Upper Airways Reactions to Cold Air
Alvaro A. Cruz, MD, and Alkis Togias, MD
Corresponding author
Alkis Togias, MD
Division of Allergy, Immunology, and Transplantation,
National Institutes of Health, 6610 Rockledge Drive, Room 3065,
Bethesda, MD 20817-6601, USA.
E-mail: togias@niaid.nih.gov
Current Allergy and Asthma Reports 2008, 8:111–117
Current Medicine Group LLC ISSN 1529-7322
Copyright © 2008 by Current Medicine Group LLC
Cold air–induced rhinitis is a common complaint of
individuals with chronic allergic or nonallergic rhinitis
and those with no chronic nasal disease. It is char-
acterized by rhinorrhea, nasal congestion, and nasal
burning that appear within minutes of exposure to cold
air and dissipate soon after exposure is terminated.
The symptoms of cold-air rhinitis are reproduced
experimentally with nasal cold-air provocation. This
procedure has shown that nasal mast cell activation
and sensory nerve stimulation are associated with
the development of nasal symptoms. Sensory nerve
activation generates a cholinergic reflex that leads to
rhinorrhea; therefore, anticholinergic agents are highly
effective in treating cold-air rhinitis. Experimental data
suggest that individuals with nasal cold-air sensitivity
may have reduced ability to compensate for the water
loss that occurs during exposure to cold air. Therefore,
the symptoms of cold air–induced rhinitis may reflect
the activation of compensatory mechanisms to restore
mucosal homeostasis.
Introduction
Interest in the reaction of the upper airways to cold air
derives not only from the clinical problem, but also from
the close relationship between upper and lower airways
and from the hypothesis that they share similar patho-
physiology, reflecting structural and functional similarities
between the nasal and bronchial mucosa [1]. This makes
the nasal reaction to cold air a possible model to study
cold air–induced asthma and exercise-induced asthma,
clinical phenomena that are almost ubiquitous in asthmatic
patients [2]. Although no study has examined whether the
magnitude of nasal reactions to cold air correlates with
that of cold air–induced lower airway reactions, one study
has documented that, compared with those who have
chronic rhinitis alone, individuals with asthma develop
stronger nasal responses when breathing cold air [3•].
Cold air–induced rhinitis describes the develop-
ment of nasal symptoms upon exposure to cold weather.
Symptoms are primarily rhinorrhea and nasal congestion,
frequently associated with a burning sensation inside the
nose. This problem becomes accentuated in windy condi-
tions. For example, rhinorrhea and nasal congestion are
common during skiing, a condition known as “skier’s
nose” [4]. Individuals who report cold-air sensitivity may
or may not be atopic. In some people, cold-air exposure
may be the only trigger of nasal symptoms.
The prevalence of cold air–induced rhinitis is not well
established. In a 1980 to 1981 survey of 912 police offi-
cers in Paris, France, 5.4% reported this problem [5]. In
a database of 206 individuals with perennial allergic rhi-
nitis and 150 with seasonal allergic rhinitis between the
ages of 18 and 55, we recorded cold air as a stimulus for
nasal symptoms in 55% and 28%, respectively [6]. This
finding suggests that cold-air rhinitis is more common in
patients with other nasal disease.
Our hypothesis is that the nasal reaction to cold air
represents the high end of a spectrum of compensatory
mechanisms activated to preserve the water/tempera-
ture homeostasis of the nasal mucosa. A corollary to
this hypothesis is that individual sensitivity to cold air
depends on the capacity to sustain mucosal water/tem-
perature homeostasis.
The Nose as an Air Conditioner
A major function of the nose is to warm and humidify
inhaled air. Many attempts have been made to monitor
the air-conditioning capacity of the nose. Most recently,
a probe was developed that can be inserted through one
nostril to sense airstream temperature and relative humid-
ity in the nasopharynx [7]. This probe has confirmed
the remarkable air-conditioning capacity of the human
nose and has produced a series of important observations
[7]. When inhaling air through the nose at subfreezing
temperatures and at high flow (20 L/min), the average air-
stream temperature in the nasopharynx is 26°C but can be
as high as 30°C. This method has also documented that
the relative humidity of air in the nasopharynx is consis-
tently around 100%, irrespective of the temperature and
flow of inhaled air. However, the temperature of air at the
nasopharynx varies significantly, depending on the tem-
perature of the air entering the nostrils and the magnitude
of airflow. If relative humidity remains constant, variable
112 Rhinitis
temperature indicates variable absolute water content.
Subtracting the water content of the air entering the nos-
trils from that in the nasopharynx yields a water gradient,
which is a measure of the air-conditioning capacity of the
human nose. Water gradient does not correlate with nasal
airway resistance, nasal volume, nasopharyngeal mucosal
temperature, or body temperature. This suggests that the
nasal mucosa possesses an intrinsic capacity to humidify
inhaled air. Using a similar methodology, another group
has shown that most of the air conditioning occurs in the
anterior segments of the nose [8].
As the nose warms and humidifies inhaled air, the
mucosa loses heat and water. Heat is lost not only in
the warming process, but also in humidification because
vaporization of water requires heat. At room temperature,
relative humidity, and normal ventilation rate, baseline
mucosal functions provide for heat and water losses.
When ambient temperature is significantly decreased, the
absolute water content of inhaled air is also lower (eg,
20°C air at 50% relative humidity contains much more
water than 0°C air at 100% relative humidity). Under this
circumstance, the nasal mucosa incurs much higher heat
and water losses in conditioning inhaled air and needs to
activate compensatory mechanisms to maintain homeo-
stasis. Increased ventilation rates (eg, during outdoor
winter sports) significantly magnify heat and water losses
and precipitate the compensatory process.
The ability of the nasal mucosa to provide heat and
water to inhaled air can be attributed largely to its structure
and function. The dense subepithelial capillary network,
characterized by fenestrations that are directed toward the
airway lumen [9], is probably the source of heat and water,
but the role of the fenestrae is not clear. In addition, the
venous sinusoid system likely contributes to the air-con-
ditioning capacity of the nose by allowing nasal mucosa
to engorge, expanding the heat- and water-exchange sur-
face [10]. Supporting this notion, studies have shown that
topical vasoconstrictors decrease the surface temperature
of the nasal mucosa [11] and the airstream temperature in
the oropharynx [12]. The nasal mucosa contains a large
number of seromucous glands—approximately 45,000
according to Tos [13]—but their role in the humidifica-
tion of inhaled air is unclear. More than 50 years ago,
Ingelstedt and Ivstam [14] demonstrated that the relative
humidity of inhaled air in the hypopharynx was reduced
after systemic injection of 1 mg of atropine. Recently,
however, using the system previously described for moni-
toring temperature and relative humidity, Assanasen et al.
[15] showed that ipratropium bromide delivered locally
to the nasal mucosa improved the ability of the nose to
warm and humidify cold air, even at high (20 L/min) flow.
This occurred despite a measured decrease in the secretory
response after the end of cold air exposure.
The most likely pathway through which water becomes
available for humidification is passive transfer across
intraepithelial junctions in response to osmotic forces
generated at the epithelium’s apical surface. At basal
conditions, during the inspiratory phase, small osmotic
gradients are probably generated by the movement of water
from the liquid into the vapor phase [16]. In this situation,
the epithelium does not generate an osmotic drive because
it predominantly absorbs sodium ions. If the rate of water
loss increases either by increased airflow or by inhalation
of substantially colder air, the periciliary fluid becomes
hypertonic, which can lead to reduced sodium absorption
followed by induction of chloride secretion [17]. These
changes will increase water transfer into the periciliary
fluid and restore homeostasis. Chloride secretion by the
epithelium is also increased by agents that induce cyclic
adenosine monophosphate (cAMP). These agents include
B2- and C-adrenergic agonists and prostaglandins (PG) E1,
E 2 , and F2a. A similar effect is produced by mediators such
as bradykinin, adenosine, eosinophil major basic protein,
substance P, and mast cell products [18,19]. Therefore,
sympathetic and tachykinin-containing nerve activation
and mucosal inflammation can increase chloride secre-
tion, resulting in water diffusion into the airway lumen.
Methacholine-induced human nasal secretions are hyper-
osmolar (approximately 340 mOsm/kg H 2O) [20], and
in vitro acetylcholine induces a large secretory flow of
sodium and chloride [17]; both observations suggest that
cholinergic stimulation also results in the generation of an
osmotic drive to provide water to the airway surface.
Some in vivo observations possibly can be attributed to
the preceding information. Using the nasal air-conditioning
monitoring system described earlier, Assanasen et al. [21]
have shown that 24 hours after a nasal allergen provoca-
tion, individuals with allergic rhinitis demonstrate increased
ability to provide water to inhaled air. This observation was
subsequently confirmed in individuals with perennial aller-
gic rhinitis [22]. Inversely, another study has demonstrated
that treatment of individuals with allergic rhinitis with
nasal glucocorticosteroids for 2 weeks decreases the ability
of the nose to humidify inhaled air [23]. The implications of
this observation are unknown, but it would not be surpris-
ing if the reduction in the water gradient caused by topical
glucocorticosteroid treatment was responsible for the devel-
opment of epistaxis (a common side effect) during winter.
Experimental Cold-air Rhinitis:
Pathophysiology of the Nasal Response
More than 20 years ago, we developed a model of cold,
dry air nasal provocation [24]. Individuals undergoing this
procedure breathe air through the nose in a unidirectional
manner (inhalation through the nose, exhalation through
the mouth) at subfreezing temperatures at 26 L/min for 15
minutes. Before and after cold-air breathing, they record
nasal symptoms in visual analog scales and undergo nasal
lavage. Inflammatory mediators or biomarkers can be
measured in the returned lavage fluids. In addition, cel-
lular analyses and measurement of the osmolarity of the
 Upper Airways Reactions to Cold Air Cruz and Togias 113
fluids can be performed. As a negative control, we have
used nasal breathing of warm (37°C) and moist (100%
relative humidity) air under the same flow.
The nasal cold air–breathing model offers substantial
information on the pathophysiology of cold air–induced
rhinitis and shows clear differences between two subject
groups. Subjects selected for a history of ambient cold
air–induced nasal symptoms develop rhinorrhea, nasal
congestion, and a burning sensation when they undergo
experimental cold-air challenge. In contrast, subjects cho-
sen because they lack cold air–induced symptoms upon
natural exposure do not develop symptoms upon experi-
mental nasal cold-air challenge. In the first group, nasal
lavage fluids obtained within 10 minutes after cold-air
provocation demonstrate increased levels (compared with
baseline) of mast-cell activation markers, including hista-
mine, PGD2 [24], and tryptase [25]. In addition, lavage
fluids contain increased levels of biomarkers of glandular
activation and plasma extravasation (eg, lysozyme and
albumin). No changes in the content of nasal lavage fluids
were observed in the cold air–insensitive group. Breathing
warm, moist air caused no or minimal symptoms and did
not lead to changes in the content of nasal lavage fluids.
We have further observed that cold air inhalation stimu-
lates sensory nerves and generates a cholinergic secretory
response [26]. When the challenge is performed only through
one nostril, secretions are generated in both nostrils. When a
local anesthetic is used in the challenged nostril, the contra-
lateral response is reduced. The same result is obtained when
the contralateral nostril is treated with atropine. Overall,
atropine reduces the cold air–induced rhinorrhea scores and
the levels of biomarkers of glandular activation, but does
not reduce nasal congestion or the levels of markers of mast
cell activation and plasma exudation [27], indicating that
the cholinergic response is not the sole mechanism through
which the nasal reaction takes place.
The clinical significance of mast cell activation dur-
ing the nasal reaction to cold air is not known. A topical
antihistamine that had been shown previously to block
allergen-induced symptoms and mast cell activation in
the human nose was not effective against the clinical
response to nasal cold-air challenge [28]. Seven days
of treatment with a nasal glucocorticosteroid, which is
known to inhibit the symptoms and mediator release of
the acute allergic reaction in the nose, did not reduce
nasal symptoms after cold-air challenge, although treat-
ment inhibited the cold air–induced increase in histamine
levels in nasal fluids [29].
Therefore, the clinical response to cold air cannot be
attributable to mast cell activation, but appears to be pri-
marily mediated by neural mechanisms with a sensory
element in the nasal mucosa and an effector element that
is mostly cholinergic. In support of this concept, cold-air
responses can be reduced with repetitive application of intra-
nasal capsaicin, which results in the defunctionalization of
tachykinergic sensory nerves (c-fibers) [30]. In addition,
anticholinergic agents can reduce rhinorrhea in skiers [4].
The Initiating Step in Cold-air Rhinitis:
Drying versus Cooling
Is heat loss or water loss the stimulus that elicits the nasal
mucosal reaction to cold air? Alternatively, could this
response reflect mechanical stimulation of the mucosa
by high airflow? The latter possibility is unlikely because
warm and moist air delivered at the same flow rate to the
nose of subjects who are sensitive to cold air causes mini-
mal, if any, nasal symptoms.
Based on the substantial loss of mucosal heat and
water during cold-air breathing, the obvious stimuli to be
considered responsible for the nasal reaction to cold air
should be cooling and hyperosmolarity. A debate is ongo-
ing regarding the role of these stimuli in exercise-induced
asthma, where warm and moist air can attenuate the
bronchoconstrictive response and cold air can potentiate
it [31,32]. Hyperventilation of cold air can induce bron-
choconstriction even in the absence of exercise.
Heat and water loss are tightly related: heating the air
in the nasal cavities cools the mucosa; at the same time,
water evaporates to humidify the air and mucosal water
loss occurs, potentially creating a hyperosmolar environ-
ment. Water evaporation, which requires large amounts
of heat, magnifies the cooling effect.
The temperature of the nasal mucosa can decrease
substantially during cold-air breathing: the nasopharyn-
geal mucosa is 32°C at baseline, but the temperature can
be reduced to approximately 23°C if cold air (-5°C) is
inhaled in a unidirectional manner (inhalation through
the nose, exhalation through the mouth) at a flow of 20
L/min for 8 minutes [15]. Can cooling lead to the patho-
physiologic phenomena observed during experimental
nasal cold-air challenge?
Mast cells show reduced ability for activation when
operating at lower temperatures: optimal temperature is
37°C for lung and intestinal and 32°C for skin mast cells
[33]. Cooling, on the other hand, could activate nasal
sensory nerves. Cation channels that act as cold receptors
have been identified and cloned [34–36]. These include
the transient receptor potential (TRP) melastatin 8 (M8)
receptor and the TRP ankyrin-like 1 (TRPA1) receptor,
the latter regarded as a nociceptor and the former as a
gentle cooling and menthol-sensing receptor [37•]. These
receptors have been identified on rodent trigeminal sen-
sory nerves; we do not know yet whether they are present
in sensory nerve endings of the human nose. In rodents,
the TRPA1 receptor is closely associated with the heat-
and capsaicin-sensing receptor TRPV1 [38], which is
probably present in human nasal mucosal sensory nerves.
At the end of a nasal cold-air provocation, increased
osmolarity of nasal secretions can be detected; however,
114 Rhinitis
this has been observed only in cold air–sensitive individu-
als and not in cold air–insensitive controls [20,39].
Human lung mast cells become activated and release
mediators when exposed to a hyperosmolar medium in
vitro [40]. Introduction of a hyperosmolar mannitol
solution in the human nose results in histamine and
PGD2 release in nasal lavage fluids, indicating in vivo
mast cell activation [41]; however, mast cell tryptase
cannot be detected [25]. Evidence for mast-cell activa-
tion has also been obtained when mannitol in powder
form is inhaled in the lower airways. Compared with
individuals who deny any nasal sensitivity to cold air,
those who develop nasal reactions to a cold-air challenge
also demonstrate a stronger response to nasal challenge
with hyperosmolar mannitol [42].
A hyperosmolar stimulus can certainly activate nasal
sensory nerves. Sanico et al. [43] applied 10-mm-diameter
filter paper discs impregnated with 50 μL of 5.13M saline
for 1 minute onto the septal mucosa of a single nostril.
This resulted in a bilateral secretory response. Pretreat-
ment of the challenged nostril with lidocaine reduced the
ipsilateral secretory response and almost completely abol-
ished the contralateral response. A hypertonic stimulus
probably activates capsaicin-sensitive nociceptor nerves. It
appears that the osmotic stimulus acts on the nonselective
cation channel TRPV1 [44], which is also the heat-sens-
ing capsaicin receptor [45]. In support of this concept,
hypertonic challenge in the human nose causes a burn-
ing sensation and repetitive capsaicin application in the
nasal mucosa down-regulates the response to hypertonic
saline [43]. Sensory nerve stimulation by hyperosmolarity
not only leads to the generation of a central reflex (eg, a
contralateral secretory response), but can also cause the
release of inflammatory neuropeptides by the same nerves.
Baraniuk et al. [46] clearly demonstrated that Substance
P is released in nasal secretions upon provocation with
hyperosmolar saline.
Theoretically, both cooling and water loss/hypertonic-
ity are good candidates as the primary stimulus for nasal
reactions to cold air. Yet, a stronger body of evidence
supports water loss/hypertonicity as the key stimulus. It
is quite possible that the two stimuli may work in concert
or that the relative importance of each is a function of
individual susceptibility.
Mucosal Dysfunction Underlying Cold
air–induced Rhinitis
Why does cold air–induced rhinitis primarily occur only
in some humans and not universally? The common belief
that “everybody’s nose runs in cold weather” probably
reflects the fact that, when the temperature of ambient
air is low, exhaled air rapidly cools and water vapor con-
denses, generating the perception of “runny nose.” This
is quite different from the nasal reaction that takes place
during an experimental cold-air challenge in which
condensation is not possible because cold air is inhaled
through the nose and exhaled through the mouth.
Individuals with cold air–induced rhinitis largely con-
stitute two categories: those who report cold-air sensitivity
among many nasal complaints (ie, who suffer from chronic
rhinitis), and those who report nasal cold-air sensitivity as
a single problem. Among individuals with chronic rhinitis,
more than 50% of those with perennial allergic disease
report cold air as a symptom trigger [6], and cold-air chal-
lenges elicit stronger responses in these persons compared
with healthy controls. Very interestingly, individuals with
asthma and allergic rhinitis are more responsive to nasal
cold-air challenge, compared with individuals who have
only allergic rhinitis [3•]. The prevalence of cold-air sen-
sitivity in nonallergic chronic rhinitis is not known. Like
patients with allergic rhinitis, those with chronic nonaller-
gic rhinitis have a stronger response to cold-air challenge
compared with healthy controls [47].
From the preceding observations, one could suggest
that cold air–induced rhinitis reflects a nonspecific state
of nasal hyperresponsiveness whereby a relatively small
increase in osmolarity or a slight decrease in nasal mucosal
temperature can generate a strong symptomatic mucosal
response. This response would rapidly restore mucosal
homeostasis and prevent epithelial damage. However,
the nasal response to histamine, which is regarded as an
acceptable measure of nasal hyperresponsiveness, does
not differ between individuals with and without cold-
air nasal sensitivity [42]. This apparent discrepancy may
reflect different molecular targets. Histamine-1 receptors,
which mediate histamine-induced sneezing and vascular
permeability in the human nose, are not present, at least
in the guinea pig, on the same sensory nerves as TRPV1,
the capsaicin receptor, which may be important in the
cold-air reaction [48]. Stimuli that activate TRPV1, such
as capsaicin and possibly hypertonic stimuli, do generate
augmented responses in individuals with allergic rhinitis
[43,49]. Therefore, some patients with allergic rhinitis
may manifest nasal hyperresponsiveness because of up-
regulation of TRPV1-driven pathways, whereas others
respond because of histamine-1 pathways. Cold-air sensi-
tivity would be categorized in the former group. A similar
hypothesis of pathway-specific hyperresponsiveness could
explain the unique sensitivity to cold air in patients with
nonallergic, noninfectious rhinitis [47], but could also
apply to individuals without chronic rhinitis.
Several additional features characterize individu-
als with cold air–induced rhinitis, including 1) increased
responsiveness to hypertonic stimuli [42], 2) increased
tonicity of nasal secretions at the end of a cold-air provo-
cation [39], and 3) increased numbers of epithelial cells
in nasal lavage fluids at the end of a cold-air provoca-
tion [50•]. Based on these characteristics, an alternative
hypothesis could be proposed that cold air rhinitis reflects
a defect of the mucosa to compensate for the water loss
that occurs with nasal inhalation of cold air (Fig. 1). If
 Upper Airways Reactions to Cold Air Cruz and Togias 115
Mucosal
Heat loss
cooling
Cold-air
breathing
Increased
Water loss
osmolarity
Desiccation
In individuals with Epithelial shedding
reduced ability to
condition air
Long-term consequences
of mucosal dysfunction?
Increased antigen penetration?
Altered innate immunity?
Chronic inflammation?
Figure 1. A schematic of our hypothesis concerning the pathophysiology of upper airway reactions to cold air.
water loss is not readily replenished, a strongly hypertonic
environment may develop rapidly in the luminal surface of
nasal epithelium. This can have two consequences: first,
hypertonicity may stimulate sensory nerves and mast-cell
mediator release, leading to the symptoms of cold-air rhi-
nitis; and second, hypertonicity may injure the epithelium,
leading to increased epithelial cell numbers in lavage fluids
after the end of cold-air exposure. One could argue that
the symptoms induced by cold air—rhinorrhea and nasal
congestion—are meant to restore mucosal homeostasis. If
this hypothesis were correct, one would expect the water
content gradient between the air in the nasopharynx and
the air in the entrance of the nose to be lower in indi-
viduals with cold air–induced rhinitis compared with cold
air–insensitive controls (who are less able to provide water
to inhaled air). This postulate has not been tested.
A defect in the ability of the mucosa to compensate
for excessive water loss may be primary or acquired. A
recent publication suggests that the nasal air-conditioning
capacity follows a familial aggregation pattern, support-
ing the notion of a primary “defect” [51]. One should
also raise the question whether such a condition can pro-
duce negative long-term consequences, including chronic
mucosal inflammation with increased antigen penetration
and mucosal innate immunity dysfunction, leading to an
increase in infections. This question is also unanswered, but
some intriguing observations are worth mentioning. First,
Assanasen et al. [52] have reported that the air-condition-
ing capacity of the nose of asthmatic patients with rhinitis
is lower than that of individuals with active allergic rhini-
tis alone. Second, we have reported that asthmatic patients
with rhinitis have stronger nasal responses to cold air,
compared with individuals with rhinitis alone [3•]. Third,
a respiratory epidemiology study published two decades
ago reported that cold-air rhinitis is a risk factor for lower
forced expiratory volume in 1 second [5]. Although this
line of thinking has several gaps, a hypothesis that a nasal
air-conditioning “defect” may have a pathogenetic role in
Sensorineural • Changes in epithelial
Homeostasis
stimulation ion transport
• Increased blood flow
Mast cell • Vascular engorgement Nasal symptoms
• Glandular activation
activation (short duration)
Clinical response
accentuated in the
presence of an
inflammatory condition
(eg, allergic rhinitis)
the development of chronic lower airways disease deserves
examination. This hypothesis may be of particular value
given the plethora of reports of elite winter sport athletes
developing asthma-like syndromes [53,54].
Conclusions
The reaction of the upper airways to cold air, which
reflects a frequent clinical complaint, offers a unique
opportunity to study nasal physiology and to understand
how the airway mucosa can maintain, lose, and subse-
quently restore heat and water homeostasis. In addition,
the nasal reaction constitutes a prototype for the reaction
induced by cold air in the lower airways, which manifests
with bronchoconstriction. Quite possibly, exercise-induced
bronchoconstriction is another form of the same response.
Cold air induces nasal sensory nerve and mast cell
activation. However, the role of mast cell mediators in
generating nasal symptoms after challenge with cold air
is questionable. The mechanism through which sensory
nerves and mast cells are activated is not clear, but more
evidence points to an increase in the osmolarity of the epi-
thelial surface milieu as opposed to mucosal cooling.
Intriguing observations raise the hypothesis that the
clinical sensitivity of the nasal airways to cold air reflects
a “defect” in the ability of the mucosa to keep up with
excessive water loss. The possibility also exists that this
impairment is stronger in patients with asthma because
their nasal responsiveness to cold air is more potent than
that of nonasthmatics. This may have implications in our
understanding of the genesis of asthma. We hope that
more effort will be devoted to this line of investigation in
the future.
Disclosures
No potential conflicts of interest relevant to this article
were reported.
116 Rhinitis
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