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The effect of intranasal carbon dioxide on the acute response to nasal challenge with allergen

Fuad M. Baroody, M.D., Laura Gavanescu, M.D., Jiang Hong Wang, M.D., Marcy DeTineo, B.S.N., and Robert M. Naclerio, M.D.

ABSTRACT Intranasal carbon dioxide (CO2) was shown to reduce symptoms of seasonal allergic rhinitis (SAR). This study was designed to evaluate the effect of CO2 on nasal allergen challenge. We conducted a randomized, controlled, crossover trial in 12 subjects with SAR outside their pollen season. Thirty minutes after a 20-second exposure to CO2 or no exposure, subjects underwent a unilateral, localized, nasal allergen challenge. Filter paper disks were placed on the nasal septum to deliver a sham challenge followed by 2 increasing doses of either grass or ragweed allergen. Secretions were collected from both sides of the septum to evaluate the nasonasal reflex and were assayed for histamine. Nasal and eye symptoms were recorded. The primary outcome measure was the contralateral, reflex, secretory response to allergen as measured by secretion weights. Secondary outcome measures included ipsilateral nasal secretion weights, nasal and eye symptoms, levels of histamine in nasal secretions, and eosinophils in nasal scrapings. Subjects reported a transient burning sensation during exposure to CO2. Compared with no treatment, active treatment resulted in a significant reduction in sneezes (p 0.05), contralateral secretion weights (p 0.04), and bilateral runny nose symptoms (p 0.01). Ipsilateral secretion weights were numerically reduced. Histamine levels in ipsilateral nasal secretions increased significantly when the subjects received sham treatment but did not increase after pretreatment with CO2. Treatment with nasal CO2 resulted in partial reduction of the acute response to allergen challenge. Reflex responses were reduced, supporting an effect on neuronal mechanisms, which predict usefulness in the treatment of allergic rhinitis. Registered with the U.S. National Institutes of Health clinicaltrials.gov. Identifier: NCT00618410. (Allergy Asthma Proc 32:206 212, 2011; doi: 10.2500/aap.2011.32.3442) llergic rhinitis is a common disease that causes significant morbidity and adversely affects the patients quality of life.1 The pathophysiology of the disease involves an acute response dominated by mast cell release of inflammatory mediators such as histamine and leukotrienes. In addition to this acute release of mediators, the nasal mucosa becomes infiltrated with inflammatory cells including eosinophils and lymphocytes.2 This inflammation results in spontaneous symptoms and heightened reactivity of the nasal mucosa to further allergen exposure and nonspecific irritants.2 Challenge of allergic subjects with the relevant allergen in a laboratory setting has shown that the allergic response is amplified by the nasonasal35 and nasal ocular reflexes.6 The nasonasal reflex is a secretory

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From The Section of OtolaryngologyHead and Neck Surgery, The University of Chicago Medical Center and The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois Presented at the meeting of the American Academy of Allergy Asthma and Immunology, March 17, 2009, Washington, D.C. Supported in part by the McHugh Otolaryngology Research Fund and a grant from CAPNIA, Inc. The authors have no conflicts to declare pertaining to this article Address correspondence and reprint requests to Fuad M. Baroody, M.D., F.A.C.S., Section of OtolaryngologyHead and Neck Surgery, 5841 South Maryland Avenue, MC1035, Chicago, IL 60637 E-mail address: fbaroody@surgery.bsd.uchicago.edu Copyright 2011, OceanSide Publications, Inc., U.S.A.

reflex in the contralateral nasal cavity in response to unilateral allergen3 or other sensory stimulants such as cold dry air,7 histamine,8 and capsaicin.9 Although histamine is only released on the side of the challenge with antigen, an oral H1-antihistamine reduces the contralateral response to unilateral nasal allergen challenge,5 and a topical antihistamine inhibits the nasal ocular reflex,6 suggesting that histamine contributes to the initiation of the reflex. The secretory reflex is also effectively reduced by topical anticholinergic agents applied to the contralateral nasal cavity, suggesting that the efferent limb is parasympathetically mediated.3 Other evidence supporting the role of nerves in the nasal allergic response centers on the identification of sensory nerve peptides in the nasal mucosa and the recovery of these neuropeptides in nasal secretions after allergen provocation.10 Despite the availability of multiple treatments for allergic rhinitis, a large number of patients continue to have bothersome symptoms.11,12 In an attempt to explore novel therapies for the disease, Casale and colleagues administered intranasal noninhaled carbon dioxide (CO2) and examined its effects on allergic symptoms during natural seasonal exposure.13 The results showed that intranasal CO2 resulted in improvement in the total nasal symptoms of allergic rhinitis compared with placebo. Similar beneficial effects were noted in patients with perennial allergic rhinitis.14

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The rationale for the use of CO2 is that it has been shown to inhibit neuronal activation and calcitonin gene-related peptide (CGRP) release when administered to cultures of trigeminal neurons in buffered media.15 Because trigeminal neuronal activation and release of CGRP occur in allergic rhinitis,10 it is speculated that intranasally applied CO2 might have an inhibitory effect on the disease via this mechanism. Furthermore, intranasal CO2 has also been shown to be effective in the abortive treatment of migraine headache,16,17 with a proposed mechanism of action of inhibitory activity associated with the same neuronal processes. Another potential mechanism of action of CO2 in allergic disease is the inhibition of mast cell histamine release, which has been shown in rat peritoneal mast cells in vitro.18 To investigate possible mechanisms of CO2 in allergic rhinitis, we examined the effect of intranasal CO2 on nasal challenge with allergen with special emphasis on nasonasal reflexes and mast cell histamine release. METHODS Study Design We performed a randomized, two-way crossover study in subjects with seasonal allergic rhinitis out of season. Subjects came to the Nasal Physiology Laboratory for screening, where they completed an allergy questionnaire and underwent skin-prick testing for confirmation of a grass or ragweed allergy. The skin test included positive and negative controls and the results were graded compared with the controls as 1 to 4 (1, wheal larger than negative control and smaller than positive control; 2, wheal 57 mm; 3, wheal 710 mm; 4, any reaction with a wheal 10 mm or pronounced pseudopodia). Subjects with positive skin test (between 2 and 4) and a positive history of allergic symptoms during the relevant seasons then underwent a screening nasal challenge with either grass or ragweed allergen. Subjects who passed the screening challenge (twofold increase in either ipsilateral or contralateral nasal secretions after allergen challenge compared with diluent) had a 2-week washout period and returned to the laboratory, where they were randomized to receive intranasal treatment with either CO2 or no treatment. Thirty minutes after treatment, subjects underwent a nasal challenge with allergen. Seven subjects were challenged with ragweed and five subjects were challenged with grass. Subjects had another 2-weeks washout period and were then crossed over to the other treatment followed by a similar challenge. Previous work in our laboratory using a similar challenge system showed that allergen-induced inflammatory changes are back to baseline 2 weeks after the challenge.19 The study was approved by the Institutional Review Board of The University of Chi-

cago and all subjects gave written informed consent before entry. Subjects Twelve subjects participated. Subjects were studied outside their allergy season. All subjects were healthy except for mild asthma requiring only as-needed bronchodilators. They were not on any medications and had not received antihistamines or leukotriene receptor antagonists for at least 1 week and intranasal steroids for at least 1 month before enrollment and for the duration of the study.

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Treatment CO2 was applied for 10 seconds in each nostril using a special applicator (plastic tight-seal nosepiece) attached to a CO2 canister and a flow control valve. It was delivered at a flow rate of 0.5 standard L/min with the mouth open to prevent inhalation. Thus, for 20second duration of administration, the total dose of CO2 delivered was 167 mL. The amount of CO2 delivered to the mucosa is unknown. The no-treatment arm involved placement of the device but no gas was delivered. Therefore, neither the subjects nor the investigators were blinded to the treatment administered. The no-treatment arm did not involve the delivery of air without CO2 to the nose because we were concerned that blowing dry air into the nose might cause a mucosal reaction that could confound the results. We have previously shown that cold, dry air challenges create a hyperosmolar environment, triggers mast cell activation, and induces a nasonasal reaction.7 Thus, because our primary outcome was the objective measure of the nasonasal reflex, we avoided this possibility.

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Nasal Challenge The subjects were allowed 15 minutes to acclimatize to the laboratory environment before challenge. Baseline sneezes reflecting the 15 minutes of acclimatization and nasal and eye symptoms were recorded followed by collection of a nasal scraping for quantitation of eosinophils in nasal secretions (Fig. 1). Sneezes were recorded by the subjects during each of the assessed intervals of the challenge protocol. The subjects were reminded to keep track of the number of sneezes by the research coordinator who was present for the duration of the challenges. Intranasal CO2 or sham was then applied for 10 seconds to each nostril. Thirty minutes later, sneezes and symptoms were recorded again, to reflect the 30-minute time period, and nasal challenge was initiated. Because we were interested in evaluating the effect of the treatment on allergen-induced nasal reflexes, we used filter paper disks to perform the challenges and monitor the secretory response as previously described.3

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Figure 1. Treatment and challenge protocol. Timeline for pretreatment with CO2 (or no treatment) and allergen challenge protocol. The numbers under the timeline are all in minutes except the last number, which denotes 24 hours. The length of the lines is not proportional to the time denoted under them. After completion of one such challenge, the subjects were allowed to wash out for 2 weeks and were crossed over to the other treatment and an identical challenge protocol. Snz, sneezes; Sxs, symptoms; scraping, nasal scraping obtained for eosinophils; Dil, diluent for the allergen extract; Antigen, either grass or ragweed allergens.

Briefly, 8-mm filter paper disks (Shandon, Inc., Pittsburgh, PA) were used for both nasal challenge and collection of resultant secretions. They were placed on the anterior nasal septum, beyond the mucocutaneous junction, under direct vision using a nasal speculum, forceps, and a headlight. Fifty microliters of challenge solutions were placed on the disks, which were then applied to the nasal septum for 1 minute. Thirty seconds after removal, two preweighed filter paper disks were placed on both sides of the nasal septum for 30 seconds, collecting nasal secretions from the challenge site (ipsilateral) and the contralateral nostril. These disks were then immediately placed back into microtubes and weighed. The difference in their weight before and after challenge was the weight of produced nasal secretions, which was recorded in milligrams. Ten minutes after each challenge, the number of sneezes as well as symptoms on each side were recorded by the subjects reflective of the 10-minute interval (Fig. 1). The first challenge was performed using phenol-buffered saline, the diluent for the allergen extracts, and this was followed by 2 increasing doses of grass or ragweed allergen (Fig. 1). The time from treatment administration to the first allergen challenge was 40 minutes and to the second allergen challenge, 50 minutes. The amount of allergen applied on the paper disks for challenge were 333 and 1000 BAU (bioequivalent allergy unit) of grass allergen extract (HollisterStier, Spokane, WA) or 50 L of ragweed antigen extract at concentrations of 1:666 and 1:200 w/v (HollisterStier). The subjects came back to the laboratory 24 hours later and underwent a scraping of their nasal secretions to evaluate for eosinophil influx.

for each nasal cavity separately, whereas eye symptoms reflected the status of both eyes.

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Secretion and Mediator After collection of nasal secretions, the filter paper disks were replaced in Eppendorf tubes and the disk/ tube combination was weighed to record produced secretions. Three hundred microliters of 0.9% sodium chloride solution was then placed in the tubes and mediators were allowed to elute from the disks for 24 hours at 4C. The eluate was then transferred to tubes and stored at 20C until assayed for histamine.3 Histamine Assay Histamine was assayed by ELISA (Oxford Biomedical Research, Oxford, MI). The lower limit of detection of the assay is 2.5 ng/mL and samples below the detection limit were arbitrarily assigned a value of 1.25 ng/mL.

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Eosinophil Quantitation A scraping of the septal mucosa was obtained before and 24 hours after the allergen challenges using a Rhinoprobe (Arlington Scientific, Inc., Springville, UT). The secretions were smeared on a slide, air-dried, and stained with a modified Wrights stain (DiffQuick Stain Set; Dade Behring, Inc., Newark, DE) and covered. The slides were then evaluated by an independent observer under oil immersion and 1000 magnification. The number of eosinophils per 200 white blood cells was counted and the percentage of eosinophils was recorded. Statistics A power calculation was performed before the initiation of the study based on our previous work with the same challenge system showing the nasonasal reflex.3,4 The calculation was based on the total change from the diluent response in the contralateral secretory response to

Symptoms The number of sneezes was recorded after each challenge, reflecting the time period since the challenge. Symptoms of congestion, rhinorrhea, itchy nose/ throat, itchy eyes, and watery eyes were rated on a scale from 0 to 3 (0, none; 1, mild; 2, moderate; 3, severe) by the subjects. Nasal symptoms were recorded

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Table 1 Allergen-induced nasal responses after no treatment Parameter Sneezes (no.) SW ipsi (mg) SW con (mg) RN ipsi (score) RN con (score) SN ipsi (score) SN con (score) Eye tot (Score) His ipsi (ng/mL) His con (ng/mL) Dil 0 (00) 4.2 (1.88.6) 5.5 (2.510.3) 0 (01) 0 (01) 0.5 (02) 0 (02) 0 (01) 1.3 (1.31.3) 1.3 (1.31.3) Ag 1 0.5 (05) 12.5 (2.521.8) 14.2 (2.433.5) 1.0 (03) 0.5 (03) 1.5 (03) 1.0 (03) 0 (02) 2.8 (1.37.7) 1.3 (1.34.2) Ag 2 0 (011) 21.0 (3.748.5) 15.8 (2.334.3) 1.5 (03) 1.5 (03) 2.0 (03) 1.5 (03) 0.5 (03) 2.0 (1.37.2) 1.3 (1.37.3) ANOVA p Value 0.001 0.001 0.097 0.001 0.001 0.001 0.001 0.001 0.013 0.15 p Value Dil vs Ag 1 0.03 0.006 * 0.006 0.023 0.01 0.003 0.025 0.018 * p Value Dil vs Ag 2 0.04 0.002 * 0.007 0.01 0.07 0.03 0.02 0.028 *

Numbers are depicted as medians (range). All p values are significant except the ones set in bold type. *ANOVA analysis was not significant so no post hoc testing was performed. Dil diluent; Ag allergen; Ipsi ipsilateral to challenge; Con contralateral to challenge; SW secretion weights; RN runny nose; SN stuffy nose; Tot total; His histamine.

allergen challenge and showed that having 12 subjects would have 80% power of detecting a difference of 8 mg between treatments. The primary outcome measure was therefore the contralateral secretory response to allergen as measured by contralateral secretion weights. All other evaluated measures were secondary. The data obtained from the challenges were not normally distributed and were analyzed using nonparametric statistics and graphed as either medians or individual data points and median bars. We first evaluated the response to allergen after the no-treatment arm to indicate the existence of a significant response to allergen. This was achieved by performing a Friedman analysis of variance to assess for overall significance of the responses (baseline, diluent, and allergen). Post hoc analysis was then conducted to determine the significance between the diluent response and the respective allergen responses using the Wilcoxon signed-ranks test. To compare the two treatments, we calculated the net change from the diluent response by subtracting the diluent response from each allergen response and summing those numbers. These net changes were then compared between treatments using the Wilcoxon signed-ranks test. Statistical analysis was performed using SYSTAT 12 software (Systat Software, Inc., Richmond, CA).

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fore the initiation of the allergen challenge. There were no significant effects of administration of CO2 on the number of sneezes or nasal or eye symptoms (p 0.05).

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Responses after Allergen Challenge in the No-Treatment Arm The responses after diluent and both allergen challenges with the patients on no therapy are depicted in Table 1. As can be seen, there were significant increases in most parameters after allergen challenge compared with diluent except for contralateral secretion weights and histamine levels in nasal secretions. Contralateral secretion weights, our primary outcome measure, showed an increase after allergen challenge compared with diluent but the differences were not statistically significant. Contralateral runny nose scores did, however, show a significant increase after allergen compared with the diluent response, suggesting a nasonasal secretory reflex response. The reason behind the discrepancy between the results of objective and subjective measures of the nasonasal reflex secretory response are not clear but are probably related to individual variability of these responses. It is to be kept in mind that the trends are very similar. Effect of Active Treatment As mentioned previously, the net change from the diluent response for every response parameter was calculated after active and no-treatment arms. These values were compared to determine treatment effect and are shown in Table 2. Pretreatment with intranasal CO2 resulted in a significant reduction in sneezes (Fig. 2), ipsilateral and contralateral runny nose symptoms (Fig 3.), and contralateral secretion weights (our primary out-

RESULTS Safety Although the subjects complained of a short-lasting, temporary, burning sensation after CO2 administration, treatment was well tolerated and there were no other adverse effects throughout the study of either treatment or allergen challenge. Sneezes and nasal and eye symptoms were evaluated at baseline and after treatment, be-

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Table 2 Effect of pretreatment with CO2 on allergen-induced nasal responses Parameter Sneezes (no.) SW ipsi (mg) SW con (mg) RN ipsi (score) RN con (score) SN ipsi (score) SN con (score) Eye tot (score) His ipsi (ng/mL) His con (ng/mL) Sham 2.0 (014) 32.6 (049.7) 19.6 (055.2) 2.0 (06) 2.0 (05) 2.0 (16) 2.0 (16) 1.0 (04) 2.04 (010.4) 0.0 (09.1) CO2 0 (05) 9.0 (4.890.4) 6.0 (3.154.1) 0.0 (04) 0.0 (04) 0.0 (16) 0.0 (16) 0.5 (25) 0.0 (2.716.6) 0.0 (1.21.7) p Value 0.05 0.099 0.041 0.014 0.014 0.1 0.07 0.7 0.26 0.14

The numbers in the Sham and CO2 columns represent the net change from the diluent response after allergen challenge. Numbers depicted are medians (range). The p value is the comparison between treatments. Significant P values are denoted in bold. Ipsi ipsilateral to challenge; Con contralateral to challenge; SW secretion weights; RN runny nose; SN stuffy nose; Tot total; His histamine.

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Figure 2. The effect of intranasal CO2 on the sneezing response. The graph on the left represents median responses at baseline (Base) after treatment (Post Rx), and after dilvent (Dil) and allerge (Ag) challenges. The graph on the right represents the net change from the diluent response after allergen challenges. Individual data are plotted. Bars represent median values (*p 0.05 versus sham treatment and diluent).

Figure 3. The effect of intranasal CO2 on contralateral runny nose scores. The graph on the left represents median responses X-axis labels identical to Fig. 2. The graph on the right represents the net change from the diluent response after allergen challenges. Individual data are plotted. Bars represent median values.*(p 0.02 versus sham treatment and diluent).

come measure), (Fig. 4) compared with sham treatment. There were no significant effects on ipsilateral secretion weights, stuffy nose symptoms, total eye symptoms, or histamine levels (Fig. 5) in secretions. There were no significant increases in the percentage of eosinophils after allergen challenge after either no treatment or CO2 treatment and no effect of CO2 on this negligible response (data not shown).

DISCUSSION Our study supports the previously documented positive inhibitory effect of intranasal CO2 on the symptoms reported by patients with allergic rhinitis.13,14 The difference between our study and the seasonal study, performed by Casale and colleagues, is that they examined the effect of CO2 on natural seasonal disease whereas we studied the pathophysiology in a chal-

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Figure 4. The effect of intranasal CO2 on contralateral secretion weights. The graph on the left represents median responses. X-axis labels identical to Fig. 2. The graph on the right represents the net change from the diluent response after allergen challenges. Individual data are plotted. Bars represent median values (*p 0.04 versus sham treatment).

Figure 5. The effect of intranasal CO2 on levels of histamine at the site of nasal challenge. The graph on the left represents median responses. X-axis labels identical to Fig. 2. The graph on the right represents the net change from the diluent response after allergen challenges. Individual data are plotted. Bars represent median values. NS, not significant.

lenge system in allergic subjects out of season. Therefore, in addition to studying the effect of CO2 treatment on nasal symptoms, we were able to look at its effects on neural reflexes (sneezing and the nasonasal and nasal ocular reflexes), as well as mast cell degranulation as assessed by histamine release. Another difference is that they administered a higher total dose of CO2 to the subjects. We used a total dose of 167 mL of CO2 administered for 10 seconds in each nostril and they used a total dose of 1200 mL administered over 60 seconds to each nostril. Pretreatment with intranasal CO2 in our study resulted in inhibition of the sneezing response after allergen challenge, a symptom related to stimulation of sensory nerves by the mediators generated during the allergic reaction. Furthermore, nasal challenge resulted in a contralateral nasal secretory reflex (increase in runny nose symptoms) as well as a significant increase in ocular symptoms when the subjects were exposed to no treatment duplicating the previously described nasonasal and nasal ocular reflexes.3,6 Pretreatment with CO2 resulted in inhibition of contralateral nasal secretions and runny nose symptoms, supporting its inhibitory effect on neural reflexes. Ipsilateral secretions are the result of the direct stimulation of nasal glands by the mediators released after allergen challenge, vascular leakage stimulated by the same mediators, and a potential axonal reflex secondary to allergen challenge. CO2 might not have been as effective in inhibiting this response. There was a tendency for CO2 to inhibit the

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nasal ocular reflex as evidenced by lack of a significant increase in total eye symptoms after allergen challenge compared with the diluent response. However, when the net change from the diluent response was compared between treatments, the reduction of that parameter by CO2 was not statistically significant. This could be related to the fact that the number of subjects used for this study did not provide enough power to show an effect of the treatment on the nasal ocular reflexes. In our previous studies evaluating the effect of intranasal treatments on this reflex, 20 patients were used.6,20 Our current study was powered for establishment of an inhibition of the nasonasal reflex, which it achieved. When examining the effect of treatment on levels of histamine in ipsilateral nasal secretions; there was no effect of active treatment on these levels when the net change from the diluent responses was analyzed. When one examines the data further, there was a significant increase in histamine levels after the 2 allergen doses compared with diluent when the patients received no pretreatment, whereas there was no significant similar increase when the subjects were premedicated with CO2 (Fig. 5). This suggests that there was a tendency of the treatment to inhibit the release of histamine. If indeed so, then this would, in turn, result in inhibition of the histamine-induced nasonasal reflex responses. In fact, in the current study, there was a positive correlation between histamine release on the side of challenge and the contralateral, reflex, increase in nasal secretions. The correlation was stronger when

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the patients received no treatment (r2 0.39) than after they were pretreated with CO2 (r2 0.06). This further supports the role of allergen-induced histamine release in the initiation of the nasonasal reflex response. Support for the possible inhibitory effect of CO2 on mast cell histamine release is provided by recent in vitro data that evaluated the effect of CO2 on rat peritoneal mast cells.18 In these experiments, the investigators report a significant inhibitory effect of CO2 on 48/80 stimulated mast cell release. Whether or not this would also apply to human in vivo nasal mast cell histamine release has not been studied except in the data presented in this article and would certainly warrant confirmation in other experiments that would be powered to show effects on antigen-induced histamine release. Intranasal CO2 has been shown to affect nerves in multiple settings. Noninhaled intranasal CO2 is effective in the abortive treatment of migraine headache.16,17 Migraine headache is associated with trigeminal neuronal activation and release of CGRP, a neuropeptide also implicated in allergic rhinitis. In vitro studies with cultured neurons have shown that CO2 reduces intracellular pH while simultaneously suppressing neuropeptide secretion, in particular, CGRP.15 Indeed, the drop in pH after intranasal exposure to CO2 has been documented in humans by measurements of nasal mucosal pH.21 Furthermore, the transient pain experienced by the subjects after CO2 administration speaks to an effect on nasal nerves. Thus, it is plausible that premedication of the nasal mucosa with CO2 resulted in a reduction in the pH of the nasal mucosa and subsequent inhibition of neural transmission leading to an inhibition of the nasonasal reflex responses. Intranasal CO2 could also inhibit allergen-induced inflammation by its inhibitory effect on the release of neuropeptides, which might be responsible for the positive effect observed in earlier clinical studies.13,14 This potential mechanism was not addressed by our study, because we focused on histamine release and nasal reflex responses. In summary, our data support a previously established inhibitory effect of intranasal CO2 administration on the nasal allergic response. The effect was evident on sneezes, nasal symptoms, and nasonasal reflexes. It is difficult to conclude from our results whether the inhibitory effect of CO2 was related to its reduction of histamine release after challenge or to a direct effect on nerve stimulation in response to histamine or both. Our experiment was not designed to address these mechanisms and was intended to provide preliminary objective evidence of the efficacy of intranasal CO2 in allergic rhinitis. This objective data and the results of clinical studies using patient reported outcomes warrant serious study of CO2 as a possible therapeutic agent in allergic rhinitis.

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