Modulation of innate immunity in airway epithelium for host-directed therapy.

Innate immunity of the mucosal surfaces provides the first-line defense from invading pathogens and pollutants conferring protection from the external environment. Innate immune system of the airway epithelium consists of several components including the mucus layer, mucociliary clearance of beating cilia, production of host defense peptides, epithelial barrier integrity provided by tight and adherens junctions, pathogen recognition receptors, receptors for chemokines and cytokines, production of reactive oxygen species, and autophagy. Therefore, multiple components interplay with each other for efficient protection from pathogens that still can subvert host innate immune defenses. Hence, the modulation of innate immune responses with different inducers to boost host endogenous front-line defenses in the lung epithelium to fend off pathogens and to enhance epithelial innate immune responses in the immunocompromised individuals is of interest for host-directed therapy. Herein, we reviewed possibilities of modulation innate immune responses in the airway epithelium for host-directed therapy presenting an alternative approach to standard antibiotics.

The chemokine landscape: one system multiple shades.

Leukocyte trafficking is mainly governed by chemokines, chemotactic cytokines, which can be concomitantly produced in tissues during homeostatic conditions or inflammation. After the discovery and characterization of the individual chemokines, we and others have shown that they present additional properties. The first discoveries demonstrated that some chemokines act as natural antagonists on chemokine receptors, and prevent infiltration of leukocyte subsets in tissues. Later on it was shown that they can exert a repulsive effect on selective cell types, or synergize with other chemokines and inflammatory mediators to enhance chemokine receptors activities. The relevance of the fine-tuning modulation has been demonstrated in vivo in a multitude of processes, spanning from chronic inflammation to tissue regeneration, while its role in the tumor microenvironment needs further investigation. Moreover, naturally occurring autoantibodies targeting chemokines were found in tumors and autoimmune diseases. More recently in SARS-CoV-2 infection, the presence of several autoantibodies neutralizing chemokine activities distinguished disease severity, and they were shown to be beneficial, protecting from long-term sequelae. Here, we review the additional properties of chemokines that influence cell recruitment and activities. We believe these features need to be taken into account when designing novel therapeutic strategies targeting immunological disorders.

Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients.

Background: Deep metabolomic, proteomic and immunologic phenotyping of patients suffering from an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Several studies have described the role of small as well as complex molecules such as metabolites, cytokines, chemokines and lipoproteins during infection and in recovered patients. In fact, after an acute SARS-CoV-2 viral infection almost 10-20% of patients experience persistent symptoms post 12 weeks of recovery defined as long-term COVID-19 syndrome (LTCS) or long post-acute COVID-19 syndrome (PACS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these biomolecules altogether govern pathophysiology is largely underexplored. Thus, a clear understanding of how these parameters within an integrated fashion could predict the disease course would help to stratify LTCS patients from acute COVID-19 or recovered patients. This could even allow to elucidation of a potential mechanistic role of these biomolecules during the disease course. Methods: This study comprised subjects with acute COVID-19 (n=7; longitudinal), LTCS (n=33), Recov (n=12), and no history of positive testing (n=73). 1H-NMR-based metabolomics with IVDr standard operating procedures verified and phenotyped all blood samples by quantifying 38 metabolites and 112 lipoprotein properties. Univariate and multivariate statistics identified NMR-based and cytokine changes. Results: Here, we report on an integrated analysis of serum/plasma by NMR spectroscopy and flow cytometry-based cytokines/chemokines quantification in LTCS patients. We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls (HC) or acute COVID-19 patients. Subsequently, correlation analysis in LTCS group only among cytokines and amino acids revealed that histidine and glutamine were uniquely attributed mainly with pro-inflammatory cytokines. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared with HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their phenylalanine, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except for IL-18 chemokine, which tended to be higher in LTCS patients. Conclusion: The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients.

New genetic and epigenetic insights into the chemokine system: the latest discoveries aiding progression toward precision medicine.

Over the past thirty years, the importance of chemokines and their seven-transmembrane G protein-coupled receptors (GPCRs) has been increasingly recognized. Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes, including host homeostasis and responses to disease. Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity. Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases, including cancer, immune and inflammatory diseases, and metabolic and neurological disorders, which render the system a focus of studies aiming to discover therapies and important biomarkers. The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states, including, among others, coronavirus disease 2019 (COVID-19). In this review, by reporting the latest advances in chemokine biology and results from analyses of a plethora of sequencing-based datasets, we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network, focusing on chemokine-mediated inflammation and cancer. Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.

Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.

Chemokine production by epithelial cells is crucial for neutrophil recruitment to sites of inflammation during viral infection. However, the effect of chemokine on epithelia and how chemokine is involved in coronavirus infection remains to be fully understood. Here, we identified an inducible chemokine interleukin-8 (CXCL8/IL-8), which could promote coronavirus porcine epidemic diarrhea virus (PEDV) infection in African green monkey kidney epithelial cells (Vero) and Lilly Laboratories cell-porcine kidney 1 epithelial cells (LLC-PK1). IL-8 deletion restrained cytosolic calcium (Ca2+), whereas IL-8 stimulation improved cytosolic Ca2+. The consumption of Ca2+ restricted PEDV infection. PEDV internalization and budding were obvious reductions when cytosolic Ca2+ was abolished in the presence of Ca2+ chelators. Further study revealed that the upregulated cytosolic Ca2+ redistributes intracellular Ca2+. Finally, we identified that G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-store-operated Ca2+ (SOC) signaling was crucial for enhancive cytosolic Ca2+ and PEDV infection. To our knowledge, this study is the first to uncover the function of chemokine IL-8 during coronavirus PEDV infection in epithelia. PEDV induces IL-8 expression to elevate cytosolic Ca2+, promoting its infection. Our findings reveal a novel role of IL-8 in PEDV infection and suggest that targeting IL-8 could be a new approach to controlling PEDV infection. IMPORTANCE Coronavirus porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that caused severe economic losses worldwide, and more effort is needed to develop economical and efficient vaccines to control or eliminate this disease. The chemokine interleukin-8 (CXCL8/IL-8) is indispensable for the activation and trafficking of inflammatory mediators and tumor progression and metastasis. This study evaluated the effect of IL-8 on PEDV infection in epithelia. We found that IL-8 expression improved cytosolic Ca2+ in epithelia, facilitating PEDV rapid internalization and egress. G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-SOC signaling was activated by IL-8, releasing the intracellular Ca2+ stores from endoplasmic reticulum (ER). These findings provide a better understanding of the role of IL-8 in PEDV-induced immune responses, which will help develop small-molecule drugs for coronavirus cure.

Time evolution of cytokine profiles associated with mortality in COVID-19 hospitalized patients.

Background: High cytokine levels have been associated with severe COVID-19 disease. Although many cytokine studies have been performed, not many of them include combinatorial analysis of cytokine profiles through time. In this study we investigate the association of certain cytokine profiles and its evolution, and mortality in SARS-CoV2 infection in hospitalized patients. Methods: Serum concentration of 45 cytokines was determined in 28 controls at day of admission and in 108 patients with COVID-19 disease at first, third and sixth day of admission. A principal component analysis (PCA) was performed to characterize cytokine profiles through time associated with mortality and survival in hospitalized patients. Results: At day of admission non-survivors present significantly higher levels of IL-1α and VEGFA (PC3) but not through follow up. However, the combination of HGF, MCP-1, IL-18, eotaxine, and SCF (PC2) are significantly higher in non-survivors at all three time-points presenting an increased trend in this group through time. On the other hand, BDNF, IL-12 and IL-15 (PC1) are significantly reduced in non-survivors at all time points with a decreasing trend through time, though a protective factor. The combined mortality prediction accuracy of PC3 at day 1 and PC1 and PC2 at day 6 is 89.00% (p<0.001). Conclusions: Hypercytokinemia is a hallmark of COVID-19 but relevant differences between survivors and non-survivors can be early observed. Combinatorial analysis of serum cytokines and chemokines can contribute to mortality risk assessment and optimize therapeutic strategies. Three clusters of cytokines have been identified as independent markers or risk factors of COVID mortality.

Intranasal administration of sodium nitroprusside augments antigen-specific mucosal and systemic antibody production in mice.

The coronavirus disease 2019, i.e., the COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has profoundly impacted global society. One approach to combat infectious diseases caused by pathogenic microbes is using mucosal vaccines, which can induce antigen-specific immune responses at both the mucosal and systemic sites. Despite its potential, the clinical implementation of mucosal vaccination is hampered by the lack of safe and effective mucosal adjuvants. Therefore, developing safe and effective mucosal adjuvants is essential for the fight against infectious diseases and the widespread clinical use of mucosal vaccines. In this study, we demonstrated the potent mucosal adjuvant effects of intranasal administration of sodium nitroprusside (SNP), a known nitric oxide (NO) donor, in mice. The results showed that intranasal administration of ovalbumin (OVA) in combination with SNP induced the production of OVA-specific immunoglobulin A in the mucosa and increased serum immunoglobulin G1 levels, indicating a T helper-2 (Th2)-type immune response. However, an analog of SNP, sodium ferrocyanide, which does not generate NO, failed to show any adjuvant effects, suggesting the critical role of NO generation in activating an immune response. In addition, SNPs facilitated the delivery of antigens to the lamina propria, where antigen-presenting cells are located, when co-administered with antigens, and also transiently elicited the expression of interleukin-6, interleukin-1ß, granulocyte colony-stimulating factor, C-X-C motif chemokine ligand 1, and C-X-C motif chemokine ligand 2 in nasal tissue. These result suggest that SNP is a dual-functional formulation with antigen delivery capabilities to the lamina propria and the capacity to activate innate immunity. In summary, these results demonstrate the ability of SNP to induce immune responses via an antigen-specific Th2-type response, making it a promising candidate for further development as a mucosal vaccine formulation against infectious diseases.

The Immunological Profile of SARS-CoV-2 Infection in Children Is Linked to Clinical Severity and Age.

Coronavirus disease 19 (COVID-19) is clinically less severe in children, even if the wide variety and degree of severity of symptoms reported in children pose a still-unresolved challenge for clinicians. We performed an in-depth analysis of the immunological profiles of 18 hospitalized SARS-CoV-2-infected children, whose results were compared to those obtained from 13 age- and sex-matched healthy controls (HC). The patients were categorized as paucisymptomatic/moderate (55.6%) or severe/critical (44.5%) according to established diagnostic criteria and further stratified into the categories of infants (1-12 months), children (1-12 years), and adolescents (>12 years). We assessed SARS-CoV-2-specific RBD antibodies (Ab), neutralizing antibodies (nAb), and circulating cytokines/chemokines in the plasma, and the SARS-CoV-2-specific immune response was measured in PBMCs by gene expression and secretome analyses. Our results showed peculiar circulating cytokine/chemokine profiles among patients sharing a similar clinical phenotype. A cluster of patients consisting of infants with severe symptoms presented hyperinflammatory profiles, together with extremely polarized antibody profiles. In a second cluster consisting of paucisymptomatic patients, a less pronounced increase in the level of inflammatory cytokines, together with an association between the selected cytokines and humoral responses, was observed. A third cluster, again consisting of paucisymptomatic patients, showed a circulating cytokine/chemokine profile which overlapped with that of the HC. The SARS-CoV-2-stimulated production of pro-inflammatory proteins, T lymphocyte activation, and migration-specific proteins, were significantly increased in SARS-CoV-2-infected children compared to the HC. Our findings suggest that immune response activation in the course of SARS-CoV-2 infection in children is directly correlated with clinical severity and, to a lesser extent, age.

Characterization of METRNß as a novel biomarker of Coronavirus disease 2019 severity and prognosis.

Introduction: Coronavirus disease 2019 (COVID-19) is increasing worldwide, with complications due to frequent viral mutations, an intricate pathophysiology, and variable host immune responses. Biomarkers with predictive and prognostic value are crucial but lacking. Methods: Serum samples from authentic and D614G variant (non-Omicron), and Omicron-SARS-CoV-2 infected patients were collected for METRNß detection and longitudinal cytokine/chemokine analysis. Correlation analyses were performed to compare the relationships between serum METRNß levels and cytokines/chemokines, laboratory parameters, and disease severity. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were used to evaluate the predictive value of METRNß in COVID-19. Results: The serum level of METRNß was highly elevated in non-Omicron-SARS-CoV-2 infected patients compared to healthy individuals, and the non-survivor displayed higher METRNß levels than survivors among the critical ones. METRNß concentration showed positive correlation with viral load in NAPS. ROC curve showed that a baseline METRNß level of 1886.89 pg/ml distinguished COVID-19 patients from non-infected individuals with an AUC of 0.830. Longitudinal analysis of cytokine/chemokine profiles revealed a positive correlation between METRNß and pro-inflammatory cytokines such as IL6, and an inverse correlation with soluble CD40L (sCD40L). Higher METRNß was associated with increased mortality. These findings were validated in a second and third cohort of COVID-19 patients identified in a subsequent wave. Discussion: Our study uncovered the precise role of METRNß in predicting the severity of COVID-19, thus providing a scientific basis for further evaluation of the role of METRNß in triage therapeutic strategies.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Serum chemokine CC-motif ligand 17 is a predictive marker of severe COVID-19 in haemodialysis patients: A retrospective observational study.

BACKGROUND: Maintenance haemodialysis (HD) patients are at higher risk for severe coronavirus disease 2019 (COVID-19). Because of a limited number of facilities that can provide inpatient treatment for COVID-19 and HD, it is important to identify HD patients who are at high risk for severe COVID-19. For mild to moderate COVID-19 patients, chemokine CC-motif ligand 17 (CCL17) was reported to be a predictive marker for severe COVID-19; however, the validity of CCL17 among HD patients is unknown. METHODS: This retrospective observational study enrolled 107 HD patients with mild or moderate COVID-19 at hospitalization (mean age 70.1 ± 15.1 years; 71.0% male). Receiver operating characteristic and logistic regression analyses were used to examine the predictive validity of indices for severe COVID-19. RESULTS: During hospitalization, 32 patients developed severe COVID-19. Serum CCL17 collected at admission exhibited a higher area under the curve value (0.818) compared with that of other indicators including lactate dehydrogenase and C-reactive protein for the prediction of severe COVID-19. The optimal cut-off value for CCL17 was 150.5 pg/mL. A multi-variate logistic analysis revealed that CCL17 (above 150.5 pg/mL) was significantly associated with severe COVID-19 (Odds ratio, 0.063; 95% Confidence interval [CI], 0.017-0.227; p < .001) even after adjustment for covariates. The addition of the CCL17 to a model consisting of vaccination status, albumin, blood urea nitrogen, C-reacting protein and lactate dehydrogenase significantly improved classification performance for severe COVID-19 using the net reclassification (1.16, 95% CI: 0.82-1.50, p < .001) and integrated discrimination (0.18, 95% CI: 0.09-0.26, p < .001) improvement. CONCLUSION: CCL17 levels in HD patients with mild or moderate COVID-19 predict risk of developing severe COVID-19.

Different cytokine and chemokine profiles in hospitalized patients with COVID-19 during the first and second outbreaks from Argentina show no association with clinical comorbidities.

Background: COVID-19 severity has been linked to an increased production of inflammatory mediators called "cytokine storm". Available data is mainly restricted to the first international outbreak and reports highly variable results. This study compares demographic and clinical features of patients with COVID-19 from Córdoba, Argentina, during the first two waves of the pandemic and analyzes association between comorbidities and disease outcome with the "cytokine storm", offering added value to the field. Methods: We investigated serum concentration of thirteen soluble mediators, including cytokines and chemokines, in hospitalized patients with moderate and severe COVID-19, without previous rheumatic and autoimmune diseases, from the central region of Argentina during the first and second infection waves. Samples from healthy controls were also assayed. Clinical and biochemical parameters were collected. Results: Comparison between the two first COVID-19 waves in Argentina highlighted that patients recruited during the second wave were younger and showed less concurrent comorbidities than those from the first outbreak. We also recognized particularities in the signatures of systemic cytokines and chemokines in patients from both infection waves. We determined that concurrent pre-existing comorbidities did not have contribution to serum concentration of systemic cytokines and chemokines in COVID-19 patients. We also identified immunological and biochemical parameters associated to inflammation which can be used as prognostic markers. Thus, IL-6 concentration, C reactive protein level and platelet count allowed to discriminate between death and discharge in patients hospitalized with severe COVID-19 only during the first but not the second wave. Conclusions: Our data provide information that deepens our understanding of COVID-19 pathogenesis linking demographic features of a COVID-19 cohort with cytokines and chemokines systemic concentration, presence of comorbidities and different disease outcomes. Altogether, our findings provide information not only at local level by delineating inflammatory/anti-inflammatory response of patients but also at international level addressing the impact of comorbidities and the infection wave in the variability of cytokine and chemokine production upon SARS-CoV-2 infection.

D-dopachrome tautomerase in cardiovascular and inflammatory diseases-A new kid on the block or just another MIF?

Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF.

Molecular imaging of chemokine-like receptor 1 (CMKLR1) in experimental acute lung injury.

The lack of techniques for noninvasive imaging of inflammation has challenged precision medicine management of acute respiratory distress syndrome (ARDS). Here, we determined the potential of positron emission tomography (PET) of chemokine-like receptor-1 (CMKLR1) to monitor lung inflammation in a murine model of lipopolysaccharide-induced injury. Lung uptake of a CMKLR1-targeting radiotracer, [64Cu]NODAGA-CG34, was significantly increased in lipopolysaccharide-induced injury, correlated with the expression of multiple inflammatory markers, and reduced by dexamethasone treatment. Monocyte-derived macrophages, followed by interstitial macrophages and monocytes were the major CMKLR1-expressing leukocytes contributing to the increased tracer uptake throughout the first week of lipopolysaccharide-induced injury. The clinical relevance of CMKLR1 as a biomarker of lung inflammation in ARDS was confirmed using single-nuclei RNA-sequencing datasets which showed significant increases in CMKLR1 expression among transcriptionally distinct subsets of lung monocytes and macrophages in COVID-19 patients vs. controls. CMKLR1-targeted PET is a promising strategy to monitor the dynamics of lung inflammation and response to anti-inflammatory treatment in ARDS.

The Potential Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Cardiovascular System, Respiratory System and Skin.

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and xeroderma pigmentosum). Additionally, the significance of CXCL1 is described in vascular physiology, such as the effects of CXCL1 on angiogenesis and arteriogenesis.

The impact of supervised physical exercise on chemokines and cytokines in recovered COVID-19 patients.

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which induces a high release of pro-inflammatory chemokines and cytokines, leading to severe systemic disorders. Further, evidence has shown that recovered COVID-19 patients still have some symptoms and disorders from COVID-19. Physical exercise can have many health benefits. It is known to be a potent regulator of the immune system, which includes frequency, intensity, duration, and supervised by a professional. Given the confinement and social isolation or hospitalization of COVID-19 patients, the population became sedentary or opted for physical exercise at home, assuming the guarantee of the beneficial effects of physical exercise and reducing exposure to SARS-CoV-2. This study aimed to investigate the effects of a supervised exercise protocol and a home-based unsupervised exercise protocol on chemokine and cytokine serum levels in recovered COVID-19 patients. This study was a prospective, parallel, two-arm clinical trial. Twenty-four patients who had moderate to severe COVID-19 concluded the intervention protocols of this study. Participants were submitted to either supervised exercise protocol at the Clinical Hospital of the Federal University of Pernambuco or home-based unsupervised exercise for 12 weeks. We analyzed serum levels of chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ). Before the interventions, no significant differences were observed in the serum levels of chemokines and cytokines between the supervised and home-based unsupervised exercise groups. The CXCL8/IL-8 (p = 0.04), CCL2/MCP-1 (p = 0.03), and IFN-γ (p = 0.004) levels decreased after 12 weeks of supervised exercise. In parallel, an increase in IL-2 (p = 0.02), IL-6 (p = 0.03), IL-4 (p = 0.006), and IL-10 (p = 0.04) was observed after the supervised protocol compared to pre-intervention levels. No significant differences in all the chemokines and cytokines were found after 12 weeks of the home-based unsupervised exercise protocol. Given the results, the present study observed that supervised exercise was able to modulate the immune response in individuals with post-COVID-19, suggesting that supervised exercise can mitigate the inflammatory process associated with COVID-19 and its disorders. Clinical trial registration: https://ensaiosclinicos.gov.br/rg/RBR-7z3kxjk, identifier U1111-1272-4730.

Correlations of Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in the nasopharyngeal specimens with the diagnosis and severity of SARS-CoV-2 infections.

Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, p < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10-3 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, p = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.