To the Editor,We appreciate the interest and comments of Soriano and Ancochea1 regarding our papers 2. Further to the suggestion that “it would be of interest to repeat their statistics conducted during the first wave of COVID-19, again with the current estimates during the ongoing second wave, or later ones”, we would like to emphasize that our geographical observation was a type of anecdotal evidence that contributed to formulating a hypothesis. In a previous paper, we found that after adjusting for potentially relevant country-level confounders, there was a negative ecological association between COVID-19 mortality and the consumption of cabbage and cucumber in European countries 3. In this study, we acknowledged that “As in any ecological study, any inference from the observed association should be made at the country level, as the possibility of ecological fallacy precludes inferences at the individual level; and that further testing in properly designed individual studies would be of interest”. Indeed, what would be useful is testing the hypothesis in robust observational studies and/or clinical trials.Regarding our observation that COVID-19 could be considered as a disease of the Anthropocene 4 , other authors have recently provided a more complete description of the links between the disruption of the natural ecosystems that characterize the Anthropocene and the occurrence of zoonosis 5 6.1. Soriano J and Ancochea J. Saved by cabbage, killed by cabbage, and COVID-19. Allergy 2020; in press.2. Bousquet J, Anto JM, Czarlewski W, et al. Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy 2020. DOI: 10.1111/all.14549.3. Fonseca S, Rivas I, Romaguera D, et al. Association between consumption of vegetables and COVID-19 mortality at a country level in Europe. MedRix 2020; 10.1101/2020.07.17.201558464. O’Callaghan C and Anto J. COVID-19: The Disease of the Anthropocene.Env Res 2020; 187: 109683.doi: 109610.101016/j.envres.102020.109683. Epub 102020 May 109615.5. Morens DM and Fauci AS. Emerging Pandemic Diseases: How We Got to COVID-19. Cell 2020; 182: 1077-1092. 2020/08/28. DOI: 10.1016/j.cell.2020.08.021.6. Roche B, Garchitorena A, Guegan JF, et al. Was the COVID-19 pandemic avoidable? A call for a ”solution-oriented” approach in pathogen evolutionary ecology to prevent future outbreaks. Ecol Lett 2020 2020/09/02. DOI: 10.1111/ele.13586.JM AntoISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. IMIM (Hospital del Mar Research Institute), Barcelona, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.J BousquetCharité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany. MACVIA-France, Montpellier, France.
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.
In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2 and Covid-19.
In the newly published article: “Medical algorithm: Diagnosis and treatment of radiocontrast media hypersensitivity” K. Brockow , suggested an algorithm for the evaluation of hypersensitivity to radiocontrast media (RCM). However, one important aspect has been left out of the suggested algorithm, the opportunity to desensitize patients with probable or confirmed immediate hypersensitivity reactions to radiocontrast media. Especially those reacting to more than one substance. Desensitization to allergens is a standard preventative measure of anaphylaxis when patients have a history of severe immediate hypersensitivity reactions to a drug, and there are no therapeutic alternatives . Protocols for RCM desensitization are known from case reports [3,4], and need more work and research before standardized protocols can be recommended, but they can facilitate the use of radiocontrast media in important situations such as the need for acute coronary angiograms. Such situations are rare, but an algorithm should include information and pathways to facilitate the best treatment possible for all patients. Suggested change in the algorithm is to include the option “rapid desensitization” in the pathway “RCM urgently needed without test possibility and indispensable need for the RCM”, and in the pathway for ”patients with confirmed RCM hypersensitivity with immediate hypersensitivity reactions to several RCM’s for situations with indispensable need for RCM”. This would help to facilitate the best point of care for more patients with hypersensitivity to RCM. Dr. Alnæs has nothing to disclose. Dr Alnæs is the only contributor to this article. 1. Knut Brockow, Medical algorithm: Diagnosis and treatment of radiocontrast media hypersensitivity Allergy 2020 ;75:1278-1280. doi: 10.1111/all.14147. 2. P. Demoly N. F. Adkinson K. Brockow et al. International Consensus on drug allergy, Allergy 2014; 69: 420-437. https://doi.org/10.1111/all.123503. Mona Al-Ahmada and Tito Rodriguez Bouzab ,Successful desensitization to radiocontrast media in two high-risk cardiac patients. Ann Saudi Med. 2017; 37(4): 333–335. doi: 10.5144/0256-4947.2017.333 4. Saurav Uppal , Anthony E DeCicco , Anselma Intini et al. Rapid Desensitization to Overcome Contrast Allergy Prior to Urgent Coronary Angiography. Int Heart J 2018; 30; 59(3):622-625. doi: 10.1536/ihj.17-395.
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.
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.
Drug hypersensitivity reactions (DHRs) represent a global threat to healthcare systems due to their incidence, with a significant increase over last years1. DHR figures are overestimated in the general population since less than 40% of cases initially labelled as allergic can be confirmed as such when evaluated in an allergy unit2. Achieving an accurate diagnosis is complex and time consuming; besides, tests must be tailored to specific clinical manifestations and underlying mechanisms and will depend on the culprit drugs. Diagnosis often requires performing drug provocation tests (DPTs), which are especially problematic for severe reactions, making management of these patients challenging and expensive for the health care system.Clinically, DHRs are classified into immediate and non-immediate, based on the time interval between drug exposure and onset of the symptoms3. The most severe immediate reaction is anaphylaxis. This issue of the journal has been dedicated o drug hypersensitivity, which is becoming a major public health issue during the last decade, especially with the introduction of biologicals to medicine. Bilo et al. 4 evaluated the anaphylaxis mortality rate in Italy from 2004 to 2016 and found an average mortality rate for definite anaphylaxis (ICD-10 code) of 0.51 per million population per year, mostly due to the use of medications (73.7%), although in 98% of the cases culprit drugs were not identified. Regarding non-immediate reactions, one of the most challenging diagnoses is drug reaction with eosinophilia and systemic symptoms (DRESS), which is sometimes difficult, at an early stage, due to overlapping clinical symptoms with maculopapular exanthema (MPE). Pedruzzi et al. 5 identified 7 microRNAs (miRNAs) that correctly classified DRESS or MPE patients and were associated with keratinocyte differentiation/skin inflammation, type I IFN pathway viral replication, ATP-binding cassette transporters, and T lymphocyte polarisation, being all of them potential biomarkers. Non-immunologically mediated adverse reactions, such as attention-deficit/hyperactivity disorder (ADHD) are reported by Fuhrmannet al. 6 in association with systemic H1-antihistamines administration in school-age children, especially the 1st generation agents.The mechanism underlying DHR and the reason why patients treated with the same drug develop a tolerance response or an immediate or non-immediate DHR is not completely understood (Figure 1). Therefore, the prediction of who may experience a DHR, and if so, in what form, remains clinically obscure for most drugs. Goh SJR et al. 7 elegantly analyse this complexity, using non-immediate reactions to penicillins as a model. They focus on the understanding of the role of nature of the lesional T cells, the characterisation of drug-responsive T cells isolated from patient blood, and the potential mechanisms by which penicillins enter the antigen-processing and presentation pathway to stimulate these deleterious responses.Regarding specific drugs involved in allergy, betalactam antibiotics (BL) are the most frequent culprit, being many reactions mediated by IgE. This type of reaction varies among patients, with some reacting only to one BL and others to several of them; it tends to change over time and differs between European countries, depending on BL consumption. Nowadays, amoxicillin (AX), alone or in combination with the β-lactamase inhibitor clavulanic acid (CLV), is the most often prescribed BL worldwide (Figure 2) and the most common elicitor of reactions in both children and adults. It is unclear why patients after the administration of AX-CLV develop selective hypersensitivity to AX, while tolerating CLV and vice-versa. Ariza et al. 8 generated drug-specific T-cell clones from AX- or CLV-selective immediate hypersensitivity patients and found that both AX- and CLV-specific clones were generated irrespective of whether AX or CLV was the culprit, although a higher secretion of Th2 cytokines (IL-13 and IL-5) was detected when clones were activated with the culprit BL compared with clones stimulated with the tolerated BL, in which higher secretion of Th1 cytokines (IFN-γ) was observed. Regarding selective non-immediate reactions to CLV, Copaescu A et al. 9 report on a cohort of patients with a history of non-immediate reaction to CLV, who demonstrated a delayed intradermal skin test response to CLV, 17% were allergic to both CLV and ampicillin, and 83% were selective reactors with good tolerance to AX. IFN-γ release enzyme-linked immunospot (ELISpot) was performed giving a sensitivity of 33%. Other drugs such as sulphonamides, either antibiotic or non-antibiotics are important triggers of non-immediate DHRs. Vilchez-Sanchez et al. 10 showed that lymphocyte transformation tests (LTT) can help avoid the performance of DPT with a sensitivity of 75%, a specificity of 100%, and negative and positive predictive values of 72.7% and 100%, respectively.There has been a great expansion in the use of biological agents (mainly monoclonal antibodies (mAbs)), and they have greatly improved the treatment landscape of hemato-oncologic, autoimmune, inflammatory and rheumatologic diseases. In parallel, the incidence rate of reported DHRs associated with these products has increased considerably within the last years, ranging from mild to life-threatening. Yang BC et al. 11 recommend risk stratification as the first step for managing patients with DHRs to these drugs. In cases with negative skin test and mild reactions, DPT is an option, and in moderate or severe reactions, desensitisation becomes the preferred approach. In cases with positive skin test, desensitisation is the recommended course of action, especially when there is no alternative medication. Desensitisation is also widely used in the management of immediate hypersensitivity reactions to chemotherapy agents, such as platinums. There is suspicion about the presence of a longer memory of tolerance in subsequent desensitisation protocols partially resembling the regulatory tolerance mechanisms induced by allergen immunotherapy. Tüzer et al. 12 demonstrate the possible role of IL-10 in desensitisation with platinums, as they found a dynamic change in serum IL-10 levels observed as an increase during desensitisation and a decrease in between the protocols.Finally, a wide spectrum of drugs has been considered for treatment of coronavirus disease 2019 (COVID-19) and all of them can potentially induce DHRs. Gelincik A et al .13 reviewed DHRs in COVID-19 times to these drugs, with knowledge mainly coming from previous clinical experience in patients not infected with COVID-19. As in other viral infections, skin symptoms, including exanthemas, may appear during the evolution of the disease, leading to differential diagnosis with DHRs. Whether COVID-19 can aggravate T–cell mediated DHRs reactions as some viruses is at present unknown.We can conclude that new drugs are continuously introduced into the markets and confirmed as inducers of hypersensitivity reactions. We still do not completely understand the mechanisms underlying many of these reactions and further studies for improving diagnostic and management are needed even in classic and well-studied drugs as BLs.Abbreviations: AX: Amoxicillin; CLV: Clavulanic acid; COVID-19: Coronavirus disease 2019; DHR: Drug hypersensitivity reactions; DPT: Drug provocation tests; DRESS: Drug reaction with eosinophilia and systemic symptoms; ELISpot: enzyme-linked immunospot; LTT: Lymphocyte transformation tests; MPE: Maculopapular exanthema.
Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage were associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin converting enzyme 2 (ACE2). As a result of SARS-Cov-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1R) axis associated with oxidative stress. This leads to insulin resistance, lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block the AT1R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects helpful in mitigating COVID-19 severity.
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.
Immediate and non-immediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5-3% of patients receiving non-ionic ICM. The diagnosis and management of these patients is controversial among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and non-immediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Drug provocation test is the gold-standard; although, as it is a risky procedure, the decision for performing it needs to be taken based on a risk-benefit analysis. Another source of controversy is the role of in vitro tests for diagnosis and pretreatment for preventing reactions.
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.
EDITORIAL The average global temperatures on our planet are increasing due to rising anthropogenic greenhouse gases in the atmosphere, in particular carbon dioxide (CO2).1,2 There is an urgent need to call for action on global warming, which is resulting in extreme weather and related catastrophes.1 ,2 The Earth’s rising temperature is evidenced by warming of the oceans, melting glaciers, rising sea levels, and the diminished snow cover in the Northern Hemisphere. Climate-related factors can affect interactive atmospheric components (chemical and biological) and their interrelationship with human health.Climate change, a physics and meteorological event that affects health in the whole biosphere started to receive attention around the mid-twentieth century. Air pollution is the driving force of the Earth’s warming powered by the greenhouse effect (Figure 1). Environmental changes are occurring in frequency, intensity, type of precipitation, and extreme weather events, such as heatwaves, droughts, floods, blizzards, thunderstorms, sandstorms, and hurricanes. These are real and daunting challenges for the human and biosphere health, impacting the food and water supplies.1 ,2 Urbanization, with its high level of vehicle emissions and westernized lifestyle, is linked to the rising levels of particulate matter in the air, food supplies, soil, freshwater, and oceans. These environmental changes are correlated with the increased frequency of respiratory allergic diseases and bronchial asthma observed over recent decades in most industrialized countries and is continuously rising in developing countries.1-5This issue of Allergy focuses on the interrelationship between climate change, air pollution and human health.3-7Climate change is an important medical aspect in allergology as we are observing an increasing incidence of allergic diseases indirectly related to rising temperatures and are becoming a high socio-economic burden.1-3,8 Allergies and asthma appear to be at the front line of the sequelae of climate change along with infectious and cardiovascular diseases.1,5Cecchi et al. focus on the development and exacerbation of allergic diseases can be explained in terms of the exposome, a concept that includes all the environmental exposures from conception onwards. Multiple factors can trigger a pollen-induced respiratory allergy, such as airborne endotoxin levels and microbial composition of pollen, and these comprise a “pollen exposome”.4,9Susan Prescott has written an editorial in this issue bringing the attention to climate change and bidiversity aspects. At the time of Neil Armstrong’s lunar landing 50 years ago, Prof. Rene Dubos, a renowned microbiologist, delivered the seminal lecture “The Spaceship Earth”. He was ahead of his time and warned of an “altered immunity” driven by environmental problems and loss of biodiversity. Most of his predictions proved correct and we are now understanding at a molecular level the pathophysiological mechanisms involved in allergic diseases.8Climate change indirectly affects allergies by altering the pollen concentrations, allergenic potential, composition, migration of species and growth of new ones. Air pollution and climate change have resulted in the faster growth of allergenic plants, increasing the aeroallergen load for patients with inhalant allergy. Phenological studies indicate longer pollen seasons and emerge earlier in the year.1,4,5,8 Pollen and mold allergies are generally used to evaluate the interrelationship between air pollution and allergic respiratory diseases, such as rhinitis and asthma. Studies show that plants exhibit enhanced photosynthesis and reproductive effects and produce more pollen as a response to high atmospheric levels of CO2. 1,4,8 Pollen allergens have been demonstrated to trigger the release of pro-inflammatory and immunomodulatory mediators that accelerate the onset of allergy and the IgE-mediated sensitization. Lightning storms or wet conditions rupture the pollen grains releasing the allergenic proteins that cause asthma exacerbations in patients with pollinosis (thunderstorm-asthma).1,3,4,7,10 As a result of climate change, patients with seasonal allergic rhinoconjunctivitis and asthma have more intense symptoms and need stronger medication.1,4,8 In addition to respiratory illnesses, Fairweather et al. demonstrate the effect of environmental changes on cardiovascular, brain and mind, gastrointestinal, skin, immunologic and metabolic effects.1,3,4,7 The migration of stinging and biting insects to cooler climates has caused an increase in insect allergies in those areas.Prunicki et al. focus on the contribution of wildfires and deforestation and their contribution to global warming and immunological effects. It should be noted that in the last fifty years, half of the pluvial forests on Earth have been lost. Deforestation and forestation degradation is estimated to occur at a rate of 13 million hectares per year, mostly for agricultural purposes. Wildfires are becoming increasingly frequent, posing a serious risk to human health. The fine particulate matter (PM2.5) in wildfire smoke exacerbates asthma attacks, among other health problems. A study of 67 subjects demonstrated that those exposed to wildfire smoke had significantly higher levels of C-reactive protein and IL-1β compared with controls.6 The elevated levels of these two biomarkers are indicative of airway inflammation.Global warming and climate change need actions throughout the whole world with joined forces of all capabilities. These efforts are sometimes hampered by the unresponsiveness of governmental institutions and the general population, the lack of infrastructure and poverty. An action plan is needed to disseminate information on health-related problems associated with climate change. Patients with pollen allergies or asthma should be educated on the higher health risk during a thunderstorm or pollen season and the need for appropriate medication if staying outdoors. In collaboration with environmental organizations, physicians should take the lead to promote actions to mitigate air pollution and advocate the need to reduce global warming to protect our health.
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.
To the Editor, Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] is a clinically relevant nutraceutical compound present in cruciferous vegetables (Brassicaceae). It is used for the prevention and treatment of chronic diseases and may be involved in ageing.1Along with other natural nutrients, sulforaphane has been suggested to have a therapeutic value for the treatment of the coronavirus disease 2019 (COVID-19).2 Sulforaphane is an isothiocyanate stored in its inactive form glucoraphanin.3 The enzyme myrosinase, found in plant tissue and in the gut microbiome, is involved in the conversion of glucoraphanin to its active form sulforaphane.4
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
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.