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 International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes and health management. Since its first edition, the ICD has maintained a framework distributing conditions according to topography, with the result that some complex conditions, such as allergies and hypersensitivity disorders (A/H) including anaphylaxis, have been poorly represented. The change in hierarchy in ICD-11 permitted the construction of the pioneer section addressed to A/H, which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019 and the implementation is ongoing worldwide. We here present the outcomes from an online survey undertaken to reach out the allergy community worldwide in order to peer review the terminology, classification and definitions of A/H introduced into ICD-11 and to support their global implementation. Data are presented here for 406 respondents from 74 countries. All of the sub-sections of the new A/H section of the ICD-11 had been considered with good accuracy by the majority of respondents. We believe that, in addition to help during the implementation phase, all the comments provided will help to improve the A/H classification and to increase awareness by different disciplines of what actions are needed to ensure more accurate epidemiological data and better clinical management of A/H patients.

To the Editor,We read carefully the research letter “Is asthma protective of COVID-19?” by Carli et al recently published.1Important topic for asthma patients in the coronavirus disease 2019 (COVID-19) pandemic were considered, including that until recently weak evidence that patients with chronic respiratory disorders are at a lower risk of being infected or becoming severely ill with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Reflecting only about previous reports from China and Italy where asthma was underrepresented in COVID-19 patients, the authors accept the heterogeneous condition that it is asthma, speculating that T2-immunity, interferon-mediated immune responses and increased number of eosinophils in the airways could have a protective effect against COVID-19 severity.1The epidemiology of COVID-19 is changing rapidly with new data. More recent reports from the United States of America and from several European countries, in particular the United Kingdom (UK), states a higher asthma prevalence in patients with COVID-19, suggesting that asthma is more common in COVID-19 patients than it was previously reported in Asia and in the first European surveys.2Data from the UK Biobank, a large prospective case-control study, found an asthma prevalence of 17,9% in 605 COVID-19 hospitalized patients, mostly of them adults, surpassing the prevalence of asthma in the general population.3Besides that, in the OpenSAFELY Collaborative Study (UK), it was found a significant increased risk of severe CoViD-19 in patients with asthma, including death, in particular related with the recent use of oral corticosteroid (OCS).4 These findings can indicate an increased asthma severity and/or poor control and, in accordance with data from previous coronavirus outbreaks, that systemic corticosteroids were associated with a higher viral load.5We agree with Carli et al1 that further studies focused on asthma and its different phenotypes are needed to provide a better understanding of the impact of SARS-CoV-2 infection in patients with asthma.6 Nevertheless, for the moment, it seems crucial that patients with asthma do not stop their controller medication, that may lead to a higher risk of asthma exacerbations, increased OCS use and higher probability to emergency room access and hospitalization that represent themselves significant risk factors for coronavirus exposure and spread.In conclusion, according with the available data, patients with asthma must still be included in the high-risk groups for COVID-19 and more data are needed to understand the relationship between asthma and COVID-19.

The pandemic condition Coronavirus-disease (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can take asymptomatic, mild, moderate, and severe courses. COVID-19 affects primarily the respiratory airways leading to dry cough, fever, myalgia, headache, fatigue, and diarrhea and can end up in interstitial pneumonia and severe respiratory failure. Different clinical symptoms caused by involvement of organs outside the respiratory system have been also described. Interestingly, reports about the manifestation of various skin lesions and lesions of the vascular system in some subgroups of SARS-CoV-2 positive patients as such features outside the respiratory sphere, are rapidly emerging. However, knowledge about prevalence and pattern of skin involvement, time of onset, predilection, and its direct or indirect relation to SARS-CoV-2 is still limited. In order to update information gained, we provide a systematic overview of the skin lesions described in COVID-19 patients, discuss potential causative factors and describe differential diagnostic evaluations.

To the Editor Since the end of February 2020 Italy, first non- Asian Country, has reported an ever increasing number of COronaVIrus Disease 19 (COVID-19) patients, which has reached over 200,000 confirmed Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected subjects and resulted in more than 34000 deaths (data updated to June 19th, 20201).Patients with asthma are potentially more severely affected by by SARS-CoV-2 infection 2 and it is well established that respiratory viral infections are associated with severe adverse outcomes in patients with asthma, including increased risk of asthma exacerbation episodes 3. Nonetheless, according to the epidemiological studies published so far, chronic pulmonary diseases are not amongst the most common clinical conditions in COVID-19 patients4About 5-10% of entire asthma population, are severe asthmatics5 and one would expect increased vulnerability to SARS-CoV-2 infection, but no data is so fare available ti confirm this hypothesis.We investigated the incidence of COVID-19, describing its clinical course, in the population of the Severe Asthma Network in Italy (SANI), one of the largest registry for severe asthma worldwide6, and in an additional Center (Azienda Ospedaliero Univeristaria di Ferrara, Ferrara, Italy). All centers, have been contacted and inquired to report confirmed (i.e. patients with positive test result for the virus SARS-CoV-2 from analysis of nasopharyngeal or oropharyngeal swab specimens) or highly suspect cases of COVID-19 (i.e. patients with symptoms, laboratory findings and lung imaging typical of COVID-19 but without access to nasopharyngeal or oropharyngeal swab specimens because of clinical contingencies/emergency) among their cohorts of severe asthma. Demographic and clinical data of the entire cohort of severe asthmatics enrolled in the study and all reported cases of confirmed or suspect cases of COVID-19, have been obtained from the registry platform and collected from the additional Center. Additional data about COVID-19 symptoms, treatment and clinical course have been collected for all cases reported.Ethical issues and statistical analysis are reported in the online supplementary material.Twenty-six (1.73%) out of 1504 severe asthmatics had confirmed (11 out of 26) or highly suspect COVID-19 (15 out 26); eighteen (69.2%) were females and mean age was 56.2 ± 10 years. The geographical distribution of COVID-19 cases is presented in Figure 1.Nine (34.6%) infected patients experienced worsening of asthma during the COVID-19 symptomatic period; four of them needed a short course of oral corticosteroids for controlling asthma exacerbation symptoms.The most frequent COVID-19 symptoms reported were fever (100% of patients), malaise (84.6%), cough (80.8%), dyspnea (80.8%), headache (42.3%) and loss of smell (42.3%). Four patients (15.3%) have been hospitalized, one of which in intensive care unit; among hospitalized patients, two (7.7%) died for COVID-19 interstitial pneumonia. No deaths have been reported among the non-hospitalized patients.Severe asthmatics affected by COVID-19, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) compared to non-infected severe asthma patients (15.4% vs 3.8%, p=0.002; odds ratio: 4.7). No difference was found in other comorbidities (including rhinitis, chronic rhinosinusitis with or without nasal polyps, bronchiectasis, obesity, gastroesophageal reflux, arterial hypertension, cardiovascular diseases).Twenty-one patients with COVID-19 were on biological treatments: 15 (71%) were on anti-IL-5 or anti-IL5R agents (Mepolizumab n= 13; Benralizumab n=2 - counting for the 2.9% of all severe asthmatics treated with anti-IL5 in our study population) and 6 (29%) were on anti IgE (Omalizumab - 1.3% of all severe asthmatics treated with omalizumab in our study population).Table I summarizes demographic and clinical characteristics of the 26 COVID-19 patients.In conclusion, in our large cohort of severe asthmatics, COVID-19 was infrequent, not supporting the concept of asthma as a particularly susceptible condition to SARS-COV2 infection 2. This is in line with the first published large epidemiological data on COVID-19 patients, in which asthma is under-reported as comorbidity4. The COVID-19 related mortality rate in our cohort of patients was 7.7%, lower than the COVID-19 mortality rate in the general population (14.5% in Italy 1). These findings suggest that severe asthmatics are not at high risk of the SARS-CoV-2 infection and of severe forms of COVID-19. There are potentially different reasons for this. Self-containment is the first, because of the awareness of virus infections acting as a trigger for exacerbations, and therefore they could have acted with greater caution, scrupulously respecting social distancing, lockdown and hygiene rules of prevention, and being more careful in regularly taking asthma medications.Another possible explanation stands in the intrinsic features of type-2 inflammation, that characterizes a great proportion of severe asthmatics. Respiratory allergies and controlled allergen exposures are associated with significant reduction in angiotensin-converting enzyme 2 (ACE2) expression 7, the cellular receptor for SARS-CoV-2. Interestingly, ACE2 and Transmembrane Serine Protease 2 (TMPRSS2) (another protein mediating SARS-CoV-2 cell entry) have been found highly expressed in asthmatics with concomitant NIDDM8, the only comorbidity that was more frequent reported in our COVID-19 severe asthmatics.The third possible explanation refers to the possibility that inhaled corticosteroids (ICS) might prevent or mitigate the development of Coronaviruses infections. By definition, patients with severe asthma are treated with high doses of ICS 5 and this may have had a protective effect for SARS-CoV-2 infection.Noteworthy, among the patients of our case-series of severe asthmatics with COVID-19, the proportion of those treated anti-IL5 biologics was higher (71%) compared to the number of patients treated with anti-IgE (29%). Although the number of cases is too small to draw any conclusion, it is tempting to speculate that different biological treatments can have specific and different impact on antiviral immune response. In addition we may speculate of the consequence of blood eosinophils reduction: eosinopenia has been reported in 52-90% of COVID-19 patients worldwide and it has been suggested as a risk factor for more severe COVID-19 9.In conclusion, in our large cohort of severe asthmatics only a small minority experienced symptoms consistent with COVID-19, and these patients had peculiar clinical features including high prevalence of NIDDM as comorbidity. Further real-life registry-based studies are needed to confirm our findings and to extend the evidence that severe asthmatics are at low risk of developing COVID-19.

TitleA mouse model of asthma­–chronic obstructive pulmonary disease overlap induced by intratracheal papain

This systematic review evaluates the efficacyand safety of omalizumab for chronic spontaneous urticaria (CSU). Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CSU-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Ten RCTs including 1620 subjects aged 12 to 75 years old treated with omalizumab for 16 to 40 weeks were evaluated. Omalizumab 150 mg: does not result in clinically meaningful improvement(high certainty) of the urticaria activity score (UAS)7 (mean difference (MD) -5; 95%CI -7.75 to -2.25) and the itch severity score(ISS)7 (MD -2.15; 95% CI -3.2 to -1.1); does not increase (moderate certainty) quality of life (QoL) (Dermatology Life Quality Index (DLQI); MD -2.01; 95%CI -3.22 to -0.81); decreases (moderate certainty) rescue medication use (MD -1.68; 95%CI -2.95 to -0.4). Omalizumab 300 mg:results in clinically meaningful improvements(moderate certainty)of the UAS7 (MD -11.05; 95%CI -12.87 to -9.24), theISS7 (MD -4.45; 95%CI -5.39 to -3.51), and QoL (high certainty)(DLQI; MD -4.03; 95% CI -5.56 to -2.5); decreases (moderate certainty) rescue medication use (MD -2.04; 95%CI -3.19 to -0.88) and drug-related serious AEs (RR 0.77; 95%CI 0.20 to 2.91).

Dear Editor: I read with interest the report by Antonella et al.1 This report described a case of the acute scrotum caused by Anisakis . As the authors write, this condition is rare in its own right. However, I would like to discuss two other rare aspects of this case: that it occurred during childhood and that acute scrotal disease and anaphylaxis occurred simultaneously.There has been a long debate as to whether anaphylaxis caused by Anisakis occurs with the ingestion of live insect bodies only or with dead insect bodies as well.2 Since several allergen components of Anisakis have been identified and their tolerance to heat has been reported, it is theoretically possible that anaphylaxis could occur with the ingestion of dead larvae body parts. However, some reports suggest that even patients sensitized to Anisakis may not develop allergic symptoms with the ingestion of frozen Anisakis larvae.3Nevertheless, there have been very few cases of gastrointestinal anisakiasis and anaphylaxis occurring simultaneously. In fact, previous literature has shown that in 40 cases of anaphylaxis which occurred due to the ingestion of live fish, upper gastrointestinal endoscopy revealed no difference in phenotype between the 20 cases in which live larvae were found and the 20 cases in which they were not found, and even in the case of live Anisakis bodies, the abdominal symptoms were minor.4 Of the 128 cases included in our previous study, only one could be said to have developed anaphylaxis and gastric anisakiasis simultaneously.5The patient we experienced was a 36-year-old woman with a previous history of gastric anisakiasis. Urticaria, watery diarrhea and vomiting, and respiratory distress developed three hours after eating sashimi (sliced raw fish) of young yellowtail. The patient was rapidly administered adrenaline intramuscular injection, followed by H1/H2 blockers and methylprednisolone, and admitted to the hospital for observation. However, after a day of admission, she continued to complain of intermittent epigastric pain and underwent upper gastrointestinal endoscopy. A live Anisakis larva was found in the gastric cavity, and the epigastric pain disappeared after its removal. This case was negative for fish-specific IgE and positive forAnisakis -specific IgE (ImmunoCAP🄬 fluorescent enzyme immunoassay). Similar cases have been reported recently by Shikino et al.6The reason for such phenotypic variations after the ingestion of liveAnisakis is a direction for future research. From this perspective, it would be very interesting to explore what pathological changes, e.g., eosinophilic granulomatous changes, had occurred in the scrotum or lungs of the boy described in Antonella et al. I believe that these characteristics are important to determine the cause of the respiratory impairment in this case.Further, it is interesting to note that this phenomenon occurred in an 8-year-old boy. Only one in our 128 cases of fish-associated anaphylaxis was under 10 years of age, and this case was positive for the IgE specific to horse mackerel and mackerel.5 Therefore, the group I analyzed did not include cases of Anisakisanaphylaxis under the age of 10 years. The case described in Antonella’s manuscript does not appear to have undergone a specific IgE test or other skin tests. However, given the rarity of Anisakisanaphylaxis in this age group, anaphylaxis due to other culprits such as parvalbumin caused by fish ingestion should also be considered.Ryo Morishima MDDepartment of Neurology, Tokyo Metropolitan Neurological Hospital,Tokyo, JapanReferenceAntonella C, Stellario C, Aurelio M, Domenico S, Domenico S, Ilaria PP, et al. Acute scrotum in a 8-year-old Italian child caused by extraintestinal anisakiasis in a seaside area. Allergy 2020 [in press]Nieuwenhuizen NE. Anisakis – immunology of a foodborne parasitosis. Parasite Immunology 2016 Sep;38(9):548-57. doi: 10.1111/pim.12349. PMID: 27428817Alonso-Gómez A, Moreno-Accillo A, López-Serrano MC, Suarez-de-Parga JM, Daschner A, Cabañas R, et al. Anisakis simplex only provokes allergic symptoms when the worm parasitizes the gastrointestinal tract. Parasitol Res. 2004 Aug;93(5):378-84. doi: 10.1007/s00436-004-1085-9. PMID: 15221464Daschner A, Alonso-Gómez A, Cabañas R, Suarez-de-Parga JM, López-Serrano MC. J Allergy Clin Immunol. 2000 Jan;105(1 Pt 1):176-81. doi: 10.1016/s0091-6749(00)90194-5. PMID: 10629469Morishima R, Motojima S, Tsuneishi D, Kimura T, Nakashita T, Nishino H, et al. Anisakis is a major cause of anaphylaxis in seaside areas: an epidemiological study in Japan. Allergy. 2020 Feb;75(2):441-444. doi: 10.1111/all.13987. PMID: 31315145Shikino K, Ikusaka M. Anaphylaxis induced by Anisakis . Intern Med 2019 Jul 15;58(14):2121. doi: 10.2169/internalmedicine.2428-18. PMID: 30918192

Modern healthcare requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of the distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions on the efficacy of the current management of allergic diseases requires further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen-immunotherapy with a special emphasis on specific IgE, microbiome and epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.

Trained immunity refers to the fact that the innate immune system also demonstrates memory, resulting in a faster and more profound second innate reaction, days to weeks after a first reaction to another pathogen or vaccine. Thus, trained immunity is heterologous, non-specific. We applied this principle with MMR vaccination during the COVID-19 pandemic.In a prospective, observational, single-center study 255 subjects, most at high risk for infection with COVID-19, received preventive MMR vaccination; 36 got infected with COVID-19; all had a mild course, even though 40% had risk factors. This might in part be due to trained immunity, conveying innate immune memory secondary to MMR vaccination, enhancing the innate immune response once the subject gets infected with SARS-CoV-2.As a result the well-known immune suppression brought about by coronavirus might not work so well, as the innate immune system is primed, allowing the body to finally eliminate the virus more efficiently.

Asthma control, self-management and healthcare access during the COVID-19 Epidemic in BeijingChun Chang a* M.D., Linlin Zhanga*B.S., Fawu Dong a* B.S., Ying Liang a M.D., Yahong Chen a M.D., Ying Shang a B.S., Mairipaiti Abulikemua B.S., Yongchang Suna# M.D.aDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China.#, Corresponding to Yongchang Sun:Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China.North Garden Rd. 49.Haidian District, Beijing, 100191, ChinaTel: +86 010 139 1097 9132Fax +86 108 226 6989E-mail: [email protected]* Chun Chang, Linlin Zhang and Fawu Dong contributed equally to this work;To the Editor:The pandemic of COVID-19, caused by the pathogen SARS-CoV-2, has now spread around the globe. Social distancing and restriction measures during COVID-19 pandemic may have impacts on asthma control and management in terms of medication availability and healthcare access. International societies responded quickly by releasing guidance on the management of asthma during the COVID-19 pandemic1-4. However, these temporary guidelines were based largely on previous asthma guidelines and expert consensus, because evidence from related studies was lacking. Therefore, we investigated the status of asthma control, self-management, medications and healthcare utilization of asthma patients during the COVID-19 epidemic in Beijing, aiming to provide data for guideline recommendations on asthma managements during the emergency.Patients with asthma, selected randomly from our hospital database, were interviewed by phone call. Detailed description of items in the questionnaire is available in this article’s online supplementary material.We contacted 286 patients, of whom 178 (62.2%) responded with valid results. Sociodemographic data and clinical characteristics of the patients before the COVID-19 pandemic are provided as online supplements. During the COVID-19 epidemic in Beijing (January 25, 2020 to April 25, 2020), the majority (74.2%, 132/178) of the patients felt that their symptoms had not changed as compared with usual times, while 18.0% (32/178) felt better, and 7.9% (14/178) felt worse. The mean ACT score of the 178 patients was 22.76 ± 3.06 (ranging from 8 to 25) in the last 4 weeks before the survey. According to the criteria of ACT scoring from GINA, asthma was classified as well-controlled in 89.3%, not well-controlled in 6.2%, and very poorly controlled in 4.5% of the patients. During this period, only 24.7% (44/178) of the patients had ever visited a hospital or clinic for asthma, of whom 11 patients had 2 visits, and 6 had ≥3 visits, totaling 74 visits. 14.9% (11/74) of all medical visits were due to exacerbation of asthma, while the remaining visits (63/74, 85.1%) were for regular prescription of asthma medications. Only 6 patients (3.4%) sought consultation online. (Table 1)Notably, 25.6% (45/176) of the patients experienced aggravation of asthma symptoms during the COVID-19 epidemic, but 75.6% (34/45) of them did not see a doctor, because 67.6% (23/34) of the patients thought that they did not need to go to the hospital and took more medications by themselves, and the remaining 32.4% (11/34) worried about cross-infection of COVID-19 in the hospital. No patient said that they did not see a doctor because they could not arrange an appointment. Eleven patients went to the hospital due to aggravation, 81.8% (9/11) to the outpatient, while only 18.2% (2/11) to the Emergency Department (ED).Table 1 Asthma control and management during the COVID-19 epidemic in Beijing

I thank Dres. Alnaes and Helnes Bergen for their stimulating comment on my medical algorithm on the Diagnosis and Treatment of Radiocontrast Media Hypersensitivity.1 In their comment, they raised attention to the possible addition of desensitization to radiocontrast media (RCM) management, which was not depicted in the algorithm.2 I have been well aware of several reports on desensitization and have already discussed them in a previous paper, however commented there that “successful desensitization of RCM has been reported for immediate hypersensitivity reactions to RCM, but it is only used anectodically” and concluded not to include this procedure into the algorithm.3In addition to the two papers on desensitization to RCM cited by Dr. Alaes, also a handful other cases have been published, some of them older. To my knowledge, at least as far as I can access these case reports, in none of these patients a proper allergy diagnosis and management has been performed and in most, if not all of these patients, desensitization probably was unnecessary. In the described cases, skin testing has not been performed or was even negative indicating a higher probability for a non-allergic immediate hypersensitivity reaction (IHR), in the history before desensitization was performed in several cases the RCM was not changed, but the same not tolerated RCM was given again and radiologists in vain relied on premedication to prevent recurrent attacks, and no skin test-negative RCM was identified and used. None of the cases published convinced me of the need for desensitization. Performing the examination with a skin test-negative RCM would with a high probability be successful.4 I would expect the success of desensitization was rather due to changing to a different isoosmolar RCM (and probably not to adding premedication) than the desensitization procedure itself, as alone changing the implicated RCM to another one in one study reduced the risk of recurrent IHR by 67.1% (odds ratio: 0.329; P = 0.001), whereas steroid premedication did not show protective effects.5Our group of European Network on Drug Allergy experts have highlighted that rapid desensitization is a procedure that can be used to provide a temporary tolerance to a first-line drug when no alternative is available.6 This implies for RCM hypersensitivity that using a skin-test-negative RCM for the next examination as an alternative drug is next step and not immediate desensitization. One problem with desensitization is that too many doctors employ it uncritically and without prior proper allergy workup, best with drug provocation test. The high rate of successful desensitizations without prior confirmation of drug hypersensitivity in the literature is in part explained by the fact that many of those patients would not have reacted anyway. I have yet to find convincing evidence to add desensitization as a standard therapeutic option to the RCM management algorithm.Having said this, I am eagerly following up the literature on RCM desensitization with great interest to be prepared, should I encounter an own patient, who would react severely to an alternative skin test-negative RCM after following the algorithm. Until now, colleagues and I have not met such a patient, however, I would seriously consider desensitization as an option in such a situation. Thus, I thank Dres. Alnaes and Helsen Bergen for bringing up that interesting topic for discussion.

EDITORIAL Coronavirus disease‐19 (COVID‐19) is a new disease caused by SARS‐CoV2. Since the beginning of 2020, it has become one of the main challenges of our times, causing a high incidence of severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure and death1. At the root of COVID-19 lies the sudden development of ‘cytokine storms’, hyper-inflammatory responses involving the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1, IL-8, and MCP-1) that impair the gas exchange function of the lung and lead in select patients, mostly with underlying comorbidities, to multiorgan failure and death1,2. Additional complications triggered by ‘cytokine storms’ include endothelial dysfunction and hypercoagulation, increasing the risk of thromboembolytic events, and life-threatening cardiovascular complications. Anti-inflammatory therapies are thus being considered for alleviating the damaging side effects of hyper-inflammation with many trials including anti-cytokine biologicals, disease-modifying antirheumatic drugs (DMARDs) and corticosteroids being ongoing3. Surprisingly, among them dexamethasone has taken center stage as initial results from the RECOVERY trial, a large multicenter randomized open-label trial for hospitalized patients run in the United Kingdom, revealed notable efficacy in the treatment of critically ill COVID-19 patients4.Dexamethasone is one of the oldest synthetic glucocorticoid agonists synthesized in 1957 and introduced into the clinic in 1961. When administered at 6 mg daily, either orally or intravenously for 10 days, dexamethasone was shown in the RECOVERY trial to improve survival rates of hospitalized patients with severe COVID-19 receiving oxygen or being on mechanical ventilation by a remarkable 30%4. Benefit was restricted to patients requiring respiratory support whereas in milder cases this was not clear. This notable efficacy of dexamethasone treatment goes against the current view of corticosteroid use in respiratory viral infections which remains contradictory. Although corticosteroids improve ventilator weaning and can lower the intensity of the host response to the virus, tempering the ‘cytokine storm’ and limiting immunopathology, they can also reduce viral clearance and lead to more severe disease. Understanding therefore how dexamethasome mediates its effects is of paramount importance.Dexamethasone, as other corticosteroids, is held to mediate its anti-inflammatory and immunosuppressive effects via the glucocorticoid receptor. Upon ligand binding, the receptor-corticosteroid molecule complex moves into the cell nucleus, where it dimerizes and binds to glucocorticoid response elements (GRE), acting as transcriptional repressor or transactivator of diverse sets of genes. This results in the inhibition of inflammatory cell activity, including neutrophils, macrophages and lymphocytes, and the suppression of pro-inflammatory cytokines such as TNF and interleukins and other genes such as cyclooxygenase-2 and inducible nitric oxide synthase5. However, we have recently uncovered that dexamethasone can also induce the D-series proresolving lipid mediator pathway leading to the production of 17-HDHA and the protectins D1 and DX6. These are potent major players of the molecular machinery driving the resolution of inflammation, i.e. the proper regulated termination of pro-inflammatory responses involving the catabolism of pro-inflammatory mediators, the removal of inflammatory cells and the restoration of the tissue in a timely and highly coordinated manner7. Although resolution of inflammation has long been considered to occur spontaneously as a result of the waning of pro-inflammatory responses, this is now known to be an ordered and highly regulated process involving the timely production of enzymatically oxygenated lipid-derived mediators such as protectins, D-series resolvins and maresins derived from the omega-3 fatty acid docosahexaenoic acid (DHA), E-series resolvins derived from eicosapentaenoic acid (EPA), and lipoxins biosynthesized from omega-6 fatty acids following eicosanoid class switching7. Interestingly, certain lipid mediators have been shown to exert additional non-conventional functions; resolvin D4 can attenuate pathologic thrombosis, reduce NETosis and promote clot removal8 which is now recognized as a key pathology of COVID-19 infection, while resolvin E4 (RvE4) stimulates efferocytosis of senescent erythrocytes in hemorrhagic exudates especially under hypoxic conditions that characterize COVID-199. Moreover, corticosteroids have been reported to reduce fibrinogen and procoagulant factors under pro-inflammatory conditions and increase anticoagulant factors10.The ability of viral infections to induce proresolving lipids has been reported earlier. Toll-like receptor 7 (TLR7), a major pattern recognition receptor of viral RNA, activates PD1 and PDX production11. Moreover, influenza virus infection has been demonstrated to drive proresolving lipid mediator networks including the production of PD1 which limits influenza pathogenicity by directly interacting with the RNA replication machinery to inhibit viral RNA nuclear export12,13. Notably, in particularly virulent strains of influenza virus such as the H5N1 avian strain, PD1 formation is not sufficiently upregulated, leading to more efficient viral replication and host demise12. It is therefore plausible that the efficacy of dexamethasone in COVID-19 is due at least in part to its ability to induce proresolving lipid mediators that possess multiple anti-inflammatory and proresolving actions tempering down inflammation and promoting its resolution, preventing coagulation and enhancing viral and bacterial clearance (Figure 1) yet are not immunosuppressive . Whether other corticosteroids beyond dexamethasone can also mediate such effects, and to what extent, is not known. Whether inhalable corticosteroids, such as those given to asthmatic patients, can also induce proresolving lipid mediator networks locally and thus prevent the development of severe SARS‐CoV‐2 infection remains to be determined. There is evidence that asthmatic patients exhibit reduced incidence of severe and/or critical COVID-1914.Recently, COVID-19 patients showed increased association of serum arachidonate-derived proinflammatory lipid mediators, e.g. prostaglandins, in severe COVID -19 infections while some pro-resolving mediators such as resolvin E3 were up-regulated in the moderate COVID-19 group suggesting that an imbalance in lipid mediators with a swift toward pro-inflammatory mediators in severe disease may contribute to COVID-19 disease severity15. Although the involvement of proresolving lipid mediator pathways in COVID-19 is an attractive hypothesis, further evidence from human trials is needed as there are no studies at present reporting the induction or modulation of such networks in the context of the various disease stages and treatments. It is thus of uttermost priority to investigate proresolving lipid mediators in COVID-19, in a temporal and longitudinal manner, as modulating these networks either through drug treatment or direct administration of resolvin and protectins agonists has the potential to affect this highly lethal and devastating disease in a way other approaches cannot. Such studies are therefore eagerly awaited.

Article type: News and Views: Groundbreaking Discoveries in Immunology

To the Editor,The proportion of the population with allergic diseases has increased rapidly in recent decades1, 2. In addition to affecting the quality of life, a significant economic burden of these diseases was transferred to society and the national health care system1. China is a large country with a rapidly developing economy, wide geography, and diverse climate and lifestyles, which may lead to significantly regional differences in the distribution of allergens. Although a series of studies have explored the prevalence of allergen sensitization in China, the majority of them focus on one part of geography in China3-5. In 2009, a study6 was conducted to estimate the prevalence of common aeroallergens among patients with allergic asthma and/or rhinitis in mainland China. Although the study investigated the differences of the prevalence in different regions of China, it divided China into only four geographical regions, which may neglect detailed information about the characteristics of sensitization prevalence in different places in China. In that study, the skin prick test (SPT) was used to detect the sensitization to allergens. The method has low accuracy for positive results because it is heavily affected by certain factors, such as the skill of the tester, reagent used, interpretation of results and so on. Our research has the following different characteristics compared with previous studies: 1) covering a variety of allergic diseases, 2) exploring both aeroallergens and food allergens simultaneously, 3) including a large set of data from all the seven regions of mainland China, and 4) using an internationally recognized method of sIgE testing, ImmunoCAP, to detect sensitization. These advantages may help us obtain more accurate and reliable results and conclusions.Here, we conducted a large multicenter study on the prevalence patterns of serum allergen-specific IgE (sIgE) sensitization to the four most common food allergens (i.e., egg whites, cow’s milk, crab, and shrimp) and five aeroallergens (i.e., house dust mite, German cockroach, tree pollen mix, mold mix, dog dander) among 44156 patients with allergic symptoms in 52 cities from 26 provinces of all the seven geographical regions in mainland China from July 2015 to June 2018. The sIgE sensitization was tested by a certified third-party laboratory service provider with uniform and standardized procedures. This study was approved by the ethics committee of the First Affiliated Hospital of Guangzhou Medical University (Approval number: GYFYY-2017-18). Details about the methods were in the supplementary materials .Our study showed that the overall prevalence of positive sIgE responses to the 9 allergens across mainland China from the highest to the lowest was 33.74% for house dust mites, 24.5% for cockroaches, 19.97% for shrimp, 17.31% for crab, 11.62% for cow’s milk, 10.92% for egg whites, 9.35% for tree pollen mix, 4.02% for dog dander and 3.92% for mold mix (Table 1 ). Our study confirmed that an observation shown in several previous studies based on certain specific areas in China3-5 that the positive cases in sIgE fell mainly in the two low classes (i.e., classes 1 and 2) was also held in all the seven regions in mainland China (Table 1 ).Our study revealed the distinctive patterns in the prevalence of allergen sensitization among regions, gender, age groups and seasons. Geographically, there is a significant difference in the prevalence among regions for all 9 allergens except for the mold mix (Table S1 ). House dust mites were the allergen with the highest prevalence of sensitization in all seven regions, with the highest in South China (40.79%) and the lowest in Northeast China (11.21%). Allergies to German cockroaches had a higher prevalence in southern regions (Southwest China, South China and East China) than in northern regions (North China and Northeast China). The prevalence of sIgE responses to dog dander was the highest in North China and was very close to each other in the southern regions. The prevalence of the egg whites and milk in Central China, East China and South China was higher than in Southwest China, North China and Northeast China, which means that patients living in eastern, coastal and/or southern areas were more sensitive to egg whites and cow’s milk. The prevalence of crab and shrimp sensitization in Southwest China and South China was higher than that in the northern regions (North China and Northeast China). The heatmap (Figure 1 ) displays the distribution of the prevalence of the sIgE response to allergens in different regions of mainland China.The prevalence of sensitization to all nine allergens was higher overall in males than in females (Table 1 and Figure S1 ) although that may not be true in each age group for each allergen as shown in the forest plot in Figure S1 . Our study showed that, whereas the sensitization to egg whites and milk was the highest in children, the sensitization to other allergens tended to be the highest in teenagers and young adults (Figure S2 ). Figure S3displays he prevalence pattern of allergens by months across years. The prevalence of dog dander and mold mix was very stable across months; however, the prevalence of other allergens fluctuated from January to December. The prevalence of house dust mites, German cockroach, shrimp and crab were higher in the summer months (from June to August) than in other months. The prevalence of tree pollen mix was much higher in April and October than in other months.This should be the first large study to investigate the prevalence of allergen sensitization in the patients with allergic symptoms from all the seven geographic regions of mainland China. Based on this study, we found that the prevalence of sIgE sensitization to allergens displayed obvious and distinctive patterns among regions, gender, age groups and seasons. The reasons for these patterns may include lifestyle factors, socioeconomic factors, genetic predispositions, climate, sexual hormones, cross-reactivity and so on3,4,6-9. Please refer to the supplementary materials for the detailed discussion on the factors that influenced these variations. Our findings may help clinicians find effective individualized treatments for unique patient groups and direct researchers to conduct further studies on the epidemiology of allergic diseases.

Background: The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children. Objective: We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model. Methods: A mouse model of IgE-mediated cashew anaphylaxis was first developed. Based upon this model, the efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. Cashew-specific antibody titers were measured throughout treatment. Treated mice were challenged orally to cashew and anaphylactic symptoms were monitored. Additionally, plasma levels of mast-cell proteases (mMCP)-1/7 were quantified from blood samples collected after challenge to evaluate IgE-induced mast-cell activation. Results: EPIT significantly decreased anaphylactic symptoms following challenge and increased cashew-specific IgG2a (equivalent of human IgG1). Interestingly, this protection was associated with a sharp decrease in mast-cell reactivity. Conclusion: We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.

To the Editor: The spread of the coronavirus disease-2019 (COVID-19) remains a worsening global health crisis. Although many studies have reported risk factors for severe COVID-19, asthma characterization in COVID-19 is still controversial, with different early reports from China and recent reports from the Europe and United States.1 Prolonged viral shedding is not only a risk factor for poor outcome of COVID-19, but also clues to host immune response against the virus. However, there is limited data on this except for results from relative small group studies.2 In this study, 2 200 adult patients hospitalized for COVID-19 in Daegu were evaluated for prevalence of asthma and clinical outcomes with COVID-19 according to asthma. In addition, the risk factors for delayed viral clearance were evaluated.The prevalence of asthma in patients with COVID-19 was 3.2% which was not different from its prevalence in the Korea National Health and Nutrition Examination Survey (KNHANES) (Figure 1A and Table S1). By age group, the prevalence of asthma showed a similar U-shaped pattern as the general prevalence pattern in Korea. However, the prevalence of asthma in the 19–29-year age group (2.1%) was lower than that of KNHANES (Figure 1B).Table S2 compares the characteristics between the asthma group and the non-asthma group. Older age, overweight, and comorbidity of chronic obstructive pulmonary disease, and initial symptoms of dyspnea and nausea/vomiting were more common in the asthma group. Compared with the non-asthma group, the asthma group had a greater risk of death (13.6%vs. 6.4%, P = 0.02) and a greater need for high-flow oxygen therapy (18.2% vs . 10.5%, P = 0.048) (Figure 1C and Table S3). The higher mortality rate in asthma patients compared with non-asthmatic patients was particularly noticeable in female and overweight patients. Older patients (> 65 years) with asthma tended to have a higher mortality rate than those without asthma (Figure 1D). After adjusting for potential confounders, asthma had no significant association with clinical outcomes of COVID-19 (Figure 1E and Table S4). Meanwhile, older age, male gender, and comorbid diseases including overweight, diabetes, chronic kidney disease, cancer, autoimmune disease, dementia, and other psychological disorder were significant risk factors for mortality (Tables S5 and S6).Asthma is considered to have a lower risk of death than other well-known risk factors.3, 4 However, asthma is a heterogeneous disease and is often associated with atopic and eosinophilic asthma in younger patients. Meanwhile, obese asthma and elderly asthma are known to have common neutrophilic phenotypes.5, 6 The recent results of higher expression of COVID-19 receptors in respiratory specimens with neutrophilic asthma phenotype compared with the eosinophilic asthma phenotype.7 Considering prevalence and clinical outcome results, it is possible that neutrophilic asthma is a risk factor for infection and poor prognosis of COVID-19 rather than eosinophilic asthma.When delayed viral clearance was divided into two groups based on 30 days, 906 patients were included in the non-delayed viral clearance group and 415 patients in the delayed viral clearance group. After adjusting for potential confounders, delayed viral clearance was not significantly associated with asthma (Figure 1E and Table S4). However, older age >65 years (Odds ratio (OR) 2.002, 95% Confidence interval (CI) 1.292–3.101; P = 0.002), comorbid diseases including dementia (OR 3.123, 95% CI 1.833–5.321; P<0.001), and other psychological disorder (OR 2.084, 95% CI 1.178–3.687; P = 0.012), initial symptom of skin rash (OR 15.943, 95% CI 1.613–157.535; P = 0.018), and initial laboratory abnormalities including hemoglobin <10 g/dL (OR 2.156, 95% CI 1.161–4.003; P = 0.015) and C-reactive protein (CRP) ≥1.0 mg/dL (OR 1.588, 95% CI 1.061–2.377; P = 0.025) were significant risk factors for delayed viral clearance. On the other hand, male sex (OR 0.752, 95% CI 0.567–0.997; P = 0.047), hypertension (OR 0.704, 95% CI 0.519–0.953; P = 0.023), and initial symptom of headache (OR 0.673, 95% CI 0.485–0.932; P = 0.017) were significant protective factors for delayed viral clearance (Figure 2A and Table S7). In particular, when limited to the mild COVID-19 group classified as no activity limitations in the outcome parameters, older age, dementia, initial symptoms of skin rash and headache, and initial hemoglobin <10 g/dL showed significant differences (Figure 2B, Table S8).Several factors related to the nervous system were identified as important risk factors for delayed viral clearance. Previous studies have shown that the coronavirus can initially invade the peripheral nerves and enter the central nervous system through a synapse path.8 It is hypothesized that the ability of the immune system to find and remove viruses that have penetrated the nervous system is important for virus clearance. Male sex, hypertension and elevated CRP did not show a significant difference when analyzed only mild patients, and these may be indicators associated with severity rather than a direct effect on viral clearance.Anti-inflammatory drugs such as hydroxychloroquine and systemic steroid were shown to be risk factors for mortality and delayed viral clearance (Table S6 and S8). These medications were used more often when the hospitalization period was extended or when showing poor prognosis factors. Notwithstanding these, our results suggest that anti-inflammatory drugs need to be used with proper consideration of appropriate indications.On May 9, 2020, there were 6,859 patients with PCR-confirmed COVID-19 in Daegu. This data excluded asymptomatic or minimal symptomatic patients who did not require hospitalization. However, our study covered almost all hospitalized patients diagnosed with COVID-19 in Daegu from February to May ,therefore, selection bias is minimized.9 In Korea, most hospitals decided to terminate the quarantine by repeating PCR every week. In addition, the Korea Centers for Disease Control & Prevention (KCDC) thoroughly managed the criteria for quarantine termination and PCR results. Through this, in our study, we were able to perform a large-scale study to confirm the risk factors for delayed viral clearance.In summary, despite the positivity of differences depending on phenotypes, the prevalence of asthma was not significantly different in patients with COVID-19, and asthma did not affect the outcomes of COVID-19. Age, dementia, and initial presentations of headache, skin rash, and anemia were independently associated with viral clearance.

A document by Qiaoxing Liang. Click on the document to view its contents.