Severe Inflammatory Disorders Research Articles

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets.

Severe airway inflammatory disorders impose a significant societal burden, and the available treatments are unsatisfactory. High levels of neutrophil extracellular trap (NET) and cell-free DNA (cfDNA) were detected in the inflammatory microenvironment of these diseases, which are closely associated with persistent uncontrolled neutrophilic inflammation. Although DNase has proven to be effective in mitigating neutrophilic airway inflammation in mice by reducing cfDNA and NET levels, its clinical use is hindered by severe side effects. Here, we synthesized polyglycerol-amine (PGA) with a series of hydroxyl/amine ratios and covered them with black phosphorus (BP) nanosheets. The BP nanosheets functionalized with polyglycerol-50% amine (BP-PGA50) efficiently lowered cfDNA levels, suppressed toll-like receptor 9 (TLR9) activation and inhibited NET formation in vitro. Importantly, BP-PGA50 nanosheets demonstrated substantial accumulation in inflamed airway tissues, excellent biocompatibility, and potent inflammation modulation ability in model mice. The 2D sheet-like structure of BP-PGA50 was identified as a crucial factor for the therapeutic efficacy, and the hydroxyl/amine ratio was revealed as a significant parameter to regulate the protein resistance, cfDNA-binding efficacy, and cytotoxicity. This study shows the promise of the BP-PGA50 nanosheet for tackling uncontrolled airway inflammation, which is also significant for the treatment of other neutrophilic inflammatory diseases. In addition, our work also highlights the importance of proper surface functionalization, such as hydroxyl/amine ratio, in therapeutic nanoplatform construction for inflammation modulation.

Human MAIT cells inhibit alloreactive T cell responses and protect against acute graft-versus-host disease.

Adoptive transfer of immunoregulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Mucosal-associated invariant T (MAIT) cells were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAIT cells in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic GVHD model. We found that MAIT cells, whether freshly purified or short-term expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAIT cells greatly delayed GVHD onset and decreased severity when transferred early after PBMC injection but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels and increased IL-10 levels. MAIT cells acted partly in a contact-dependent manner, which likely required direct interaction of their T cell receptor with MHC class I-related molecule (MR1) induced on host-reactive T cells. These results support the setup of clinical trials using MAIT cells as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.

TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα

BackgroundHuman aging is characterized by a state of chronic inflammation, termed inflammaging, for which the causes are incompletely understood. It is known, however, that macrophages play a driving role in establishing inflammaging by promoting pro-inflammatory rather than anti-inflammatory responses. Numerous genetic and environmental risk factors have been implicated with inflammaging, most of which are directly linked to pro-inflammatory mediators IL-6, IL1Ra, and TNFα. Genes involved in the signaling and production of those molecules have also been highlighted as essential contributors. TAOK3 is a serine/threonine kinase of the STE-20 kinase family that has been associated with an increased risk of developing auto-immune conditions in several genome-wide association studies (GWAS). Yet, the functional role of TAOK3 in inflammation has remained unexplored.ResultsWe found that mice deficient in the serine/Threonine kinase Taok3 developed severe inflammatory disorders with age, which was more pronounced in female animals. Further analyses revealed a drastic shift from lymphoid to myeloid cells in the spleens of those aged mice. This shift was accompanied by hematopoietic progenitor cells skewing in Taok3−/− mice that favored myeloid lineage commitment. Finally, we identified that the kinase activity of the enzyme plays a vital role in limiting the establishment of proinflammatory responses in macrophages.ConclusionsEssentially, Taok3 deficiency promotes the accumulation of monocytes in the periphery and their adoption of a pro-inflammatory phenotype. These findings illustrate the role of Taok3 in age-related inflammation and highlight the importance of genetic risk factors in this condition.

Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin‐4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10−16, 95% confidence interval [CI] = 2.60 × 10−25–1.22 × 10−7, p = 0.001; OR = 5.28 × 10−6, 95% CI = 4.67 × 10−11–0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.

Humic substances from composted fennel residues control the inflammation induced by Helicobacter pylori infection in AGS cells.

Helicobacter pylori (H. pylori) is a common human pathogen causing inflammation. Recent studies have suggested a sophisticated interplay between mitochondria, innate immunity and inflammatory response, thus proposing mitochondrial disfunction as the hallmark of severe inflammatory disorders. In this study, humic substances isolated from composted fennel residues (HS-FEN) were tested as potential therapeutical strategy to restore the mitochondrial physiology and control the inflammation associated with H. pylori infection. The molecular features of HS-FEN were characterized by infrared spectrometry, thermochemolysis-GC/MS, NMR spectroscopy, and high-performance size-exclusion chromatography (HPSEC), which revealed the presence of aromatic polyphenolic components arranged in a rather stable conformation. In vitro results showed antioxidant and anti-inflammatory properties of HS-FEN, that was found to increase the expression level of OPA-1 and SOD-2 genes and in AGS cells stimulated with H. pylori culture filtrate (Hpcf) and concomitantly decrease the expression level of Drp-1 gene and IL-12, IL-17 and G-CSF proteins. The hydrophobic features of HS, their conformational arrangement and large content of bioactive molecules may explain the beneficial effects of HS-FEN, that may potentially become an interesting source of anti-inflammatory agents capable to counteract or prevent the H. pylori-related inflammatory disorders.

The FOXP3-924 A/G Single Nucleotide Polymorphism May Be Associated with Predictive Factors for Human T Lymphotropic Virus 1 Associated Myelopathy.

Human T lymphotropic virus 1 (HTLV-1) is a retrovirus associated with inflammatory diseases, including HTLV-1-associated myelopathy (HAM), and host genetic factors may be involved in disease evolution. The forkhead Box P3 (FOXP3) transcription factor is linked to homeostasis of the immune system, and the presence of polymorphisms in the promoter region of the FOXP3 gene should reflect its expression levels and consequent activation of regulatory T cells, which may contribute to severe inflammatory disorders, such as HAM. This study evaluated the rs2232365 polymorphism (-924 A/G) located in the promoter region of the FOXP3 gene and its association with HAM. Forty DNA samples from asymptomatic carriers and 25 samples from HAM patients were used, in addition to 130 control samples. The polymorphism was genotyped by conducting real-time polymerase chain reaction (PCR) (quantitative PCR [qPCR]) on extracted DNA. The proviral loads (PVLs) and CD4+ and CD8+ T lymphocyte counts were determined by qPCR and FACSCalibur flow cytometry, respectively. The PVLs, CD4+ T lymphocyte concentrations, and tumor necrosis factor-α dosages were considered predictive factors of the clinical profiles of HTLV-1 infection, all of which had higher levels in the HAM group. Carriers of the GG genotype for the polymorphism rs2232365 had high PVLs and CD4+ T lymphocyte concentrations.

Patient with Systemic Lupus Erythematosus who Presented with Area Postrema Syndrome after COVID-19 Vaccination

Area postrema syndrome is a disorder that is included within the neuromyelitis optica spectrum (NMOSD), a group of severe inflammatory disorders of the central nervous system that primarily affect the optic nerve and spinal cord. The cause of NMOSD is unknown, but it has been linked to infections, vaccines and associated with autoimmune diseases. We present the case of a patient with a history of systemic lupus erythematosus who presented with area postrema syndrome after vaccination with COVID-19.

Adrenomedullin Therapy in Moderate to Severe COVID-19.

The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.

Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency.

NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient's plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous typeI interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.

An adapted passive model of anti-MPO dependent crescentic glomerulonephritis reveals matrix dysregulation and is amenable to modulation by CXCR4 inhibition

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often involve focal necrotizing glomerulonephritis (FNGN) and consequent glomerular scarring, interstitial fibrosis, and chronic kidney disease. Robust murine models of scarring in FNGN that may help to further our understanding of deleterious processes are still lacking. Here, we present a murine model of severe FNGN based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS), that recapitulates acute injury and was adapted to investigate subsequent glomerular and interstitial scarring. Hematuria without involvement of other organs occurs consistently and rapidly, glomerular necrosis and crescent formation are evident at 12 days, and consequent glomerular and interstitial scarring at 29 days after initial treatment. Using mass-spectrometric proteome analysis, we provide a detailed overview of matrisomal and cellular changes in our model. We observed increased expression of the matrisome including collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarrays and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Experimental inhibition of CXCR4 using AMD3100 led to a sustained histological presence of fibrin extravasate, reduced chemokine expression and leukocyte activation, but did not markedly affect ECM composition. Altogether, we demonstrate an adapted FNGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition.

Neonatal Manifestations of Chronic Granulomatous Disease: MAS/HLH and Necrotizing Pneumonia as Unusual Phenotypes and Review of the Literature.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI), characterized by a deficient phagocyte killing due to the inability of NADPH oxidase to produce reactive oxygen species in the phagosome. Patients with CGD suffer from severe and recurrent infections and chronic inflammatory disorders. Onset of CGD has been rarely reported in neonates and only as single case reports or small case series. We report here the cases of three newborns from two different kindreds, presenting with novel infectious and inflammatory phenotypes associated with CGD. A girl with CYBA deficiency presented with necrotizing pneumonia, requiring a prolonged antibiotic treatment and resulting in fibrotic pulmonary changes. From the second kindred, the first of two brothers developed a fatal Burkholderia multivorans sepsis and died at 24days of life. His younger brother had a diagnosis of CYBB deficiency and presented with Macrophage Activation Syndrome/Hemophagocytic Lympho-Histiocytosis (MAS/HLH) without any infection, that could be controlled with steroids. We further report the findings of a review of the literature and show that the spectrum of microorganisms causing infections in neonates with CGD is similar to that of older patients, but the clinical manifestations are more diverse, especially those related to the inflammatory syndromes. Our findings extend the spectrum of the clinical presentation of CGD to include unusual neonatal phenotypes. The recognition of the very early, potentially life-threatening manifestations of CGD is crucial for a prompt diagnosis, improvement of survival and reduction of the risk of long-term sequelae.

Sonic Hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation.

Epithelial barrier tissues such as the skin and airway form an essential interface between the mammalian host and its external environment. These physical barriers are crucial to prevent damage and disease from environmental insults and allergens. Failure to maintain barrier function against such risks can lead to severe inflammatory disorders, including atopic dermatitis and asthma. Here, we discuss the role of the morphogen Sonic Hedgehog in postnatal skin and lung and the impact of Shh signalling on repair, inflammation, and atopic disease in these tissues.

Prohibitin-1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis.

BackgroundIn sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown.Methods and ResultsUsing a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT  signaling in the heart.ConclusionsThese findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.

Biologic Therapies for Allergic Rhinitis and Nasal Polyposis.

There is an emerging body of research on targeted biologic therapies for the treatment of severe inflammatory nasal disorders, especially chronic rhinosinusitis with nasal polyposis (CRSwNP). This paper will evaluate the efficacy of biologic therapies for severe nasal inflammation by summarizing key preclinical trials of biologics for animal models of allergic rhinitis and the recent phase 2 and 3 clinical trials of biologic therapies for CRSwNP. Biologics that target the IL-4 receptor (dupilumab), IgE (omalizumab), and IL-5 (mepolizumab, reslizumab, and benralizumab) in patients with CRSwNP have shown improvement of various metrics including Sino-Nasal Outcome Test (SNOT-22) scores, Nasal Polyp Scores (NPS), Nasal Congestion Scores (NCS), and Lund-Mackay sinus opacification scores. The efficacy demonstrated through the dupilumab phase 3 trials (LIBERTY NP SINUS-24 and SINUS-52) led to approval of the first biologic for the treatment of CRSwNP. Phase 3 trials for omalizumab (POLYP 1 and 2) and mepolizumab (SYNAPSE study) and post hoc analyses of phase 3 asthma studies for reslizumab and benralizumab have also demonstrated positive results for the use of biologics for patients with CRSwNP. Future efficacy studies and risk/benefit and cost analyses of these biologics and other cytokine targets for allergic rhinitis with and without nasal polyposis need to be performed.

Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress.

Rationale: The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation. Methods: Full-length or serially deleted MYLK luciferase reporter promoter activities were measured in human lung endothelial cells (ECs). SNP-containing non-muscle MYLK (nmMYLK) DNA fragments were generated and nmMYLK promoter binding by transcription factors (TFs) detected by protein–DNA electrophoretic mobility shift assay (EMSA). Promoter demethylation was evaluated by 5-aza-2′-deoxycytidine (5-Aza). A preclinical mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) was utilized for nmMLCK validation. Results: Lung EC levels of nmMLCK were significantly increased in LPS-challenged mice and LPS, tumor necrosis factor-α (TNF-α), 18% cyclic stretch (CS) and 5-Aza each significantly up-regulated EC nmMYLK promoter activities. EC exposure to FG-4592, a prolyl hydroxylase inhibitor that increases hypoxia-inducible factor (HIF) expression, increased nmMYLK promoter activity, confirmed by HIF1α/HIF2α silencing. nmMYLK promoter deletion studies identified distal inhibitory and proximal enhancing promoter regions as well as mechanical stretch-, LPS- and TNFα-inducible regions. Insertion of ARDS-associated SNPs (rs2700408, rs11714297) significantly increased nmMYLK promoter activity via increased transcription binding (glial cells missing homolog 1 (GCM1) and intestine-specific homeobox (ISX), respectively). Finally, the MYLK rs78755744 SNP (−261G/A), residing within a nmMYLK CpG island, significantly attenuated 5-Aza-induced promoter activity. Conclusion: These findings indicate nmMYLK transcriptional regulation by clinically relevant inflammatory factors and ARDS-associated nmMYLK promoter variants are consistent with nmMLCK as a therapeutic target in severe inflammatory disorders.

Polymeric Antioxidant Materials for Treatment of Inflammatory Disorders

AbstractReactive oxygen and nitrogen species (RONS) play a key role in physiological conditions as signaling molecules for regulating homeostasis in the human body. However, abnormally increased RONS levels can damage DNA, protein, and tissue, or even impair cellular signaling. Consequently, when this state is present for a long time, it can lead to severe inflammatory disorders, such as lupus, diabetes, rheumatoid arthritis, Crohn's disease, and neurodegenerative disorders. Although antioxidant therapies have been developed for a long time to treat acute or chronic inflammatory diseases, small molecule‐based antioxidants showed relatively low therapeutic effects due to rapid clearance and low stability in the bloodstream. As one of the solutions to overcome such limitations, incorporating polymers would provide enhanced blood stability, bioavailability, and even enhanced therapeutic effects. Herein, diverse polymeric antioxidant materials are introduced that are categorized into simple loading strategies and polymers with inherent antioxidative activity. Further, preclinical and clinical studies of polymeric antioxidant materials for anti‐inflammatory therapy are discussed and a better direction is provided for these to be pursued and improved in anti‐inflammatory therapy.

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors.

Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.

Guiding principles for prioritization of limited in-person dermatology appointments during the COVID-19 pandemic

Coronavirus disease 2019 (COVID-19) has led dermatology practices to severely limit in-person appointments due to social distancing and shelter-in-place measures.1Chen Y. Pradhan S. Xue S. What are we doing in the dermatology outpatient department amidst the raging of the 2019 novel coronavirus?.J Am Acad Dermatol. 2020; 82: 1034Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Even as infection rates fall and practices reopen, epidemiologic modeling predicts future resurgences of COVID-19, likely compelling practices to intermittently restrict in-person appointments again.2Kissler S.M. Tedijanto C. Goldstein E. Grad Y.H. Lipsitch M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period.Science. 2020; 368: 860-868Crossref PubMed Scopus (1466) Google Scholar Principles of scarce health care resource distribution have been applied during the COVID-19 pandemic, commonly for critical care resources.3Persad G. Wertheimer A. Emanuel E.J. Principles for allocation of scarce medical interventions.Lancet. 2009; 373: 423-431Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar,4Emanuel E.J. Persad G. Upshur R. et al.Fair allocation of scarce medical resources in the time of Covid-19.N Engl J Med. 2020; 382: 2049-2055Crossref PubMed Scopus (1694) Google Scholar However, these principles have not been modified for or applied to limited in-person dermatology appointments during the pandemic. Guiding principles can inform dermatologists about how to prioritize patients and skin diseases in this context. Our department convened an in-person appointment prioritization workgroup including the Department Chair (R.A.S.), Vice Chair (S.C.C.), Residency Program Director (J.B.M.), Pediatric Dermatology Director (L.P.L.), Dermatologic Surgery Director (T.W.B.), and Dermatopathology Head of Operations (B.K.S.), who is a Fellow at the Emory Center for Ethics and chaired the workgroup. Many institutions have encouraged telehealth during the pandemic. As suggested by our institution, the workgroup assumed that any dermatologic problem that could be adequately addressed using teledermatology would be handled in that fashion. Using a modified Delphi approach with 2 rounds, the workgroup chair drafted guiding principles that were sent to workgroup members for anonymous feedback. The workgroup then met virtually for discussion and voting on areas of disagreement. The document was revised and recirculated until consensus was reached via simple majority. The workgroup chair presented the principles to the department and then sent them to faculty, trainees, administrators, nursing representatives, and select patients for further feedback and revision before they were finalized (Table I).Table IGuiding principles for allocation of limited in-person dermatology appointments during the COVID-19 pandemicGuiding principleExamples1.Health care providers, other health care employees, and public health officials should be given priority, especially if their skin disease interferes with delivering care or other essential duties, because of their instrumental value to the health of others.•A hospitalist with an inflamed epidermoid cyst on the face interfering with masking and requiring intralesional corticosteroid injection or incision and drainage•An emergency department nurse with new-onset tense bullae on the lower extremities causing pain and edema2.Diagnostic procedures, including but not limited to skin biopsies, should be prioritized because pathologic and/or microbiologic diagnosis often allows for better characterization of risk of morbidity and mortality of malignancies, serious infections, and severe inflammatory disorders.2A.Clinical lesions or eruptions for which the differential diagnosis incudes high-risk malignancies, serious infections, or severe inflammatory disorders should be prioritized.•A patient at high risk for melanoma with a changing pigmented lesion•An immunosuppressed patient with a tender nodule concerning for severe infection requiring biopsy and/or tissue culture•A patient with acute-onset tense bullae•A patient with mycosis fungoides with new nodules or erythroderma3.Patients with severe skin disease that is life-threatening, function-limiting, and/or emotionally debilitating who would benefit most from an in-person evaluation should be prioritized over patients with mild disease or patients with severe disease who would gain less in order to maximize benefits.•A patient with moderate hidradenitis suppurativa with an acute abscess on the buttocks preventing sitting and requiring incision and drainage•A solid-organ transplant recipient with a high-risk squamous cell carcinoma on the scalp requiring excision•A patient with an enlarging keloid on the chest causing severe pain and requiring intralesional corticosteroid injection•An infant with a high-risk vascular lesion4.For patients with similar prognoses, consider a random selection process for determining who gets a particular in-person appointment.•For a list of patients with low-risk basal cell carcinoma awaiting treatment, random selection can be used to determine when each patient is scheduled for definitive treatment.5.Patients with skin disease burden resulting in substantial functional and/or emotional morbidity who do not have access to or cannot effectively use teledermatology platforms should be prioritized.•A patient without a smartphone, tablet, computer, and/or internet connectivity with widespread dermatitis Open table in a new tab The first 3 principles are grounded in maximizing benefits, an essential guiding principle for health care utilization during pandemics.4Emanuel E.J. Persad G. Upshur R. et al.Fair allocation of scarce medical resources in the time of Covid-19.N Engl J Med. 2020; 382: 2049-2055Crossref PubMed Scopus (1694) Google Scholar Health care workers have instrumental value to society because they care for others. Diagnostic procedures permit triage decisions about which subsequent treatments are most impactful. Prioritizing patients with severe disease who would gain most from in-person intervention maximizes benefits as well. The final 2 principles are rooted in justice and respond to health care access disparities during the pandemic.5Dorn A.V. Cooney R.E. Sabin M.L. COVID-19 exacerbating inequalities in the US.Lancet. 2020; 395: 1243-1244Abstract Full Text Full Text PDF PubMed Google Scholar Random allocation has been promoted for distributing resources because of recognized injustices associated with a first-come, first-served distribution method, such as favoring those who can travel quickly and wait.3Persad G. Wertheimer A. Emanuel E.J. Principles for allocation of scarce medical interventions.Lancet. 2009; 373: 423-431Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar To illustrate how our practice has put into operation this principle, which is uncommonly deployed in health care, providers were given a list of patients requiring in-person appointments and assigned each to a priority tier 1 to 3 based on the other principles. Schedulers then randomized patients within each tier and assigned them to appointment slots, such that tier 1 priority patients got the first available appointments and so on. Finally, allocating some in-person appointments to patients lacking access to or capability for teledermatology accommodates medically underserved populations during pandemics and may alleviate burdens on other specialties, such as emergency medicine. Although cancer screening is often delayed during pandemics, the workgroup addressed total-body skin examination screening. The workgroup concluded that if sufficient in-person appointment capacity for total-body skin examination screening exists, a tiered prioritization scheme that balances risk of skin cancer with risk of severe COVID-19 (Table II) can be considered.Table IIApplication of guiding principles to total-body skin examination screening (TBSE) during the COVID-19 pandemicTierDescriptionExample1 (highest priority)Patients at very high risk for skin cancer (primary, recurrent, or metastatic)A patient with a history of invasive melanoma or high-risk squamous cell carcinoma within the last 6 months2Patients with a low to moderate risk of skin cancer with strong preferences for TBSE and relatively low risk for severe COVID-19A healthy 45-year-old patient with a family history of melanoma requesting TBSE3Patients with low risk for skin cancer and high risk of severe COVID-19∗Risk factors for severe COVID-19: age >65 years, residency in a nursing home, underlying diseases: chronic lung disease, coronary artery disease, liver disease, chronic kidney disease, diabetes mellitus, obesity, hypertension, and immunosuppression.An elderly patient with chronic lung disease and few risk factors for skin cancerCOVID-19, Coronavirus disease 2019; TBSE, total-body skin examination screening.∗ Risk factors for severe COVID-19: age >65 years, residency in a nursing home, underlying diseases: chronic lung disease, coronary artery disease, liver disease, chronic kidney disease, diabetes mellitus, obesity, hypertension, and immunosuppression. Open table in a new tab COVID-19, Coronavirus disease 2019; TBSE, total-body skin examination screening. Several limitations apply to these principles. First, principles are not rules and should not dictate all appointment allocation decisions. Further, translating these principles into operations may not be immediately possible or may require adaptations for different practices. These principles may not apply when there is less appointment scarcity due to increased supply of appointments, decreased demand for them, or both. These principles provide a framework for in-person appointment prioritization during times of appointment scarcity, such as the COVID-19 pandemic.

The Effects of Dairy Product and Dairy Protein Intake on Inflammation: A Systematic Review of the Literature

Abstract Objectives Chronic inflammation is associated with obesity and chronic disease risk. Intake of dairy foods is associated with reduced risk of type 2 diabetes and cardiovascular disease; however, the impact of dairy intake on inflammation is not well established. The objective of this study was to conduct a systematic review of the literature to evaluate the effect of dairy product and dairy protein consumption on low-grade systemic inflammation in adults without severe inflammatory disorders. Methods This systematic review was conducted in accordance with the PRISMA statement and registered on PROSPERO (CRD42019129639). A literature search was completed in December 2018 and updated September 2019 using PubMed, CENTRAL, and review of reference lists from relevant review articles. The search resulted in identification and inclusion of 27 randomized controlled trials in this analysis, 19 trials which evaluated dairy products and 8 trials which evaluated dairy proteins. Results In the 19 trials which evaluated dairy products, 10 reported no inflammatory effect of the intervention, 8 reported a reduction in at least one biomarker of inflammation, and 1 reported a greater anti-inflammatory effect in the control as compared to the dairy product intervention. All 8 trials that investigated dairy protein intake on markers of inflammation reported no effect of the intervention. In the 17 trials which evaluated CRP following dairy product interventions, 12 studies reported no change, 4 studies in overweight and obese populations reported a decrease, and 1 study reported an increase in overweight and obese populations. In the 12 trials which evaluated an inflammatory-related cytokine (IL-6, TNF-α and receptors, IL-1β, and/or MCP-1), 7 studies reported no change in markers assessed, and 5 studies (4 of which were in overweight and obese populations) reported a decrease in at least one pro-inflammatory cytokine. A majority of the trials received neutral or positive quality ratings. Conclusions The available literature suggests dairy products and dairy proteins have neutral to beneficial effects on biomarkers of inflammation. Additional clinical studies designed using an inflammatory biomarker as the primary outcome, are needed to fully elucidate the effects of dairy intake on inflammation. Funding Sources National Dairy Council.

Feline Interleukin-31 Shares Overlapping Epitopes with the Oncostatin M Receptor and IL-31RA.

Interleukin-31 (IL-31) is a major protein involved in severe inflammatory skin disorders. Its signaling pathway is mediated through two type I cytokine receptors, IL-31RA (also known as the gp130-like receptor) and the oncostatin M receptor (OSMR). Understanding molecular details in these interactions would be helpful for developing antagonist anti-IL-31 monoclonal antibodies (mAbs) as potential therapies. Previous studies suggest that human IL-31 binds to IL-31RA and then recruits OSMR to form a ternary complex. In this model, OSMR cannot interact with IL-31 in the absence of IL-31RA. In this work, we show that feline IL-31 (fIL-31) binds independently with feline OSMR using surface plasmon resonance, an enzyme-linked immunosorbent assay, and yeast surface display. Moreover, competition experiments suggest that OSMR shares a partially overlapping epitope with IL-31RA. We then used deep mutational scanning to map the binding sites of both receptors on fIL-31. In agreement with previous studies of the human homologue, the binding site for IL31-RA contains fIL-31 positions E20 and K82, while the binding site for OSMR comprises the "PADNFERK" motif (P103-K110) and position G38. However, our results also revealed a new overlapping site, composed of positions R69, R72, P73, D76, D81, and E97, between both receptors that we called the "shared site". The conformational epitope of an anti-feline IL-31 mAb that inhibits both OSMR and IL-31RA also mapped to this shared site. Combined, our results show that fIL-31 binds IL-31RA and OSMR independently through a partially shared epitope. These results suggest reexamination of the putative canonical mechanisms for IL-31 signaling in higher animals.