Asthma and COVID-19: a controversial relationship.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection induces a spectrum of clinical manifestations that depend on the immune response of the patient, i.e., from an asymptomatic form to an inflammatory response with multiorgan deterioration. In some cases, severe cases of SARS-CoV-2 are characterized by an excessive, persistent release of inflammatory mediators known as a cytokine storm. This phenomenon arises from an ineffective T helper (Th)-1 response, which is unable to control the infection and leads to a reinforcement of innate immunity, causing tissue damage. The evolution of the disease produced by SARS-CoV2, known as COVID-19, has been of interest in several research fields. Asthma patients have been reported to present highly variable outcomes due to the heterogeneity of the disease. For example, the Th2 response in patients with allergic asthma is capable of decreasing Th1 activation in COVID-19, preventing the onset of a cytokine storm; additionally, IL-33 released by damaged epithelium in the context of COVID-19 potentiates either Th1 or T2-high responses, a process that contributes to poor outcomes. IL-13, a T2-high inflammatory cytokine, decreases the expression of angiotensin converting enzyme-2 (ACE2) receptor, hindering SARS-CoV-2 entry; finally, poor outcomes have been observed in COVID-19 patients with severe neutrophilic asthma. In other contexts, the COVID-19 lockdown has had interesting effects on asthma epidemiology. The incidence of asthma in the most populated states in Mexico, including Tamaulipas, which has the highest asthma incidence in the country, showed similar tendencies independent of how strict the lockdown measures were in each state. As described worldwide for various diseases, a decrease in asthma cases was observed during the COVID-19 lockdown. This decrease was associated with a drop in acute respiratory infection cases. The drop in cases of various diseases, such as diabetes, hypertension or depression, observed in 2020 was restored in 2022, but not for asthma and acute respiratory infections. There were slight increases in asthma cases when in-person classes resumed. In conclusion, although many factors were involved in asthma outcomes during the pandemic, it seems that acute respiratory infection is intimately linked to asthma cases. Social distancing during remote learning, particularly school lockdown, appears to be an important cause of the decrease in cases.

Risk factors and outcome of Chimeric Antigen Receptor T-Cell patients admitted to Pediatric Intensive Care Unit: CART-PICU study.

Introduction: Chimeric antigen receptor (CAR)T-cell CD19 therapy is an effective treatment for relapsed/refractory B-cell acute lymphoblastic leukemia. It can be associated with life-threatening toxicities which often require PICU admission. Purpose: to describe clinical characteristics, treatment and outcome of these patients. Methods: Prospective observational cohort study conducted in a tertiary pediatric hospital from 2016-2021. Children who received CAR-T admitted to PICU were included. We collected epidemiological, clinical characteristics, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), treatment, length of stay and mortality. Results: CAR T-cells (4-1BB constructs) were infused in 59 patients. Twenty-four (40.7%) required PICU admission, length of stay was 4 days (IQR 3-6). Median age was 8.3 years (range 4-24). Patients admitted to PICU presented higher disease burden before infusion: 24% blasts in bone marrow (IQR 5-72) vs. 0 (0-6.9), p<0.001. No patients with <5% blasts were admitted to PICU. Main reasons for admissions were CRS (n=20, 83.3%) and ICANS (n=3, 12.5%). Fourteen patients (58.3%) required inotropic support, 14(58.3%) respiratory. Sixteen patients (66.6%) received tocilizumab, 10(41.6%) steroids, 6(25.0%) anakinra, and 5(20.8%) siltuximab. Ten patients (41.6%) presented neurotoxicity, six of them severe (ICANS 3-4). Two patients died at PICU (8.3%) because of refractory CRS-hemophagocytic lymphohistyocitosis (carHLH) syndrome. There were no significant differences in relapse rate after CAR-T in patients requiring PICU, it was more frequently CD19 negative (p=0.344). Discussion: PICU admission after CAR-T therapy was mainly due to CRS. Supportive treatment allowed effective management and high survival. Some patients presenting with carHLH, can suffer a fulminant course.

The impact of tocilizumab treatment for cytokine release syndrome on the incidence of early blood stream infections after peripheral blood haploidentical hematopoietic cell transplantation.

Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT). Severe CRS has previously been associated with increased infection risk. IL-6 inhibitors, such as tocilizumab, are useful in moderate to severe CRS, but their effect on infection risk has not been established in this setting. We examined the effect of tocilizumab on blood stream infections (BSIs) in the early post-transplant period in 235 patients who underwent haplo-HCT from 2013 to 2020. Mild CRS was associated with a lower incidence of BSI than severe CRS (OR 0.31, 95% CI 0.13-0.74). In the tocilizumab group, 31% of patients had positive blood cultures versus 14% in the non-tocilizumab group (OR 1.61, 95% CI 0.30-8.60, p = 0.58). However, when controlling for CRS grade, tocilizumab was not independently associated with increased rates of BSIs, suggesting it does not further increase infection risk.

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, lisocabtagene maraleucel (liso-cel), is administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This analysis assessed safety and efficacy of liso-cel in Japanese patients with relapsed or refractory (R/R) aggressive large B-cell lymphoma (LBCL) in Cohort 3 of TRANSCEND WORLD (NCT03484702). Liso-cel (100 × 106 total CAR+ T cells) was administered 2-7 days after lymphodepletion. The primary efficacy endpoint was objective response rate (ORR; Lugano 2014 criteria) assessed by an independent review committee. Fourteen patients were enrolled; 10 received liso-cel infusion (median time to liso-cel availability, 23 days) and were evaluable at data cutoff (median follow-up, 12.5 months). Grade ≥ 3 treatment-emergent adverse events were neutropenia (90%), leukopenia (80%), anemia (70%), and thrombocytopenia (70%). All-grade cytokine release syndrome (CRS) was observed in 50% of patients, though no grade ≥3 CRS events were reported. Grade 1 neurological events occurred in 1 patient but were resolved without any intervention. Prolonged cytopenia (grade ≥ 3 at day 29) was reported for 60% of patients. The ORR was 70%, and complete response rate was 50%. The median duration of response was 9.1 months (95% confidence interval [CI], 2.1-not reached), and overall survival was 14.7 months (95% CI, 1.7-not reached). One patient diagnosed with central nervous system involvement after screening but before liso-cel infusion, responded to liso-cel. Liso-cel demonstrated meaningful efficacy and a manageable safety profile in Japanese patients with R/R LBCL.

Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease.

We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 × 106 ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade ≥3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Impact of cytokine storm on severity of COVID-19 disease in a private hospital in West Jakarta prior to vaccination.

BACKGROUND AND AIM: Coronavirus Disease 2019 (COVID-19) has become a worldwide pandemic and is a threat to global health. Patients who experienced cytokine storms tend to have a high mortality rate. However, to date, no study has investigated the impact of cytokine storms. MATERIALS AND METHODS: This retrospective cohort study included only COVID-19 positive patients hospitalized in a Private Hospital in West Jakarta between March and September 2020. All patients were not vaccinated during this period and treatment was based on the guidelines by the Ministry of Health Indonesia. A convenience sampling method was used and all patients who met the inclusion criteria were enrolled. RESULTS: The clinical outcome of COVID-19 patients following medical therapy was either cured (85.7%) or died (14.3%), with 14.3% patients reported to have cytokine storm, from which 23.1% led to fatalities. A plasma immunoglobulin (Gammaraas®) and/or tocilizumab (interleukin-6 receptor antagonist; Actemra®) injection was utilised to treat the cytokine storm while remdesivir and oseltamivir were administered to ameliorate COVID-19. Most (61.5%) patients who experienced the cytokine storm were male; mean age 60 years. Interestingly, all patients who experienced the cytokine storm had hypertension or/ and diabetes complication (100%). Fever, cough and shortness of breath were also the common symptoms (100.0%). Almost all (92.3%) patients with cytokine storm had to be treated in the intensive care unit (ICU). Most (76.9%) patients who had cytokine storm received hydroxychloroquine and all had antibiotics [1) azithromycin + levofloxacin or 2) meropenam for critically ill patients] and vitamins such as vitamins C and B-complex as well as mineral. Unfortunately, from this group, 23.1% patients died while the remaining 70% of patients recovered. A significant (p<0.05) correlation was established between cytokine storms and age, the presence of comorbidity, diabetes, hypertension, fever, shortness of breath, having oxygen saturation (SPO2) less than 93%, cold, fatigue, ward of admission, the severity of COVID-19 disease, duration of treatment as well as the use of remdesivir, Actemra® and Gammaraas®. Most patients recovered after receiving a combination treatment (oseltamivir + remdesivir + Antibiotics + Vitamin/Mineral) for approximately 11 days with a 90% survival rate. On the contrary, patients who received oseltamivir + hydroxychloroquine + Gammaraas® + antibiotics +Vitamin/Mineral, had a 83% survival rate after being admitted to the hospital for about ten days. CONCLUSION: Factors influencing the development of a cytokine storm include age, duration of treatment, comorbidity, symptoms, type of admission ward and severity of infection. Most patients (76.92%) with cytokine storm who received Gammaraas®/Actemra®, survived although they were in the severe and critical levels (87.17%). Overall, based on the treatment duration and survival rate, the most effective therapy was a combination of oseltamivir + favipiravir + hydroxychloroquine + antibiotics + vitamins/minerals.

Perforin, COVID-19 and a possible pathogenic auto-inflammatory feedback loop.

During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation. Excess IL-6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto-inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID-19. In addition, we outline the manner in which a pathogenic auto-inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID-19. Such an auto-inflammatory loop may be amenable to synergistic multimodal therapy.

SARS-CoV-2-associated cytokine storm during pregnancy as a possible risk factor for neuropsychiatric disorder development in post-pandemic infants.

A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.

CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma: physician preferences trading off benefits, risks and time to infusion.

Aims: We evaluated physicians' willingness to trade-off benefits, risks and time to infusion for CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Materials & methods: In a discrete-choice experiment survey, 150 US oncologists/hematologists chose between two hypothetical CAR T-cell treatments defined by six attributes. Results: Decreasing time to infusion from 113 to 16 days yielded the greatest change in preference weight (1.91). Physicians were willing to accept a >20% increase in risk of severe cytokine release syndrome and 15% increase in risk of severe neurological events in exchange for an increase in the probability of overall survival at 24 months from 40 to 55%. Conclusion: Physicians value reducing time to infusion and will accept incremental increases in serious adverse event risks to gain survival improvements.

Lay abstract CAR-T therapy is a treatment option for patients with diffuse large B-cell lymphoma that has not responded to at least two other kinds of treatments. CAR-T therapies are manufactured from a patient's white blood cells, modified to attack lymphoma cells. A CAR-T therapy takes time to manufacture after these cells are collected. CAR-T therapies can result in the reduction or disappearance of lymphoma tumors and can increase the chances of survival, but also cause serious side effects for a few patients. One of these is cytokine release syndrome (CRS), in which high levels of inflammation throughout the body may cause fever, heart problems or difficulty breathing. Another is the development of temporary but serious neurological problems such as confusion, seizures and memory problems. To understand how important physicians consider certain features of CAR-T therapies to be when deciding whether to recommend them, we asked physicians to choose between two treatment options resembling CAR-T therapies in a series of questions, with the CAR-T features varying in each question. Their answers indicated whether disappearance of tumors, a patient's chances of survival after 1 and 2 years of treatment, manufacturing time, or the risk of CRS or neurological problems was the most important factor. Physicians most wanted to reduce manufacturing time from 113 to 16 days, but also were willing to accept a >20% increase in risk of severe CRS and a 15% increase in risk of severe neurological events to increase a patient's chance of survival from 40 to 55% at 2 years.

Nonsteroidal anti-inflammatory drugs and glucocorticoids in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a wide spectrum of symptom severity, which is manifested at different phases of infection and demands different levels of care. Viral load, host innate-immune response to SARS-CoV-2, and comorbidities have a direct impact on the clinical outcomes of COVID-19 patients and determine the diverse disease trajectories. The initial SARS-CoV-2 penetrance and replication in the host causes death of infected cells, determining the viral response. SARS-CoV-2 replication in the host triggers the activation of host antiviral immune mechanisms, determining the inflammatory response. While a healthy immune response is essential to eliminate infected cells and prevent spread of the virus, a dysfunctional immune response can result in a cytokine storm and hyperinflammation, contributing to disease progression. Current therapies for COVID-19 target the virus and/or the host immune system and may be complicated in their efficacy by comorbidities. Here we review the evidence for use of two classes of anti-inflammatory drugs, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of COVID-19. We consider the clinical evidence regarding the timing and efficacy of their use, their potential limitations, current recommendations and the prospect of future studies by these and related therapies.

Can emapalumab be life saving for refractory, recurrent, and progressive cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and Janus kinase inhibitors.

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration.

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing major threat to global health and has posed significant challenges for the treatment of severely ill COVID-19 patients. Several studies have reported that cytokine storms are an important cause of disease deterioration and death in COVID-19 patients. Consequently, it is important to understand the specific pathophysiological processes underlying how cytokine storms promote the deterioration of COVID-19. Here, we outline the pathophysiological processes through which cytokine storms contribute to the deterioration of SARS-CoV-2 infection and describe the interaction between SARS-CoV-2 and the immune system, as well as the pathophysiology of immune response dysfunction that leads to acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS), and coagulation impairment. Treatments based on inhibiting cytokine storm-induced deterioration and occurrence are also described.

Posterior reversible encephalopathy syndrome (PRES) associated with COVID-19.

The novel human coronavirus disease (COVID-19) has been associated with vascular and thrombotic complications, some of which may result from endothelial dysfunction, including the posterior reversible encephalopathy syndrome (PRES). We report a case series of 8 patients with COVID-19 and PRES diagnosed at two academic medical centers between March and July of 2020. The clinical, laboratory and radiographic data, treatment, and short-term outcomes were retrospectively analyzed. The mean age was 57.9 ± 12 years, and 50% were women. Four patients had previous vascular comorbidities. All the patients suffered from severe pneumonia, requiring intensive care unit admission. Five patients were not hypertensive at presentation (all SBP < 127 mmHg). Neurologic symptoms included seizures in 7 patients; impaired consciousness in 5 patients; focal neurological signs in 3 patients; and visual disturbances in 1 patient. All patients underwent brain magnetic resonance imaging which indicated asymmetric T2 prolongation or diffusion changes (50%), extensive fronto-parieto-occipital involvement (25%), vascular irregularities (12.5%) and intracranial hemorrhage (25%). Four patients were treated with tocilizumab. Three patients were discharged without neurologic disability, 2 patients had persistent focal neurologic deficits and 2 expired. One patient's prognosis remains guarded. Together, these data support the relationship between PRES and endothelial dysfunction associated with severe COVID-19. In patients with severe COVID-19, PRES can be triggered by uncontrolled hypertension, or occur independently in the setting of systemic illness and certain medications. Like other infectious processes, critically ill patients with COVID-19 may be at greater risk of PRES because of impaired vasoreactivity or the use of novel agents like Tocilizumab.

Estrogen as a Safe Therapeutic Adjunct in Reducing the Inflammatory Storm in Trauma Hemorrhagic Shock Patients.

ABSTRACT: Trauma is a major cause of death and disability throughout the world. It is a leading cause of death with or without sepsis in about 50% of patients. Limited therapeutic options are available besides definitive care with a mortality benefit. Preclinical studies have demonstrated the mortality benefit of estrogen in trauma hemorrhagic shock (THS). Based on encouraging results from preclinical studies, we hypothesized that early administration of estrogen in male THS patients may reduce the inflammatory storm, prevent sepsis-associated problems, and subsequently reduce mortality. The authors studied the safety of early administration of estrogen as a therapeutic adjunct in the emergency department (ED) and its effects on the inflammatory storm, prevention of sepsis, and mortality during the intensive care unit stay. Forty THS patients were recruited. THS patients were divided into experimental and placebo control groups based on the estrogen administration in the ED. Serum levels of cytokines and immune cells were measured at different time points on days 0, 3, 7, and 14 in both groups of THS patients. The experimental group received intravenous estrogen (25 mg) at a single time point in the ED beside standard of care as per advanced trauma life support guidelines. Patients did not develop any major or minor adverse events and showed favorable clinical outcomes in the experimental group. The levels of T regulatory cells, monocytes, and systemic cytokines significantly reduced and showed a balanced inflammatory response in THS patients who received estrogen.In conclusion, this preliminary study showed that intravenous estrogen therapy is safe and reduced the inflammatory insult due to trauma hemorrhagic shock. It may protect THS patients from sepsis-associated complications. Future clinical trials are required to study the efficacy and mechanistic pathway.

Coronavirus Disease 19 from the Perspective of Ageing with Focus on Nutritional Status and Nutrition Management-A Narrative Review.

The novel severe acute respiratory syndrome coronavirus (COVID-19) has hit older adults harder due to a combination of age-related immunological and metabolic alterations. The aim of this review was to analyze the COVID-19 literature with respect to nutritional status and nutrition management in older adults. No studies only on people aged 65+ years were found, and documentation on those 80+ was rare. Age was found to be strongly associated with worse outcomes, and with poor nutritional status. Prevalence of malnutrition was high among severely and critically ill patients. The studies found a need for nutrition screening and management, and for nutrition support as part of follow-up after a hospital stay. Most tested screening tools showed high sensitivity in identifying nutritional risk, but none were recognized as best for screening older adults with COVID-19. For diagnosing malnutrition, the Global Leadership Initiative on Malnutrition (GLIM) criteria are recommended but were not used in the studies found. Documentation of olfactory and gustatory dysfunction in relation to nutritional status is missing in older adults. Other COVID-19-associated factors with a possible impact on nutritional status are poor appetite and gastrointestinal symptoms. Vitamin D is the nutrient that has attracted the most interest. However, evidence for supplementation of COVID-19 patients is still limited and inconclusive.

Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy.

OBJECTIVE: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS: Narrative literature review. RESULTS: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.

A possible role for ST2 as prognostic biomarker for COVID-19.

COVID-19 is a pandemic illness caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). It has been estimated that 80% of subject infected are asymptomatic or have mild to moderate symptoms. Differently, in severe cases of COVID-19, cytokine storm, acute respiratory distress syndrome (ARDS), severe systemic inflammatory response and cardiovascular diseases were observed Even if all molecular mechanisms leading to cardiovascular dysfunction in COVID-19 patients remain to be clarified, the evaluation of biomarkers of cardiac injury, stress and inflammation proved to be an excellent tool to identify the COVID-19 patients with worse outcome. However, the number of biomarkers used to manage COVID-19 patients is expected to increase with the increasing knowledge of the pathophysiology of the disease. It is our view that soluble suppressor of tumorigenicity 2 (sST2) can be used as biomarker in COVID-19. sST2 is routinely used as prognostic biomarker in patients with HF. Moreover, high circulating levels of sST2 have also been found in subjects with ARDS, pulmonary fibrosis and sepsis. Keeping in mind these considerations, in this review the possible mechanisms through which the SARS-CoV2 infection could damage the cardiovascular system were summarized and the possible role of sST2 in COVID-19 patients with CVD was discussed.

Systematic Review and Meta-analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes.

Acute lymphoblastic leukemia (ALL) typically responds better when treated with multiagent chemotherapy in the pediatric and young adolescent populations. Treatment of relapsed/refractory (RR) ALL remains a challenge. Even after stem-cell transplantation and intensive chemotherapy, the prognosis of RR-ALL remains grave. The advent of chimeric antigen receptors has demonstrated promising results in RR-ALL. Chimeric antigen receptor-modified T cells (CAR-T) and engineered T cells are used to target cancer cells. In 2017, the US Food and Drug Administration approved CD19-specific CAR-T (tisagenlecleucel) therapy for RR-B-cell ALL in patients under 25 years old. In this systematic review, we discuss the efficacy and safety of CD19-specific CAR-T therapy in RR-B-cell ALL in the pediatric and young adult population. We searched the PubMed, Embase, Web of Science, Cochrane Library, and clinical trials databases. A total of 448 patients received a CD19-specific CAR-T product, and 446 patients had evaluable data. The age range was 0 to 30 years. The incidence rate of complete remission was 82%. The cumulative incidence of relapse after CD19-specific CAR-T therapy is 36%. Similarly, the incidence rate of grade 3 or higher adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections, and cytokine release syndrome were 38%, 23%, 18%, 29%, and 19%, respectively. Our subgroup analysis shows the incidence rate of minimal residual negative complete remission was 69% with the CD28z costimulatory domain, 81% with the 4-1BB domain, and 77% with fourth-generation CD19-specific CAR-T therapy.