The coronavirus disease 2019 pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented global social and economic impact, and numerous deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung disease, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type-I interferon secretion capacity, and pregnancy. Possible complications include acute respiratory distress syndrome, shock, disseminated coagulopathy, acute kidney injury, pulmonary embolism, and secondary bacterial pneumonia. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1, Krebs von den Lungen-6 (KL-6) and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of COVID-19.
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has made widespread impact recently. We aim to investigate the clinical characteristics of COVID-19 children with different severities and allergic status. Pediatric COVID-19 patients tended to have a mild clinical course. Patients with pneumonia had higher proportion of fever and cough and increased inflammatory biomarkers than those without pneumonia. There was no difference between allergic and non-allergic COVID-19 children in aspects of incidence, clinical features, laboratory and immunological findings. Allergy was not a risk factor for developing and severity of SARS-CoV-2 infection and hardly influenced the disease course of COVID-19 in children.
Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current guidelines, which exclude patients with severe allergies from vaccination with BNT162b2, should be re-evaluated after more information and experience with the new vaccine develops.
Background Currently, the coronavirus disease 2019 (COVID-19) has become pandemic globally. 10-20% of the cases are severe and more than 397,000 deaths have occurred. The risk factors for the mortality of critically ill COVID-19 patients remain to be elucidated. Conclusions Survived severe and non-survived COVID-19 patients had distinct clinical and laboratory characteristics, which were separated by principle component analysis. Logistic regression revealed several risk factors such as elder age, greater affected lobe numbers and higher level of serum CRP for the mortality of severe COVID-19 patients. Longitudinal changes of laboratory findings indicate the advancement of the disease and may be helpful in predicting the progression of severe patients.
The basophil activation test (BAT) is a functional assay that measures the degree of degranulation following stimulation with allergen or controls by flow cytometry and is directly correlated with histamine release. From the bell-shaped curve resulting from BAT in allergic patients, basophil reactivity (given by %CD63+ basophils) and basophil sensitivity (given by EC50 or similar) are the main outcomes of the test. BAT takes into account all characteristics of IgE and allergen and thus can be more specific than sensitization tests in the diagnosis of allergic disease. BAT reduces the need for in vivo procedures, such as intradermal tests and allergen challenges, which can cause allergic reactions of unpredictable severity. As it closely reflects the patients’ phenotype, it can potentially be used to monitor the natural resolution of food allergies and to predict and monitor clinical response to immunomodulatory treatments, such as allergen-specific immunotherapy and biologicals. Clinical application of BAT requires analytical validation, clinical validation, standardization of procedures and quality assurance to ensure reproducibility and reliability of results. Currently, efforts are ongoing to establish a platform that could be used by laboratories in Europe and in the USA for certification.
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.
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.
This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared to the standard of care. Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, reslizumab-1) included 1236 adults, with follow-up 20-64 weeks. Dupilumab reduces the need for surgery (NFS) and oral corticosteroid (OCS) use (RR 0.28; 95%CI 0.20-0.39, moderate certainty) and improves with high certainty smell (mean difference (MD) +10.54; 95%CI +9.24 to +11.84) and quality of life (QoL) (MD -19.14; 95%CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95%CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95%CI 0.78 to 0.92, high certainty), decreases OCS use (RR 0.38; 95%CI 0.10-1.38, moderate certainty), improves with high certainty smell (MD +3.84; 95%CI +3.64 to +4.04) and QoL (MD -15.65; 95%CI -16.16 to -15.13), with increased TAE (RR 1.73; 95%CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95%CI 0.64 to 0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95%CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95%CI 0.41-6.50). The evidence for reslizumab is very uncertain.
Background: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 on childhood asthma outcomes. Methods: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4-18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. Results: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. Conclusion: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.
Background This systematic review used the GRADE approach to compile evidence to inform an anaphylaxis guideline from the European Academy of Allergy and Clinical Immunology (EAACI). Methods We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18,449 participants: 29 randomised controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarised narratively because studies were too heterogeneous to conduct meta-analysis. Results It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. Adrenaline is the cornerstone of first-line emergency management of anaphylaxis but, due to ethical constraints, little robust research has assessed its effectiveness . Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. Adrenaline prophylaxis prior to snake bite anti-venom may reduce anaphylaxis but the impact of prophylactic corticosteroids and antihistamines is uncertain. There was insufficient evidence about the impact of other anaphylaxis management strategies. Conclusions Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.
SARS-CoV-2 caused one of the most devastating pandemics in the recent history of mankind. Due to various countermeasures, including lock-downs, wearing masks and increased hygiene, the virus has been controlled in some parts of the world. More recently, the availability of vaccines, based on RNA or Adenoviruses, have greatly added to our ability to keep the virus at bay, again in some parts of the world only. While available vaccines are effective, it would be desirable to also have more classical vaccines at hand for the future. Key feature of vaccines for long-term control of SARS-CoV-2 would be inexpensive production at large scale, ability to make multiple booster injections and long-term stability at +4 oC. Here we describe such a vaccine candidate, consisting of the SARS-CoV-2 receptor binding motif grafted genetically onto the surface of the immunologically optimized cucumber mosaic virus, called CuMV TT-RBM. Using bacterial fermenter production and continuous flow centrifugation, the productivity of the production process is estimated to be >2.5 million doses per 1000 liter fermenter run and the vaccine candidate is stable for at least 14 months at 4°C. We further demonstrate that the candidate vaccine is highly immunogenic in mice and rabbits and induces more high avidity antibodies compared to convalescent human sera and antibodies induced are more cross-reactive to mutant RBDs for variants of concern (VoC). Furthermore, antibody responses are neutralizing and long-lived. This, the here presented VLP-based vaccine may be a good candidate for use as conventional vaccine in the long-term.
In past ten years, microRNAs (miRNAs) have gained scientific attention due to their importance in the pathophysiology of allergic diseases and their potential as biomarkers in liquid biopsies. They act as master post-transcriptional regulators that control most cellular processes. As one miRNA can target several mRNAs, often within the same pathway, dysregulated expression of miRNAs may alter particular cellular responses and contribute or lead to the development of various diseases. In this review, we give an overview of the current research on miRNAs in allergic diseases, including atopic dermatitis, allergic rhinitis and asthma. Specifically, we discuss how individual miRNAs function in the regulation of immune responses in epithelial cells and specialized immune cells in response to different environmental factors and respiratory viruses. In addition, we review insights obtained from experiments with murine models of allergic airway and skin inflammation and offer an overview of studies focusing on miRNA discovery using profiling techniques and bioinformatic modelling of the network effect of multiple miRNAs. In conclusion, we highlight the importance of research into miRNA function in allergy and asthma to improve our knowledge of the molecular mechanisms involved in the pathogenesis of this heterogeneous group of diseases.
Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells and epithelial cells. During recent years, clinical and experimental studies on human mast cells as well as experiments using animal models have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity and reactivity. We also highlight the development in our understanding of mast cell driven-diseases and discuss the development of novel strategies to treat such conditions.
Interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), rhinitis and airway hyperreactivity. In AD, IL-31 has been identified as one of the main ‘drivers’ of its cardinal symptom pruritus. Here, we aim to summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-produced cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, and stimulating itch and neuronal outgrowth through activation of the heterodimer receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor β. IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well as various innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31 downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo nodularis. For example, whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Following the emergency use authorization of the vaccine mRNA-1273 on 18th December 2020 in the US and the vaccine BNT162b2 one week earlier, two mRNA vaccines are in currently used for the prevention of coronavirus disease 2019 (COVID-19). Phase 3 pivotal trials on both vaccines excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and in the US, anaphylactic reactions have been reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000), which is contained in both vaccines as PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEG-ylated lipids are rarely IgE-mediated, but may result from complement activation-related pseudoallergy (CARPA) that has been described to similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to e.g. gadolinium-based or iodinated contrast media. Skin prick-, intradermal-, epicutaneous- tests, in vitro sIgE assessment, evaluation of sIgG/IgM, as well as basophil activation test are in use to demonstrate allergic reactions to various components of the vaccines.
To the Editor, Severe asthma (SA) is a chronic disease affecting around 3-8% of adult asthma population in Europe, with the refractory form estimated to occur in 0.1% of the general population (1,2). SA is characterized by increased use of healthcare resources (i.e. emergency room/hospital admissions, access to intensive care units (ICU), use of biologics) due to exacerbations compared to the less severe form. In the current SARS-CoV-2 pandemic, there is an ongoing debate on the role of asthma and use of immunomodulating drugs, like corticosteroids and biologics, on COVID-19 outcomes. According to available data on COVID-19 hospitalizations, asthma seems to play little role on the clinical severity or access to health resources, unlike other chronic conditions such as hypertension, obesity and chronic obstructive pulmonary disease (3). However, to date, no information is available on the burden of SA on COVID-19 severity and hospitalization rates.A questionnaire was submitted to the Italian Registry of Severe Asthma (IRSA) network (4), assessing the prevalence and clinical characteristics of patients with SA who contracted COVID-19 during the outbreak in Italy (February 24th - May 18th 2020), and 41 out of 78 centers distributed evenly among different Italian regions participated to the survey (Figure 1a).Among the 558 subjects surveyed, 7 subjects contracted COVID-19 (1.25% of the national sample), with an average age of 54.5 years: 5 isolated at home/received home care (71.5%), while 2 subjects were admitted to the hospital (28.5%), none required accessed to ICU and no deaths were reported. All COVID-19 subjects with SA came from 2 regions of Northern Italy (6 Lombardy, 1 Emilia-Romagna, 3.7% of the regional population), all showing one or more comorbidities, and were treated with high-dose inhaled corticosteroids plus long-acting beta-2 agonists (ICS-LABA) and biologics (see Table 1).We then compared our results with data provided by the Italian Department for Civil Protection in the same time period from the affected geographic areas (5), and we observed that the frequency of COVID-19 among subjects referred to IRSA centers strongly correlated with the prevalence of SARS-CoV-2 infection in the corresponding province (Figure 1b). Furthermore, the hospitalization rate in COVID-19-SA subjects was not significantly different from the general population (24.1%, 23.6-24.6 95% C.I.; p=0.25, Chi-squared test). Lastly, we could not observe a significantly increased COVID-19 frequency in subjects undergoing high-dose ICS-LABA and biologics compared to SA treated with ICS-LABA alone (p=0.09, Fisher exact test).These findings from the IRSA registry offer some insights on the susceptibility to SARS-CoV-2 infection, access to healthcare resources and mortality by SA patients.Given the low prevalence of SA in Italy (2), we expected less COVID-19-SA cases per region than what reported by the IRSA survey. However, we observed that the geographic location of COVID-19-SA patients mostly reflected the bimodal distribution of the COVID-19 outbreak in Italy, mainly clustered in Lombardy and neighboring regions, where the highest cumulative COVID-19 cases were recorded (>500/100000 cases per inhabitants) (5). In these areas, the prevalence of positive cases by province also strongly correlated with the frequency of COVID-19-SA patients observed in each IRSA center (Figure 1b), suggesting that patients with SA most likely contract the infection when high circulation of the virus within the area of residence is present. The lack of positive cases reported in Southern regions further proves this hypothesis, and demonstrates the efficacy of the lockdown measures adopted to contain the further spread of the virus.Our results also suggest no increased risk of contracting COVID-19 in SA treated with biologics compared to ICS-LABA alone. Although there is currently no strong evidence that biologics used in asthma might affect the risk of contracting COVID-19, new evidence suggests a protective effect of inhaled corticosteroids against viral entry by ACE2 receptor downregulation, that are usually prescribed at a high dose in SA (6), thus a possible explanation to the lack of observed differences in our cohort.Despite the severity of asthma and reported comorbidities, no ICU admissions were reported, and hospital admissions in COVID-19-SA subjects did not differ from the median rate observed in the same geographic areas (5). Furthermore, we could observe no difference in the median monthly hospitalization rate of SA patients in 2019 compared to 2020 in Lombardy region where both hospital-admitted subjects reside (0.97 vs 0.9%, IRSA data).Our result is consistent with recent literature, showing that asthma in Western countries was not associated with an increased hospitalization rate and ICU admissions due to COVID-19 (3,8). It is still debated if a protective effect of Th2-inflammation in a significant proportion of asthma sufferers (7), or concomitant anti-inflammatory therapy could be the reasons for such outcomes (6). However, if asthma patients with COVID-19 require intubation, the duration of hospitalization was shown to be longer than average (8).As for the role of biologics in COVID-19 disease progression, we could not observe an increase in hospital admissions in patients with SA treated with biologics compared to the general population, with the majority isolating at home and requiring no additional treatment. Considering that, in areas with high prevalence of SARS-CoV-2 infection, 68.2% of SA subjects were treated with either omalizumab or mepolizumab, our observations further prove the safety of biologics during the COVID-19 pandemic.Lastly, we did not observe any deaths in our cohort, but we speculate that this outcome is most likely due to the small sample size and younger average age. In fact, advanced age seems to be the most determining risk factor on mortality due to COVID-19 compared to other causes. (9)Taken together, our results point at a neutral role of SA in the COVID-19 disease course and hospital admissions. One major strengths of our study is that, by using a fast and inexpensive tool, we could outline the salient features of severe asthma and COVID-19 at a national level, while the major weakness is the limited number of SA subjects diagnosed with COVID-19, that could lead to sampling bias and low accuracy. Further confirmation of these results with an increased sample size is therefore warranted
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
Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.