Urine Mast Cell Mediators in the Evaluation and Diagnosis of Mast Cell Activation Syndrome.

PURPOSE OF REVIEW: Mast cell activation syndrome is defined by severe, episodic, and recurrent symptoms induced by mast cell mediators with objective measurement of increase in biomarkers of mast cell activation and treatment response with mast cell therapies. Increase in serum tryptase from baseline during a mast cell activation episode is currently the most accepted biomarker measurement of mast cell release. However, during symptomatic episodes, serum tryptase can be difficult to obtain as it is a venipuncture procedure. Other objective measures of mast cell activation are needed to complement serum tryptase. RECENT FINDINGS: Urine mast cell mediators can be collected at home and are non-invasive tests. There is emerging evidence for the utility of urine mast cell mediators including histamine, cysteinyl leukotrienes, and prostaglandins in the diagnosis of mast cell activation syndrome. In this review, clinically available urine mast cell mediators will be discussed including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. We discuss the rationale for the use of these urine mast cell mediators and examine the studies analyzing their performance for identifying mast cell activation.

Secretory leukocyte protease inhibitor protects against severe urinary tract infection in mice.

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes, and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial, and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a preclinical model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC-infected SLPI-deficient (Slpi-/-) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi-/- mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18-49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with a history of recent or recurrent UTI, suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI promotes clearance of UPEC in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.IMPORTANCEAnnually, millions of people suffer from urinary tract infections (UTIs) and more than $3 billion are spent on work absences and treatment of these patients. While the early response to UTI is known to be important in combating urinary pathogens, knowledge of host factors that help curb infection is still limited. Here, we use a preclinical model of UTI to study secretory leukocyte protease inhibitor (SLPI), an antimicrobial protein, to determine how it protects the bladder against infection. We find that SLPI is increased during UTI, accelerates the clearance of bacteriuria, and upregulates genes and pathways needed to fight an infection while preventing prolonged bladder inflammation. In a small clinical study, we show SLPI is readily detectable in human urine and is associated with the presence of a uropathogen in patients without a previous history of UTI, suggesting SLPI may play an important role in protecting from bacterial cystitis.

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice.

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a mouse model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC infected SLPI-deficient (Slpi-/-) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi-/- mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18-49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with history of recent or recurrent UTI (rUTI), suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI protects against acute UTI in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.

Systematic Identification of Copositivity Groups in Standard Series Patch Testing Through Hierarchical Clustering.

Importance: Patients are frequently copositive for multiple allergens simultaneously, either due to chemical similarity or simultaneous sensitization. A better understanding of copositivity groups would help guide contact avoidance. Objective: To use patient data to systematically determine copositivity groups in the Mayo Clinic Standard Series. Design, Setting, and Participants: In this retrospective cross-sectional analysis, the Mayo Clinic patch test database was queried for pairwise copositivity rates in the 80 allergen Mayo Clinic Standard Series between 2012 and 2021. Data were collected from 3 tertiary care sites of the Mayo Clinic Contact Dermatitis Group and a total of 5943 patients were included, comprising all patients undergoing patch testing to the Mayo Clinic Standard Series allergens. Main Outcomes and Measures: Copositivity rates between every 2 allergens in the 80-allergen Mayo Clinic Standard Series were estimated. After background correction, copositivity rates were analyzed using unsupervised hierarchical clustering to systematically identify copositivity groups in an unbiased manner. Results: Overall, 394 921 total patches were applied to 5943 patients (4164 [70.1%] women, 1776 [29.9%] men, with a mean [SD] age of 52.3 [18.8] years ), comprising 9545 positive reactions. After background correction based on overall positivity rates, hierarchical clustering revealed distinct copositivity groups. Many were supported by prior literature, including formaldehyde releasers, cobalt-nickel-potassium dichromate, acrylates, 3-dimethylaminopropylamine-amidoamine-oleamidopropyl dimethylamine, alkyl glucosides, budesonide-hydrocortisone-17-butyrate, certain fragrances, compositae-sesquiterpene lactone mix, mercapto mix-mercaptobenzothiazole, carba mix-thiuram mix, and disperse orange-p-phenylenediamine. However, novel associations were also found, including glutaraldehyde-sorbitan sesquioleate, benzalkonium chloride-neomycin-bacitracin, bronopol-methylchloroisothiazolinone-methylisothiazolinone, and benzoic acid-iodopropynyl butylcarbamate. Conclusions and Relevance: This retrospective cross-sectional analysis found that copositivity rates varied between allergens; allergens with extremely high positivity rates demonstrated nonspecific copositivity to multiple other allergens. Background correction based on positivity rates followed by hierarchical clustering confirmed prior known copositivity groups, contaminants and/or excipients leading to copositivity, and novel associations to guide contact avoidance.

Female sex as a risk factor for penicillin drug allergy in the inpatient setting.

Background: Penicillin is the most common reported drug allergy. Previous literature suggests that there is increased prevalence of penicillin drug allergy in female patients in the outpatient setting. However, this is poorly described in the inpatient setting. Objective: This study was performed to determine whether female sex is an independent risk factor for penicillin allergy in the inpatient setting. Methods: A retrospective review of electronic medical records (January 1, 2001-December 31, 2017) was performed for patients with a history of penicillin allergy who underwent penicillin skin testing (PST). Each chart review included the age at initial skin testing, sex, medications, and medical co-morbidities. The study was approved by the institutional review board. Results: 30,883 patients underwent PST with 29,354 and 1,529 occurring in the outpatient and inpatient setting respectively. 170 patients tested positive with a ≥ 5x5 wheal. Of the 170 positive patients, 122 were female (72%) and 48 were male (28%). 15 patients tested positive in the inpatient setting. Of the 1506 adult patients tested in the inpatient setting, 809 were female and 697 were male. 12 females (92.3%) and 1 one male (7.7%) tested positive with a ≥ 5x5 wheal (OR-10.5; 95% CI-1.4-80.8; p-value=0.02). 23 pediatric patients were tested in the inpatient setting. Two pediatric male patients were positive and no female pediatric patients tested positive (OR-1.7; 95% CI-0.5-5.9; p-value=0.5). Conclusion: In the inpatient setting, adult females are 10 times more likely to have a positive PST compared to males. Female sex may be a potential risk factor for objective penicillin drug allergy in the inpatient setting.

The promise of the gut microbiome as part of individualized treatment strategies.

Variability in disease presentation, progression and treatment response has been a central challenge in medicine. Although variability in host factors and genetics are important, it has become evident that the gut microbiome, with its vast genetic and metabolic diversity, must be considered in moving towards individualized treatment. In this Review, we discuss six broad disease groups: infectious disease, cancer, metabolic disease, cardiovascular disease, autoimmune or inflammatory disease, and allergic and atopic diseases. We highlight current knowledge on the gut microbiome in disease pathogenesis and prognosis, efficacy, and treatment-related adverse events and its promise for stratifying existing treatments and as a source of novel therapies. The Review is not meant to be comprehensive for each disease state but rather highlights the potential implications of the microbiome as a tool to individualize treatment strategies in clinical practice. Although early, the outlook is optimistic but challenges need to be overcome before clinical implementation, including improved understanding of underlying mechanisms, longitudinal studies with multiple data layers reflecting gut microbiome and host response, standardized approaches to testing and reporting, and validation in larger cohorts. Given progress in the microbiome field with concurrent basic and clinical studies, the microbiome will likely become an integral part of clinical care within the next decade.

Newer Biological Agents in the Treatment of Severe Asthma: Real-World Results from a Tertiary Referral Center.

PURPOSE: To determine the efficacy of IL-5 inhibitory therapy in severe, refractory asthma in a real-world clinical setting from a tertiary referral center. METHODS: A retrospective chart review of patients with severe asthma treated with IL-5 biologic therapy for ≥ 6 months at Mayo Clinic in Rochester, Minnesota between January 1, 2013 and August 31, 2019. RESULTS: Over the study period, we identified 63 patients with a mean age of 54 who received an IL-5 inhibitor for ≥ 6 months. A total of 55 patients received mepolizumab, 2 received benralizumab, and 9 patients received both. Patients were followed up for a mean of 25 months. The mean number of months of oral prednisone use prior to biologic initiation was 64. There was a significant reduction in the median dose of prednisone in the 24 months after drug initiation (15 mg vs. 0 mg; p = < 0.0001). Similarly; there was a significant decline in the median number of asthma exacerbations in the 24 months before and after drug initiation (7 vs. 2; p = < 0.0001). The mean number of emergency room (ER) visits and hospitalizations decreased from 5.1 and 2.0 to 1.6 and 0.4 in the 24 months before and after therapy initiation (p < 0.0001 and p = 0.007, respectively) CONCLUSIONS: IL-5 inhibitory therapy is associated with significant and long-term sustained reductions in asthma exacerbation frequency, ER visits, hospitalizations, as well as oral steroid usage in a patient population with refractory steroid-dependent asthma referred to a tertiary referral center.

Minor Determinants of Penicillin and Amoxicillin Are Still Key Components of Penicillin Skin Testing.

BACKGROUND: The positive rate and pattern of penicillin skin test (PST) has been reported to be decreasing and changing. Previous studies differ about which penicillin component is the dominant component in positive PST result. OBJECTIVE: To characterize past and current PST patterns to determine whether different determinants in PST have changed over time. METHODS: A retrospective review of electronic medical records (January 2001-December 2017) was performed for patients who underwent PST. Data were divided into 4 cohorts to see whether trends occurred over time. The cohorts were divided as follows: cohort 1 (2001-2005), cohort 2 (2006-2010), cohort 3 (2011-2015), and cohort 4 (2016-2017). RESULTS: A total of 30,883 patients underwent PST with the following breakdowns per cohort: cohort 1, 6,536; cohort 2, 10,372; cohort 3, 10,640; and cohort 4, 3,335. Of these, 329 patients (1.0%) had a positive PST result with a wheal of 3 × 3 mm or greater, with 110 in cohort 1, 130 in cohort 2, 67 in cohort 3, and 22 in cohort 4, whereas 170 patients (0.5%) had a positive PST result with a wheal of 5 × 5 mm or greater, with 54 in cohort 1, 72 in cohort 2, 34 in cohort 3, and 10 in cohort 4. When the positive PST rates of cohort 2 (1.25%), cohort 3 (0.6%), and cohort 4 (0.6%) were compared with those of cohort 1 (1.7%), there was a significant decrease in positive PST rates (P = .0278; P < .0001; P < .0001, respectively). When cohort 1 positive rate to benzylpenicillin polylysine among the positive PST (wheal of 3 × 3 mm or greater) was compared with those of the other cohorts (cohorts 2-4), the percent positive of benzylpenicillin polylysine in PST was 27% compared with 21% (P = .38), 34% (P = .5), and 18% (P = .6), respectively. When the positive PST result was defined as a wheal of 5 × 5 mm or greater, the positive rate for benzylpenicillin polylysine in PST increased over time (cohort 2: 22%, P = .8; cohort 3: 32%, P = .3; cohort 4: 40%, P = .264) compared with cohort 1 (19%). CONCLUSIONS: Positive PST rate is decreasing. We demonstrate that despite benzylpenicillin polylysine solely positive rates remaining relatively stable, the minor penicillin determinants and amoxicillin play an important role in PST and their adoption into standard protocol for routine PST should be considered.