinically significant outcomes and predictors of increased
mortality (hospital admission, persisting respiratory failure, non-
adherence and quality of life) as outcome measures rather than
polysomnographic variables. We did, however, use polysomnography to
titrate CPAP and NIV at the commencement of the project in order to
eliminate respiratory events and minimise persisting hypoxaemia and
hypoventilation. In terms of demonstrating laboratory effectiveness of
therapy, none of the participants required the addition of nocturnal
oxygen for persisting hypoxaemia on treatment, in contrast to other
trials, although we did not measure the apnoea hypopnoea index on the
final study settings. [5] We agree that assessment of long term outcomes,
including mortality is important and 12 month outcome data from this
cohort will be available shortly.
Some of the participants in our trial had treatment prior to trial
randomisation. The trial recruited OHS participants during acute hospital
admissions with respiratory failure as well as from ambulatory settings
that were the focus of previous trials. The design allowed for initial
treatment with NIV for correction of acute respiratory acidosis prior to
randomisation to CPAP or NIV. We acknowledge that this may have
influenced baseline measures, however it was not considered ethical to
withhold treatment in acutely unwell patients and there was no difference
in prior treatment use between the groups. Given the results from the
three published randomised controlled trials that have found similar
outcomes for CPAP and NIV in OHS, and in line with recent editorial
opinion, we believe that it is reasonable to use CPAP for treatment of OHS
following initial stabilisation of acute respiratory acidosis, with
careful observation of the response. [7], Further evidence may influence
optimal therapy in different OHS subgroups.
1.Howard ME, Piper AJ, Stevens B, et al. A randomised controlled trial of
CPAP versus non-invasive ventilation for initial treatment of obesity
hypoventilation syndrome. Thorax. 2016. Epub 2016/11/18.
2.Ojeda Castillejo
E, de Lucas Ramos P, Lopez Martin S, et al. Noninvasive mechanical ventilation in patients with obesity hypoventilation syndrome. Long-term outcome and prognostic factors. Arch Bronconeumol. 2015;51(2):61-8. Epub 2014/04/08.
3.Mokhlesi B, Tulaimat A. Recent Advances in Obesity
Hypoventilation Syndrome. Chest.2007;132(4):1322-36.
4.Piper AJ, Wang D, Yee BJ, et al. Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal
desaturation. Thorax. 2008;63(5):395-401. Epub 2008/01/22.
5.Masa JF,
Corral J, Alonso ML, et al. Efficacy of Different Treatment Alternatives
for Obesity Hypoventilation Syndrome. Pickwick Study. Am J Respir Crit
Care Med. 2015;192(1):86-95. Epub 2015/04/29.
6.Masa JF, Corral J,
Caballero C, et al. Non-invasive ventilation in obesity hypoventilation
syndrome without severe obstructive sleep apnoea. Thorax. 2016;71(10):899-
906. Epub 2016/07/14.
7.Noda JR, Masa JF, Mokhlesi B. CPAP or non-invasive
ventilation in obesity hypoventilation syndrome: does it matter which one
you start with? Thorax. 2017. Epub 2017/01/29.
Conflict of Interest:
MEH reports grants from Resmed Foundatio & non-financial support from Philips Respironics. AJP reports grants from Resmed Foundation, personal fees from ResMed, personal fees from Philips Respironics & personal fees from SenTec. DM reports grants from Resmed Foundation, National Health & Medical Research Council & Victoria Neurotrauma Initiative. BS, AEH, BJY, ED, ATB, DF, CB, LR, NS, DH and DJB report a grant from Resmed Foundation.
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is in...
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is increasing data to suggest the clinical entity of obesity related respiratory failure (ORRF) encompasses several different phenotypes including; hypercapnic OSA, OSA/OHS and lone OHS. The underlying pathophysiology is likely to differ between these phenotypes and will therefore respond differently to treatment[2]. Not all the participants underwent nocturnal respiratory polygraphy, and it is thus difficult to determine which clinical phenotype was being treated, especially given the wide standard deviation (for AHI mean = 82 events / hr (SD 45) and for SpO2 less than 90% mean = 67% of the sleep period (SD 31.4%). This is in keeping with data by Kawata et al[3], who also demonstrated that in patients with hypercapnic OSA, only half of patients responded to continuous positive airway pressure (CPAP) therapy. Those who failed to respond had a higher AHI and BMI, suggesting nocturnal polygraphy parameters may predict who will respond to CPAP therapy alone. More than 50% of patients had previously used either non-invasive ventilation (NIV) or CPAP therapy, it is unclear whether there was a wash out period and prior use of PAP therapy which may have affected compliance in these individuals and therefore outcomes. We note the mean CPAP was 15.2 cm H2O (SD 2.8); in our clinical experience we often find patients with OHS/OSA trialled on CPAP therapy who require higher CPAP pressures (>10cmH2O) have ongoing nocturnal events, particularly persistent hypoxia. The authors have not provided nocturnal data on PAP therapy, we are therefore unable to determine whether the CPAP group had a reduction in nocturnal events to within normal range. This is especially important given the fact that, although reduced, the PaCO2 in the CPAP group remained higher than the NIV group at three months. The authors also comment that PaCO2 at presentation was predictive of treatment failure, with an eightfold increase in risk when PaCO2 was greater than 62mmHg (8.27kPa). This is noteworthy since there is much debate about the diagnostic criteria for OHS[4-6], a cut-off level for PaCO2 to determine which patients may fail therapy would be clinically important in identifying patients who should be treated with NIV in the first instance. Lastly, only outcomes at 3 months have been presented. We wonder what the longer term outcomes for these patients would be; whether there would be an increase in the CPAP failure rate and, most importantly, a difference in mortality rates? We recognise the significance of this paper and acknowledge there may be a cohort of OHS/hypercapnic OSA patients who can be treated successfully with CPAP. However, this group is yet to be identified; much of this distinction may lie in a universal definition of OHS encompassing nocturnal and daytime parameters. We suggest that NIV is a safer treatment option until further phenotyping studies are conducted to comprehensively identify those patients requiring NIV and those for whom CPAP will be adequate.
References:
1. Howard ME, Piper AJ, Stevens B, et al. A randomised controlled trial of CPAP versus non-invasive ventilation for initial treatment of obesity hypoventilation syndrome. Thorax 2016 doi: 10.1136/thoraxjnl-2016-208559[published Online First: Epub Date]|.
2. Masa JF, Corral J, Caballero C, et al. Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea. Thorax 2016:thoraxjnl-2016-208501
3. Kawata N, Tatsumi K, Terada J, et al. DAytime hypercapnia in obstructive sleep apnea syndrome*. Chest 2007;132(6):1832-38 doi: 10.1378/chest.07-0673[published Online First: Epub Date]|.
4. Manuel AR, Hart N, Stradling JR. Is a raised bicarbonate, without hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation? CHEST Journal 2015;147(2):362-68
5. Murphy PB, Janssens J-P. NIV for OHS without severe OSAS: is it worth it? Thorax 2016 doi: 10.1136/thoraxjnl-2016-208986[published Online First: Epub Date]|.
6. Hart N, Mandal S, Manuel A, et al. Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax 2014;69(1):83-4 doi: 10.1136/thoraxjnl-2013-204298[published Online First: Epub Date]|.
We thank Professors Lipworth and Anderson for their very thoughtful
comments in their response to our piece1, and for pointing out clear
strategies for treating obesity-associated asthma without expensive
therapies, e.g., with improved delivery of inhaled corticosteroids and/or
weight reduction.
It should be noted however, that the focus of the piece was on
mechanisms by which obesity might cause asthma,...
We thank Professors Lipworth and Anderson for their very thoughtful
comments in their response to our piece1, and for pointing out clear
strategies for treating obesity-associated asthma without expensive
therapies, e.g., with improved delivery of inhaled corticosteroids and/or
weight reduction.
It should be noted however, that the focus of the piece was on
mechanisms by which obesity might cause asthma, with the idea that a
greater understanding of disease mechanisms causing obesity-associated
asthma might lead to improved therapies, and possibly to even cost
effective ones. From a pathogenesis point of view, even pilot studies
showing the efficacy of any therapy might be extremely valuable in
identifying specific molecular mechanisms of disease. In that regard, the
impetus of the article was that obesity-associated asthma represents a
significant and growing unmet medical need, characterized by increased
healthcare utilization and reduced quality of life, and refractory to even
oral corticosteroid treatment and other current therapies. These current
therapies include inhaled corticosteroids and weight reduction programs,
although improved delivery or compliance with these measures, as suggested
by Professors Lipworth and Anderson, could improve the clinical result.
It is also worth mentioning that studies of obesity-associated
asthma, as mentioned in the piece1, indicate that there are at least two
forms of the disease, an early onset form and a late onset form, one of
which is much more responsive to weight reduction (late onset form) than
the other. We would therefore advocate further study of disease
mechanisms causing asthma in obese individuals, including subpopulations
thereof, along with improved implementation of current inexpensive
treatments, that might lead to an improved understanding and possibly to
new therapies for this very significant, growing and costly public heath
problem.
1. Umetsu, D.T. Mechanisms by which obesity impacts asthma. Thorax
(2016).
We read with interest the state of the art review by Umetsu on
mechanisms by which obesity impacts asthma [1]. He has clearly outlined
the extent to which molecular targets, both within allergic (T-helper 2
[TH2]) and non-allergic mechanistic pathways of asthma, need further
evaluation and drug development for obese asthmatics. This was on the
basis that current standard therapies for asthma such as inhaled
corticoste...
We read with interest the state of the art review by Umetsu on
mechanisms by which obesity impacts asthma [1]. He has clearly outlined
the extent to which molecular targets, both within allergic (T-helper 2
[TH2]) and non-allergic mechanistic pathways of asthma, need further
evaluation and drug development for obese asthmatics. This was on the
basis that current standard therapies for asthma such as inhaled
corticosteroids (ICS) appear to be less effective in these individuals.
Whilst these novel molecular targets are clearly an exciting step forward,
we believe there are several other issues that need to be addressed as
well when it comes to standard asthma treatment with ICS in the obese.
Umetsu touched on altered lung mechanics in the obese stating more
restriction of lung volumes[2]. We have found previously that overweight asthmatics (body mass index [BMI]???25kg/m2) appear to have attenuated
fractional exhaled nitric oxide (FeNO) and symptom responses as the dose
of inhaled budesonide was increased up to 800?g/day compared to normal
weight (BMI<25kg/m2) counterparts receiving the same ICS dose ramp[3].
However, there were no differences seen between responses in airway
calibre as measured by forced expiratory volume in 1s (FEV1), or indeed
airway hyperresponsiveness (AHR) to methacholine. Therefore, altered
corticosteroid response at a molecular level alone does not necessarily
explain the equal response in these latter two outcomes. Certainly, in
significantly overweight individuals their lung volumes are reduced, but
we did not see this difference in our cohort, presumably reflecting a
modestly increased mean BMI of 30kg/m2.
It may be, therefore, that either the ICS is not being delivered to the
peripheral small airways sufficiently in obese asthmatics, in the presence
of normal proximal delivery[4]. A previous study examined the effects of
bariatric surgery on measures of peripheral small airway function and
asthma between asthmatic and non-asthmatic obese individuals finding that
the peripheral airways are more collapsible in obese asthmatics than in
their non-asthmatic counterparts[5]. Indeed small airway dysfunction
itself is associated with poorer asthma control[6 7], which could feasibly
have a greater impact in obese asthmatics.
Therefore, strategies to improve delivery of ICS to the peripheral airways
might be a more cost-effective first step for certain obese asthmatics
than going directly to more expensive biological therapies to improve
their asthma control. We believe further prospective study is required
into the lung distribution and clinical utility of extra-fine particle ICS
in obese asthmatics, as well to establish if higher than usual doses of
ICS are required to achieve the same effect as in normal weight
asthmatics. It goes without saying that strategies which target
significant weight loss - including bariatric surgery where necessary -
are likely to be even more cost-effective in the first place, as this will
not only impact on improving asthma control but also on comorbidities such
as diabetes and hypertension.
References
1. Umetsu DT. Mechanisms by which obesity impacts asthma. Thorax 2016.
2. King GG, Brown NJ, Diba C, et al. The effects of body weight on airway calibre. Eur Respir J 2005;25(5):896-901.
3. Anderson WJ, Lipworth BJ. Does body mass index influence responsiveness to inhaled corticosteroids in persistent asthma? Ann Allergy Asthma Immunol 2012;108(4):237-42.
4. Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. The Lancet Respiratory medicine 2014;2(6):497-506.
5. Al-Alwan A, Bates JH, Chapman DG, et al. The nonallergic asthma of obesity. A matter of distal lung compliance. Am J Respir Crit Care Med 2014;189(12):1494-502.
6. Manoharan A, Anderson WJ, Lipworth J, et al. Small airway dysfunction is associated with poorer asthma control. Eur Respir J 2014;44(5):1353-5.
7. Shi Y, Aledia AS, Tatavoosian AV, et al. Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol 2012;129(3):671-8.
We thank Dr. Lacasse and the HP Study Group for their correspondence
regarding 'A diagnostic model for chronic hypersensitivity pneumonitis',
and appreciate their thoughtful consideration of our work.(1) We agree
that these two studies are complementary, and hope that both will serve to
improve diagnostic accuracy in the evaluation of patients with suspected
HP. We further concur that much work remains to be done to advan...
We thank Dr. Lacasse and the HP Study Group for their correspondence
regarding 'A diagnostic model for chronic hypersensitivity pneumonitis',
and appreciate their thoughtful consideration of our work.(1) We agree
that these two studies are complementary, and hope that both will serve to
improve diagnostic accuracy in the evaluation of patients with suspected
HP. We further concur that much work remains to be done to advance our
understanding of HP.
The HP Study was a pivotal paper in our field, the first to define a
clinically applicable prediction model to diagnose acute, subacute and
chronic HP.(2) However, the HP Study cohort included patients with
'active' disease, specifically excluding patients with fibrotic sequelae
or 'residual inactive HP'. Notably, an inciting antigen was identified in
114/116 (97%) of patients with HP. Our focus was on a different clinical
population and conundrum - the differentiation of chronic, commonly
fibrotic HP from other fibrotic interstitial lung diseases, in particular
idiopathic pulmonary fibrosis (IPF). These HP patients typically do not
present with an acute pulmonary syndrome, and previous data from our
center have demonstrated 60% to be antigen indeterminate, despite thorough
investigation,(3) consistent with data from similar sub-specialty
centers.(4) We required surgical lung biopsy as part of our gold standard
multi-disciplinary discussion-based diagnosis of HP given the lack of
universally accepted non-histopathological criteria in this clinical
scenario.
The study of HP is challenging, attributable to a lack of universally
accepted diagnostic criteria, the conundrum of antigen indeterminate
disease and controversies over the clinical utility of bronchoalveolar
lavage fluid analysis, serum specific antibodies, and inhalational
challenge. A recent review suggests focused areas for future research and
we are enthused by the increasing interest in this area.(5) Along with the
HP Study group, we remain hopeful that our complementary contributions to
clinical prediction models will lead to an overall better diagnostic
accuracy of HP in all its forms, and ultimately improved patient care.
Kerri A. Johannson MD MPH, University of Calgary, Calgary AB Canada;
Brett M. Elicker MD, University of California, San Francisco, San
Francisco CA USA;
Eric Vittinghoff PhD, University of California, San Francisco, San
Francisco CA USA;
Deborah Assayag MD, McGill University, Montreal QC Canada;
Kaissa de Boer MD, University of Ottawa, Ottawa ON Canada;
Jeffrey A. Golden MD, University of California, San Francisco, San
Francisco CA USA;
Kirk D. Jones MD, University of California, San Francisco, San Francisco
CA USA;
Talmadge E. King Jr. MD, University of California, San Francisco, San
Francisco CA USA;
Laura L. Koth MD, University of California, San Francisco, San Francisco
CA USA;
Joyce S. Lee MD, University of Colorado, Denver, Aurora CO USA;
Brett Ley MD, University of California, San Francisco, San Francisco CA
USA;
Paul J. Wolters MD, University of California, San Francisco, San Francisco
CA USA;
Harold R. Collard MD, University of California, San Francisco, San
Francisco CA USA.
References
1. Johannson KA, Elicker BM, Vittinghoff E, Assayag D, de Boer K,
Golden JA, Jones KD, King TE, Koth LL, Lee JS, Ley B, Wolters PJ, Collard
HR. A diagnostic model for chronic hypersensitivity pneumonitis. Thorax
2016.
2. Lacasse Y, Selman M, Costabel U, Dalphin JC, Ando M, Morell F,
Erkinjuntti-Pekkanen R, Muller N, Colby TV, Schuyler M, Cormier Y.
Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care
Med 2003; 168: 952-958.
4. Fernandez Perez ER, Swigris JJ, Forssen AV, Tourin O, Solomon JJ, Huie
TJ, Olson AL, Brown KK. Identifying an inciting antigen is associated with
improved survival in patients with chronic hypersensitivity pneumonitis.
Chest 2013; 144: 1644-1651.
5. Salisbury ML, Myers JL, Belloli EA, Kazerooni EA, Martinez FJ, Flaherty
KR. Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia. Where
We Stand and Where We Need to Go. Am J Respir Crit Care Med 2016.
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and
often relies on an array of clinical symptoms and signs developed in an
appropriate setting, with the demonstration of radiographic and
tomographic abnormalities, serum precipitating antibodies against
offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage,
and/or a granulomatous reaction on lung biopsies. Taken...
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and
often relies on an array of clinical symptoms and signs developed in an
appropriate setting, with the demonstration of radiographic and
tomographic abnormalities, serum precipitating antibodies against
offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage,
and/or a granulomatous reaction on lung biopsies. Taken separately, all
these manifestations are nonspecific and only the combination of several
of them may help clinicians to arrive at a correct diagnosis. By
providing better estimates of the probability of a disease than clinical
judgement, prediction rules (i.e., tools that quantifies the contribution
that various components of the history, physical examination and basic
laboratory results makes toward the diagnosis in an individual patient)
may guide clinical practice.[1] In this regard, we read with much
interest Johannson and colleagues' report of a multidimensional diagnostic
model for chronic hypersensitivity pneumonitis (HP).[2] This research
parallels the HP Study previously reported, the objective of which was to
develop a clinical prediction rule for the diagnosis of active HP.[3]
Johannson's study bears some resemblance to the HP study, especially
in its statistical methods. However, similarities end here. The HP study
was a prospective multicenter study of 661 patients presenting with an
acute pulmonary syndrome for which HP was considered in the differential
diagnosis. Johannson's study is a single-center retrospective analysis of
190 patients with biopsy-proven, chronic HP. The HP study specifically
applied to active acute, subacute and chronic HP, and only excluded
inactive residual HP. It included consecutive patients, chosen in an
unbiased fashion and representing a wide spectrum of diseases from a
variety of institutions, hence increasing generalizability. By including
only patients who required surgical lung biopsy, Johannson and colleagues
likely preselected difficult cases of HP and non-HP interstitial lung
disease, with the consequence of underestimating the accuracy of their
prediction models. The HP Study looked at simple and objective clinical
criteria and used high resolution computed tomography (HRCT) in the gold
standard definition of HP, whereas Johansson's study incorporated
radiological features from HRCT and a radiologist's diagnostic impression
in their prediction model. Bronchoalveolar lavage was obtained in all
patients in the HP study but it was not considered in Johannson's study.
Johannson's study and the HP Study are not competing studies; they
are complementary and their results cannot be directly compared. Although
the two studies had different patient populations and case selection, they
may be useful in the appropriate setting. Both studies have another point
in common: to be elevated in the hierarchy of evidence for clinical
decision rules, they should be validated again in different
populations.[1]
Yves Lacasse MD, Institut universitaire de cardiologie et de
pneumologie de Quebec, Universite Laval, Quebec, Canada
Moises Selman MD, Instituto Nacional de Enfermedades Respiratorias,
Mexico DF, Mexico
1 McGinn TG, Guyatt GH, Wyer PC, et al. Users' guides to the medical
literature: XXII: how to use articles about clinical decision rules.
Evidence-Based Medicine Working Group. JAMA 2000;284:79-84.
2 Johannson KA, Elicker BM, Vittinghoff E, et al. A diagnostic model for
chronic hypersensitivity pneumonitis. Thorax 2016;71:951-4.
3 Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of
hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952-8.
Conflict of Interest:
Yves Lacasse was the principal investigator of the HP Study. All co-authors of this letter were co-investigators of the HP Study.
We would like to congratulate Bissett et al on performing a
clinically important study in a challenging cohort of Intensive Therapy
Unit (ITU) patients. Any information in assisting the weaning process of
ITU patients is clearly very important and clinically very useful.
It is interesting that Maximum Inspiratory Pressure (MIP) was used to
assess the inspiratory muscle strength (IMS), one of the primary
endpoint...
We would like to congratulate Bissett et al on performing a
clinically important study in a challenging cohort of Intensive Therapy
Unit (ITU) patients. Any information in assisting the weaning process of
ITU patients is clearly very important and clinically very useful.
It is interesting that Maximum Inspiratory Pressure (MIP) was used to
assess the inspiratory muscle strength (IMS), one of the primary
endpoints. A reliable MIP requires patients to achieve a good mouth seal,
which may not always be possible on ITU. Patients are unlikely to be
familiar with the manoeuvre and this may lead to suboptimal technique.
Sniff Nasal Inspiratory Pressure (SNIP) is a simple, non-invasive test but
as a natural process, patients will have greater aptitude for this
investigation. It is particularly useful in patients with neuromuscular
disorders with facial weakness (1). It has a smaller range of normal
values than mouth pressures (2,3) achieving equal or more pressure than
static maximal efforts (3,4). We believe this should be considered as an
adjunctive test of IMS as this involves a similar technique to MIP
manoeuvre and may only be conferring training to perform this
investigation and therefore we would recommend multiple assessments of
respiratory muscle strength (5).
However, as are volitional assessments of IMS, SNIP and MIP rely on
motivation, co-operation and functional ability which may be impaired in
ITU patients. It can be difficult to prevent learning and training from
repeated testing affecting the results (6,7). Non-volitional
investigations using magnetic stimulation of the phrenic nerve to measure
twitch trans diaphragmatic pressure (TwDPI) measurement (8,9,10) and
diaphragmatic EMG using multi-pair oesophageal probes have been found to
be effective in measuring diaphragmatic muscle strength and can be
performed in ITU patients(11). Although these are invasive investigations
and not widely available, they would more definitively confirm the
validity of inspiratory muscle training (IMT) in this patient group. The
importance of this must be emphasised as IMT has not universally been
shown to improve outcomes in healthy volunteers and Chronic Obstructive
Pulmonary Disease (COPD) patients (5,6,7) and a review (12) suggested that
improvement in outcomes following IMT seen in a meta-analysis (13) might
be a placebo effect.
In conclusion, we congratulate Bissett et al for performing a challenging
and a clinically relevant study. We would however suggest using multiple
assessments of IMS, such as SNIP in addition to MIP. However the value of
IMT in ITU patients can only definitively be determined by including a non
-volitional investigation of IMS.
References
(1) N. Mustfa, J. Moxham. Respiratory muscle assessment in motor
neurone disease. QJM Sep 2001, 94 (9) 497-502
(2) Miller JM, Moxham J, Green M. The maximal sniff in the assessment
of diaphragm function in man. Clin Sci 1985;69:91-96.
(3) Laroche CM, Mier AK, Moxham J, Green M. The value of sniff
esophageal pressures in the assessment of global inspiratory muscle
strength. Am Rev Respir Dis 1988;138:598-603.
(4) Polkey MI, Green M, Moxham J. Measurement of respiratory muscle
strength. Thorax 1995;50:1131-1135.
(5) Nikoletou D, Man WD, Mustfa N, Moore J, Rafferty G, Grant RL,
Johnson L, Moxham J. Evaluation of the effectiveness of a home-based
inspiratory muscle training programme in patients with chronic obstructive
pulmonary disease using multiple inspiratory muscle tests. Disability and
rehabilitation. 2016 Jan 30;38(3):250-9.
(6) Polkey MI, Moxham J. Improvement in volitional tests of muscle
function alone may not be adequate evidence that inspiratory muscle
training is effective. Eur Respir J 2004; 23: 5-6.
(7) Hart N, Sylvester K, Ward S, et al. Evaluation of an inspiratory
muscle trainer in healthy humans. Respir Med 2001; 95: 526-531.
(8) Similowski T, Fleury B, Launois S, Cathala HP, Bouche P, Derenne
JP. Cervical magnetic stimulation: a new painless method for bilateral
phrenic nerve stimulation in conscious humans. J Appl Physiol 1989;
67:1311-1318
(9) Hamneg?rd CH, Wragg SD, Mills GH, et al. Clinical assessment of
diaphragm strength by cervical magnetic stimulation of the phrenic nerves.
Thorax. 1996;51(12):1239-1242.
(10) Mills GH, Kyroussis D, Hamnegard CH, et al. Bilateral magnetic
stimulation of the phrenic nerves from an anterolateral approach. Am J
Respir Crit Care Med 1996;154:1099-105.
(11) Luo YM, Moxham J, Polkey MI. Diaphragm electromyography using an
oesophageal catheter: current concepts. Clin Sci (Lond). 2008
Oct;115(8):233-44.
(12) Polkey MI, Moxham J, Green M. The case against inspiratory
muscle training in COPD. European Respiratory Journal Feb 2011, 37 (2)
236-237;
(13) Gosselink R, De Vos J, van denHeuvel SP, et al. Impact of
inspiratory muscle training in patients with COPD: what is the evidence?
Eur Respir J 2011; 37: 416-425
We appreciate the comments by Dr Eisenhut.(1) We did not focus on the
sensitivity analysis in our study as we were primarily interested in
establishing the impact of BCG on interpretation of tuberculin skin test
(TST) responses, which we considered especially relevant in the context of
the new NICE guidance.(2) The points raised by Dr Eisenhut are interesting
and we agree that the hypotheses put forwa...
We appreciate the comments by Dr Eisenhut.(1) We did not focus on the
sensitivity analysis in our study as we were primarily interested in
establishing the impact of BCG on interpretation of tuberculin skin test
(TST) responses, which we considered especially relevant in the context of
the new NICE guidance.(2) The points raised by Dr Eisenhut are interesting
and we agree that the hypotheses put forward need further exploration.
However, we strongly disagree with the conclusion that interferon-
gamma release assays (IGRAs) can be used to reliably exclude tuberculosis
(TB) infection in children. We and others have very clearly shown that
IGRA is a rule in test, not a rule out test, given that there is no gold
standard for TB infection in adults or children.(3) The negative
predictive value cannot be easily determined in young children who are
routinely placed on isoniazid preventive treatment in accordance with
published guidelines. Both TST and IGRA have acknowledged flaws as
screening tests. Neither can rule out TB infection or indeed disease; both
tests can be negative even in individuals with microbiologically confirmed
TB.
References
1. Eisenhut M. Hypotheses to explain the reduced sensitivity of tuberculin
skin test in BCG immunised young children. Thorax. 2016.
2. National Institue for Health and Care Excellence. Tuberculosis 2016.
Available at: http://www.nice.org.uk/guidance/ng33/resources/tuberculosis-
prevention-diagnosis-management-and-service-organisation-1837390683589
(accessed 16 September 2016)
3. Kampmann B, Whittaker E, Williams A, et al. Interferon-gamma release
assays do not identify more children with active tuberculosis than the
tuberculin skin test. Eur Respir J. 2009;33(6):1374-1382.
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.
Dear Editor, We thank Dr Mansell for her comments regarding our recently published trial. [1] We agree that there are different phenotypic variations within the obesity hypoventilation syndrome (OHS), although it remains to be determined whether OHS with co-existent obstructive sleep apnoea (OSA) responds differently to treatment in comparison to OHS without OSA. [2] Acknowledging that the presence and severity of OSA in...
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is in...
We thank Professors Lipworth and Anderson for their very thoughtful comments in their response to our piece1, and for pointing out clear strategies for treating obesity-associated asthma without expensive therapies, e.g., with improved delivery of inhaled corticosteroids and/or weight reduction.
It should be noted however, that the focus of the piece was on mechanisms by which obesity might cause asthma,...
We read with interest the state of the art review by Umetsu on mechanisms by which obesity impacts asthma [1]. He has clearly outlined the extent to which molecular targets, both within allergic (T-helper 2 [TH2]) and non-allergic mechanistic pathways of asthma, need further evaluation and drug development for obese asthmatics. This was on the basis that current standard therapies for asthma such as inhaled corticoste...
We thank Dr. Lacasse and the HP Study Group for their correspondence regarding 'A diagnostic model for chronic hypersensitivity pneumonitis', and appreciate their thoughtful consideration of our work.(1) We agree that these two studies are complementary, and hope that both will serve to improve diagnostic accuracy in the evaluation of patients with suspected HP. We further concur that much work remains to be done to advan...
To the Editor,
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and often relies on an array of clinical symptoms and signs developed in an appropriate setting, with the demonstration of radiographic and tomographic abnormalities, serum precipitating antibodies against offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage, and/or a granulomatous reaction on lung biopsies. Taken...
We would like to congratulate Bissett et al on performing a clinically important study in a challenging cohort of Intensive Therapy Unit (ITU) patients. Any information in assisting the weaning process of ITU patients is clearly very important and clinically very useful.
It is interesting that Maximum Inspiratory Pressure (MIP) was used to assess the inspiratory muscle strength (IMS), one of the primary endpoint...
Dear Editor,
We appreciate the comments by Dr Eisenhut.(1) We did not focus on the sensitivity analysis in our study as we were primarily interested in establishing the impact of BCG on interpretation of tuberculin skin test (TST) responses, which we considered especially relevant in the context of the new NICE guidance.(2) The points raised by Dr Eisenhut are interesting and we agree that the hypotheses put forwa...
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...
Pages