The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.

Background: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. Objective: We sought to characterize age-related changes in the AD profile. Methods: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-tosevere AD (n 5 246) and age-matched control subjects (n 5 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and > _61 years). Results: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P 5 .873), dendritic cell infiltrates (CD1b 1 and FcεRI 1 , P < .05) decreased with age. T H 2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T H 2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r 5 20.24 and r 5 20.23, respectively; P < .05). T H 22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of T H 1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and T H 17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T H 2 downregulation (CCL26; r 5 20.32, P < .1) and T H 1 upregulation (IFN-g; r 5 0.48, P < .01) with age. Conclusion: The adult AD profile varies with age. Although T H 1/T H 17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T H 2/T H 22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.

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A major component of COVID-19 severe respiratory syndrome is the patient’s immune response to the SARS-CoV-2 virus and the consequential multi-organ inflammatory response. Several studies suggested a potential role of CD4+ T cells in COVID-19 severe respiratory syndrome. We first hypothesized that there is a type 2 helper (Th2)/type 1 helper (Th1) imbalance in older age, male, asthma, smokers, and high ACE2 expression phenotype in the airway of non-infected patients. Next, we hypothesized that a Th2/Th1 imbalance may predict higher mortality in COVID-19 infected hospitalized patients with and without patient reported current asthma. We first analyzed publicly available gene expression from the sputum of 118 moderate-to-severe asthma patients and 21 healthy controls, and from nasal epithelium of 26 healthy current smokers and 21 healthy never smokers. Secondly, we profiled 288 new serum proteomics samples measured at admission from patients hospitalized within the Mount Sinai Health System with positive SARS-CoV-2 infection. We first computed Th1 and Th2 pathway enrichment scores by gene set variation analysis and then compared the differences in Th2 and Th1 pathway scores between patients that died compared to those that survived, by linear regression. The level of Th2/Th1 imbalance, as determined by the enrichment score, was associated with age, sex, and ACE2 expression in sputum, and with active smoking status in nasal epithelium (p &lt; 0.05). Th2/Th1 imbalance at hospital admission in sera of patients was not significantly associated with death from COVID-19 (p = 0.11), unless evaluated in the asthmatic strata (p = 0.01). Using a similar approach we also observed a higher Th17/Th1 cytokine imbalance in all deceased patients compared to those that survived (p &lt; 0.001), as well as in the asthmatic strata only (p &lt; 0.01). Th2/Th1 imbalance is higher in the sera of asthma patients at admission that do not survive COVID-19, suggesting that the Th2/Th1 interplay may affect patient outcomes in SARS-CoV2 infection. In addition, we report that Th17/Th1 imbalance is increased in all patients that die of COVID-19.

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What is already known about this topic? Preliminary data suggest increased type 2 cytokines during the COVID-19 cytokine storm. However, it remains unclear how COVID-19 outcomes differ between patients with atopic dermatitis (AD) on type 2etargeting agents (dupilumab) and those treated with other systemics or topical treatments.What does this article add to our knowledge? This is the first study to directly compare the severity of COVID-19 symptoms in patients with moderate-to-severe AD on different treatments, shedding important light on the treatment of patients with AD during the pandemic and beyond.How does this study impact current management guidelines? Our results suggest that type 2 targeting with dupilumab may attenuate COVID-19 responses, supporting the safety of specific type 2etargeting agents in patients with AD during the COVID-19 pandemic, and potentially extending to other viral infections.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). OBJECTIVE: Because it is believed that type 1/Th1 immunity controls viral infections and that there is a Th1/Th2 counterregulation, we hypothesized that Th2 targeting with the IL-4Ra-antagonist, dupilumab, in patients with moderate-to-severe AD would rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. METHODS: A total of 1237 patients with moderate-to-severe AD 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

To the Editor, The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects certain populations, such as older individuals. 1 In contrast, children comprise <2% of cases and generally exhibit milder symptoms. 2 These disparate observations in children versus adults may be attributed to both environmental and host immune factors, including an immature and developing immune system. 3 A key breakthrough in understanding the infectious mechanism of COVID-19 was the discovery of angiotensin-converting enzyme 2/ACE2, the receptor that SARS-CoV-2 uses to gain entry into human host cells. 4 ACE2 expression is observed in the upper and lower respiratory tract and in extrapulmonary tissues that are prone to SARS-CoV-2 infection (e.g. gastrointestinal tract, cardiovascular system, skin). 5 Lower maturity and function of ACE2 have been hypothesized to explain less disease prevalence in children. 3 Recently, one study evaluated ACE2 gene expression in nasal epithelial samples in children and adults, reporting higher ACE2 expression in older children (10-17 years old) and adults (≥18 years old) versus younger children (<10 years old), and these associations remained significant after adjusting for sex and asthma.

We identified tryptic peptides in yeast cell lysates that map to translation initiation sites downstream of the annotated start sites using the peptide-spectrum matching algorithms OMSSA and Mascot. To increase the accuracy of peptide-spectrum matching, both algorithms were run using several standardized parameter sets, and Mascot was run utilizing a, b, and y ions from collision-induced dissociation. A large fraction (22%) of the detected N-terminal peptides mapped to translation initiation downstream of the annotated initiation sites. Expression of several truncated proteins from downstream initiation in the same reading frame as the full-length protein (frame 1) was verified by western analysis. To facilitate analysis of the larger proteome of Drosophila, we created a streamlined sequence library from which all duplicated trypsin fragments had been removed. OMSSA assessment using this "stripped" library revealed 171 peptides that map to downstream translation initiation sites, 76% of which are in the same reading frame as the full-length annotated proteins, although some are in different reading frames creating new protein sequences not in the annotated proteome. Sequences surrounding implicated downstream AUG start codons are associated with nucleotide preferences with a pronounced three-base periodicity N1^G2^A3.