Title: Some OPA once told me “LKB1 is going to rule me”: the OPA1-LKB1 axis in immune responseAuthors: Contreras N1,2*, Macías-Camero A1,2*, Delgado-Dolset MI1,2.Affiliations: 1Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.2Instituto de Medicina Molecular Aplicada Nemesio Díez (IMMA-NM), Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.*These authors contributed equallyCorrespondence to: María Isabel Delgado-Dolset , Instituto de Medicina Molecular Aplicada Nemesio Díez (IMMA-NM), Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.Campus Montepríncipe. Crtra. Boadilla del Monte km 5.3.CP 28668 Boadilla del Monte. Madrid, Spain.Tlf: +34 91 372 47 00 ext. 15068E-mail: email@example.comConflict of interest: The authors have no conflicts of interest to declare.Funding information: The authors received no specific funding for the elaboration of this article.Authorship: All the authors approved the final version of the manuscript as submitted and agreed to be accountable for all aspects of the work.Acknowledgments: The authors acknowledge the support by Instituto de Salud Carlos III (PI18/01467 and PI19/00044), co-funded by FEDER “Investing in your future” for the thematic network and co-operative research centres ARADyAL RD16/0006/0015 and RICORS Red de Enfermedades Inflamatorias (REI) RD21 0002 0008. Authors would also like to recognize the funding by the Ministry of Science and Innovation in Spain (PCI2018-092930), co-funded by the European program ERA HDHL—Nutrition and the Epigenome, project Dietary Intervention in Food Allergy: Microbiome, Epigenetic and Metabolomic interactions (DIFAMEM); and by Fundación Mutua Madrileña (AP177712021). N.C. and A.M.C. are supported by FPI-CEU predoctoral fellowships. The authors would like to thank Dr Domingo Barber, Dr María M Escribese and Dr Alma Villaseñor for their asserted comments.List of abbreviations : 2-HG: 2-HidroxyGlutarate, α-KG: α-KetoGlutarate, CD4: Cluster of Differentiation 4, ETC: Electron Transport Chain, IL17A: InterLeukin 17A, LKB1: Liver-associated Kinase B1, NET: Neutrophil Extracellular Trap, OPA1: Optic Atrophy 1, PHGDH: PHosphoGlycerate DeHydrogenase, Treg: Regulatory T Helper, TH: T HelperIn the last 20 years, increasing evidence has arisen challenging the belief that mitochondria are mere ATP-synthesizing machines, shedding light on their role in cell signaling (1). Metabolites, energy mediators, and physical interactions involving membrane rearrangements are some of the mechanisms involved in mitochondria-driven cell regulation (1). In this sense, energetics plays a role in the development and function of immune cells, and immunometabolism is a flourishing field. Nonetheless, how mitochondria signaling networks, including membrane dynamics, affect T cell development and differentiation remains unclear (2).In a recently published work, Baixauli et al (3) investigated how CD4+ T cell differentiation is influenced by mitochondrial membrane morphology. In vitro analysis showed that elongated mitochondria with tight cristae in TH17 cells correlated with higher levels of the long isoform protein of OPA1 (L-OPA1) when compared to TH1 and TH2 cells. Moreover, they developed an OPA1 knockout mouse model (Opa1Cd4-cre ) which showed that, besides controlling mitochondrial membrane dynamics, OPA1 also regulated IL17A production, suggesting its potential role in the regulation of TH17 cells effector function.To address this matter, a multi-omic approach, including epigenomics, transcriptomics, proteomics, and metabolomics, was applied. They found several changes in the mitochondria due to the lack of OPA1 that could lead to the loss of Il17a expression. First, as a result of a disrupted inner mitochondrial membrane, electron transport chain (ETC) subunits uncouple, leading to an increase in the NADH/NAD+ ratio. Higher levels of NADH, together with an increase in the oxidation of glutamine, promote α-ketoglutarate (α-KG) conversion towards 2-hidroxyglutarate (2-HG) by phosphoglycerate dehydrogenase (PHGDH). 2-HG accumulation increases histone and DNA methylation that lastly alters chromatin accessibility in immune response genes interfering with Il17a expression.Pathway analysis was performed to determine OPA1 intracellular biological mediators, raising LKB1 as its major upstream regulator. While LKB1 activity was increased inOpa1Cd4-cre mice, authors demonstrated thatLkb1 deletion restored cell carbon metabolism and Il17aexpression by reducing the production of PHGDH and other serine biosynthesis enzymes.This article provides a perspective of the OPA1-LKB1 axis and its role in immune regulation in TH17 cells, which grants a deep understanding on how the different types of molecules are intertwined in the disease (4). As for possible limitations, this work was done using solely a mouse model, which, despite being as extraordinary as it is, does not necessarily match the conditions and metabolic changes that take place in human cells (1). It would have been interesting to see some of these experiments being done in T cells from human donors to corroborate these findings, which would be possible by using CRISPR/Cas technology to delete OPA1 and/or LKB1 .Furthermore, it is still necessary to understand how, if at all, OPA1-LKB1 axis regulates other subsets of T cells, such as TH1 or Treg. It is known that LKB1 affects other immune cell types, even within the innate immune response. For example, LKB1 deficiency in mouse dendritic cells results in higher levels of Treg in vivo that promote an immune-suppressed phenotype through mTOR signaling, impairing tumor growth control and protecting against allergic asthma development (5). Moreover, deletion of Lkb1 in mice alveolar macrophages leads to more severe asthma and higher susceptibility to S. aureusinfection through the AMPK pathway (6); and an increased number of neutrophils. Additionally, it has been described that OPA1-dependent ATP production is needed for neutrophil extracellular trap (NET) formation and effective antibacterial defense both in human and mouse neutrophils (7). However, these studies fail to analyze the OPA1-LKB1 relation, which, to our knowledge, has been described for the first time by Baixauli et al. All in all, these authors have uncover the great potential of the OPA-LKB1 axis in the immunometabolism research field.REFERENCES1. Picard M, Shirihai OS. Mitochondrial signal transduction. Cell Metab 2022;34 :1620–1653.2. Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells.Cell Res 2020;30 :649–659.3. Baixauli F, Piletic K, Puleston DJ, Villa M, Field CS, Flachsmann LJ et al. An LKB1–mitochondria axis controls TH17 effector function.Nature 2022;610 :555–561.4. Radzikowska U, Baerenfaller K, Cornejo-Garcia JA, Karaaslan C, Barletta E, Sarac BE et al. Omics technologies in allergy and asthma research: An EAACI position paper. Allergy2022;77 :2888–2908.5. Pelgrom LR, Patente TA, Sergushichev A, Esaulova E, Otto F, Ozir-Fazalalikhan A et al. LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells.Cell Res 2019;29 :406–419.6. Wang Q, Chen S, Li T, Yang Q, Liu J, Tao Y et al. Critical Role of Lkb1 in the Maintenance of Alveolar Macrophage Self-Renewal and Immune Homeostasis. Front Immunol 2021;12 :1–12.7. Amini P, Stojkov D, Felser A, Jackson CB, Courage C, Schaller A et al. Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production. Nat Commun 2018;9 :2958.
TitleMaternal and infant serum carotenoids are associated with infantile atopic dermatitis developmentTo the Editor,Various epidemiological studies have shown that eczema/atopic dermatitis (AD) in infancy is a risk for skin sensitization1 and development of allergic diseases later in life2.Carotenoids are natural pigments biosynthesized by bacteria, fungi, and plants, but not by mammals3; thus, they need to be supplied via dietary intake of vegetables and fruits or certain animal products. Carotenoids positively impact human health and prevents allergic reactions via their provitamin A activity and high antioxidant potential. However, previous studies using food frequency questionnaires that evaluated the association between maternal vegetable intake during pregnancy and eczema in offspring have shown inconsistent results4–6. As these studies did not measure the levels of individual carotenoids in the serum of mothers or children and in breast milk, appropriate nutritional interventions in maternal and early infant intake of vegetables for the prevention of AD remain unclear.In this study, we have measured the levels of total carotenoids and some of their sub-types in the serum of mothers and children and in maternal breast milk, to evaluate the association between carotenoid levels and the presence of AD at 1 year of age in infants.We compared participants’ characteristics and exposures by 1 year of age (Table S1); carotenoid, retinol, and α-tocopherol levels (Table 1) in the serum of participants, with and without AD at 1 year of age, were compared to those in the serum and breast milk of their respective mothers. We found that both the presence of eczema (OR, 31.7; 95%CI[13.2–76.0]) and S. aureus carriage in the skin by 6 months of age (OR, 5.20; 95%CI[2.30–11.75]) were associated with higher odds of AD development at 1 year of age. On the contrary, certain carotenoid levels in the serum and breast milk, including total carotenoids in the maternal blood, were associated with lower odds of AD at 1 year.To avoid multicollinearity in the regression analysis, we selected seven relevant predictive variables among the carotenoid data using VIP scores in the PLS analysis (Table S2). Stepwise logistic regression analysis using explanatory baseline characteristics, exposure by 1 year of age, and the seven selected carotenoid levels revealed that the following variables were significantly related to AD at 1 year of age (Table 2): presence of eczema by 6 months of age (OR, 34.5; P < 0.0001), maternal blood lutein level (unit OR, 0.002; P = 0.002), and infant blood lycopene level at 1 year (unit OR, 0.01; P = 0.007).One strength of this study is that multiple biological sample types were used as proxies for carotenoid intake. The lutein concentration in the maternal blood at 36 weeks of gestation, which was associated with a reduced AD risk at 1 year of age in the multivariate analysis, was significantly correlated with the cord blood lutein level (Table S3). This suggests that lutein ingested during pregnancy is transferred to the fetus and may have an inhibitory effect on the development of AD in infancy. Another strength of this study is that multiple carotenoids were evaluated simultaneously; the concentrations of lutein, zeaxanthin, α-carotene, β-carotene, and lycopene were strongly correlated, suggesting that these nutrients are absorbed together (Table S4).In conclusion, the results of this study suggest that children of mothers with low carotenoid intake during pregnancy are at higher risk for developing infantile AD and are ideal targets for early intervention in allergy prevention. Further studies are needed to clarify whether carotenoid supplementation during pregnancy/in lactating mothers and infants after weaning has a preventive effect on AD development in infancy.Table 1 Levels of each carotenoid, total carotenoids, retinol, and α-tocopherol in each type of sample in participants with or without atopic dermatitis at 1 year of age
The field of food allergy has seen tremendous change over the past 5-10 years with seminal studies redefining our approach to prevention and management and novel testing modalities in the horizon. Early introduction of allergenic foods is now recommended, challenging the previous paradigm of restrictive avoidance. The management of food allergy has shifted from a passive avoidance approach to active interventions that aim to provide protection from accidental exposures, decrease allergic reaction severity and improve the quality of life of food-allergic patients and their families. Additionally, novel diagnostic tools are making their way into the clinical practice with the goal to reduce the need for food challenges and assist physicians in the -- often complex -- diagnostic process. With all the new developments and available choices for diagnosis, prevention and therapy, shared decision-making has become a key part of the medical consultation, enabling patients to make the right choice for them, based on their values and preferences. Communication with patients has also become more complex over time, as patients are seeking advice online and through social media, but the information found online may be outdated, incorrect, or lacking in context. The role of the allergist has evolved to embrace all the above exciting developments and provide patients with the optimal care that fits their needs. In this review, we discuss recent developments, as well as the evolution of the field of food allergy in the next decade.
Background. Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. Methods. Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data was analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). Results. α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year. Conclusions. Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 Type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
As many other physicians and researchers, we have had the great pleasure to be fellows in the laboratory of Dean Metcalfe, the Laboratory of Allergic Diseases, National Institute of Allergic and Infectious Diseases (NIAID), NIH, Bethesda, USA (Figure (#fig-cap-0001)). The open atmosphere, research driven by curiosity, hypotheses originating from clinical observations, and mutual trust and respect are the cornerstones of Dean’s mentorship. Dean and his laboratory have made major contributions on mast cell biology, from basic studies on the regulation of mast cell development and functions, to clinical studies on mast cells in diseases, such as systemic mastocytosis. After more than 50 years of exploring human mast cells, Dean’s impact on what we know today about these cells, their biology and how they affect diseases is outstanding and unique.
Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins 4/13, key and central drivers of type 2 inflammation. The LIBERTY ASTHMA TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who had participated in a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Methods: This analysis includes patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose inhaled corticosteroids (ICS) at parent study baseline (PSBL) and enrolled in TRAVERSE. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (pre-BD) FEV 1 (L), asthma control (5-item asthma control questionnaire), and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Results: Of patients with type 2 asthma (n=1,666) in this analysis, 891 (53.5%) were receiving high‑dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab vs placebo were 0.517 vs. 1.883 (phase 2b) and 0.571 vs. 1.300 (QUEST) over 52 weeks of the parent study, and remained low throughout TRAVERSE (0.313–0.494). Improvements in pre-BD FEV 1 from PSBL were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.
The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma are not well understood. We investigated whether the ambient levels of fine PM with aerodynamic diameter ≤ 2.5 microns (PM 2.5) are associated with alterations in circulating monocytes in children with or without asthma. Increased exposure to ambient PM 2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or LPS. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.
BACKGROUND Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 ®) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19. METHODS We conducted an open-label, randomized controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 ® (3.7mg and 11.1 mg/day: groups 1 and 2, respectively) in comparison with standard etiotropic drug treatment (group 3) in patients hospitalized with moderate COVID-19. The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization. RESULTS Patients from group1 had a significantly reduced (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) time to clinical improvement compared to patients from group 3 (8 days (95% CI: 7-10). Normalized oxygen saturation (SpO 2>94%) occurred quicker in the group 1 (median 5 days (95% CI: 4–5, HR 1.59, P=0.0033) than in the group 3 (6 days, 95% CI: 5–8). Treatment with MIR 19® was well tolerated and safe. CONCLUSIONS MIR 19 ®, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe and significantly reduces time to clinical improvement in hospitalized moderate COVID-19 patients compared to standard therapy in a randomized controlled trial. MIR 19 ® treatment targets a sequence which is identical in all SARS-CoV-2 variants known so far and hence should be applicable for all of them.
Fenebrutinib is an orally administered, selective and reversible BTK inhibitor. Metz et al recently published a double-blind, placebo-controlled, phase 2 trial where fenebrutinib (50mg daily, 150mg daily or 200mg twice-daily) or placebo were randomly administered to 93 adults with CSU refractory to up-dosed H 1-antihistamines during 8 weeks. Fenebrutinib was more effective than placebo in reducing weekly Urticaria Activity Score (UAS7) after 8 weeks, achieving rates of well-controlled disease (UAS7≤6) of up to 57% (with a 200mg twice-daily dose).
Background Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of severe adult asthma patients eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. Methods This was a prospective cohort study that included adult severe asthma patients from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance and hospital admissions. Results In the matched analysis (n=350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p<0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs 20.55% reduction; p=0.023).) There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). Conclusions In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes, however anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.
Background: Food allergy affects up to 8% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS). Methods: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0-24h. Distribution of relevant cell subsets was confirmed using single cell nuclear sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed. Results: PCIS viability was maintained for 24h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction. Conclusion: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.
Prodromes predict attacks of Hereditary Angioedema: results of a prospective StudyTo the Editor,Hereditary Angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.1 Early signs, symptoms and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.2-3 Using an new HAE-specific instrument, we have recently shown that patients can identify prodromes and able to predict oncoming attacks.4 However, that study was retrospective, which might have been affected by recall bias.In the present study a cohort of 48 HAE patients prospectively reported four events of prodromes followed by attack, attacks not preceded by a prodrome and incidents with only a prodrome. Pre-defined domains (clusters of body locations) and scalable dimensions (pain, severity, impairment and functionality), time of onset and termination were assessed in each episode.3-4 (Statistical methods are described in the supplementary data ). The study was approved by the ethics committees of Tel-Aviv University, Sheba Medical Center and Barzilai Medical center. All patients signed an informed-consent form. Mean age was 35.25 years (SD ±16.4), Median 30.0 (age range 10-70) and 27 (56.25%) were females. Mean age of onset was 8.3 years and age at diagnosis 10.9 years (2.7 years diagnostic gap) (Table S1 ).We received reports on 119 prodromes and 192 attacks. The majority experienced a prodrome before at least one of their attacks, and 64% affirmed that they can predict an oncoming attack by having a prodrome.(Table S1) .Significant differences were found between prodromes and attacks across all dimensions of the predefined clusters of body locations. Statistical analysis verified that prodromes could be discriminated from attacks for all parameters. (Table 1) Positive correlations were found between the same attributes of prodromes and attacks, most notably in the abdominal and extremity clusters (Table S2, Fig S1A-E) . Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The predictive power analysis indicates that individuals who experience a prodrome had higher risk for having an attack in the same region. Sensitivity of the prodrome as a predictor of attack was 95% to 99%, and specificity 18% to 64%. (Table 2).HAE prodromes represents a continuity of pathophysiologic events, initiated by the activation of the bradykinin-forming cascade and ending with a breach in vascular endothelial integrity.2, 5(Fig S2 ) In this study we aimed to capture the critical elements of prodromes and their association with consequent attacks and evaluate their predictive power as an early warning sign.2-4 The HAE-EPA instrument reliably captures patient’s experience by using the same metrics, and the prospective design better reflects patients’ experience in real-time, which may have been missed in our previous study.The study shades light on the predictive value of prodromes as forecasters of attacks.2-4 It affirms that patients can clearly distinguish prodromes from attacks. The positive correlations support our basic assumption that prodromes could predict attack location and severity, which is particularly germane in the abdomen. In most cases a high intensity attack was predated by a high intensity prodrome. This substantiate our observation on inter-personal differences between subjects4 Mean disease duration of the cohort (27 years) may surmise that the study subjects were experienced patients, who could recognize early pre-attack cues.Treating oncoming attack at the prodromal stage may enhance resolution of attacks.6, 7 Therefore; experienced patients can use prodromes as an efficient strategy in managing attacks by employing early interventions. Such approach can apply in other diseases with relapsing-remitting pattern and advance the concept of prodrome-triggered intervention.8In conclusion , the study ascertained that HAE patients can distinguish prodromes from attacks and a prodrome may predict attack in the same location. Having a prodrome increase the likelihood of subsequent attack, alerting the patients and assisting in early initiation of therapy.Table 1: Within-subject differences between prodrome and attacks
There has been an important change in the clinical characteristics and immune profile of COVID-19 patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4 and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) has been identified as an important cause of death of children with COVID-19. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. Atopic diseases, such as allergic asthma and rhinitis, have been shown to be associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, EAACI developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging SARS-CoV-2 variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID.