Cytokine release syndrome in severe COVID-19 Moore, John B; June, Carl H
Science (American Association for the Advancement of Science),
05/2020, Letnik:
368, Številka:
6490
Journal Article
Recenzirano
Odprti dostop
Lessons from arthritis and cell therapy in cancer patients point to therapy for severe disease
In December 2019, a new strain of coronavirus, severe acute respiratory syndrome–coronavirus 2 ...(SARS-CoV-2), was recognized to have emerged in Wuhan, China. Along with SARS-CoV and Middle East respiratory syndrome–coronavirus (MERS-CoV), SARS-CoV-2 is the third coronavirus to cause severe respiratory illness in humans, called coronavirus disease 2019 (COVID-19). This was recognized as a pandemic by the World Health Organization (WHO) in March 2020 and has had considerable global economic and health impacts. Although the situation is rapidly evolving, severe disease manifested by fever and pneumonia, leading to acute respiratory distress syndrome (ARDS), has been described in up to 20% of COVID-19 cases. This is reminiscent of cytokine release syndrome (CRS)–induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. Given this experience, urgently needed therapeutics based on suppressing CRS, such as tocilizumab, have entered clinical trials to treat COVID-19.
Abstract Background Fibrinolysis is a physiologic process to maintain microvascular patency by breaking down excessive fibrin clot. Hyperfibrinolysis (HF) is associated with a doubling of mortality. ...Fibrinolysis shutdown (SD), an acute impairment of fibrinolysis, has been recognized as a risk factor for increased mortality. The purpose of this study was to assess the incidence and outcomes of fibrinolysis phenotypes in two urban trauma centers. Study Design Injured patients admitted 2010-2013, who were ≥18 years of age, had an injury severity score (ISS) >15 were included in the analysis. Admission fibrinolysis phenotypes were determined by the clot lysis at 30 minutes (LY30): SD ≤0.8%, physiologic 0.9-2.9%, HF ≥3%. Logistic regression was used to adjust for age, arrival blood pressure, ISS, mechanism, and facility. Results 2540 patients met inclusion. Median age was 39(IQR 26-55) and median ISS was 25(IQR 20-33) with a mortality rate of 21%. Fibrinolysis shutdown was the most common phenotype (46%) followed by physiologic (36%) and hyperfibrinolysis(18%). HF was associated with the highest death rate (34%), followed by SD(22%), and physiologic (14%, p<0.001). The risk of mortality remained increased for HF(OR=3.3, 95%C: 2.4-4.6, p<0.0001) and SD(OR 1.6 95%CI 1.3-2.1, p=0.0003) compared to physiologic when adjusting for age, ISS, mechanism, head injury, and blood pressure (AUROC=0.82, 95% CI 0.80-0.84). Conclusions Fibrinolysis SD is the most common phenotype upon admission and is associated with increased mortality. Moreover, these data provide additional evidence of distinct phenotypes of coagulation impairment and that individualized hemostatic therapy may be required.
Hemorrhage remains the leading cause of death in trauma patients. Proximal aortic occlusion, usually performed by direct aortic cross-clamping via thoracotomy, can provide temporary hemodynamic ...stability, permitting definitive injury repair. Resuscitative endovascular balloon occlusion of the aorta (REBOA) uses a minimally invasive, transfemoral balloon catheter, which is rapidly inserted retrograde and inflated for aortic occlusion, and may control inflow and allow time for hemostasis. We compared resuscitative thoracotomy with aortic cross-clamping (RT) with REBOA in trauma patients in profound hemorrhagic shock.
Trauma registry data was used to compare all patients undergoing RT or REBOA during an 18-month period from two Level 1 trauma centers.
There was no difference between RT (n = 72) and REBOA groups (n = 24) in terms of demographics, mechanism of injury, or Injury Severity Scores (ISSs). There was no difference in chest and abdominal Abbreviated Injury Scale (AIS) scores between the groups. However, the RT patients had lower extremity AIS score as compared with REBOA patients (1.5 0-3 vs. 4 3-4, p < 0.001). Of the 72 RT patients, 45 (62.5%) died in the emergency department, 6 (8.3%) died in the operating room, and 14 (19.4%) died in the intensive care unit. Of the 24 REBOA patients, 4 (16.6%) died in the emergency department, 3 (12.5%) died in the operating room, and 8 (33.3%) died in the intensive care unit. In comparing location of death between the RT and REBOA groups, there were a significantly higher number of deaths in the emergency department among the RT patients as compared with the REBOA patients (62.5% vs. 16.7%, p < 0.001). REBOA had fewer early deaths and improved overall survival as compared with RT (37.5% vs. 9.7%, p = 0.003).
REBOA is feasible and controls noncompressible truncal hemorrhage in trauma patients in profound shock. Patients undergoing REBOA have improved overall survival and fewer early deaths as compared with patients undergoing RT.
Therapeutic study, level IV.
Noncompressible truncal hemorrhage is a leading cause of potentially preventable death in trauma and acute care surgery patients. These patients are at high risk of exsanguination before potentially ...life-saving surgical intervention may be performed. Temporary aortic occlusion is an effective means of augmenting systolic blood pressure and perfusion of the heart and brain in these patients. Aortic occlusion temporarily controls distal bleeding until permanent hemostasis can be achieved. The traditional method for temporary aortic occlusion is via resuscitative thoracotomy with cross clamping of the descending aorta. While effective, resuscitative thoracotomy is highly invasive and may worsen blood loss, hypothermia, and coagulopathy by opening an otherwise uninjured body cavity. Resuscitative endovascular balloon occlusion of the aorta (REBOA) achieves temporary aortic occlusion using an occlusive balloon catheter that is introduced into the aorta via endovascular access of the common femoral artery. For this reason it is thought that REBOA could provide a less-invasive method for temporary aortic occlusion. Our purpose is to describe our experience with the implementation of REBOA at our Level 1 trauma center.
A retrospective case series describing all cases of REBOA performed at a prominent level 1 trauma center between October 2011 and September 2015. The study inclusion criteria were any patient that received a REBOA procedure in the acute phases after injury. There were no exclusion criteria. Data were collected from electronic medical records and the hospital's trauma registry.
A total of 31 patients underwent REBOA during the study period. The median age of REBOA patients was 47 (interquartile range IQR = 27 to 63) and 77% were male. A majority (87%) of patients sustained blunt trauma. The median injury severity score was 34 (IQR = 22 to 42). The overall survival rate was 32% but varied greatly between subgroups. Balloon inflation resulted in a median increase in systolic blood pressure of 55-mm Hg (IQR 33 to 60), in cases where the data were available (n = 20). A return to spontaneous circulation was noted in 60% of patients who had arrested before REBOA (n = 10). Overall, early death by hemorrhage was 28% with only 2 deaths in the emergency department before reaching the operating room.
REBOA is an effective method for achieving temporary aortic occlusion in trauma patients with noncompressible truncal hemorrhage. Balloon inflation correlated with increased blood pressure and temporary hemorrhage control in a vast majority of patients.
Mild traumatic brain injury (mTBI) results from a transfer of mechanical energy into the brain from traumatic events such as rapid acceleration/deceleration, a direct impact to the head, or an ...explosive blast. Transfer of energy into the brain can cause structural, physiological, and/or functional changes in the brain that may yield neurological, cognitive, and behavioral symptoms that can be long-lasting. Because mTBI can cause these symptoms in the absence of positive neuroimaging findings, its diagnosis can be subjective and often is based on self-reported neurological symptoms. Further, proper diagnosis can be influenced by the motivation to conceal or embellish signs and/or an inability of the patient to notice subtle dysfunctions or alterations of consciousness. Therefore, appropriate diagnosis of mTBI would benefit from objective indicators of injury. Concussion and mTBI are often used interchangeably, with concussion being primarily used in sport medicine, whereas mTBI is used in reference to traumatic injury. This review provides a critical assessment of the status of current biomarkers for the diagnosis of human mTBI. We review the status of biomarkers that have been tested in TBI patients with injuries classified as mild, and introduce a new concept for the discovery of biomarkers (termed symptophenotypes) to predict common and unique symptoms of concussion. Finally, we discuss the need for biomarker/biomarker signatures that can detect mTBI in the context of polytrauma, and to assess the consequences of repeated injury on the development of secondary injury syndrome, prolongation of post-concussion symptoms, and chronic traumatic encephalopathy.
The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well ...defined. We showed that
Nlrx1
−/−
mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation,
Nlrx1
−/−
mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically,
Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.
► NLRX1 attenuates IFN induction by preventing the interaction between RIG-I and MAVS ► NLRX1 functions as a negative regulator of IFN-I and IL-6 during influenza infection ► NLRX1 attenuates inflammation by intersecting the TRAF6 pathway to affect NF-κB
The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent ...advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.
Adult hippocampal neurogenesis has been shown to be required for certain types of cognitive function. For example, studies have shown that these neurons are critical for pattern separation, the ...ability to store similar experiences as distinct memories. Although traumatic brain injury (TBI) has been shown to cause the loss of newborn hippocampal neurons, the signaling pathway(s) that triggers their death is unknown. Endoplasmic reticulum (ER) stress activates the PERK-eIF2α pathway that acts to restore ER function and improve cell survival. However, unresolved/intense ER stress activates C/EBP homologous protein (CHOP), leading to cell death. We show that TBI causes the death of hippocampal newborn neurons via CHOP. Using CHOP KO mice, we show that loss of CHOP markedly reduces newborn neuron loss after TBI. Injured CHOP mice performed significantly better in a context fear discrimination task compared with injured wild-type mice. In contrast, the PERK inhibitor GSK2606414 exacerbated doublecortin cell loss and worsened contextual discrimination. Administration of guanabenz (which reduces ER stress) to injured male rats reduced the loss of newborn neurons and improved one-trial contextual fear memory. Interestingly, we also found that the surviving newborn neurons in brain-injured animals had dendritic loss, which was not observed in injured CHOP KO mice or in animals treated with guanabenz. These results indicate that ER stress plays a key role in the death of newborn neurons after TBI. Further, these findings indicate that ER stress can alter dendritic arbors, suggesting a role for ER stress in neuroplasticity and dendritic pathologies.
The hippocampus, a structure in the temporal lobe, is critical for learning and memory. The hippocampus is one of only two areas in which neurons are generated in the adult brain. These newborn neurons are required for certain types of memory, and are particularly vulnerable to traumatic brain injury (TBI). However, the mechanism(s) that causes the loss of these cells after TBI is poorly understood. We show that endoplasmic reticulum (ER) stress pathways are activated in newborn neurons after TBI, and that manipulation of the CHOP cascade improves newborn neuron survival and cognitive outcome. These results suggest that treatments that prevent/resolve ER stress may be beneficial in treating TBI-triggered memory dysfunction.
The survival and function of brain cells requires uninterrupted ATP synthesis. Different brain structures subserve distinct neurological functions, and therefore have different energy ...production/consumption requirements. Typically, mitochondrial function is assessed following their isolation from relatively large amounts of starting tissue, making it difficult to ascertain energy production/failure in small anatomical locations. In order to overcome this limitation, we have developed and optimized a method to measure mitochondrial function in brain tissue biopsy punches excised from anatomically defined brain structures, including white matter tracts. We describe the procedures for maintaining tissue viability prior to performing the biopsy punches, as well as provide guidance for optimizing punch size and the drug doses needed to assess various aspects of mitochondrial respiration. We demonstrate that our method can be used to measure mitochondrial respiration in anatomically defined subfields within the rat hippocampus. Using this method, we present experimental results which show that a mild traumatic brain injury (mTBI, often referred to as concussion) causes differential mitochondrial responses within these hippocampal subfields and the corpus callosum, novel findings that would have been difficult to obtain using traditional mitochondrial isolation methods. Our method is easy to implement and will be of interest to researchers working in the field of brain bioenergetics and brain diseases.
Vascular complications from resuscitative endovascular balloon occlusion of the aorta (REBOA) have been reported in as high as 13% with some patients requiring lower-extremity amputation. We sought ...to review our institution series of REBOA and assess our vascular complications.
Retrospective review of all patients undergoing REBOA from October 2011 through July 2016. Data were gathered from the Memorial Hermann Trauma Registry and the hospital electronic medical records. Operative details and vascular injuries from arterial access for REBOA insertion were recorded.
Forty-eight patients underwent REBOA during our study period. Thirty-eight had the 14 Fr. system placed and 10 had the 7 Fr. system placed. Of the 24 surviving the removal of the 14 Fr. sheath, 19 had primary repair of the arteriotomy without vascular complication. The other five required additional vascular procedures to repair arteriotomy with no lower-extremity amputations. There were no vascular complications of sheath removal with the 7 Fr. system, with no amputations.
Implementation of REBOA can be done safely without increased risk of vascular access complications or limb loss. The 14 Fr. system will more likely require further vascular procedures to address the access site, whereas the 7 Fr. system will not.
Therapeutic/care management, level II.
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