Editorials
with episodic viral wheeze who clinicians see in droves in the au-
tumn and winter months, most of whom are not at high risk for
asthma and allergic disease. In a large randomized, controlled
trial of prednisolone for viral episodic wheeze (10) only 124
of 700 children enrolled were judged to be at high risk of asthma
in later years using a recognized risk score (13). Hence the
findings of these birth cohorts, although they have an important
role in elucidating mechanisms of asthma etiology, do not help
us predict whether children with episodic viral wheeze will re-
spond to available treatments or indeed whether they will de-
velop asthma in later years. Paradoxically, these are the
questions parents would most like answered. The strength of
the present study is to suggest mechanisms by which allergic
sensitization and inflammation may lead to rhinovirus wheeze
and asthma. The authors rightly point out that the results of
allergen avoidance strategies have been disappointing. The
COAST cohort should reinvigorate the search for novel ther-
apeutic interventions to prevent allergic sensitization and
asthma.
Author disclosures are available with the text of this article at www.atsjournals.org.
Alan R. Smyth, M.A., M.B.B.S., M.D.
School of Clinical Sciences
University of Nottingham
Nottingham, United Kingdom
References
1. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L,
Symington P, O’Toole S, Myint SH, Tyrrell DAJ, et al. Community
study of role of viral infections in exacerbations of asthma in 9–11 year
old children. BMJ 1995;310:1225–1229.
2. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL,
Pappas TE, Printz MC, Lee WM, Shult PA, Reisdorf E, et al.
Wheezing rhinovirus illnesses in early life predict asthma development
in high-risk children. Am J Respir Crit Care Med 2008;178:667–672.
3. Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, Lee W-M,
Gern JE, Lemanske RF Jr. Evidence for a causal relationship between
allergic sensitization and rhinovirus wheezing in early life. Am
J Respir Crit Care Med 2012;185:281–285.
Vitamin D and Chronic Obstructive Pulmonary Disease:
Justified Optimism or False Hope?
To imagine that we might be able to cure all ills in the West by
simply popping a nutrient supplement each day is an appealing
and seductive thought, but probably naive. The fact that over
a third of the United Kingdom (UK) population report having
taken supplements in the previous year (1) is a testament to
the widespread belief among the general public that they are
effective in disease prevention. This, despite a lack of evidence
from randomized trials that such practice is beneficial and, in
the case of antioxidants, in the face of evidence that supple-
ments may even be harmful (2). Certainly there have been dis-
appointments in respiratory research; promising observational
data, suggesting possible beneficial effects of dietary antioxidants
Supported by National Institute of Health Research Programme grant RP-PG-
0407-10398 (A.R.M.). The views expressed in this article are those of the authors
and not necessarily those of the National Health Service, the National Institute of
Health Research, or the Department of Health.
239
4. Hide DW, Matthews S, Matthews L, Stevens M, Ridout S, Twiselton R,
Gant C, Arshad SH. Effect of allergen avoidance in infancy on al-
lergic manifestations at age two years. J Allergy Clin Immunol 1994;93:
842–846.
5. Peat JK, Mihrshahi S, Kemp AS, Marks GB, Tovey ER, Webb K, Mellis
CM, Leeder SR; for the Childhood Asthma Prevention Study Team.
Three-year outcomes of dietary fatty acid modification and house dust
mite reduction in the Childhood Asthma Prevention Study. J Allergy
Clin Immunol 2004;114:807–813.
6. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P,
Simpson A, Custovic A, NAC Manchester Asthma and Allergy Study
Group. Early life environmental control: effect on symptoms, sensitiza-
tion, and lung function at age 3 years. Am J Respir Crit Care Med 2004;
170:433–439.
7. Maas T, Kaper J, Sheikh A, Knottnerus J, Wesseling G, Dompeling E,
Muris J, van Schayck C. Mono and multifaceted inhalant and/or food
allergen reduction interventions for preventing asthma in children at
high risk of developing asthma. Cochrane Database Syst Rev 2009;
CD006480.
8. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan
WJ. Asthma and wheezing in the first six years of life. N Engl J Med
1995;332:133–138.
9. Brand PLP, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA,
Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, et al.
Definition, assessment and treatment of wheezing disorders in pre-
school children: an evidence-based approach. Eur Respir J 2008;32:
1096–1110.
10. Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth
A, Grigg J. Oral prednisolone for preschool children with acute virus-
induced wheezing. N Engl J Med 2009;360:329–338.
11. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten
J, Tozzi CA, Polos P. Montelukast reduces asthma exacerbations in 2-
to 5-year-old children with intermittent asthma. Am J Respir Crit Care
Med 2005;171:315–322.
12. Wilson N, Sloper K, Silverman M. Effect of continuous treatment with
topical corticosteroid on episodic viral wheeze in preschool children.
Arch Dis Child 1995;72:317–320.
13. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical
index to define risk of asthma in young children with recurrent
wheezing. Am J Respir Crit Care Med 2000;162:1403–1406.
Published 2012 by the American Thoracic Society
DOI: 10.1164/rccm.201111-1952ED
on asthma risk, have not translated into secondary prevention in
adults when supplementation trials were performed (3).
Recently, the spotlight has moved away from antioxidants
and onto vitamin D. Research publications have been increas-
ing exponentially, and in some quarters vitamin D supplemen-
tation is being touted as a possible panacea for most diseases
afflicting the Western world, with evangelical zeal. So does vi-
tamin D hold more promise than antioxidants as a “magic
bullet”? With respect to respiratory disease, there is consider-
able interest in whether vitamin D deficiency may be a risk
factor for various infections and exacerbations of asthma and
chronic obstructive pulmonary disease (COPD) (4). A number
of vitamin D supplementation trials have been performed in
relation to tuberculosis, influenza, and upper respiratory tract
infections, and the evidence to date is conflicting, with some
studies reporting positive results (5, 6) and some negative (7,
8). Similarly, supplementation trials are underway aimed at pri-
mary and secondary prevention of asthma, although supportive
240 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
observational evidence in children underpinning these trials is
stronger for asthma severity than it is for asthma inception.
Although vitamin D deficiency, as measured using the gold
standard measure of vitamin D status, 25-hydroxyvitamin
D (25(OH)D) (9), has been linked to increased severity (10),
inferences about low prenatal vitamin D status as a risk factor
for asthma prevalence have been made based on associations
with maternal dietary intake of vitamin D in pregnancy (11).
This is surprising, given the minor contribution to overall vita-
min D status compared with that of ultraviolet B exposure; in-
deed, the value of analyzing dietary vitamin D intake alone as
a means of establishing the influence of vitamin D on outcomes
has been questioned (9).
Is there evidence to suggest that vitamin D deficiency might
play a role in the development and severity of COPD? Might
there be scope for primary or secondary prevention of acceler-
ated lung function decline? Data from observational studies are
conflicting, both from studies of patients with COPD and from
population-based research. A recent cross-sectional study ob-
served a positive association between 25(OH)D concentrations
and FEV1 in patients with COPD (12). In contrast, a longitudinal
study of continuous smokers with COPD found no difference in
baseline 25(OH)D concentrations between individuals who had
a rapid decline in lung function and those with a slow decline
(13). Although strong positive cross-sectional associations be-
tween serum 25(OH)D and FEV1 and FVC were reported in
the population-based Third National Health and Nutrition Ex-
amination Survey in the United States (14), we did not confirm
any relation with lung function or spirometrically defined COPD
in an older community-based population in the UK (15). To date,
population-based data on the relation of 25(OH)D to lung func-
tion decline are lacking, although preliminary data, reported in
the form of an abstract, have suggested a possible relation be-
tween lower vitamin D status and faster decline in the FEV1/FVC
ratio (but not FEV1) in an elderly population (16).
What about COPD exacerbations? In this issue of the Jour-
nal, Kunisaki and colleagues (pp. 286–290) have investigated
whether lower vitamin D status is a risk factor for COPD exac-
erbations in patients with severe COPD, who were at high risk
of exacerbations (17). Their analyses were performed post hoc
within a randomized controlled trial designed to determine
whether daily antibiotic treatment would reduce COPD exac-
erbations. After controlling for season and other potential con-
founders, they found that plasma concentrations of 25(OH)D,
measured at baseline, did not predict time to first COPD exac-
erbation, nor rate of exacerbations. This observational study
was well conducted but, inevitably, cannot provide definitive
answers. For example, less than 10% of study participants had
profound deficiency, as defined by a plasma 25(OH)D concen-
tration less than 10 ng/ml (25 nmol/L). This may partly reflect
the tendency of healthier individuals to take part in trials, the
fact that the majority of participants were white, and that vita-
min D fortification, for example of milk, is performed in the
United States. Although the authors tried to examine whether
profound deficiency influenced exacerbation risk, they had lim-
ited statistical power and hence could not rule out such an
effect. It may also be that vitamin D deficiency is only a risk
factor for COPD exacerbations in subgroups of individuals de-
fined by genotype. For example, the effects of vitamin D defi-
ciency on susceptibility to tuberculosis appear to be modified by
polymorphisms in the vitamin D receptor and vitamin D–bind-
ing protein (18, 19). It would have been of interest to explore
interactions between these gene variants and baseline vitamin D
status on risk of COPD exacerbations in the study by Kunisaki
and colleagues (17); confirmation of effect modification in such
an observational study could also strengthen causal inference.
VOL 185 2012
Ultimately, only randomized trials can determine whether in-
creasing vitamin D status can reduce the risk of exacerbations in
patients with COPD. A recent trial in Belgium has found some
evidence to suggest that vitamin D supplementation may reduce
the incidence of COPD exacerbations in profoundly deficient
patients with moderate to severe COPD (20). Another trial
(ViDiCO, NCT00977873) is currently underway in the UK, where
profound deficiency is common (particularly in certain ethnic
minority groups), to determine whether vitamin D supplementa-
tion reduces exacerbations in patients with less severe COPD.
Author disclosures are available with the text of this article at www.atsjournals.org.
Seif O. Shaheen, Ph.D.
Adrian R. Martineau, Ph.D.
Centre for Primary Care and Public Health
Blizard Institute
Barts and The London School of Medicine and Dentistry
London, United Kingdom
References
1. Department of Health and Food Standards Agency. National Diet and
Nutrition Survey. Headline results from Years 1 and 2 (combined) of
the Rolling Programme (2008/09–2009/10) [Internet]. Bates B, Lennox
A, Bates C, Swan G, editors; c2011 [accessed 2011 Nov 23]. Available from:
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/
digitalasset/dh_128550.pdf
2. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality
in randomized trials of antioxidant supplements for primary and sec-
ondary prevention: systematic review and meta-analysis. JAMA 2007;
297:842–857.
3. Feary J, Britton J. Dietary supplements and asthma: another one bites
the dust. Thorax 2007;62:466–468.
4. Martineau AR. Vitamin D and respiratory health. Curr Respir Med Rev
2011;7:394–395.
5. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H.
Randomized trial of vitamin D supplementation to prevent seasonal
influenza A in schoolchildren. Am J Clin Nutr 2010;91:1255–1260.
6. Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton
AP, Packe GE, Moore-Gillon JC, Darmalingam M, et al. High-dose
vitamin D3 during intensive-phase antimicrobial treatment of pulmo-
nary tuberculosis: a double-blind randomised controlled trial. Lancet
2011;377:242–250.
7. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, Berbari N.
A randomized controlled trial of vitamin D3 supplementation for the
prevention of symptomatic upper respiratory tract infections. Epi-
demiol Infect 2009;137:1396–1404.
8. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen
PL, Glerup H, Sodemann M. Vitamin D as supplementary treatment
for tuberculosis: a double-blind, randomized, placebo-controlled trial.
Am J Respir Crit Care Med 2009;179:843–850.
9. Millen AE, Bodnar LM. Vitamin D assessment in population-based
studies: a review of the issues. Am J Clin Nutr 2008;87:1102S–
1105S.
10. Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM,
Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, et al. Serum vi-
tamin D levels and markers of severity of childhood asthma in Costa
Rica. Am J Respir Crit Care Med 2009;179:765–771.
11. Erkkola M, Kaila M, Nwaru BI, Kronberg-Kippila C, Ahonen S,
Nevalainen J, Veijola R, Pekkanen J, Ilonen J, Simell O, et al. Ma-
ternal vitamin D intake during pregnancy is inversely associated with
asthma and allergic rhinitis in 5-year-old children. Clin Exp Allergy
2009;39:875–882.
12. Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert
I, Coolen J, Mathieu C, Decramer M, Lambrechts D. Vitamin D de-
ficiency is highly prevalent in COPD and correlates with variants in
the vitamin D-binding gene. Thorax 2010;65:215–220.
13. Kunisaki KM, Niewoehner DE, Singh RJ, Connett JE. Vitamin D status
and longitudinal lung function decline in the lung health study. Eur
Respir J 2011;37:238–243.
Editorials
14. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin D
and pulmonary function in the Third National Health and Nutrition
Examination Survey. Chest 2005;128:3792–3798.
15. Shaheen SO, Jameson K, Robinson SM, Boucher BJ, Syddall HE, Aihie
Sayer A, Cooper C, Holloway JW, Dennison EM. Relationship of
vitamin D status to adult lung function and COPD. Thorax 2011;66:
692–698.
16. Jiang R, Cheng B, Kestenbaum B, Krishnan JA, Hansel N, Kapur V,
Barr RG. Vitamin D levels and longitudinal change in lung function in
the elderly: The Cardiovascular Health Study [abstract]. Am J Respir
Crit Care Med 2011;183:A2654.
17. Kunisaki KM, Niewoehner DE, Connett JE; COPD Clinical Research
Network. Vitamin D levels and risk of acute exacerbations of chronic
obstructive pulmonary disease: a prospective cohort study. Am
J Respir Crit Care Med 2012;185:286–290.
Pharyngeal Neuropathy in Obstructive Sleep Apnea:
Where Are We Going?
Obstructive sleep apnea (OSA) syndrome corresponds to recur-
rent episodes of partial or complete pharyngeal collapse occur-
ring during sleep. It is an established health concern affecting up
to 5% of middle-aged men and women in the general population
(1). As illustrated in the figure, there are numerous possible
causes of upper airway (UA) collapse as well as complex inter-
actions. This actually links to a major issue: there are different
OSA phenotypes and physiological traits causing OSA.
Overall mechanisms of UA collapse may be summarized as fol-
lows (2, 3): The wakefulness state provides compensatory neuro-
nal activation of dilator muscles in an anatomically compromised
collapsible pharynx; accordingly, when this activation is lost at
sleep onset, the airway narrows and/or collapses. Pharyngeal col-
lapse occurrence is therefore multifactorial, including reduction
in UA volume, increase in pharyngeal collapsibility, changes in
UA resistance during sleep occurring both during inspiration and
expiration, and alterations in pharyngeal muscle activity (4, 5)
and in UA protective reflex (6). It should also be noted that these
different mechanisms are contributing differently at different
ages during the lifespan (Figure 1).
The hypoglossal nerve is a key player in the motor control of
the pharyngeal musculature and is involved in UA protective
reflexes. The relative contribution of hypoglossal dysfunction
and pharyngeal neuropathy deserves assessment in the context
of the various other mechanisms underlying OSA.
In this issue of the Journal (pp. 322–329), Saboisky and col-
leagues studied the association between OSA and structural
remodeling of the peripheral branches of the hypoglossal nerve
(7). Neurogenic changes were likely to arise in patients with
OSA as a result of denervation, collateral sprouting, and rein-
nervation, and were associated with the severity of intermittent
hypoxia (i.e., oxygen nadir) occurring during sleep.
The occurrence of pharyngeal neuropathy with an impairment
in pharyngeal sensation has previously been evidenced in several
clinical (8, 9) and mechanistic (10, 11) studies. In OSA, there is
a link between local inflammation and denervation at the pharyn-
geal level (10). This is associated with pharyngeal sensory impair-
ment that may reduce the efficacy of the protective pharyngeal
reflexes and contribute to UA collapse. We have also evidenced
that sleep apnea is nearly systematic in the context of a generalized
Author Contributions: Drafting the manuscript for important intellectual content:
P.L., M.D., and J.L.P.
241
18. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright
D, Latif M, Davidson RN. Influence of vitamin D deficiency and vita-
min D receptor polymorphisms on tuberculosis among Gujarati Asians
in west London: a case-control study. Lancet 2000;355:618–621.
19. Martineau AR, Leandro ACCS, Anderson ST, Newton SM, Wilkinson
KA, Nicol MP, Pienaar SM, Skolimowska KH, Rocha MA, Rolla VC,
et al. Association between Gc genotype and susceptibility to TB is
dependent on vitamin D status. Eur Respir J 2010;35:1106–1112.
20. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van
Eldere J, Decallone B, Bouillon R, Decramer M, Janssens W. High
doses of vitamin D to reduce exacerbations in COPD: a randomised
controlled trial. Ann Intern Med (In press)
Copyright ª 2012 by the American Thoracic Society
DOI: 10.1164/rccm.201111-2014ED
neuropathy (12). In patients presenting with Charcot-Marie-
Tooth (CMT) disease, the most common peripheral neuropathy,
OSA severity was proportional to peripheral nerve impairment
(12). Although not directly evidenced, the occurrence of sleep
apnea without other significant favoring factors in the three dif-
ferent generations of this family study suggested that pharyngeal
neuropathy could have been the main cause of OSA in patients
with CMT (12). Although a high prevalence of OSA has been
further confirmed in this population, a direct evidence of pharyn-
geal neuropathy remains to be provided.
As stated by Saboisky and coworkers, assessing the role of
neuromuscular dysfunction in patients with OSA remains chal-
lenging, as UA muscle biopsies are invasive. It is then tempting
to indirectly assess neurogenic dysfunction by developing stan-
dardized UA sensory testing. The phenotypic trait of impairment
in UA sensation may be helpful for OSA diagnosis. When assess-
ing pharyngeal sensitivity in a nonselected OSA population, we
found a very strong correlation between pharyngeal sensory im-
pairment and OSA severity (6). Actually, there were indeed
some false negatives, meaning that pharyngeal sensory impair-
ment was not mandatory for UA collapse occurrence in this
population. But the high positive predictive value suggested
that it may be used as a screening technique (6), which remains
to be tested in a large clinical trial.
Whether pharyngeal neuropathy is initially induced by pro-
longed heavy snoring and associated vibratory lesions of the
pharynx (13) or more related to the degree of nocturnal hypox-
emia as evidenced in peripheral neuropathy (14) remains to be
determined. The cross-sectional design of the study by Saboisky
and colleagues does not allow establishing the causative nature
of hypoglossal nerve remodeling. However, in this study as well
as in previous studies, there is a significant overlap between
controls and patients with OSA as regards pharyngeal sensitive
or motor alterations. This suggests that pharyngeal neuropathy
could rather be a consequence, although possibly contributing
to the persistence or aggravation of sleep breathing disorders
(Figure 1). Obesity may also aggravate local inflammation by
adding systemic inflammation. Local inflammation at the UA
level likely contributes to UA neuromuscular dysfunction, and
may trigger a vicious circle favoring the occurrence of sleep
apnea. In this context, it remains to be demonstrated whether
early continuous positive airway pressure treatment could have
been useful, even though secondary nerve lesions may also be
irreversible (15).
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