Exposure to air pollution in epidemiological studies in Kuwait: A systematic review (preprint)

Objective To systematically review the epidemiological studies of human exposure to air pollution in Kuwait. Methods Specific keywords related to air pollution and health effects in Kuwait were systematically searched using PubMed and BASE search engines for published research in English language from the year 1990 up to June 2020. Non eligible studies were those which published in non-English studies, studies on animals, plants, exposure to pollutants other that air pollutants, studies related to oil fires caused by Iraqi invasion to Kuwait in 1991. After duplicates were removed, titles and abstracts of eligible studies were screened and full text of publications meeting the inclusion criteria was read. Non-epidemiological studies were included only to compare their numbers to the epidemiological studies, and to help in future studies. Results Total of 85 studies including epidemiological and non-epidemiological studies, only 8 of them found to be an epidemiological study, which 4 of them concerned with mortality and 3 with morbidity, and 1 with both morbidity and mortality. Two of these studies concern with respiratory disease, 1 of them concerned with atopic dermatitis and was the only study measured indoors (i.e. house), and 1 study concerned with rheumatoid arthritis. One study measured ETS, 4 studies measured dust, 2 studies measured PM10 and PM2.5, and 1 study measured NO2, SO2, O3, CO. All studies found that exposure to air pollution has adverse effect on health problems (i.e. respiratory problems, atopic dermatitis, rheumatoid arthritis) and mortality except one study found no significant correlation between exposure to air pollution (i.e. dust) and mortality. Conclusion Epidemiological studies related to human exposure to air pollution in Kuwait are underestimated and insufficient, there are extremely limited studies that cannot be compared to each other. Since currently Kuwait have many major constructions in major roads in and out the capital which alters the air pollution, adding to that the new study which found that the new current global epidemic namely coronavirus COVID-19 is correlated to air pollution (i.e. NO2), new researches need to be done measuring the different pollutants in both indoor and outdoor exposure examining different health problems, these researches need to be done during and after these circumstances for comparison.

COVID-19 symptoms are attenuated in atopic dermatitis patients treated with dupilumab Short running title: Reduced COVID-19 symptoms in dupilumab-treated AD (preprint)

Background: In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Since it is believed that Type 1/Th1immunity controls viral infections, and that there is a Th1/Th2 counter-regulation, we hypothesized that Th2 targeting with the IL-4Rα-antagonist, dupilumab, in patients with moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. Methods: : 1,237 moderate-to-severe AD patients in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic[0]-fatal[5]). Scores were compared among 3 treatment groups: dupilumab (n=632), other systemic treatments (n=107), and limited/no treatment (n=498). Demographic and comorbid covariates were adjusted by multivariate logistic regression models. Results: : The dupilumab-treated group showed reduced incidence and severity of COVID-19 symptoms versus other treatment groups. Dupilumab-treated patients were less likely to experience moderate-to-severe symptoms versus patients on other systemics (p=0.01) and on limited/no treatment (p=0.04), and less likely to experience any symptoms versus patients on other systemics (p=0.01). This effect was seen in our entire cohort and in the subgroup of patients with verified COVID-19 or high-risk exposure. Conclusions: : Patients on dupilumab experienced less severe COVID-19 manifestations and lesser symptoms compared to patients on other systemics and on limited/no treatment. These results suggest that Th2 modulation with dupilumab may have a protective effect on anti-viral immune response in AD patients.

Pathogenic helper T cells as the novel therapeutic targets for immune-mediated intractable diseases.

Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.

A case of complete recovery in a hypereosinophilic dermatitis patient with dupilumab.

BACKGROUND: Hypereosinophilic dermatitis (HED) is a subtype of hypereosinophilic syndrome (HES). Glucocorticoids are preferred for treatment but carry substantial side effect profiles. Symptoms of HED may recur after systemic glucocorticoid tapering. As an interleukin-4 receptor (IL-4Rα) monoclonal antibody targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), dupilumab might be an efficacious adjuvant therapy for HED. METHOD: We report a young male diagnosed with HED who suffered from erythematous papules with pruritus for over five years. Once reducing the dosage of glucocorticoid was, his skin lesions relapsed. RESULTS: After using dupilumab, the patient's condition significantly improved with the glucocorticoid dosing decreased successfully. CONCLUSION: In conclusion, we report a new application of dupilumab in HED patients, especially with difficulties in reducing the glucocorticoid dose.

The impact of the COVID-19 surge on phototherapy in Taiwan: Focusing on the patient profile, adherence, and attitude before and after the surge.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused changes in the medical practice. However, it is unclear whether the patients receiving phototherapy for their dermatoses have been affected. OBJECTIVES: This study aimed to identify the impact of the COVID-19 pandemic on phototherapy, focusing on the patient profile, adherence, and attitude before and after the surge. METHODS: The study encompassed the time 5 months prior to and after the surge of the COVID-19 pandemic (from May to July, 2021), resulting in the temporary closure of our phototherapeutic unit. RESULTS: Nine hundred eighty-one patients received phototherapy during this period. Vitiligo, psoriasis (Ps), and atopic dermatitis (AD) represented the groups with the highest patient numbers. For vitiligo, Ps and AD, 39.6%, 41.9%, and 28.4% of the patients resumed phototherapy after the pandemic-related shutdown (PRS). No significant difference was noted in age, gender, and number of weekly sessions between those who resumed or stopped phototherapy after PRS among three groups. Patients who resumed phototherapy after PRS tended to receive more weekly sessions of phototherapy than those who initiated after PRS. Additionally, patients who resumed phototherapy showed no significant difference in the number of weekly sessions before and after PRS. CONCLUSIONS: This study reveals a significant impact of the COVID-19 pandemic on patients undergoing phototherapy. Although the patient number remained similar before and after PRS, a significant portion of patients discontinued phototherapy after PRS. New strategies and continued education are needed to improve patient management in times of pandemic.

Management of Atopic Dermatitis During the COVID-19 Pandemic: Key Questions and Review of the Current Evidence.

Since the outbreak of COVID-19, management of atopic dermatitis (AD) has been widely discussed. Key issues include the risk of COVID-19 infection and related outcomes in AD patients, the efficacy and safety of COVID-19 vaccination in AD populations, and management of AD in the COVID-19 pandemic. Recent studies have shown that patients with AD have a slightly increased risk of COVID-19 infection but are not associated with a worse outcome than the non-AD population. COVID-19 vaccination is generally effective and safe in patients with AD. However, temporary discontinuation of certain systemic immunomodulatory agents after vaccination is suggested. During the pandemic, continuation of all immunomodulating agents is suggested, but these agents should be paused when patients with AD are infected with COVID-19 until recovery. Further studies are warranted to investigate the long-term interaction between AD and COVID-19 to aid clinical decisions during the pandemic.

DrugRep-KG: Toward Learning a Unified Latent Space for Drug Repurposing Using Knowledge Graphs.

Drug repurposing or repositioning (DR) refers to finding new therapeutic applications for existing drugs. Current computational DR methods face data representation and negative data sampling challenges. Although retrospective studies attempt to operate various representations, it is a crucial step for an accurate prediction to aggregate these features and bring the associations between drugs and diseases into a unified latent space. In addition, the number of unknown associations between drugs and diseases, which is considered negative data, is much higher than the number of known associations, or positive data, leading to an imbalanced dataset. In this regard, we propose the DrugRep-KG method, which applies a knowledge graph embedding approach for representing drugs and diseases, to address these challenges. Despite the typical DR methods that consider all unknown drug-disease associations as negative data, we select a subset of unknown associations, provided the disease occurs because of an adverse reaction to a drug. DrugRep-KG has been evaluated based on different settings and achieves an AUC-ROC (area under the receiver operating characteristic curve) of 90.83% and an AUC-PR (area under the precision-recall curve) of 90.10%, which are higher than in previous works. Besides, we checked the performance of our framework in finding potential drugs for coronavirus infection and skin-related diseases: contact dermatitis and atopic eczema. DrugRep-KG predicted beclomethasone for contact dermatitis, and fluorometholone, clocortolone, fluocinonide, and beclomethasone for atopic eczema, all of which have previously been proven to be effective in other studies. Fluorometholone for contact dermatitis is a novel suggestion by DrugRep-KG that should be validated experimentally. DrugRep-KG also predicted the associations between COVID-19 and potential treatments suggested by DrugBank, in addition to new drug candidates provided with experimental evidence. The data and code underlying this article are available at https://github.com/CBRC-lab/DrugRep-KG.

[Atopic dermatitis in adults during the COVID-19 pandemic]. / Dermatitis atópica en adultos durante la pandemia por COVID-19.

OBJECTIVE: To evaluate the clinical course of atopic dermatitis (AD) in adults during the COVID-19 pandemic and to evaluate their comorbidities and cardiovascular risk. METHODS: A cross-sectional study was conducted in adults with AD. Severity and control of AD, quality of life, levels of psychological stress, depression and cardiovascular risk were measured. RESULTS: Forty-two patients were included. A decrease in POEM score (11.83 vs 10.12; p=0.004) and PO-SCORAD (37.77 vs 32.49; p= 0.001) was observed in comparison to the scores at pandemic onset. The quality of life correlated with the severity of AD (p<0.0001) while the levels of stress and depression did not show association. Most patients had a low cardiovascular risk. CONCLUSIONS: The results suggest a decrease in the current severity of AD compared with severity before pandemic. Quality of life is associated with AD severity.

OBJECTIVO: Evaluar el curso clínico de pacientes adultos con dermatitis atópica durante la pandemia por COVID-19, e identificar las comorbilidades y el riesgo cardiovascular. MÉTODOS: Estudio transversal, llevado a cabo en adultos con dermatitis atópica. Se evaluó la gravedad y el control de la dermatitis, la calidad de vida, el grado de estrés psicológico, depresión y riesgo cardiovascular. RESULTADOS: Se seleccionaron 42 pacientes.Se observó una disminución en el puntaje del POEM (11.83 vs 10.12; p=0.004) y del PO-SCORAD (37.77 vs 32.49; p= 0.001) con relación al inicio de la pandemia. La calidad vida se correlacionó con la gravedad de la dermatitis atópica (p<0.0001) a diferencia de los grados de estrés y depresión. La mayoría de los pacientes tuvo riesgo cardiovascular bajo. CONCLUSIONES: Se encontró disminución de la gravedad actual de la dermatitis atópica comparada con la gravedad antes de la pandemia. La calidad de vida se asocia con la gravedad de la dermatitis atópica.

Upadacitinib treatment in patients with moderate to severe atopic dermatitis: A retrospective single-centre Australian review of 14 patients post phase 3 clinical trial.

Recent phase 2b and phase 3 clinical trials support the safety and efficacy of the selective Janus kinase (JAK)-1 inhibitor upadacitinib (UPA) in the treatment of moderate to severe atopic dermatitis (AD). However, to date, there is little experience with UPA therapy for AD in Australia. We report findings from a retrospective study to better understand the therapeutic response and side effects noted in a single-centre Australian cohort.

Immunotherapy in atopic dermatitis.

In the past decade, the emergence of biologics targeting human cytokine networks has advanced a new era in atopic dermatitis therapy. Dupilumab, in particular, the most widely studied and used IL-4/IL-13 inhibitor, has been considered a milestone in the treatment of patients with moderate-to-severe atopic dermatitis. In addition to the IL-4 and IL-13 pathways, many other cytokines and receptors have been newly targeted as therapeutic options. In this review, the authors provide an overview of the approved and tested biologics and JAK inhibitors for the treatment of atopic dermatitis, including their advantages and limitations.

Gut microbiome predicts atopic diseases in an infant cohort with reduced bacterial exposure due to social distancing (preprint)

Several hypotheses link altered microbial exposure in affluent societies to increased prevalence of allergies, but none have been experimentally tested in humans. Here we capitalize on the opportunity to study a cohort of infants (CORAL) raised during COVID-19 associated social distancing measures to test the interactions between bacterial exposure and fecal microbiome composition with atopic outcomes. We show that fecal Clostridia levels were significantly lower in CORAL infants and correlated with a microbial exposure index. Microbiota composition was the most significant component of regression models predicting risk of atopic dermatitis (AUC 0.86) or food allergen sensitization (AUC 0.98) and mediated the effects of multiple environment factors on disease risk. Although diet had a larger effect on microbiota composition than environmental factors linked to dispersal, most effects were mediated through the microbiota. This study provides critical information to refine existing hypothesis on the importance of the gut microbiota to immune development.

Is antenatal or early-life vitamin D associated with eczema or food allergy in childhood? A systematic review.

OBJECTIVE: To summarise the associations between antenatal or early-life blood vitamin D and the development of eczema/food allergy in childhood. DESIGN: A systematic review and meta-analyses were conducted to synthesize the published literature. Two reviewers independently performed the study selection and data extraction on Covidence. We assessed the risk of bias for observational studies by using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool for clinical trials. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). DATA SOURCES: We systematically searched PubMed and Embase from inception and April 2022. ELIGIBILITY CRITERIA: Human studies that investigated prospective associations between antenatal or early-life blood vitamin D levels, dietary intake or supplementation and childhood eczema/food allergy. RESULTS: Forty-three articles including six randomised controlled trials (RCTs) were included. Four RCTs of vitamin D supplementation during pregnancy showed no evidence of an effect on the incidence of eczema (pooled odds ratio [OR] = 0.85; 0.67-1.08, I2  = 6.7%, n = 2074). Three RCTs reported null associations between supplementation in pregnancy/infancy and food allergy. From six cohort studies, increasing cord blood vitamin D levels were associated with reduced prevalence of eczema at/close to age one (OR per 10 nmol/L increase = 0.89; 0.84-0.94, I2  = 0%, 2025 participants). We found no evidence of an association between maternal antenatal or infant vitamin D level or dietary intake and the development of food allergy or eczema in offspring. CONCLUSIONS: We found an association between higher vitamin D levels in cord blood and reduced risk of eczema in cohort studies. Further trials with maternal and infant supplementation are needed to confirm if vitamin D supplementation can effectively prevent eczema or food allergy in childhood. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, No. CRD42013005559.

Delayed cutaneous hypersensitivity reactions following the use of infliximab or adalimumab in patients with coronavirus disease 2019.

Recent evidence has emerged concerning delayed cutaneous hypersensitivity reactions after infliximab or adalimumab applications in patients with coronavirus disease 2019 (COVID-19). A few real-world studies compared the events, clinical features, and prognosis of infliximab- or adalimumab-related delayed cutaneous hypersensitivity reactions in COVID-19 patients. Disproportionality analysis and Bayesian analysis were utilized to determine the suspected adverse events of delayed cutaneous hypersensitivity reactions after infliximab or adalimumab use based on the Food and Drug Administration's Adverse Event Reporting Systems (FAERS) from May 2020 to December 2021. Additionally, the times to onset and fatality rates of delayed cutaneous hypersensitivity reactions following infliximab or adalimumab were compared. In total, 475 reports of delayed cutaneous hypersensitivity reactions were associated with infliximab or adalimumab. Females were affected almost twice more than males. Among the two therapies, infliximab had the highest association with delayed cutaneous hypersensitivity reactions based on the highest reporting odds ratio (2.14, 95% two-sided confidence interval [CI] = 1.2-3.81), proportional reporting ratio (1.95, χ2 = 7.03), and empirical Bayesian geometric mean (1.94, 95% one-sided CI = 1.2). Infliximab-related delayed cutaneous hypersensitivity reactions had earlier onset (0 [interquartile range (IQR): 0-0] days vs. 166.5 (IQR: 18-889.5) days, p < 0.05), while adalimumab-related delayed cutaneous hypersensitivity reactions have higher fatality rate (0.44% vs. 0.00%). Based on the FAERS database, we profiled delayed cutaneous hypersensitivity reactions related to infliximab or adalimumab application in patients with COVID-19 with more points of occurrences, clinical characteristics, and prognosis.

The need of an updated culture of "occupational" atopic hand dermatitis in children at the time of COVID-19.

During the COVID-19 outbreak, handwashing emerged as an essential tool to prevent the spread of SARS-CoV-2 virus. It can put into practice using warm water and soap or, if not available, alcohol-based hand sanitizers (ABHS). Anyway, the use of warm water and soap is not always possible. On the contrary, ABHS are frequently used for their versatility, but can represent a risk factor for atopic dermatitis exacerbations in the pediatric age. At the same time, the Italian Ministry of Health established a school regulation, asking the students to periodically disinfect hands with sanitizing gel, or soap and water, especially before entering classrooms and laboratories, immediately after contact with everyday objects, after using the toilet, after throwing away the handkerchief and before and after eating. No rules have been personalized in this statement for children affected by atopic dermatitis attending the school. Based on this observation, we reported two case reports, involving children with a known diagnosis of atopic dermatitis, who attended our Pediatric Allergy Unit in Mantua, Italy. They experienced a worsening of symptoms related to AD on their hands in the last year for an intensive handwashing with ABHS before entering all classrooms and laboratories every day at school. Avoiding ABHS at school and washing their hands with a non-alcohol and additives soap and water solved their problem and brought their atopic dermatitis back to good control. So, it seems appropriate to consider ABHS as a "school trigger" and the low-controlled atopic dermatitis of these two patients as an "occupational dermatitis". An adequate pediatric culture of atopic dermatitis at the time of COVID 19 is needed.

Oxidative Stress and Phototherapy in Atopic Dermatitis: Mechanisms, Role, and Future Perspectives.

Atopic dermatitis is a chronic inflammatory skin disease in which the overproduction of reactive oxygen species plays a pivotal role in the pathogenesis and persistence of inflammatory lesions. Phototherapy represents one of the most used therapeutic options, with benefits in the clinical picture. Studies have demonstrated the immunomodulatory effect of phototherapy and its role in reducing molecule hallmarks of oxidative stress. In this review, we report the data present in literature dealing with the main signaling molecular pathways involved in oxidative stress after phototherapy to target atopic dermatitis-affected cells. Since oxidative stress plays a pivotal role in the pathogenesis of atopic dermatitis and its flare-up, new research lines could be opened to study new drugs that act on this mechanism, perhaps in concert with phototherapy.