The epidemiological situation of tuberculosis in Spain according to surveillance and hospitalization data, 2012-2020.

BACKGROUND: Before the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent. In Spain, TB notifications are registered through the National Epidemiological Surveillance Network (RENAVE). The Minimum Basic Data Set (CMBD) provides information on TB hospital discharges. This study aims to assess both registries to complete the picture of TB in order to improve national control strategies and make further progress toward its elimination. METHODS: A retrospective study was performed considering CMBD´s hospital discharges with TB as first diagnosis and notifications to RENAVE between 2012 and 2020. After describing the records of both systems and their differences by using descriptive and multivariate analysis, annual incidences rates were calculated in order to evaluate temporal trends and geographical patters. RESULTS: According to the CMBD database, there were 29,942 hospitalizations due to TB (65% pulmonary forms and 66% male) during the study period. RENAVE collected 44,520 reported cases, mostly males (62%) with pulmonary forms (72%). Young children were similar in both groups, showing the high frequency of hospitalization in this group. Almost all autonomous communities showed a downward trend, especially Asturias. Hospitalizations in 2020 were analyzed by month separately, and comparing with previous years, the impact of the COVID-19 pandemic can be seen. CONCLUSIONS: A decreasing trend on TB incidence was observed in Spain since 2012, although this trend might change after COVID-19 pandemic. The analysis of both databases, CMBD and RENAVE, has contributed to improve our knowledge of TB in Spain and will help improve the control of this disease.

Biomarkers of immediate drug hypersensitivity.

Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non-IgE, cytokine release, Mast-related G-protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase-1 (COX-1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life.

Upregulation of Platelet-Activating Factor Receptor Expression and Lyso-Platelet-Activating Factor Isoforms in Human Nasal Polyp Tissues.

BACKGROUND: The Platelet-Activating Factor (PAF)/receptor (PAFR) system is involved in asthma and allergic rhinitis; however, its role in chronic rhinosinusitis (CRS) is still unclear. This study aimed to assess the expression of PAFR and the concentration of Lyso-PAF isoforms in the nasal polyps (NP) of patients suffering from CRS with/without comorbidities such as asthma and NSAID-exacerbated respiratory disease (N-ERD) compared to healthy nasal mucosa (NM) from control subjects. METHODS: NM (n = 8) and NP tissues were obtained from patients undergoing surgery for septal deviation/turbinate hypertrophy or endoscopic sinus surgery, respectively. Three phenotypes were studied: CRSwNP with no asthma (n = 6), CRSwNP with non-steroidal anti-inflammatory drug (NSAID)-tolerant asthma (n = 6), and CRSwNP with NSAID-exacerbated respiratory disease (n = 6). PAFR protein and mRNA were assessed via immunochemistry, immunofluorescence, Western blot, and real-time quantitative PCR. Lyso-PAF isoforms (C16, C18, and C18:1) were quantified via mass spectrometry. RESULTS: PAFR protein was expressed in the NM and NP, concretely in epithelial cells and submucosal glands. Compared to NM, PAFR mRNA expression was higher in all NP phenotypes (p < 0.05) while all Lyso-PAF isoform concentrations were higher in the NP from asthmatic patients (p < 0.05). Lyso-PAF C16 and C18 concentrations were higher in the NP from asthmatic patients than in the NP from patients without asthma. CONCLUSIONS: The PAF/PAFR system could play a pathophysiological role in CRSwNP pathogenesis.

Prevalence of atopic dermatitis in the adolescent population of Catalonia (Spain).

BACKGROUND: Studies on the prevalence of atopic dermatitis (AD) for the adolescent cohort in general-based large populations are scarce worldwide. We performed a retrospective population--based observational cohort study of 76,665 adolescent patients diagnosed with AD in Catalonia (Spain). We studied the prevalence of AD by age, gender, disease severity, comorbidities, serum total immunoglobulin E (tIgE) and appropriate medical treatment (AMT) for the Catalan population. METHODS: Adolescent individuals (12-17 years) diagnosed with AD by medical records at different health care levels (primary, hospital, emergency) from the Catalan Health System (CHS) were included. Statistical analyses evaluated sociodemographic characteristics, prevalence, comorbidities, serum tIgE and AMT. RESULTS: The overall diagnosed AD prevalence in the adolescent Catalan population (76,665) was 16.9%, being higher for the non-severe (16.7%) than for the severe (0.2%) populations. Topical corticosteroids were the most prescribed drug (49.5%), and the use of all prescribed treatments was higher in severe AD patients, especially systemic corticosteroids (49.7%) and immunosuppressants (45.4%). AD patients had, on average, a serum tIgE of 163.6 KU/L, which was higher for severe than non-severe disease (155.5 KU/L vs 101.9 KU/L, respectively). Allergic rhinitis (15.0%) and asthma (13.5%) were among the most frequent comorbid respiratory and allergy diseases. CONCLUSIONS: This is the first Spanish study reporting the overall diagnosed prevalence for a large-scale adolescent cohort (12-17 years old) from Catalonia. It provides new and robust evidence of AD's prevalence and related characteristics in this region.

MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway.

MRGPRX2, a G-protein-coupled-seven transmembrane domain receptor, is mainly expressed in mast cells and neurons and is involved in skin immunity and pain. It is implicated in the pathophysiology of non-IgE-mediated immediate hypersensitivity and has been related to adverse drug reactions. Moreover, a role has been proposed in asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. Although it has a prominent role in disease, its signaling transduction is poorly understood. This study shows that MRGPRX2 activation with substance P increased Lysyl t-RNA synthetase (LysRS) translocation to the nucleus. LysRS is a moonlighting protein with a dual role in protein translation and IgE signaling in mast cells. Upon allergen- IgE-FcεRI crosslinking, LysRS is translocated to the nucleus and activates microphthalmia-associated transcription factor (MITF) activity. In this study, we found that MRGPRX2 triggering led to MITF phosphorylation and increased MITF activity. Therefore, overexpression of LysRS increased MITF activity after MRGPRX2 activation. MITF silencing reduced MRGPRX2-dependent calcium influx and mast cell degranulation. Furthermore, a MITF pathway inhibitor, ML329, impaired MITF expression, calcium influx, and mast cell degranulation. Moreover, drugs such as atracurium, vancomycin, and morphine, reported to induce MRGPRX2-dependent degranulation, increased MITF activity. Altogether, our data show that MRGPRX2 signaling enhances MITF activity, and its abrogation by silencing or inhibition resulted in defective MRGPRX2 degranulation. We conclude that MRGPRX2 signaling involves the LysRS and MITF pathway. Thus, MITF and MITF-dependent targets may be considered therapeutic approaches to treat pathologies where MRGPRX2 is implicated.

A community outbreak of Legionnaires' disease caused by outdoor hot tubs for private use in a hotel.

During the period October-November 2017, an outbreak of Legionnaires' disease involving 27 cases occurred in the tourist area of Palmanova (Mallorca, Spain). The majority of cases were reported by the European Centre of Disease Prevention and Control (ECDC) as travel associated cases of Legionnaires' disease (TALD). Most cases belonged to different hotel cluster alerts. No cases were reported among the local population residing in the area. All tourist establishments associated with one or more TALD cases were inspected and sampled by public health inspectors. All relevant sources of aerosol emission detected were investigated and sampled. The absence of active cooling towers in the affected area was verified, by documents and on-site. Samples from hot tubs for private use located on the terraces of the penthouse rooms of a hotel in the area were included in the study. Extremely high concentrations (> 106 CFU/l) of Legionella pneumophila, including the outbreak strain, were found in the hot tubs of vacant rooms of this hotel thus identifying the probable source of infection. Meteorological situation may have contributed to the geographical distribution pattern of this outbreak. In conclusion, hot tubs for private use located outdoors should be considered when investigating community outbreaks of Legionnaires' disease of unclear origin.

Cofactors in food anaphylaxis in adults.

Around 25% to 50% of food-induced allergic reactions in adults cause anaphylaxis, and epidemiologic evidence suggests that food is the most common cause of anaphylaxis. Reaction severity is unpredictable, and patients will often experience reactions of variable severity, even to an identical exposure (both dose and allergen). A common explanation for this phenomenon has been the impact of "cofactors"-factors that might contribute to reaction severity independent of the allergen exposure. Cofactors can influence reaction severity in 2 ways: either by reducing the reaction threshold (ie, the dose needed to trigger any symptoms) so that patients have no symptoms in the absence of the cofactor and only react with the cofactor present, or by increasing reaction severity such that individuals have only mild symptoms in the absence of the cofactor, but a more severe reaction when the cofactor is present. Indeed, the same patient may have reactions with different cofactors or even need more than one cofactor to develop a severe reaction. Cofactors reportedly play a role in approximately 30% of anaphylaxis reactions in adults. Exercise, nonsteroidal, anti-inflammatory drugs, alcohol, and sleep deprivation are the most frequent cofactors reported. Routine evaluation of the possible involvement of cofactors is essential in managing patients with food anaphylaxis: in patients with a suggestive history but a negative oral food challenge, cofactors should be taken into account to provide appropriate advice to reduce the risk of future anaphylaxis.

MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation.

Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance highlight the need for alternative treatment strategies. Previously, we reported that the adaptor molecule SH3 binding protein 2 (SH3BP2 or 3BP2) regulates KIT expression at the transcriptional level and microphthalmia-associated transcription factor (MITF) expression at the post-transcriptional level in human mast cells and gastrointestinal stromal tumor (GIST) cell lines. Lately, we have found that the SH3BP2 pathway regulates MITF through miR-1246 and miR-5100 in GIST. In this study, miR-1246 and miR-5100 were validated by qPCR in the SH3BP2-silenced human mast cell leukemia cell line (HMC-1). MiRNA overexpression reduces MITF and MITF-dependent target expression in HMC-1. The same pattern was observed after MITF silencing. In addition, MITF inhibitor ML329 treatment reduces MITF expression and affects the viability and cell cycle progression in HMC-1. We also examine whether MITF downregulation affected IgE-dependent mast cell degranulation. MiRNA overexpression, MITF silencing, and ML329 treatment reduced IgE-dependent degranulation in LAD2- and CD34+-derived mast cells. These findings suggest MITF may be a potential therapeutic target for allergic reactions and deregulated KIT mast-cell-mediated disorders.

Prevalence of atopic dermatitis in the adolescent population of Catalonia (Spain)

Background: Studies on the prevalence of atopic dermatitis (AD) for the adolescent cohort in general-based large populations are scarce worldwide. We performed a retrospective population--based observational cohort study of 76,665 adolescent patients diagnosed with AD in Catalonia (Spain). We studied the prevalence of AD by age, gender, disease severity, comorbidities, serum total immunoglobulin E (tIgE) and appropriate medical treatment (AMT) for the Catalan population. Methods: Adolescent individuals (12–17 years) diagnosed with AD by medical records at different health care levels (primary, hospital, emergency) from the Catalan Health System (CHS) were included. Statistical analyses evaluated sociodemographic characteristics, prevalence, comorbidities, serum tIgE and AMT. Results: The overall diagnosed AD prevalence in the adolescent Catalan population (76,665) was 16.9%, being higher for the non-severe (16.7%) than for the severe (0.2%) populations. Topical corticosteroids were the most prescribed drug (49.5%), and the use of all prescribed treatments was higher in severe AD patients, especially systemic corticosteroids (49.7%) and immunosuppressants (45.4%). AD patients had, on average, a serum tIgE of 163.6 KU/L, which was higher for severe than non-severe disease (155.5 KU/L vs 101.9 KU/L, respectively). Allergic rhinitis (15.0%) and asthma (13.5%) were among the most frequent comorbid respiratory and allergy diseases. Conclusions: This is the first Spanish study reporting the overall diagnosed prevalence for a large-scale adolescent cohort (12–17 years old) from Catalonia. It provides new and robust evidence of AD’s prevalence and related characteristics in this region (AU)

Exhaustive diagnosis of breast implants with capsular contracture: The microbiology laboratory as a major support.

The most frequent complications of post-mastectomy reconstructions are breast implant (BI) infection and capsular contracture (CC). The diagnosis of BI colonization is based on cultures from the sonicated BI and from the capsule tissue. Therefore, we first aimed to assess the yield of conventional culture and molecular techniques in periprosthetic fluid, in addition to BI and capsular tissue. Moreover, we compare colonization and biofilm production between patients with and without CC. During 19 months, we prospectively included patients whose BIs had been removed and divided them into two groups: A (CC, Baker III-IV) and B (no CC). Samples were obtained for conventional culture, 16 s rRNA PCR, and MALDI-TOF. Biofilm production was also evaluated. We included 81 BIs from 69 patients with CC (22) and without CC (53). Forty-three (53.1%) of the 81 BIs had ≥1 positive culture. The culture was positive in 57.1% and 50.9% in groups A and B, respectively (p = 0.645). The highest 16 s rRNA PCR positivity rate was detected in capsular tissue (40.5%). MALDI-TOF was unable to detect colonization in any of the samples. High biofilm production was the following: high biomass: A, 29.8%; B, 39.7% (p = 0.293); high metabolic activity: A, 36.2%; B, 34.5% (p = 0.857). We confirm that cultures from different sites are mandatory to ensure a proper diagnosis of BI colonization. Our study is the first to demonstrate that CC was not associated with BI colonization or high biofilm production. The application of molecular techniques in BI samples was not substantially useful for predicting colonization.

Low Levels Matter: Clinical Relevance of Low Pru p 3 sIgE in Patients With Peach Allergy.

Many clinical lab settings still use 0.35 KUA/L as the cut-off for serum specific-IgE (sIgE) immunoassays, while the detection limit is 0.1 KUA/L. The clinical relevance of -low-level sIgE (0.1-0.35 KUA/L) remains controversial. Pru p 3 sIgE is considered to be the main routine tool for assessing lipid transfer protein (LTP) sensitization. We aimed to evaluate the clinical relevance of Pru p 3 sIgE low levels in a population diagnosed with LTP allergy. Adults diagnosed with LTP allergy and Pru p 3 sIgE ≥ 0.1 KUA/L between 2012 and 2019 were included. Clinical data were reviewed. nPru p 3 basophil activation test (BAT) was performed and basophil reactivity (BR) and sensitivity (BS) correlated with the peach allergy symptoms. Pru p 3 sIgE from 496 subjects was recorded, 114 (23.0%) between 0.1 and 0.34 KUA/L (grLOW), the rest ≥ 0.35 KUA/L (grB). A total of 44.7% in grLOW and 59.9% in grB were allergic. Urticaria was more frequent in grLOW. In grLOW, Pru p 3 sIgE was higher in patients with local compared with systemic symptoms. In grB, Pru p 3 sIgE was higher in allergic patients. Pru p 3/Total IgE ratios were higher in allergic vs. tolerant in both groups. In BAT, BR was similar in both groups. In grLOW, it was higher on allergic compared with tolerant (p = 0.0286), and on those having systemic vs. local symptoms (p = 0.0286). BS showed no significant difference between groups. Patients with low levels represent a non-negligible fraction and around 45% are peach allergic. BAT showed functional sIgE in them. Pru p 3 sensitizations should be carefully evaluated even when sIgE levels are low.

Efficacy of Povidone Iodine Against Microbial Biofilms in Breast Implants With Different Textures: Results From an in vitro Study.

Background: In the practice of breast augmentation and reconstruction, implant irrigation with various solutions has been widely used to prevent infection and capsular contracture, but to date, there is no consensus on the optimal protocol to use. Recently, application of povidone iodine (PI) for 30 min has shown in vitro to be the most effective irrigating formula in reducing contamination in smooth breast implants. However, as 30 min is not feasible intraoperatively, it is necessary to determine whether shorter times could be equally effective as well as to test it in both smooth and textured implants. Methods: We tested the efficacy of 10% PI at 1', 3', and 5' against biofilms of 8 strains (2 ATCC and 6 clinical) of Staphylococcus spp. on silicone disks obtained from Mentor® and Polytech® implants of different textures. We analyzed the percentage reduction of cfu counts, cell viability and bacterial density between treatment (PI) and control (sterile saline, SS) groups for each time of application. We consider clinical significance when > 25% reduction was observed in cell viability or bacterial density. Results: All textured implants treated with PI at any of the 3 exposure times reduced 100% bacterial load by culture. However, none of the implants reached enough clinical significance in percentage reduction of living cells. Regarding bacterial density, only 25-50 µm Polytxt® Polytech® implants showed significant reduction at the three PI exposure times. Conclusion: PI is able to inhibit bacterial growth applied on the surface of breast implants regardless of the exposure time. However, no significant reduction on living cells or bacterial density was observed. This lack of correlation may be caused by differences in texture that directly affect PI absorption.

The role of biofilm production in Cutibacterium acnes strains isolated from breast implants.

The role of C. acnes biofilm production in the pathogenesis of breast implants infections has not been deeply assessed. We analyze biofilm production (in terms of biomass and metabolic activity) between 40 Cutibacterium acnes strains isolated from breast implants and 32 from other sites. C. acnes strains isolated from breast implants showed higher metabolic activity than those isolated from other-locations and, especially, those from patients with capsular contracture .

SARS-CoV-2 vaccine excipients polyethylene glycol and trometamol do not induce mast cell degranulation, in an in vitro model for non-IgE-mediated hypersensitivity.

The development of vaccines against SARS-CoV2 brought about several challenges, including the management of hypersensitivity reactions to these formulations. The search for underlying mechanisms involved in these adverse events initially focused on excipients which may trigger mast cell activation responses via non-IgE pathways: polyethylene glycol and trometamol. We sought to determine whether these components, in their pure form, were capable of stimulating mast cells directly. To test this hypothesis, we used an in vitro model for non-IgE-mediated activation that has previously shown degranulation responses induced via MRGPRX2 with known drug agonists of the receptor. Human LAD2 mast cells were incubated with different concentrations (1, 10, 50 mg/ml) of trometamol and of purified polyethylene glycol/Macrogol (molecular weights: 2,000, 3,350, 4,000, and 6,000). Mast cell degranulation was assessed using a beta-hexosaminidase read-out. Interestingly, degranulation responses for all reagents tested showed no significant differences from those obtained from the negative control (basal degranulation). Receptor-silencing assays were therefore not conducted. In summary, purified PEG and trometamol did not induce mast cell degranulation in this in vitro model for the study of non-IgE mechanisms of drug hypersensitivity, previously shown to be useful in the investigation of MRGPRX2 ligands. Studies using complete vaccine formulations, lipid conjugates, and receptor gene variants are needed to further clarify mechanisms of vaccine hypersensitivity.

Detection of Wheat Lipid Transfer Protein (Tri a 14) Sensitization: Comparison between Currently Available Diagnostic Tools.

BACKGROUND: Wheat lipid transfer protein (LTP; Tri a 14) and ω5-gliadin have been described as major allergens in wheat allergy (WA) and relevant in wheat-induced anaphylaxis, frequently associated with cofactors. OBJECTIVE: The objective of this study was to compare tools currently available in routine diagnosis to detect Tri a 14 sensitization, its clinical relevance, and cosensitization to ω5-gliadin and other LTPs. METHODS: One hundred eighteen adults sensitized to rTri a 14 by ImmunoCAP® (cutoff ≥0.1 kUA/L) identified among 210 LTP allergic patients were included. We evaluated (1) wheat skin prick test (SPT), (2) specific IgE (sIgE) to wheat, rTri a 14, rTri a 19, peach, apple, walnut, hazelnut, and peanut LTPs using ImmunoCAP® and microarray ImmunoCAP®ISAC (cutoff ≥0.3I SU), and (3) wheat-related symptoms. RESULTS: Wheat SPT and sIgE were positive in 31% and 85% of subjects, respectively. rTri a 14 by microarray was detected in 25%. Eight percent showed cosensitization to ω5-gliadin. Thirty percent referred symptoms (gastrointestinal [13%], urticaria [11%], and anaphylaxis [8%]). Cofactors (45%) were significantly associated with systemic reactions. CONCLUSION: WA due to Tri a 14 is frequently related with systemic reactions and because are frequently related to cofactors, the culprit may not be suspected. Together with the poor performance to identify Tri a 14 sensitization of the current routine diagnostic tools based on the analysis of whole wheat extract, such as wheat SPT or sIgE, there is a high risk that WA may be overlooked. Thus, when WA is suspected, sIgE Tri a 14 assessment is recommended, together with wheat and ω5-gliadin, preferably in the singleplex format, and carefully evaluated considering ≥0.1 kUA/L as a cutoff.