Daniel A. Ramirez

The natural history of mountain cedar pollinosis

During the winter months, pollen from the mountain cedar (MC) (Juniperus sabinoides) causes severe respiratory tract allergy in central Texas. We have been impressed with the fact that many of our MC-allergic patients had only allergic rhinitis and were only sensitive to MC pollen. We therefore studied 234 unselected MC-allergic patients at the end of the MC season. The main criteria for inclusion into the study was a bona fide history of MC pollinosis confirmed by a positive skin test. All patients completed a detailed history questionnaire, were prick skin tested by using 1:20 w/v, extracts, and had a total IgE determined with commercially available reagents (PRIST). Thirty-four percent of patients were found to be allergic only to MC and 66% were allergic to MC and other aeroallergens. As a group, patients allergic only to MC had significantly lower total IgE levels (84 IU/ml vs. 360, p less than 0.001) (normal less than 180), required much longer exposure intervals to cedar pollen before developing MC pollinosis (14.4 yr vs. 5.69, p less than 0.001), had less of a family history of allergic disease (43% vs. 88%, p less than 0.001), had less of a history of asthma or eczema (11% vs. 39%, p less than 0.001), and developed allergic disease at a later age (39 yr vs. 13, p less than 0.001) when compared to patients with multiple allergies. These results suggest that the MC pollen may be unique in causing allergic rhinitis in patients who have no other sensitivities. A possible explanation may lie in the carbohydrate nature of the main allergen of the MC pollen, which may facilitate allergen transport through the respiratory tract mucosa and subsequent sensitization.

Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes

BACKGROUND The level of concordance between allergic symptoms induced on exposure to pollen in a pollen challenge chamber (PCC) versus the natural season is unknown. OBJECTIVE We sought to test the hypothesis that the symptom levels of allergic rhinoconjunctivitis elicited after out-of-season exposure to short ragweed in a PCC and during the natural season for giant ragweed pollen are highly correlated. METHODS Thirty-one ragweed-sensitive participants recorded symptoms for 15 days during the natural giant ragweed season in San Antonio, Texas. Twenty-six of these participants were challenged to short ragweed pollen in a PCC for 3 hours per day for up to 4 days. RESULTS In the PCC participants were dichotomized into those in whom low versus high levels of symptoms developed slowly or rapidly (ie, slow/low vs rapid/high). Each successive exposure visit associated with a progressive increase in symptom levels that approximated those experienced during the natural season. Hierarchic clustering identified 3 endotypes: endotypes I and II reflected concordantly low (n= 7) versus high (n = 14) total symptom scores (TSSs) in both the natural season and the PCC, respectively. Accordingly, the correlation between the TSSs recorded in the natural season and in the PCC for these 21 participants was very high. Although participants with endotype III (n = 5) had greater TSSs in the natural season than in the PCC, the degree of correlation between the TSSs remained high. CONCLUSIONS Our findings affirm our hypothesis, underscore the high cross-reactivity between distinct pollens, and highlight the utility of the PCC to identify novel allergy endotypes that might have contrasting mechanistic underpinnings and potentially therapeutic responses.

Effect of confounding cofactors on responses to pollens during natural season versus pollen challenge chamber exposure.

BACKGROUND The severity of allergic rhinoconjunctivitis (AR) symptomatology elicited after exposure to pollen in the absence versus the presence of confounding cofactors, such as in a pollen challenge chamber (PCC) and the natural pollinating season, respectively, might differ. OBJECTIVE We sought to determine the correlation of AR severity in the natural season versus out-of-season PCC exposures. METHODS Twenty-four Virginia live oak (VLO)-positive, 14 VLO-negative, 16 mountain cedar (MC)-positive, 8 MC-negative, and 26 ragweed-positive participants recorded AR symptoms (total symptom score [TSS]) during the VLO, MC, and ragweed pollinating seasons and during 2 consecutive PCC exposures of 3 hours each to these pollens separately. RESULTS The TSSs recorded before the natural season were higher than the pre-PCC values. This prepriming was greater among VLO(+) than MC(+) participants, and it blunted further increases in TSSs during the VLO natural season. Nonatopic participants were nonreactive in the PCC. There was wide variation in the level of AR symptomatology after exposure to VLO, MC, or ragweed pollen in the PCC. Prepriming formed the basis for higher AR responses observed in the natural season than in the PCC, resulting in the identification of distinct PCC/natural season endophenotypes and a partial correlation between the TSSs recorded in the natural season versus those recorded in the PCC (r = 0.34, 0.54, and 0.65 for VLO(+), MC(+), and ragweed-positive participants, respectively). CONCLUSIONS Prepriming in the natural pollinating season might obscure the true correlation between AR severity in the natural season versus the PCC. By mitigating confounding cofactors, PCC exposures have utility for evaluation of novel AR therapeutics.

Assessment of high-sensitivity C-reactive protein as a marker of airway inflammation in asthma

BACKGROUND Limited data are available on the presence of a systemic measure of inflammation in asthma. One marker that has been reported is C-reactive protein (CRP). OBJECTIVE To examine the correlation between high-sensitivity CRP (hsCRP) and asthma activity. METHODS Fifty-four patients with physician-diagnosed asthma, ages 6 to 58 years, were enrolled in the study. In addition to medical history and physical examination, asthma was assessed according to the National Asthma Education and Prevention Program (NAEPP) control score, fractional exhaled nitric oxide (FeNO), and spirometry. The relationships between hsCRP and each of the asthma control measures (ie, NAEPP control scores, presence of wheeze, FeNO, and forced expiratory volume in 1 second [FEV1]) were calculated. RESULTS The hsCRP levels in all patients ranged from less than 0.5 to 14.1 mg/L, with a mean (SD) of 2.1 (2.9 mg/L), compared with less than 0.5 mg/L expected in healthy individuals. The FEV1 percentage predicted ranged from 48% to 130%, with a mean (SD) of 96.5% (17.5%). Correlation coefficients for hsCRP vs FEV1 and FeNO were 0.07 and -0.03, respectively. Neither of these values reached statistical significance. The chi2 analysis values for hsCRP vs the NAEPP scores, wheeze, FEV1, and FeNO were 0.00, 2.16, 1.32, and 2.08, respectively, with none being statistically significant. CONCLUSIONS Our study of patients with asthma, mostly of a mild severity, did not reveal any significant correlation between hsCRP and wheeze, NAEPP control score, FEV1, or FeNO. Larger studies with a more diverse level of asthma control are warranted in examining the utility of hsCRP in the evaluation of asthma.

Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.

Background: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. Objective: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. Methods: Twenty‐three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M−) participants completed 3‐hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing–derived expression profiles of nasal cells, before and after HDM exposure. Results: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M− participants; gross differences in these parameters were not observed at baseline (pre‐exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T‐cell activation levels initially decreased in M− participants versus increased in M+ participants. Second, in M− compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament‐aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. Conclusion: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T‐cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

Redness response phenotypes of allergic conjunctivitis in an allergen challenge chamber

BACKGROUND There are few direct data concerning symptom dynamics of allergic conjunctivitis (AC) in an allergen challenge chamber (ACC). OBJECTIVE To determine the AC dynamics on subsequent exposures to ragweed pollen (RW) in individuals with allergic rhinitis in an ACC. To determine whether consecutive exposures in an ACC have any persistent detrimental ocular physical effects. METHODS Participants underwent 3 exposures to RW in an ACC. Ocular symptoms of itching and tearing were self-assessed. Ocular redness and lid swelling were assessed by trained ophthalmic technicians. Complete ophthalmic examinations (COEs) were performed by an ophthalmologist. RESULTS A total of 188 of 201 participants (93%) developed an ocular redness score of 2 or more in each eye in ACC exposure 1. Reproducibility of redness occurred in approximately 70% of individuals completing ACC exposures 1 through 3. There were no significant changes between baseline COE and end of study COE. Phenotypes were identified by redness responses during and after exposure. Baseline total ocular symptom scores, at 24 hours after a priming exposure, were identified as late-phase reactions rather than enhanced sensitivity. CONCLUSION When assessed by trained professionals, AC was present with a very high frequency in selected individuals allergic to RW monitored in an ACC. Intrasubject reproducibility of redness was consistent across 3 ACC allergen exposures. Phenotypes were identified as early-phase responses, protracted early-phase responses, dual responses, and late-phase responses. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02079649.