Editorials
partnerships with patients within an evolving team-based primary care treatment guided by airway hyperresponsiveness in children: a randomised
structure. controlled tria. Eur Respir J 2007;30(3):457-66.
[Link]
Commissioned article; not externally peer-reviewed; accepted 20th December 2011; 5. Koenig SM, Murray JJ, Wolfe J, et al. Does measuring BHR add to guideline derived
online 24th January 2012 clinical measures in determining treatment for patients with persistent asthma?
© 2012 Primary Care Respiratory Society UK. All rights reserved Respir Med 2008;102(5):665-73. [Link]
[Link] 6. Harris MF, Jayasinghe U, Taggart J, et al. Multi-disciplinary Team Care Plans in the
Prim Care Respir J 2012; 21(1): 4-5 management of patients with chronic disease in Australian general practice. Med J
Aust 2011;194(5):236-9.
Conflicts of interest The author declares that he has no conflicts of interest
7. Australian Government Department of Health and Ageing. MBS Primary Care
in relation to this article.
Items. Chronic Disease Management (CDM) Medicare Item numbers .
[Link]
References chronicdiseasemanagement
1. Brannan J. Bronchial Hyperresponsiveness in the assessment of asthma control:
8. Lin CCW, Hass M, Maher C, Machado L, van Tulder M. Cost-effectiveness of
airway hyperresponsiveness in asthma: its measurement and clinical significance.
general practice care for low back pain. A systematic review. Eur Spine J
Chest 2010;138:11S-17S. [Link]
2011;20:1012-23. [Link]
2. Turton J, Glasgow N, Brannan J. Feasibility and acceptability of using bronchial
9. Utens C, Gossens L, Smeenk L, et al. Effectiveness and cost-effectiveness of early
hyperresponsiveness to manage asthma in primary care: a pilot study. Prim Care
assisted discharge for Chronic Obstructive Pulmonary Disease exacerbations: the
Respir J 2012;21:28-34. [Link]
design of a randomised controlled trial. BMC Public Health 2010;10:618.
3. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. The
[Link]
AMPUL Study Group. Clinical control and histopathologic outcome of asthma
[Link]
when using airway hyperresponsiveness as an additional guide to long-term
10. Gialamos A, Yelland L, Ryan P, et al. Does point of care testing lead to the same or
treatment. Am J Respir Crit Care Med 1999;159:1043-51.
better adherence to medication? A randomised control trial. The POCT in General
4. Nuijsink M, Hop WC, Sterk PJ, Duiverman EJ, de Jongste JC. Long-term asthma
Practice Trial in General Practice. Med J Aust 2009;191:487-91.
Statins for COPD: a challenge to conventional beliefs?
See linked article by Lawes et al. on pg 35 However, it is a large study, subject inclusion was unselected – i.e. all
acute COPD admissions in New Zealand, the prescribing of statins in
primary care was independent of the admission and collected via an
*Mike Pearsona automated link, and death is an unequivocal outcome.
a
Professor of Clinical Evaluation, University of Liverpool, UK A further caveat is that absolute numbers of deaths in the two
groups, i.e. those prescribed and not prescribed statins, were similar
*Correspondence: Professor Mike Pearson, Clinical Sciences
at 4 years. The differences are only seen when statistical controls are
Building, University Hospital Aintree, Longmoor Lane, Liverpool,
L9 7AL. Tel: +44 (0)151 529 3857 Fax: +44 (0)151 529 2873 added. However, to argue that those with cardiovascular or diabetes
E-mail: [Link]@[Link] co-morbidity should have similar outcomes to those without flies in
the face of every known epidemiological study. An odds ratio showing
30% fewer deaths puts statin therapy into the same league as
Every now and then a paper comes along which challenges the oxygen, but with applicability to a wider range of patients. The
mould. Chronic obstructive pulmonary disease (COPD) is an changes in the study are not explained by the expected lipid or
airway condition that results from inhaling “dusts” (particularly cardiovascular effects, leading to the implication that statins may be
the tar of cigarettes). So when a paper suggests that a drug altering the underlying COPD. Until this hypothesis is formally tested
affecting the vascular system may alter outcome, it questions our it remains exciting but unproven – but for a moment let us follow the
standard beliefs. In this issue of the PCRJ is a paper from Lawes potential trail of what it might mean.
et al. describing how statin use is associated with a 30% Statins were introduced for their lipid-lowering effect which, by
reduction in mortality in COPD over 4 years1 - an outcome effect reducing deposition of cholesterol in arteries, is cardio-protective. But
that is an order of magnitude greater than the current mainstays they also act on platelets and clotting2,3 and perhaps vasculitis.4 These
of COPD drug treatments, inhaled steroids and long-acting non-lipid effects are debated5 but some are claiming that the effects
bronchodilators. Indeed, these have disappointingly little or no of statins go beyond fat metabolism such that cardiovascular patients
effect on disease progression, although they do reduce obtain a double benefit.6 Those arguing for a polypill7 suggest that
exacerbation rates and improve quality of life. Only oxygen in the statin benefits are independent of cholesterol levels, which may imply
late hypoxic phase is disease modulating. So, even a hint of a that the primary effect of statins is on non-lipid mechanisms.
disease modifying effect by statins has to provoke interest. Yet there are no suggestions that statins act to reduce or block the
But could this paper be wrong? It is observational and thus cannot effect of inflammation due to smoke deposits or other dusts in the
prove causality, and the authors are appropriately cautious in their lung, or on elastases. While it is possible that this is because no one
inferences, especially with neither smoking nor lung function data. has looked, the alternative is to ask more radical questions:
PRIMARY CARE RESPIRATORY JOURNAL 5
[Link]
Editorials
• Could COPD be a vascular disease in which the small airway and the coal dust from mining are neither highly irritant nor
disease is due to a failure of vascular supply leading to airway loss? vasoconstrictor in nature. Perhaps the indoor smoke of indoor cooking
Could COPD be Buerger’s disease of the lung? pollution may be different? The claimed effects of the pollution and
• Is it possible that the tars with all their active chemicals depositing industrial dust studies have been markedly less than for smoking, and
on major bifurcations are the main agent for cancer, while it is the it has been difficult to separate out potential competing effects,
vasoconstriction of the nicotine that is responsible for the small particularly as almost all the studies are cross-sectional or do not
airway disease of COPD? include the same individuals longitudinally. It is fair to state that many
Despite two decades of active research, the causal mechanisms of have been convinced by the collective body of papers, but this author
COPD remain unclear. The emphysema-elastin degradation story has always retained doubts, largely because of the dependence on
applies to some patients, but many have physiologically fixed statistics to describe small effect sizes (an order of magnitude less than
obstruction with little or no emphysema on scans or at post mortem. the effects of smoking) and the potential for uncontrolled co-
The inflammation of COPD includes neutrophils and CD8 variation. Space does not allow a fuller discussion, but a thoughtful
lymphocytes, which overlaps with the pattern seen in post- recent paper describes how the complexities of the statistics may
transplantation bronchoalveolitis obliterans when the bronchial mislead when there are several co-variate factors – e.g. ageing, cohort
arterial supply is damaged.8 Chronic ischaemia of the brain9 and of the effects, cumulative smoking, and cumulative pollution/work
heart10 has some similar features – so is there a possibility that the exposures, all of which increase with time.13 This statins paper1 also
COPD inflammation results from failure of the bronchial artery supply depends on statistical control, so an open mind is important. But if the
to the small airways? vascular pathogenesis theory holds up, we may need to re-examine
Cigarette smoke consists of very fine particulates (mostly < 0.1 µm the putative roles of air pollution, coal dust and other agents with
in diameter) that cool and aggregate as they pass into the airway, but fresh eyes.
they still contain many active chemicals when the particles deposit at What might this mean for COPD patients? An urgent prospective
airway bifurcations where there is most turbulence.11 Deposition is study to test whether or not statins have a significant effect on COPD
relatively higher in the upper lobes where both emphysema and is needed. If that study were positive, it would significantly alter the
tumours are most common. The irritant chemicals would be expected prescribing advice for all COPD patients. Bronchodilators, pulmonary
to lead to local inflammation and mucus production. The relationship rehabilitation, and oxygen in established symptomatic disease will
to cancer would stand, but is it the tar and chemicals that causes the remain treatment mainstays, but would we still feel as passionate
COPD? Or could it be the nicotine? – a known vasoconstrictor that will about the inhaled steroids?
be present in concentrations higher than the peak cerebral levels that Stopping smoking will remain the first choice for preventing
lead to addiction – in which case the bronchial arterial supply could be disease progression, but is it possible that statins might slow disease
affected leading to ischaemic damage of the airways. The bronchial progression even in continuing smokers by preventing local thrombi
arteries are complex structures with an interlacing network of vessels and preserving oxygenation of the small airway tissues? Perhaps the
that are within and without the bronchial wall. Most of the anatomic nicotine substitutes used to assist smokers to quit should be
work on the bronchial circulation is more than 30 years old, and reconsidered; could they be making things worse, albeit leading to
current textbooks simply state that, because of the multiple less nicotine in the longer term? – or are the relatively low peak doses
anastomotic branching, damage is unlikely. But as vessels become safe?
smaller their vulnerability is likely to increase, and if with each cigarette This statins paper from Lawes et al.1 may be an observational
just one or two vessels were damaged and the tissue supplied did not study to be interpreted cautiously, but given the paucity of therapy
have adequate collateral supply, then localised infarction might result available for COPD it is quite exciting to speculate about something
in cell death and a space appearing in the centre of the lobule. Such that might improve outcomes significantly. It would be even more
speculation might seem fanciful, but a seminal recent paper12 exciting if this were to lead to a new understanding of COPD disease
describes how small airways of 2mm diameter or less are reduced in mechanisms and thus accelerate progress. But there have been false
number – i.e. somehow airways have been destroyed – and also dawns before…
suggests that the reduction in numbers may precede the development
of centri-lobular emphysema. Conflicts of interest The author declares that he has no conflicts of interest
in relation to this article.
There are other observations that might fit. Most respiratory
physicians have a few patients who have inhaled cocaine and then Commissioned article; not externally peer-reviewed; accepted 29th January 2012 ;
present with severe COPD perhaps two decades earlier than cigarette online 20th February 2012
© 2012 Primary Care Respiratory Society UK. All rights reserved
smokers. Cocaine is a potent vaso-constrictor. The addictive “high”
[Link]
from cigarettes arises from the very high peak cerebral nicotine level – Prim Care Respir J 2012; 21(1): 5-7
implying even higher levels in the bronchioles – and the switch to low
tar cigarettes does not reduce disease as patients puff harder to obtain References
the cerebral nicotine which thus goes to the bronchioles. 1. Lawes CMM, Thornley S, Young R, et al. Statin use in COPD patients is associated
However, we are left with some difficulty in explaining the dust with a reduction in mortality: a national cohort study. Prim Care Respir J 2012;
pollution story, since the PM10 particulates inhaled from air pollution 21(1):35-40. [Link]
PRIMARY CARE RESPIRATORY JOURNAL 6
[Link]
Editorials
2. Paraskevas KI, Bessias N, Perdikides TP, Mikhailidis DP. Statins and venous infarctions induce differential lesional interleukin-16 (IL-16) expression confined to
thromboembolism: A novel effect of statins? Current Medical Research and infiltrating granulocytes, CD8+ T-lymphocytes and activated
Opinion 2009; 25(7):1807-09. [Link] microglia/macrophages. Journal of Neuroimmunology 2001;114:232-24.
3. Waters DD. Exploring new indications for statins beyond atherosclerosis: Successes [Link]
and setbacks. J Cardiol 2010;55(2):155-62. 10. Heart Stabile E, Kinnaird T, la Sala A, et al. CD8+ T Lymphocytes Regulate the
[Link] Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel
4. Muscal E, Brey RL Antiphospholipid syndrome and the brain in pediatric and adult Development and Recruiting CD4 Mononuclear Cells Through the Expression of
patients. Lupus 2010;19(4):406-11. [Link] Interleukin-16. Circulation 2006,113:118-24.
5. Pedersen TR. Pleiotropic effects of statins: evidence against benefits beyond LDL- [Link]
cholesterol lowering. Am J Cardiovasc Drugs 2010;10(Suppl 10). 11. National Research Council. "10 Tobacco Smoke and Toxicology." Clearing the
6. Morales-Villegas EC, Di Sciascio G, Briguori C. Statins: Cardiovascular Risk Smoke: Assessing the Science Base for Tobacco Harm Reduction. Washington, DC:
Reduction in Percutaneous Coronary Intervention—Basic and Clinical Evidence of The National Academies Press, 2001.)
Hyperacute Use of Statins. Int J Hypertens 2011;904742. 12. McDonough JE, Yuan R, Suzuki M. Small-Airway Obstruction and Emphysema in
7. Wald DS, Wald NJ. The Polypill in the prevention of cardiovascular disease. Prev Chronic Obstructive Pulmonary Disease. N Engl J Med 2011;365:1567-75.
Med 2011;52(1):16-17. [Link] [Link]
8. Dark J, Corris PA. Lung Transplantation in Respiratory Medicine. Eds Gibson J, 13. Schwartz J. A spine for our time. Thorax 2011;66:841-2.
Geddes D, Costabel U et al. Saunders, London 2003 pp496 [Link]
9. Schwab JM, Nguyen TD, Meyermann R, Schluesener HJ. Human focal cerebral
Oral immunotherapy for peanut allergy: an evidence-based
medicine assessment
See linked article by Sheikh et al. on pg 41 Peanuts are widely used as a nutritious oral aliment (providing protein,
vitamins and minerals) and are the most common food-related cause
of IgE-mediated allergic reactions.7 Patients with atopic dermatitis can
*Jan Lötvalla, Moisés A Calderónb increase their risk to sensitisation to peanuts and subsequently the
a
Professor of Clinical Allergy, Krefting Research Centre, development of peanut allergy due to cutaneous exposure to peanut
University of Gothenburg, Göteborg, Sweden oil-containing creams.8 Reactions to peanuts are immediate and can
a
Section of Allergy and Clinical Immunology, Imperial College – be severe, even life-threatening. Symptoms range from a relatively
National Heart and Lung Institute, Royal Brompton Hospital, mild urticarial rash, vomiting, diarrhoea, wheezing, and dyspnoea, to
London, UK severe throat angioedema, cardiovascular collapse or fulminant
*Correspondence: Professor Jan Lötvall, Professor of Clinical anaphylaxis.9 Patients with well-documented peanut allergy often
Allergy, Krefting Research Centre, University of Gothenburg, have to carry rescue medication such as adrenaline auto-injectors to
BOX 424, SE 40530 Göteborg, Sweden treat themselves if severe reactions occur.9 Measures to prevent (or
Tel: + 46 31 786 6717 Fax: +46 31 786 67 30 even cure) food allergies such as peanut allergy are therefore a high
E-mail: [Link]@[Link] scientific priority in the field of allergic disease, and many attempts to
induce tolerance to peanut are under way.
In this issue of the Primary Care Respiratory Journal, Sheikh and
Food-induced allergic disorders mediated by IgE represent a major colleagues present a timely systematic review10 of studies that have
health problem, affecting children and adults worldwide.1 Even attempted to induce desensitisation and tolerance to peanut by oral
though the exact prevalence of food allergy is difficult to determine, immunotherapy in patients with such allergy. A thorough search of
it has been reported that in some countries IgE-mediated food the major biomedical databases was conducted using a previously
allergy affects up to 6-8% of children and up to 2-4% of adults.1-3 designed study protocol. In total, 1,672 potentially eligible studies
Some food allergies such as egg, milk, soy and wheat may be were identified. After a systematic evaluation, only six studies met the
outgrown within the first decade of life, whilst others such as study inclusion criteria, enrolling 85 patients in total. Surprisingly, the
peanut, tree nuts, fish and shellfish are often lifelong.4 Food allergy duration of oral immunotherapy treatment varied between studies,
has different clinical manifestations involving many body systems ranging from 6 days to 36 months. Four studies were multicentre and
including the skin, the gastrointestinal and respiratory tracts, and the two single centre. Four studies were conducted in the USA and two in
cardiovascular system. Furthermore, the incidence of food-related Europe. All studies used a “case series” design, and so this systematic
anaphylaxis primarily in children seems to be increasing globally. review lacks the strength that can be provided by randomised
Individuals with both severe or difficult asthma and a history of food prospective placebo-controlled studies. This situation was stated by
allergy are those at highest risk of developing life-threatening the authors to be at high risk of bias. Regardless, the studies overall
anaphylactic reactions. argue that oral immunotherapy may have some future, since the
One of the major food allergens in many countries is peanut.5,6 treated patients tolerated higher doses of peanut after the
PRIMARY CARE RESPIRATORY JOURNAL 7
[Link]