Overall symptom severity as a patient-reported outcome measure for chronic rhinosinusitis: what it reflects and how to measure it.

BACKGROUND: The objective of this study was to identify how - and to what extent - overall symptom severity (OSS) score reflects individual chronic rhinosinusitis (CRS) symptoms and whether it can be measured using alternatives to the standard visual analog scale (VAS). METHODS: CRS patients from four sites across three continents rated their OSS scores, severities of nasal obstruction, nasal drainage, decreased sense of smell, facial pain/pressure and sleep disturbance using a standard VAS, VAS with labeled tick marks at every 1 centimeter, and by writing down their OSS on a scale of 0 - 100 (which was divided by 10), all of which lead to severity scores ranging from 0 - 10 in 0.1 intervals. Quality of life was measured using the SNOT-22 and EQ-5D VAS. RESULTS: In 311 CRS patients, OSS score was significantly correlated with SNOT-22 and EQ-5D VAS. OSS score was most greatly associated with the mean of all individual symptom severity scores. From individual CRS symptoms, OSS was most greatly associated with nasal obstruction followed by nasal drainage and facial pain/pressure severities. These results held true for participants with and without nasal polyps. Measurement of OSS and individual symptom severity scores using a standard VAS, tick-marked VAS, and write-in option had near-perfect consistency. CONCLUSIONS: We demonstrate for the first time that OSS largely reflects the mean of individual CRS symptom severities, although OSS is=== most weighted by nasal obstruction severity. OSS and individual symptom severity scores can be measured using a standard VAS, tick-marked VAS or write-in prompt with near-perfect consistency.

Efficacy and safety of switching between biologics in chronic rhinosinusitis with nasal polyps or N-ERD.

BACKGROUND AND OBJECTIVE: The effectiveness of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP) is well-established. However, real-world experience on the effectiveness of transitioning between two monoclonal antibodies is scarce. Therefore, we aimed to analyze the safety and efficacy of antibody switching in treatment of chronic rhinosinusitis. METHODS: All patients with CRSwNP or nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) requiring a switch between biologics were retrospectively studied. Analysis included changes in polyp size, quality of life parameters, asthma control, and side effects. RESULTS: Out of 195 patients treated with biologics for CRSwNP or N-ERD in our center, 23 (11.8%) required transition to a different monoclonal antibody. The majority switched from omalizumab to dupilumab (17/23, 73.9%), mostly due to inadequate symptom control. Nine out of these 17 patients (52.9%) were switched without a washout period. All patients showed significant improvement in nasal polyp score, asthma control test and sino-nasal outcome test-22 after changing to dupilumab. Keratoconjunctivitis sicca was the side-effect (4.3%) reported after the switch from omalizumab to dupilumab, which lead to termination of therapy in one patient. Due to limited sample size, other antibody transitions were reported in a descriptive manner. CONCLUSION: The transition to dupilumab is an effective option in patients with inadequate treatment response or side-effects of omalizumab in nasal polyposis. Our preliminary results indicate that a wash-out period may not be necessary when switching between biologics, however, these findings require further investigations. Other monoclonal antibody transitions also show promising results, but warrant validations in larger cohorts due to small patient samples in our study.

Intranasal administration of allergen increases specific IgE whereas intranasal omalizumab does not increase serum IgE levels-A pilot study.

BACKGROUND: Administration of the therapeutic anti-IgE antibody omalizumab to patients induces strong increases in IgE antibody levels. OBJECTIVE: To investigate the effect of intranasal administration of major birch pollen allergen Bet v 1, omalizumab or placebo on the levels of total and allergen-specific IgE in patients with birch pollen allergy. METHODS: Based on the fact that intranasal allergen application induces rises of systemic allergen-specific IgE, we performed a double-blind placebo-controlled pilot trial in which birch pollen allergic subjects were challenged intranasally with omalizumab, placebo or birch pollen allergen Bet v 1. Total and allergen-specific IgE, IgG and basophil sensitivity were measured before and 8 weeks after challenge. For control purposes, total, allergen-specific IgE levels and omalizumab-IgE complexes as well as specific IgG levels were studied in subjects treated subcutaneously with either omalizumab or placebo. Effects of omalizumab on IgE production by IL-4/anti-CD40-treated PBMCs from allergic patients were studied in vitro. RESULTS: Intranasal challenge with Bet v 1 induced increases in Bet v 1-specific IgE levels by a median of 59.2%, and this change differed significantly from the other treatment groups (P = .016). No relevant change in allergen-specific and total IgE levels was observed in subjects challenged with omalizumab. Addition of omalizumab did not enhance IL-4/anti-CD40-induced IgE production in vitro. Significant rises in total IgE (mean IgE before: 131.83 kU/L to mean IgE after: 505.23 kU/L) and the presence of IgE-omalizumab complexes were observed after subcutaneous administration of omalizumab. CONCLUSION: Intranasal administration of allergen induced rises of allergen-specific IgE levels, whereas intranasal administration of omalizumab did not enhance systemic total or allergen-specific IgE levels.

Poor association of allergen-specific antibody, T- and B-cell responses revealed with recombinant allergens and a CFSE dilution-based assay.

BACKGROUND: The adaptive immunity underlying allergy comprises two components, the allergen-specific antibody (i.e. IgE, IgG) and the T-cell response. These two components are responsible for different disease manifestations and can be targeted by different therapeutic approaches. Here, we investigated the association of allergen-specific antibody and T- as well as B-cell responses in pollen-allergic patients using recombinant (r) major birch pollen allergen rBet v 1 and major timothy grass pollen allergen rPhl p 5 as defined antigens. METHODS: Allergen-specific IgE and IgG antibody responses were determined by ELISA, and allergen-specific T- and B-cell responses were measured in peripheral blood mononuclear cells using a carboxyfluorescein-diacetate-succinimidylester (CFSE) dilution assay. RESULTS: CFSE staining in combination with T-cell- and B-cell-specific gating allowed discriminating between allergen-specific T-cell and B-cell responses. Interestingly, we identified patients where mainly T cells and others where mainly B cells proliferated in response to allergen stimulation. No association between the level of allergen-specific Ig responses and B- or T-cell proliferation was observed. CONCLUSION: Purified recombinant allergens in conjunction with CFSE staining allow the dissection of allergen-specific B- and T-cell responses. The dissociation of allergen-specific antibody, and B- and T-cell responses may explain the occurrence of selective IgE- and T-cell-mediated manifestations of allergic inflammation and may be important for the development of diagnostic and therapeutic strategies selectively targeting B cells and T cells.

An assay that may predict the development of IgG enhancing allergen-specific IgE binding during birch immunotherapy.

BACKGROUND: It has been shown that birch pollen immunotherapy can induce IgG antibodies which enhance IgE binding to Bet v 1. We aimed to develop a serological assay to predict the development of antibodies which enhance IgE binding to Bet v 1 during immunotherapy. METHODS: In 18 patients treated by Bet v 1-fragment-specific immunotherapy, the effects of IgG antibodies specific for the fragments on the binding of IgE antibodies to Bet v 1 were measured by ELISA. Blocking and possible enhancing effects on IgE binding were compared with skin sensitivity to Bet v 1 after treatment. RESULTS: We found that fragment-specific IgG enhanced IgE binding to Bet v 1 in two patients who also showed an increase of skin sensitivity to Bet v 1. CONCLUSION: Our results indicate that it may be possible to develop serological tests which predict the induction of unfavourable IgG antibodies enhancing the binding of IgE to Bet v 1 during immunotherapy.

The majority of allergen-specific IgE in the blood of allergic patients does not originate from blood-derived B cells or plasma cells.

BACKGROUND: The production of allergen-specific IgE antibodies is a hallmark of IgE-mediated allergy but the contribution of blood cells to allergen-specific IgE production in allergic patients has not been studied in detail. OBJECTIVE: Aim of this study was the characterization of IgE-producing cells in the blood of allergic patients and the determination of the amount of IgE antibodies which are produced by these cells in relation to total amounts of circulating specific IgE. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from allergic patients and cell populations were purified or depleted using magnetically labelled antibodies directed against specific cell surface markers (CD19, CD20, CD22, CD27, CD38, CD126, CD138, CD203c). Allergen-specific IgE was measured in serum samples and cell culture supernatants by quantitative ImmunoCAP measurements and by ELISA using purified recombinant allergens. IgE transcripts were detected using RT-PCR with primers specific for human IgE. RESULTS: We found that allergen-specific IgE levels in PBMC supernatants correlated strongly with specific serum IgE but represented less than 1% of circulating IgE. Depletion of basophils resulted in substantial reduction of allergen-specific IgE levels in PBMC culture supernatants suggesting that an important source of allergen-specific IgE in PBMC supernatants could be IgE derived from the surface of basophils. Newly synthesized IgE was derived from CD138+ plasma cells, but not from B and B memory cells, and accounted for only approximately 0.2% of circulating IgE in blood. CONCLUSION AND CLINICAL RELEVANCE: Our finding that the majority of allergen-specific IgE in the peripheral blood is not derived from IgE-secreting cells in the blood suggests local IgE production in tissues as a major source for allergen-specific IgE and possible target for therapeutic intervention.

Basophils are not the key antigen-presenting cells in allergic patients.

BACKGROUND: Recent data obtained in mouse models have initiated a controversy whether basophils are the key antigen-presenting cells (APCs) in allergy. Here, we investigate whether basophils are of importance for the presentation of allergen and the induction of T cell proliferation in allergic patients. METHODS: T cells, basophils, and APCs depleted of basophils were purified from allergic patients. Co-culture systems based on purified major allergens were established to study allergen-specific T cell responses using proliferation assays. RESULTS: Only co-cultures of T cells with APCs depleted of basophils but not with basophils proliferated in response to allergen. Even addition of IL-3 to T cell-basophil co-cultures failed to induce allergen-specific T cell proliferation. CONCLUSIONS: Our data demonstrate by classical in vitro proliferation assays that basophils are not key antigen-presenting cells that promote T cell proliferation in secondary immune responses to allergen in allergic patients.