Reduced Cytokine Release Syndrome and Improved Outcomes with Earlier Immunosuppressive Therapy in Haploidentical Stem Cell Transplantation.

The optimal timing of immunosuppression and post-transplantation cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is unknown. However, cytokine release syndrome (CRS) following haplo-HSCT is associated with worse transplantation outcomes, and the incidence of CRS may be affected by the timing of immunosuppression and PTCy. In this study, we compared CRS and other transplantation outcomes in 2 cohorts receiving different immunosuppression and PTCy schedules following haplo-HSCT. This was a retrospective cohort study of 91 patients who underwent haplo-HSCT at the Intermountain Health Blood and Marrow Transplant Program. The original or standard haplo-HSCT GVHD prophylaxis regimen included PTCy on days +3 and +4, with mycophenolate mofetil (MMF) and tacrolimus starting on day +5. The modified regimen adopted in November 2020 changed PTCy to days +3 and +5, with earlier introduction of tacrolimus and MMF, on day -1 and day 0, respectively. Grade ≥1 CRS occurred in 32% of patients in the modified regimen, in 82% of patients in the standard regimen (P <.0001), and 65% overall. Likewise, grade ≥2 CRS was lower with the modified regimen (16% versus 57%; P = .0002). The mean duration of CRS symptoms was longer with the standard regimen (3.14 days versus 1.44 days; P = .0003). The incidence of acute graft-versus-host disease grade III-IV or extensive chronic GVHD (cGVHD) at 1 year was lower in the modified regimen (6% versus 32%; P = .0068). No differences between the standard and modified regimens were seen in overall survival, relapse, or GVHD-free relapse-free survival (GRFS), although there appeared to be a trend toward improved GRFS with the modified regimen. Post hoc analysis comparing GRFS in patients with CRS and those without CRS found that CRS was associated with lower GRFS at 1 year (36% versus 63%; P = .0138). The duration of broad-spectrum antibiotic therapy was decreased by 7.5 days (P = .0017) and the time to hospital discharge was reduced by 7.1 days (P = .0241) with the modified regimen. This is the first analysis to evaluate and find a difference in CRS with early initiation of immunosuppressive therapy in haplo-HSCT. Our results suggest that this modified GVHD regimen benefits patients by reducing CRS and high-grade GVHD compared to the standard PTCy-based GVHD prophylaxis regimen in haplo-HSCT. Additionally, this novel regimen did not appear to negatively impact outcomes.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

Current Pharmacology and Modulation of the Purinergic System in Takotsubo Syndrome Triggered by Cytokine Storm.

Studies show that with the COVID-19 pandemic, the world's population went through multiple stress and anxiety factors, generating serious psychological problems, in addition, the virus also caused damage and physical stress to those contaminated. In this way, the intense emotional experiences and stressful effects on the body caused by SARS-CoV-2 are capable of triggering the excessive release of catecholamines in the body. Thus, the framework of Takotsubo Syndrome is characterized by myocardial dysfunction as a response of cardiac receptors to the spillage of such hormones in an unregulated way in the human body. The purinergic system plays a central role in this process, as it actively participates in actions responsible for the syndromic cascade, such as the stress generated by the cytokine storm triggered by the virus and the stimulation of deregulated catecholamine release. Therefore, further pharmacological studies on the role of purines in this pathology should be developed in order to avoid the evolution of the syndrome and to modulate its P1 and P2 receptors aiming at developing means of reversing or treating the Takotsubo Syndrome.

Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection.

INTRODUCTION: Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency disorder characterized by absent or dysfunctional T lymphocytes, leading to defective cellular and humoral immunity requiring urgent hematopoietic stem cell transplantation (HSCT). We report a case of SCID with disseminated Bacille Calmette-Guérin (BCG) infection who developed cytokine release syndrome (CRS) and possible Immune reconstitution inflammatory syndrome (IRIS) after Haploidentical HSCT with post-transplant cyclophosphamide. METHODS: Data were retrospectively retrieved from electronic medical records. RESULT: A 5-month-old male infant was referred with fever, cough, and generalized maculopapular rash for 15 days, and had pallor without hepatosplenomegaly or lymphadenopathy. He had a history of previous male sibling death at 6 months of age due to pneumonia. Investigations: hemoglobin: 4.7 g/dL, TLC-6.37×103/uL, absolute lymphocytes: 0.98×103/uL, platelets: 319×103/uL, bilateral patchy opacities in both lung fields, and low immunoglobulin levels. Lymphocyte subset analysis revealed T-, B+, NK- SCID. Genetic analysis showed a hemizygous mutation in IL2RG (c.314A>G). The child received intravenous (IV) antibiotics, antifungal, antitubercular drugs, irradiated blood products, and IV immunoglobulins. Urgent haploidentical HSCT from the mother was planned. Conditioning was Fludarabine-40 mg/m2/d for 4 days, cyclophosphamide: 14.5 mg/kg/d for 2 days. He received peripheral blood hematopoietic stem cells with CD34- 15×106 cells/kg and CD3- 805×106 cells/kg. Within 2 hours of stem cell infusion, he developed respiratory distress, fever, shock, and flaring of rash. Methylprednisolone was started in view of CRS. On day+2, he had sudden desaturation and bradycardia needing mechanical ventilation and inotropes. His inflammatory markers were elevated (Ferritin: 3640 ng/mL, IL-6:5000 pg/mL, CRP:255 mg/L). In view of high-grade CRS, he received an injection of tocilizumab 8 mg/kg on day +2 and day +4. He received post-transplant cyclophosphamide 5 mg/kg on day +3. The endotracheal secretion GeneXpert was positive for Mycobacterium supporting the diagnosis of disseminated tuberculosis. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG, which were transferred to the infant with peripheral blood stem cell product. He succumbed to severe acute respiratory distress syndrome and multiorgan dysfunction on day +5 post-transplant. CONCLUSIONS: In haploidentical HSCT of SCID, post-transplant course can be complicated by CRS and IRIS as these patients are inefficient in mounting any response to infused donor lymphocytes resulting in their unregulated growth.

Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications.

BACKGROUND: Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis. METHODS: In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87). RESULTS: Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1). CONCLUSIONS: Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.

The Multifaceted Immunology of Cytokine Storm Syndrome.

Cytokine storm syndromes (CSSs) are potentially fatal hyperinflammatory states that share the underpinnings of persistent immune cell activation and uninhibited cytokine production. CSSs can be genetically determined by inborn errors of immunity (i.e., familial hemophagocytic lymphohistiocytosis) or develop as a complication of infections, chronic inflammatory diseases (e.g., Still disease), or malignancies (e.g., T cell lymphoma). Therapeutic interventions that activate the immune system such as chimeric Ag receptor T cell therapy and immune checkpoint inhibition can also trigger CSSs in the setting of cancer treatment. In this review, the biology of different types of CSSs is explored, and the current knowledge on the involvement of immune pathways and the contribution of host genetics is discussed. The use of animal models to study CSSs is reviewed, and their relevance for human diseases is discussed. Lastly, treatment approaches for CSSs are discussed with a focus on interventions that target immune cells and cytokines.

The Liver in Hemophagocytic Lymphohistiocytosis: Not an Innocent Bystander.

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystemic hyperinflammatory disease commonly associated with hepatic dysfunction. Liver injury is mediated by unchecked antigen presentation, hypercytokinemia, dysregulated cytotoxicity by natural killer and CD8 T cells, and disruption of intrinsic hepatic metabolic pathways. Over the past decade, there have been significant advances in diagnostics and expansion in therapeutic armamentarium for this disorder allowing for improved morbidity and mortality. This review discusses the clinical manifestations and pathogenesis of HLH hepatitis in both familial and secondary forms. It will review growing evidence that the intrinsic hepatic response to hypercytokinemia in HLH perpetuates disease progression and the novel therapeutic approaches for patients with HLH-hepatitis/liver failure.

The interplay between hypovitaminosis D and the immune dysfunction in the arteriovenous thrombotic complications of the sever coronavirus disease 2019 (COVID-19) infection.

Thromboembolic complications including cerebrovascular accidents, pulmonary embolism, myocardial infarction, deep vein thrombosis and disseminating intravascular coagulopathy are serious encounters in sever coronavirus disease 2019 (COVID-19) infected patients. This worsens the prognosis and may lead to death or life long morbidities. The laboratory finding of the disturbed haemostasias and the hyperinflammatory response are almost invariably present in COVID-19 patients. Multiple treatment modalities are utilized by the healthcare professionals to overcome the cytokine storm, oxidative stress, endothelial dysfunction, and coagulopathy in these patients. The combined actions of vitamin D (VitD) as a steroid hormone with anti-inflammatory, immunomodulatory, and antithrombotic properties increase the potential of the possible involvement of hypovitaminosis D in the thromboembolic complications of COVID-19 infection, and stimulated researchers and physicians to administer VitD therapy to prevent the infection and/or overcome the disease complications. The current review highlighted the immunomodulatory, anti-inflammatory, antioxidative and hemostatic functions of VitD and its interrelation with the renin-angiotensin-aldosterone system (RAAS) pathway and the complement system. Additionally, the association of VitD deficiency with the incidence and progression of COVID-19 infection and the associated cytokine storm, oxidative stress, hypercoagulability, and endothelial dysfunction were emphasized. Normalizing VitD levels by daily low dose therapy in patients with hypovitaminosis D below (25 nmol/l) is essential for a balanced immune response and maintaining the health of the pulmonary epithelium. It protects against upper respiratory tract infections and decreases the complications of COVID-19 infections. Understanding the role of VitD and its associated molecules in the protection against the coagulopathy, vasculopathy, inflammation, oxidative stress and endothelial dysfunction in COVID-19 infection could lead to new therapeutic strategies to prevent, treat, and limit the complications of this deadly virus infection.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome.

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.

Carotid free-floating thrombus in COVID-19: a cerebrovascular disorder of cytokine storm-related immunothrombosis.

BACKGROUNDS: Several neurological manifestations, including stroke, have been reported in COVID-19 patients. The putative role of the COVID-19-related hyperinflammatory state in cerebrovascular disorders remains unclear. METHODS: From March 2020 to September 2021, we searched for patients who exhibited an ischemic stroke related to carotid free-floating thrombus (CFFT) to investigate its incidence and relationship with COVID-19. RESULTS: Of 853 ischemic strokes referred to our Stroke Centre during the study period, 5.7% (n = 49) were positive for SARS-CoV-2. Six had CFFT, of which two tested positive for SARS-CoV-2 (2/49 = 4.1%), and four did not (4/802 = 0.5%). The former were two middle-aged men suffering from COVID-19 pneumonia. Floating thrombi were promptly extracted by endarterectomy and endovascular thrombectomy, respectively, with no early and long-term complications. Notably, our COVID-19 patients exhibited little or no atherosclerosis burden on CT angiography, markedly elevated D-dimer levels, and extensive thrombus length. CONCLUSIONS: COVID-19-induced immunothrombosis possibly played a significant pathogenic role in CFFT.

Intravenous anakinra to curb cytokine storm in adult-onset Still's disease and in macrophage activation syndrome: A case series.

OBJECTIVE: Adult-onset Still's disease (AOSD) is an auto-inflammatory polygenic disorder, for which the diagnosis is essentially clinical. The exclusion of mimickers [such as common bacterial and viral infections, hematologic malignancies, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] is necessary to confirm the diagnosis. Anti-interleukin (IL)-1 therapy is considered a treatment milestone for AOSD. Herein, we present a short series of newly-diagnosed AOSD or upcoming macrophage activation syndrome (MAS) cases who received intravenous (IV) anakinra, an IL-1 receptor blocker. METHODS: Four patients with newly-diagnosed AOSD or upcoming MAS were treated with IV anakinra at the Rheumatology Unit of Padova University Hospital, Italy. We obtained informed consent from the patients for use of their cases and medical images for publication purposes. RESULTS: All patients presented with AOSD or MAS during the COVID-19 pandemic, making diagnosis challenging due to similar immunological and clinical characteristics across both pathologies. All patients presented with hyperpyrexia and elevated inflammatory markers; two patients had a skin rash typically seen in AOSD. IV anakinra slowed down AOSD progression in all patients, prevented severe outcomes and mitigated the risk of multiorgan failure. All cases improved within 24hours of anakinra administration. CONCLUSION: We found that administration of anakinra in patients with newly-diagnosed AOSD and/or upcoming MAS reduced hyperinflammation and prevented life-threatening complications. The IV route appears to be preferable in the hospital setting, where comorbidities such as coagulopathies and thrombocytopenia can complicate the use of other routes of administration.

Non-viral precision T cell receptor replacement for personalized cell therapy.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

Neurological Presentations in Patients with COVID-19 in Cytokine Storm.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection causes a wide variety of neurological disorders by affecting both central and peripheral nervous systems. The cytokine storm (CS) has been blamed for the development of severe neurological disorders in COVID-19. However, the relationship between COVID-19 CS and neurological manifestations has not been adequately studied. Thus, we aimed to investigate the neurological presentations in patients with COVID-19 CS. METHODS: The study population consisted of hospitalized moderate-to-severe COVID-19 patients. It was divided into two groups CS (36 patients, 29.3%) and non-CS (87 patients, 70.7%) based on significant clinical symptoms, elevated inflammatory marker levels, radiological findings, and interleukin-6 levels (IL-6). RESULTS: The three most common neurological symptoms in the CS group were altered level of consciousness, headache, and unsteadiness. Altered level of consciousness was higher in the CS group (69.4%) than the non-CS group (25.3%) (p:0.001). The frequency of headache was comparable in both groups (p:0.186). The number of patients requiring intensive care unit and intubation was higher in the CS group (p:0.005 and p:0.001). The mortality rate in the CS group (38.9%) was higher than the non-CS group (8.0%) (p:0.001). IL-6, CRP, ferritin, neutrophil-lymphocyte ratio, procalcitonin, and D-dimer levels were higher in the CS group (for all p:0.001) while lymphocyte count was lower (p:0.003). CONCLUSION: The most common neurological presentation in patients with CS was altered level of consciousness. The presence of CS was an independent risk factor for high mortality.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells.

The therapeutic effect of CAR-T is often accompanied by sCRS, which is the main obstacle to the promotion of CAR-T therapy. The JAK1/2 inhibitor ruxolitinib has recently been confirmed as clinically effective in maintaining control over sCRS, however, its mechanism remains unclear. In this study, we firstly revealed that ruxolitinib significantly inhibited the proliferation of CAR-T cells without damaging viability, and induced an efficacy-favored differentiation phenotype. Second, ruxolitinib reduced the level of cytokine release not only from CAR-T cells, but also from other cells in the immune system. Third, the cytolytic activity of CAR-T cells was restored once the ruxolitinib was removed; however, the cytokines released from the CAR-T cells maintained an inhibited state to some degree. Finally, ruxolitinib significantly reduced the proliferation rate of CAR-T cells in vivo without affecting the therapeutic efficacy after withdrawal at the appropriate dose. We demonstrated pre-clinically that ruxolitinib interferes with both CAR-T cells and the other immune cells that play an important role in triggering sCRS reactions. This work provides useful and important scientific data for clinicians on the question of whether ruxolitinib has an effect on CAR-T cell function loss causing CAR-T treatment failure when applied in the treatment of sCRS, the answer to which is of great clinical significance.

Disorders of the Cholinergic System in COVID-19 Era-A Review of the Latest Research.

The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body's cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.

Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19.

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

NSAIDs/nitazoxanide/azithromycin repurposed for COVID-19: potential mitigation of the cytokine storm interleukin-6 amplifier via immunomodulatory effects.

INTRODUCTION: Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. AREAS COVERED: We analyze selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the results that suggested a potential survival benefit of low-dose aspirin and colchicine when used for COVID-19. EXPERT OPINION: Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that are unfortunately currently at best of second choice after paracetamol, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their anti-inflammatory and immunomodulatory properties. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials.

Thrombocytopathy vs Platelet hyper-reactivity in COVID-19: diverse pathologies, disease outcomes and therapeutic implications.

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.

How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.

Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.