BackgroundPollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose.MethodsPatients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31–41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship.ResultsIn total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature.ConclusionsPQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.

BACKGROUND: Differentiating preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome from thrombotic thrombocytopenic purpura (TTP) can present a diagnostic dilemma. CASE: We report the case of a 34-year-old woman, G1P0, with monochorionic diamniotic twins who presented with new-onset blurry vision, hypertension, and a platelet count of 4×109/L. After a multidisciplinary discussion, a diagnosis of atypical HELLP syndrome was made, despite overlapping features concerning for TTP. Her platelet count and ADAMTS13 activity testing showed appropriate recovery after delivery, without plasma exchange therapy, supporting the diagnosis of HELLP syndrome. CONCLUSION: Hemolysis, elevated liver enzymes, and low platelet count syndrome may present with severe thrombocytopenia and severe ADAMTS13 activity deficiency in ranges otherwise known to be more common with TTP.

RATIONALE: An unbiased investigation of age-related gene expression changes in nasal polyps (NP) may provide new treatment targets, especially for the elderly. METHODS: Affymetrix microarrays using NP tissues and control uncinate tissues (elderly, age > _65 vs non-elderly, age 18-49; n54 each group) were performed and differentially regulated genes were analyzed with a cutoff p value <0.05 and a cutoff gene expression change >2-fold. Real-time PCR (qRT-PCR), immunohistochemistry (IHS), periodic acid-Schiff (PAS) and trichrome staining were used to validate the microarray results. RESULTS: Microarray analysis identified genes regulated differentially by disease and age; 340 in NP vs controls, 446 in elderly controls vs nonelderly controls, 45 in elderly NP vs non-elderly NP, 320 in non-elderly NP vs non-elderly controls, and 190 in elderly NP vs elderly controls. qRT-PCR confirmed downregulation of PLAT (tissue-plasminogen activator-1, tPA), upregulation of SERPINE1 (plasminogen activator inhibitor-1, PAI-1) and SERPINB2 (PAI-2), and downregulation of submucosal glandrelated genes such as SCGB1D2, SCGB2A2, MUC7 and LPO (lactoperoxidase) in NP vs controls. SERPINE1 expression was significantly increased in elderly NP compared to elderly controls and PLAT expression was downregulated in non-elderly NP compared to non-elderly controls. IHC confirmed significantly reduced expression of anti-microbial proteins, MUC7 and lactoperoxidase, in NP. There was age-related reduction of serous submucosal glandular cells and relative increase of PAS-stained mucous glandular cells. Trichrome staining showed increased collagen deposition with age. CONCLUSIONS: This study demonstrates age-associated dysregulated genes in human NP, PAI-1 and tPA, which can be potential treatment targets, especially in the elderly.

RATIONALE: The results of this Phase II study [EudraCT 2017-000333-31] evaluated the dose response relationship for a modified grass allergen subcutaneous immunotherapy (SCIT) product (1.0 ml) with modified allergen tyrosine adsorbate (MATA) and monophosphoryl lipid A (MPL) adjuvants for the treatment of allergic rhinoconjunctivitis (ARC) due to grass pollen. METHODS: In total 447 patients with grass pollen-induced ARC were enrolled in this randomized, double-blind, placebo-controlled, parallel group study. Patients were randomized to one of five dose regimens of 5100, 14400, 27600 and 35600 SU and placebo. As a secondary endpoint the immunoglobulin markers (total IgE, grass-specific IgE, grass-specific IgG4 and specific IgE/total IgE ratio) were evaluated. RESULTS: For all immunoglobulin markers a strong statistically significant dose-response was shown for a wide range of cumulative doses from 5100 SU to 35600 SU. Grass-specific IgE, grass-specific IgG4 and specific IgE/total IgE ratio demonstrated statistically significant increases compared to placebo for all cumulative doses (P<0.01), including the currently marketed dose of 5100 SU in Europe. CONCLUSIONS: An ultra-short course of 6 injections with allergoid grass SCIT treatment with adjuvants MATA and MPL is associated with significant increases in immunoglobulin markers for a wide range of cumulative dose levels indicating a strong therapeutic response. RATIONALE: In the U.S., subcutaneous immunotherapy (SCIT) doses are typically prepared by medical staff removing a given volume from an extract vial at a patient's injection visit. We report a novel methodology using pharmacist-prepared individual SCIT doses at an urban county hospital. METHODS: SCIT extracts are prepared by a pharmacist using dosing recommendations in the U.S. practice parameters. Individual SCIT doses are prepared by a pharmacist prior to a patient's appointment based on the patient's dosing schedule. Doses are placed in labeled syringes in patientspecific baggies. Nurses administer the pre-filled syringes to patients at their appointment. We analyzed data from January 2014 to July 2018 using this methodology. RESULTS: A total of 4203 doses were prepared; 3811 (90.6%) injections were given and 54 doses were held (1.2% of doses prepared). There were a total of 2323 patient appointments and 191 missed appointments (8% of total appointments). There were a total of 36 systemic reactions (0.9% of injections given) ranging from grade 1a -2z, with no grade 3-5 reactions. This rate of systemic reactions per injection is similar to what has been reported in the published literature of approximately 0.2% (Cox et al, 2010), and also comparable to previously reported incidences of non-fatal SCIT systemic reactions in two large cohorts. CONCLUSIONS: We describe a unique approach to delivering SCIT doses yielding a low rate of systemic reactions per injection and minimizing dosing errors. This method may be appropriate for multidisciplinary clinics with frequently changing staff to enhance patient sa...