Article

Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study)

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Abstract

Introduction Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as “cytokine storm”, and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical. Materials and methods This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients’ condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline. Results The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001). Conclusion Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism.

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... Given the mildly elevated ESR, suspected inflammatory immune response, and data that systemic steroids can suppress the systemic inflammatory response associated with COVID-19 infection, 13 the patient was prescribed oral methylprednisolone 4mg. The following day, he continued to deteriorate with increasing disc edema (23um increase in RNFL thickness to 176um), increasing macular edema (37um increase in CMT to 358um), and further darkening of his vision. ...
... The following day, however, he deteriorated further with increasing disc edema (RNFL of 214um OS) and some evidence of retinal whitening, suggesting a worsening of the arteriolar component of the vascular thrombosis. Given the disc edema which has the appearance of nonarteritic ischemic optic neuropathy (NAION), data which suggests high dose systemic steroids might be useful, 13 the history of elevated ESR, and the inflammatory immune response to COVID infection and presumably the vaccine as well, high dose IV methylprednisolone was recommended: 1 gram per day for three days. 13 The day after the first dose of IV methylprednisolone, there was clearly some improvement in some areas, and the patient also noted improvement with recovery of vision to 20/400. ...
... Given the disc edema which has the appearance of nonarteritic ischemic optic neuropathy (NAION), data which suggests high dose systemic steroids might be useful, 13 the history of elevated ESR, and the inflammatory immune response to COVID infection and presumably the vaccine as well, high dose IV methylprednisolone was recommended: 1 gram per day for three days. 13 The day after the first dose of IV methylprednisolone, there was clearly some improvement in some areas, and the patient also noted improvement with recovery of vision to 20/400. After a 3-day course of IV methylprednisolone and 4 days of apixaban, the patient's BCVA improved to 20/80, and we started him on an oral prednisone taper beginning at 80mg QD. ...
Article
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Purpose: To report a case of combined central retinal vein and artery occlusion that evolved into ischemic optic neuropathy following the Pfizer COVID-19 vaccination. Methods: Patient was followed with optical coherence tomography (OCT), fluorescein angiography, and Humphrey visual field. Results: Patient was able to recover vision from count fingers to 20/30 on a combination of aflibercept, steroidal and non-steroidal anti-inflammatories, a diuretic (acetazolamide), antiplatelet agents (aspirin and pentoxifylline), and an anticoagulant (apixaban). Conclusion: COVID-19 vaccination may be associated with a myriad of sight-threatening ocular thrombotic conditions, which may respond to a combination of anti-inflammatory and anticoagulant therapies.
... Moreover, SARS-CoV-2 is a cytopathic virus that causes pyroptosis, progressive systemic inflammation, low lymphocyte, and high neutrophil counts [12][13][14]. This systemic inflammation releases cytokines and chemokines by the immune cells, creating cytokine storms [15]. COVID-19 patient's report shows high levels of interleukins (such as IL-1 β, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-17), vascular endothelial growth factor, macrophage inflammatory proteins, tumor necrosis factor-alpha, other proinflammatory chemokines, cytokines, and signaling proteins presence in blood. ...
... In September 2020, the World Health Organization (WHO) had recommended the use of CSs (such as dexamethasone, hydrocortisone, or prednisone) to treat severe and critically ill COVID-19 patients [19]. However, the high availability of CSs is encouraging physicians to use these medicines randomly to treat COVID-19 patients, especially in complications like inflammation and cytokine storms [15]. Studies demonstrate that inappropriate CSs dose increases the risk of developing thrombosis and venous thromboembolism (VTE) in COVID-19 patients. ...
... Studies demonstrate that inappropriate CSs dose increases the risk of developing thrombosis and venous thromboembolism (VTE) in COVID-19 patients. Additionally, CSs therapy can cause various moderate and longterm adverse effects, including increased insulin resistance, increased cardiovascular risk, the risk of bacterial infection, glucose metabolism disorder, increased risk of thrombotic and thromboembolic complications, super-infection, dermatological complications, complications in metabolism, musculoskeletal disease, nervous system, ophthalmic complications, reproductive system, and allergic reaction, etc. [15,[20][21][22][23][24]. The motive of this review is to analyze the result of CSs therapy on COVID-19 patients from different metaanalyses, cohorts, and case studies to understand the longterm effect of CS therapy on COVID-19 recovered patients. ...
Article
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Pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced COVID-19 implied the presence of excessive proinflammatory cytokines and chemokines in patients causing significant morbidity and mortality. To diminish systemic hyper inflammation, a few physicians and researchers have utilized corticosteroids. Corticosteroid implementation has increased after the publication of interim guidelines regarding corticosteroid use in COVID-19 patients by WHO, despite the remaining controversies regarding long-term side effects and disease progression capability of corticosteroids. In different studies, the implementation of corticosteroids on COVID-19 patients revealed controversial results, which require further intensive research. This review will present the current outcomes and possibilities of using corticosteroids to treat COVID-19 patients.
... was higher in Group 3 in the continuance of the treatment, this was not statistically different from the other groups (p > 0.05). There are single-center studies and reviews with limited numbers of patients with different results regarding the corticosteroid treatment modalities applied to COVID-19 patients in the literature (14,15,16,17). It can be indicated that the common features of these studies is stating the "need for more relevant studies", different doses of corticosteroids, and heterogeneous groups. ...
... In the study by Mareev et al conducted on 34 patients, the steroid group received methylprednisolone for 3 days at a dose of 1 g/ day and were maintained on dexamethasone at a dose of 8 mg/day, and this group was compared with the control group who did not receive steroids (15). The results of this study using a dose similar to that used in Group 3, were similar to the present study. ...
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Objectives: The aim of this study was to determine the efficacy of pulse steroid therapy administered to patients critically ill with COVID-19 progressing into severe pneumonia. Methods: A total of 600 patients included in this retrospective study were divided into three groups. Group 1 (control group): 200 patients who did not receive steroid treatment, Group 2: 200 patients who received dexamethasone 1x8 milligram (mg) or methylprednisolone 1x80 mg, Group 3: (pulse steroid therapy group): 200 patients who received 1 g methylprednisolone followed by 1x80 mg methylprednisolone. Demographic and laboratory data were recorded. Results: Mortality rates in groups 1, 2 and 3 were 77 %, 53.55 %, and 58.5 %, respectively. The ratios of intubated patients in groups 1, 2 and 3 were 70 %, 45.5 % and 56 %, respectively. The numbers of patients whose D‑dimer values were above 2,250 ng/mL (cut-off value for D-dimer in this study) in groups 2, 1 and 3 were 65, 107, and 105, respectively. Conclusion: Pulse steroid therapy does not shorten the duration of hospital stay, does not reduce the need for intubation and increases the risk of thrombosis by significantly increasing the level of D-dimer among patients critically and severely ill with COVID-19 (Tab. 4, Fig. 3, Ref. 20) Keywords: COVID-19, pulse steroid therapy, thrombosis, d-dimer, corticosteroid.
... Several observational studies assessing corticosteroid pulse versus low-dose corticosteroids for patients with Covid-19 have been reported, many with favorable results on clinical outcomes (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Main characteristics and results of these studies are available in Table 1. ...
... 64 Although high-dose glucocorticoid pulse therapy has a rapid anti-inflammatory effect, it also increases the neutrophil/lymphocyte ratio and D-dimer level, increasing the risk of thromboembolism. 65 For newly diagnosed diabetic patients, frequent use of glucocorticoids may exacerbate hyperglycemia. 66 Obata et al found that the bacterial infection rate (25%/13.1%, ...
Article
The recent outbreak of coronavirus disease 2019 (COVID-19) has become a global epidemic. Corticosteroids have been widely used in the treatment of severe acute respiratory syndrome (SARS), and the pathological findings seen in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are very similar to those observed in severe acute respiratory syndrome-related coronavirus (SARS-CoV) infection. However, the long-term use of corticosteroids (especially at high doses) is associated with potentially serious adverse events, particularly steroid-induced avascular necrosis of the femoral head (SANFH). In today's global outbreak, whether corticosteroid therapy should be used, the dosage and duration of treatment, and ways for the prevention, early detection, and timely intervention of SANFH are some important issues that need to be addressed. This review aims to provide a reference for health care providers in COVID-19 endemic countries and regions. Article focus: Hormones are a double-edged sword. This review aims to provide a reference for health care providers in coronavirus disease 2019 (COVID-19) endemic countries and regions, especially with respect to the pros and cons of corticosteroid use in the treatment of patients with COVID-19. Key messages: In today's global outbreak, whether corticosteroid therapy should be used, the dosage and duration of treatment, and ways for the prevention, early detection, and timely intervention of SANFH are some important issues that need to be addressed. Strengths and limitations: Since SARS was mainly prevalent in China at that time, many evidences in this paper came from the reports of Chinese scholars. There is a bias in the selection of data, which may ignore the differences in environment, race, living habits, medical level and so on. SANFH may be the result of multiple factors. Whether the virus itself is an independent risk factor for SANFH has not been confirmed. In this paper, through literature retrieval, some reference opinions on glucocorticoid usage, diagnosis and treatment of SANFH are given. However, due to the lack of large-scale research data support, it can not be used as the gold standard for the above problems.
... Разработка таких предикторов позволила бы проводить стратификацию риска, направить интервенционные исследования на пациентов с повышенным риском развития тяжёлого течения заболевания, оптимизировать распределение ограниченных человеческих и технических ресурсов в условиях продолжающейся пандемии. Более того, определение лабораторных параметров, позволяющих различать тяжелые и нетяжелые случаи, а также случаи с высоким или низким риском летального исхода, позволит значительно улучшить не только маршрутизацию пациентов, но и клинические протоколы лечения [3,4]. ...
Article
Purpose : to study the relationship of the indicators of the general blood test with the severity of the course of COVID-19 in hospitalized patients. Materials and methods: the study included 165 patients (92 men — 55.8%, and 73 women — 44.2%, the average age — 59.9 years) who were treated at the Moscow State University Medical Center in the period from April to June 2020 with a diagnosis of COVID-19. All patients underwent: general blood test, CRP, CT of the lungs. The severity of the clinical condition was assessed using the SHOCK-COVID and NEWS-2 scales. Results: a more severe clinical condition of patients and a greater severity of lung damage on admission were statistically significantly associated with a decrease in the number of red blood cells and hemoglobin, as well as with a greater width of the distribution of red blood cells (RDW-SD). The rate of erythrocyte sedimentation (ESR) was significantly associated with the clinical condition of patients evaluated by SHOCK-COVID (r=0.61, p<0.001) and the marker of CRP inflammation (r=0.55, p<0.001). An increase in the absolute number of neutrophils (N), a decrease in the absolute number of lymphocytes (L), and, as a result, an increase in the N/L ratio index was a marker of a more severe course of the disease. It was the N/L index that had the maximum correlation coefficient with the most commonly used marker of systemic inflammation - CRP (r=0.50, p<0.001). The decrease in the level of CRP by discharge was associated with a significant decrease in ESR (r=0.36, p<0.001), the index of the ratio of neutrophil and lymphocyte levels (N/L) (r=0.39, p<0.001), and an increase in the width of the distribution of red blood cells (RDW-SD r=0.25, p<0.01; RDW-CV r=0.57, p<0.001). Conclusions: the most informative indicators of the general blood test at admission to the hospital, allowing to assess the severity of the disease — the width of the distribution of red blood cells, the index of the ratio of neutrophils to lymphocytes and ESR.
... [64] In the absence of conclusive scientific evidence, the regular use of corticosteroids in COVID-19 patients with pneumonia or ARDS is not suggested by WHO unless indicated for other conditions, such as asthma, exacerbation of chronic obstructive pulmonary disease (COPD), or septic shock. [65,66] The majority of data on corticosteroid use in COVID-19 patients is based on observational research data so large scale randomized controlled trials are needed to understand the risks and benefits of corticosteroid use in these patients. ...
Article
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The coronavirus disease 2019 (COVID-19) pandemic caused by infection of the SARS-CoV-2 virus has affected millions of people in the world. The pathogenesis and clinical manifestations of COVID-19 disease are tightly influenced by the host immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In some condition, the immune response might be uncontrolled, giving rise to hyperinflammatory conditions marked by excessive release of proinflammatory cytokines (cytokine storms) in severe COVID-19 patients, which then can cause acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Furthermore, treatment using immunomodulator agents including immunostimulatory and immunosuppressive agents can be an option in achieving successful treatment. In this review, we discuss the pathogenesis of the disease, including host immune responses to SARS-CoV-2 virus infection, and immune mechanisms which contribute to the disease severity and death as well as several potential immunomodulatory agents which can be used in the management of hyperinflammatory syndrome of severe COVID-19.
... In a single-blinded randomized controlled trial from Iran that included 68 patients, the mean age of the patients was 55.8 ± 16.4 years [3]. In a single-center retrospective cohort study from Russia that included 34 patients, the median age was 59 years (interquartile range, 52-67 years) [9]. In our previous case series, which included seven patients, the median age was 69 years (range 41-77), similar to that of the surviving group in this study [4]. ...
Article
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Background: Corticosteroids have been reported to reduce the mortality rates in patients with coronavirus disease 2019 (COVID-19). Additionally, the role of high-dose methylprednisolone pulse therapy in reducing mortality in critically ill patients has also been documented. The purpose of this study is to identify patients with COVID-19 who are suitable for methylprednisolone pulse therapy. Methods: This was a retrospective study that included patients with COVID-19 receiving methylprednisolone pulse therapy (≥250 mg/day for 3 days) with subsequent tapering doses at our hospital between June 2020 and January 2021. We examined the differences in background clinical factors between the surviving group and the deceased group. Results: Out of 156 patients who received steroid therapy, 17 received methylprednisolone pulse therapy. Ten patients recovered (surviving group) and seven patients died (deceased group). The median age of the surviving and deceased groups was 64.5 years (range, 57-85) and 79 years (73-90), respectively, with a significant difference (p=0.004). Five of the deceased patients (71%) had developed serious complications associated with the cause of death, including pneumothorax, pneumomediastinum, COVID-19-associated pulmonary aspergillosis, cytomegalovirus infection, and bacteremia. On the other hand, out of the 10 survivors, only one elderly person had cytomegalovirus infection and the rest recovered without complications. Conclusion: Administration of methylprednisolone pulse therapy with subsequent tapering may be an effective treatment in patients with COVID-19 up to the age of early 70s; however, severe complications may be seen in elderly patients.
... The use of corticosteroids reduces the anti-inflammatory response to infection, reduces the need for oxygen and the need for ICU. However, methylprednisolone and dexamethasone do not prevent the negative effects and complications of the virus (avascular necrosis, psychosis, diabetes, delayed viral clearance) [4][5][6]. ...
Article
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ARS-CoV-2 causes predominantly lung disease, but by way of binding to the angiotensin-converting enzyme 2 (ACE2) receptors, it can attack key metabolic organs and may lead to alterations ofglucose metabolism.The aim of the study was to examine the effect of methylprednisolone compared withdexamethasone on the glycaemic control as well as the development of new-onset diabetes in patients whowere hospitalized due toCOVID-19 pneumonia.We reviewed the records of 203 consecutive patients who were hospitalized with a clinicalpresentation of COVID-19 pneumonia in the modular hospital at the University Clinic for InfectiousDiseases and Febrile Conditions in Skopje, from December 2020until May 2021.We identified 65 patients with diabetes (32,0%), 49 patients (75%) of whichwith pre-existingdiabetes, and 16 (25%) with newly diagnosed diabetes.Impaired glycoregulation was recorded in 19,2% of patients, of whom 5,5% did not receive anycorticosteroid-therapy, 22,4% were treated with methylprednisolone – pulse doses,and 21,4% were treatedwith dexamethasone. Patients with diabetes had a 1,9 times (CI 0,9-3,9) higher mortality rate than non-diabetic patients.We suggest that, if corticosteroid therapy is necessary during the treatment of COVID-19pneumonia, it is safer to administer dexamethasone than methylprednisolone, especially in patients whohave pre-existingdiabetes or are at risk ofdeveloping diabetes.Deterioration of glycoregulation and the need to replace oral antidiabetic therapy with insulin arecommon. New-onset diabetes often persists even after recovering from Covid-19. (22) (PDF) THE EFFECT OF METHYLPREDNISOLONE VERSUS DEXAMETHASONE IN INCREASING THE DIABETOGENIC EFFECT OF SARS-CoV-2 INFECTION AND THE DEVELOPMENT OF A NEW-ONSET DIABETES MELLITUS. Available from: https://www.researchgate.net/publication/360507690_THE_EFFECT_OF_METHYLPREDNISOLONE_VERSUS_DEXAMETHASONE_IN_INCREASING_THE_DIABETOGENIC_EFFECT_OF_SARS-CoV-2_INFECTION_AND_THE_DEVELOPMENT_OF_A_NEW-ONSET_DIABETES_MELLITUS [accessed Jul 08 2022].
... With respect to disease severity and clinical heterogeneity, we know that COVID-19 not only presents with cardiopulmonary symptoms ranging from mild to severe but, in a subgroup of patients, is also associated with systemic autoimmune inflammation as evidenced by elevated inflammatory markers (C-reactive protein, ferritin, D-dimer, IL-1, IL-2, IL-6, IL-7, tumor necrosis factor α, granulocyte-macrophage colonystimulating factor, macrophage inflammatory protein 1-α; the so-called "cytokine storm") [12].This dysregulated systemic inflammation is thought to be a key contributor to the COVID-19-associated fatality rate and will typically lag behind active viral replication [13].In contrast to periods with high viral replication, it is both logical and evidence-based to anticipate that corticosteroids would be of benefit amongst this subset of patients in their course of clinically evident disease. For the better part of 6 decades we have understood that corticosteroids downregulate proinflammatory cytokine transcription, consequently preventing an over-extended cytokine response and accelerating the resolution of pulmonary and systemic inflammation [14,15]. ...
Article
The aim of this manuscript is to discuss the practice of antenatal corticosteroids administration for fetal maturation in severe acute respiratory syndrome coronavirus 2 positive pregnant women. Recent high-quality evidence supports the use of dexamethasone in the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Randomized disease outcome data have identified an association between disease stage and treatment outcome. In contrast to patients with more severe forms who benefit from dexamethasone, patients with mild disease do not appear to improve and may even be harmed by this treatment. Therefore, indiscriminate usage of fluorinated corticosteroids for fetal maturation, regardless of disease trajectory, is unadvisable. Obstetrical care needs to be adjusted during the COVID-19 pandemic with careful attention paid to candidate selection and risk stratification.
... Avoiding the migration of neutrophils is to avoid three catastrophes: 1) cytokine storm that leads the patient to respiratory failure and, consequently, orotracheal intubation; 2) development of autoantibodies by NETose and by activation of the complement system secondary to the formation of immune complexes; 3) immunoparalysis, a phase in which phagocytes lose the ability of phagocytosis to secrete IL-6 intensely; in an environment tending to tolerance [6] [7] [8]. ...
Article
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Based on Russian and the Middle East corticosteroids trials in MERS-CoV, we performed methylprednisolone pulse therapy (MPT), resulting in a clinical trial still without result. Our previous cohort (not compared n = 18) showed 76% of MPT patients did not progress to orotracheal intubation as MTP blocked the cytokine storm, a lower result compared to Tehran's study explained by performing MPT in any lung phase. The Middle East study had been carried out during the initial lung phase. We are in an international emergency. Considering previous protocols and clinical practice, we understand that MPT must be used in COVID-19, and the indication to avoid going to the hospital when the first symptoms appear should be changed urgently for the population with inflammatory comorbidities. This article aims to: 1) show the Iranian protocol to reduce deaths and intubations by COVID-19; 2) present a possible approach to the patient COVID-19 with methylpredni-solone pulse and strict criteria for orotracheal intubation to avoid hypoxemia; 3) highlight that there is already a protocol that can be an international guideline-based on the Iranian work for the treatment of COVID-19; and 4) argue that corticosteroids are not controversial, but their use in a period outside the best timing period makes it controversial; and 5) emphasise the urgency of modifying the current protocol that postpones the visit of patients to the hospital in case of symptoms, since late hospital evaluation has been catastrophic for a world population.
... p=0.04). 43 The authors suggested that therapy with high doses of GCS exerted a rapid anti-inflammatory effect, but also elevated NLR and D-dimer levels, increasing the risk of VTE. ...
Article
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Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), has been an important cause of sudden in-hospital death. Studies have shown that the immune/inflammatory response plays an important role in the pathogenesis of vascular disease, with representative markers in the blood including the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), systemic immune/inflammatory index (SII), etc. However, there is a variety of immune/inflammatory indicators. Moreover, most previous studies have been single-center investigations involving one or two indicators, with varying nature of cases, number of cases and study objectives, thereby making it difficult to reach consensus conclusions with good clinical guidelines. This article reviews the clinical value of immunoinflammatory indicators for VTE based on previous studies, including the diagnostic and prognostic capabilities. In conclusion, NLR provides promising predictive capability for the onset and prognosis of VTE and deserves extensive application in clinical practice. PLR also has certain diagnostic and prognostic value, but further studies are warranted to identify its reliability and stability. Monocytes, eosinophils and platelet-related indicators show some clinical association with VTE, although the predictive capabilities are mediocre. SII is of promising potential value for VTE and deserves further investigations. This review will provide new clues and valuable clinical guidance for the diagnosis and therapy of VTE.
... They concluded that pulse MPS exerted a rapid anti-inflammatory effect but increased the N/L ratio and the D-dimer level, which in turn increased the risk of thromboembolism. [26] On the contrary, a randomized study compared high dose MPS (≥250 mg/day) with standard dose (1-1.5 mg/kg/day) and concluded that the MPS pulse was associated with a higher mortality (P < 0.001) and an increased risk of mechanical ventilation (P = 0.001). The risk of developing a severe ARDS was similar between groups. ...
Article
Background: India recently encountered fierce second wave of coronavirus disease (COVID-19), and scarcity of novel medications added to the management challenges. Various studies have highlighted the effectiveness of tocilizumab and high-dose steroids in severe COVIDs, but none has compared their efficacy. Materials and methods: This retrospective multi-centric analysis compares intravenous tocilizumab (8 mg/kg/day, maximum dose-800 mg), and intravenous Methylprednisolone Pulse (MPS-1 g/day for 3 days) in severe COVID-19. Both the groups had additionally received the standard of care COVID treatment as per protocol. Outcomes were assessed at 30 days. Results: A total of 336 patients, with 249 receiving MPS and 87 receiving tocilizumab were compared. Majority of these were males (72.9%) with a mean age of 57.4 ± 13.6 years. Diabetes was the most common comorbidity. Patients in both groups had comparable age distribution, comorbidities, presenting mean-arterial pressures, d-Dimer levels, serum ferritin, serum leukocyte-dehydrogenase, and procalcitonin. However, the tocilizumab group had more number of males, higher incidence of coronary artery disease, more tachypnea and leukocytosis, more number of patients with severe acute respiratory disease syndrome (PaO2/FiO2 ratio <100), and higher C-reactive protein levels at presentation. Both groups had comparable adverse events' profile. Tocilizumab group had lesser requirement of invasive ventilation than MPS group (17% vs. 29%, P = 0.038), however mortality at the end of 30 days follow-up was similar (36% vs. 34% respectively; P = 0.678). Conclusions: Tocilizumab decreased the need for invasive ventilation in severe COVID-19; however, it did not translate to improved survival. A planned prospective randomized study is recommended in this respect to compare their efficacy.
... A lower 28-day mortality rate and a shorter hospitalization stay was significantly demonstrated in the treatment subgroup of patients that were in need for oxygen support or mechanical ventilation [96]. Interestingly, the combination of methylprednisolone and dexamethasone therapy increased the risk of thromboembolism, despite achieving a rapid anti-inflammatory effect [97]. As for the hyper-inflammatory disease phase, biological treatment was in need in order to neutralize the effect of elevated plasma pro-inflammatory cytokines including interleukins (IL-2, 6, 7, 10, gCSF, INFγ, TNFα). ...
Article
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The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.
... Cathepsin G increased platelet surface expression of P-selectin (an activation-dependent neutrophil binding site), the glycoprotein IIb/IIIa complex (fibrinogen receptor), and glycoprotein IV (thrombospondin receptor), and decreased surface expression of glycoprotein Ib (von Willebrand factor) ( Figure 5) [86][87][88]. Serotonin has a mitogenic effect on megakaryocytopoiesis. This effect may be mediated via the 5-HT2 receptor, which is known to be coupled to G protein. ...
Article
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Introduction: There is a significant imbalance in the generation of NAD/NADH+ (niacin), which affects chemical reactions in the intracellular environment in COVID-19 and yellow fever. From tryptophan and its metabolic pathways and oxidative stress, the process of understanding SARS-CoV-2 infection becomes more concrete, as the infection seems to interfere in these metabolic pathways, in addition to the paradoxical role of kynurenine that causes inflammation by blocking the BH4 pathway. Understanding metabolic changes in the elderly, people with type 2 diabetes (DM2), obese people or other chronic diseases with an inflammatory profile is to understand the severity of COVID-19 to improve clinical management. Hypothesis: SARS-CoV-2 may control the human immune response by acting on Furins and Cathepsins or triggering significant hypoxia; promotes the internalization of ACE-2, resulting in low absorption of some amino acids in the intestine, triggering immune suppression and metabolic syndrome (MS). Results: From overweight people to people with higher Body Mass Index (BMI) or insulin resistance, there is a tendency to hyperthermia by thermogenesis due to the consumption of serotonin (5-HT) and norepinephrine (NOR) in fat cells, triggering an increased inflammatory state and cell damage. It is typical of critically ill patients with COVID-19 who have been treated with antipyretic and antimicrobial drugs at elevated temperatures, but the correct treatment is an insulin pump. It is not fever; it is hyperthermia. The state of inflammation is related to the Kynurenine/BH4 imbalance. Objectives: This article aims to raise doubts to generate more discussions and bring more substrates to improve the patient's COVID-19. The primary pathophysiology of COVID-1 may be tryptophan syndrome due to kynurenine/BH4 imbalance and the maintenance of the hypoxic environment that causes immunosuppression, tolerance and inflammation due to oxidative stress. A signature of innate immunity, oxidative stress, and tryptophan pathway imbalance.
... Mareev et al used an even higher dose. 15 They used 1000 mg of methylprednisolone for 3 days followed by 8 mg of dexamethasone for another 3-5 days in 17 patients with severe COVID-19 pneumonia. Results showed marked decrease in inflammatory markers. ...
Article
Pulse steroids therapy is widely used to treat flare-ups of autoimmune diseases, such as systemic lupus erythematosus. The main assumption is that severe inflammation caused by an autoimmune disease must be aggressively quelled before it causes further damage. We present a series of 9 cases that explore the use of high-dose pulse steroids in hypoxemic respiratory failure. We used high-dose steroids to alter the outcome of some patients, using commonly accepted protocols such as 6 mg of dexamethasone via IV, baricitinib, and tocilizumab. The outcome of each case is discussed. The patients were treated with 500 mg of high-dose methylprednisolone via IV for 3 days, followed by 250 mg via IV for 3 days; followed by 12 or 6 mg of dexamethasone was administered daily by mouth or IV. A retrospective review of patients who received a computerized tomography pulmonary angiogram showed that these patients had organizing pneumonia features. Eight out of nine cases had a favorable outcome.
... Many patients hospitalized for COVID-19 also face cardiovascular problems, with unexpectedly high rates of blood clots, due to inflammatory reactions to this infection that lead to stroke, heart attack, lung blockages, neurological problems, and other complications with serious and lasting effects (82)(83)(84)(85)(86). ...
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In December 2019, a novel coronavirus, COVID-19, was discovered to be the causal agent of a severe respiratory infection named SARS-CoV-2, and it has since been recognized worldwide as a pandemic. There are still numerous doubts concerning its pathogenesis and particularly the underlying causes of the various clinical courses, ranging from severe manifestations to asymptomatic forms, including acute respiratory distress syndrome. The major factor responsible for acute respiratory distress syndrome is the so-called “cytokine storm,” which is an aberrant response from the host immune system that induces an exaggerated release of proinflammatory cytokines/chemokines. In this review, we will discuss the role of cytokine storm in COVID-19 and potential treatments with which counteract this aberrant response, which may be valuable in the clinical translation.
Article
Objective: to evaluate the effectiveness and safety of anticoagulant and glucocorticosteroid therapy in patients with COVID-19, to determine step-by-step solutions in the prescription of drug therapy at the inpatient stage. Materials and methods. We performed two randomized continuous prospective comparative studies including 1,801 patients diagnosed with COVID-19 pneumonia who were undergoing inpatient treatment in November-December 2020 (1,004 patients) in Gomel Regional Clinical Hospital for the Disabled of World War II and in February 2021 (797 patients) in Gomel City Clinical Hospital No. 3. Results. The step-by-step strategy for treating patients with pneumonia associated with COVID-19 is to divide the patients into groups of high and moderate risks of adverse outcomes (based on the developed predictors) on the first day of hospitalization. In moderate-risk patients, the “protocol” therapy stabilizes the condition; in high-risk patients, it is not effective. Early preemptive anticoagulant therapy (ACT) and individual hormone therapy (prior to pulse therapy) may stabilize the condition of the patients, increase the survival rate from 82.1 % to 96.8 %, p = 0.0001. The additional steps are: targeted use of tocilizumab in the Somatic Department before the Intensive Care Department (70 % survival, p = 0.031), oxygen therapy, pronposition, catheterization of patients, use of the domestic hepatoprotector, membrane-stabilizing antiischemic drug “Thiotriazoline” in patients with high blood lactate levels (lactate dehydrogenase (LDH)), which stabilizes metabolic processes in the affected organs (in dynamics by 342.7 ± 92.8 units/l for 5 days compared to the control group, p=0.0001). When the patient’s condition gets stabilized, the use of respiratory and physical rehabilitation are the final steps of the recovery strategy at the inpatient stage. Conclusion . Therapeutic anticoagulant and individual glucocorticosteroid therapy in combination with oxygen therapy, the use of thiotriazoline in some COVID-19 patients being at a high risk of adverse outcomes have led to an increased survival rate — from 82.1 % to 96.8 % at the hospital stage, p = 0.0001.
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Aim . To study the dynamics and patterns of medical publications in Russian, made during the year from February 2020, in order to assess the completeness of data on the etiology, pathogenesis, prevention and treatment of coronavirus disease 2019 (COVID-19), as well as rehabilitation and healthcare management during a pandemic. Material and methods . We searched for publications using the Pubmed database and the Elpub platform. The search was carried out using the following requests: “COVID-19” and “SARS-CoV-2”. Thematic sections were allocated according to source type, specialization and research design. The publications were classified according to keywords and meaning. The publication time was estimated by the date it was accepted for publication. Values were assessed using numerical values and graphs. Results . One hundred fifteen (28,5%) publications presented data from original research, while 288 (71,5%) — reflected the results of already existing sources. An increase in proportion of primary sources with the pandemic spread was established. There were following most common study designs: case series — 87 (77,7%); case reports — 15 (13,4%); cohort studies — 8 (7,1%); randomized clinical trials — 2 (1,8%). By topic, the largest number of articles are devoted to the diagnosis and treatment of COVID-19 — 250 (62%), epidemiology — 36 (8,9%), etiology and pathogenesis — 36 (8,9%), healthcare management — 30 (7,4%), “Other” — 20 (4,9%), and policy papers from expert communities — 13 (3,25%). The smallest number of publications is directly related to cardiology and prevention, including immunoprophylaxis — 12 (2,9%), as well as rehabilitation — 6 (1,5%). Conclusion . The dynamics and patterns of publications on COVID-19 in Russian are generally in line with global trends and reflect the pandemic characteristics in Russia. Due to disease novelty, there is currently a knowledge gap in the treatment, prevention and long-term outcomes of COVID-19. In the future, studies with a higher evidence level are needed on possible methods of treatment, prevention, including cardiology issues and vaccination, as well as rehabilitation.
Article
Since the outbreak of COVID-19, research has been focused on establishing effective treatments, especially for patients with severe pneumonia and hyperinflammation. The role and dose of corticosteroids remain obscure. We evaluated 58 patients with severe COVID-19 during two periods. 24 patients who received methylprednisolone pulses (250 mg/day intravenously for 3 days) were compared with 34 patients treated according to the standard dexamethasone protocol of 6 mg/day. Among non-intubated patients, the duration of hospitalization was shorter for those who received methylprednisolone pulses (9.5 vs 13.5, p<0.001). In a subgroup analysis of patients who required intubation, those treated with the dexamethasone protocol demonstrated a relative risk=1.89 (p=0.09) for dying, in contrast to the other group which showed a tendency towards extubation and discharge from the hospital. A 'delayed' need for intubation was also observed (6 vs 2 days, p=0.06). Treatment with methylprednisolone pulses significantly reduced hospitalization time. Although there was no statistically significant influence on the necessity for intubation, methylprednisolone pulses revealed a tendency to delay intubation and hospital discharges. This treatment could benefit patients in the hyperinflammatory phase of the disease.
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Background: C-reactive protein (CRP) is a key laboratory biomarker for anti-inflammatory treatment initiation. Unfortunately, biochemical blood analyzers are not always easily accessible in medical institutions located far from major regional health facilities. Aim: To develop an approach for inflammatory status estimation based on blood test results in patients with COVID-19 in cases with limited laboratory equipment availability. Methods: The present retrospective study included 423 patients (male 54.6%; female 45.4%; mean age 59.1 years) receiving hospital treatment due to COVID-19 in Medical Research and Educational Center of Lomonosov Moscow State University from April 21st to June 13th 2020. All patients donated blood for full biochemistry and hematology testing and underwent chest computer tomography (CT). Results: CRP levels (60 mg/L) qualitative estimation model was developed based on hematologic test results. It included erythrocyte sedimentation rate and neutrophils to lymphocytes ratio. According to the results of Receiver Operating Characteristic (ROC) analysis present model was characterized by sensitivity of 70.2%, specificity of 74.6%, and area under the ROC-curve of 0.781. Comparison of key clinical parameters reflecting COVID-19 severity, such as length of hospitalization, lung damage at CT (hospital admission and discharge), revealed statistically significant difference between groups with routinely measured CRP levels 60 mg/L and 60 mg/L for all the above-mentioned parameters (p 0.05). These differences remained significant when measured CRP levels were substituted with estimated CRP values, indicating interchangeability of these approaches to CRP levels determination, regarding clinically important parameters. Conclusions: Presented model for inflammatory status estimation based on hematologic test results might be used to overcome clinical challenges in cases with limited laboratory equipment availability.
Article
Objectives: The results of the RECOVERY trial identified dexamethasone as the first pharmacological therapy that reduces mortality in patients with COVID-19. The aim of this paper is to conduct a systematic literature review on safety and efficacy of pulse glucocorticoid therapy for Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV), Middle East Respiratory Syndrome (MERS)-CoV or SARS-CoV-2 infections and describe a case-series of COVID-19 patients treated with off-label pulse doses of methylprednisolone. Methods: We performed a systematic literature review on safety and efficacy of pulse therapy for betacoronaviridae infections as described in the protocol registered on PROSPERO (CRD42020190183). All consecutive patients admitted to Arcispedale Santa Maria Nuova di Reggio Emilia or Guastalla Hospital with COVID-19 between March 1st and April 30th, 2020 and treated with methylprednisolone 1 gram/day for at least three days were included in the case series. A retrospective review of available computed tomography (CT) scan and chest x-ray was performed independently by two radiologists blinded to clinical data, and discordances were resolved by consensus. Results: Twenty papers were included for SARS, but only two were comparative and were included in the primary endpoint analysis. Likewise, eleven papers were included for COVID-19, four of which were comparative and were considered for the primary outcome analysis. Included studies for both SARS and COVID-19 are mostly retrospective and highly heterogeneous, with lethality ranging from 0% to 100% and ICU admission rate ranging from 9% to 100%. Fourteen patients were included in our case series, 7 males and 7 females. Conclusions: No randomised controlled trial is available yet for corticosteroids pulse-therapy defined as at least ≥500mg/day methylprednisolone in patients with emerging coronavirus pneumonia. Lethality among our cohort is high (4/14), but this finding should be interpreted with caution due to the fact that in our setting pulse-steroids were used in patients not eligible for other treatments because of comorbidities or as rescue therapy. The incidence of steroid-related adverse events seems low in our cohort. The quality of the evidence on glucocorticoid pulse-therapy in SARS, MERS and COVID-19 is poor. Randomised controlled trials are greatly needed.
Article
Purpose: Although the use of steroids in the management of COVID-19 has been addressed by a few systematic review and meta-analysis, however, they also used data from "SARS-CoV" and "MERS-CoV." Again, most of these studies addressed only one severity category of patients or addressed only one efficacy endpoint (mortality). In this context, we conducted this meta-analysis to evaluate the efficacy and safety of steroid therapy among all severity categories of patients with COVID-19 (mild to moderate and severe to critical category) in terms of "mortality," "requirement of mechanical ventilation," "requirement of ICU" and clinical cure parameters. Methods: 11 databases were screened. Only randomized controlled trials (RCTs) or high quality (on the basis of risk of bias analysis) comparative-observational studies were included in the analysis. RevMan5.3 was used for the meta-analysis. Results: A total of 15 studies (3 RCT and 12 comparative-observational studies) were included. In the mechanically-ventilated COVID-19 population, treatment with dexamethasone showed significant protection against mortality (single study). Among severe and critically ill combined population, steroid administration was significantly associated with lowered mortality (risk ratio [RR] 0.83 [0.76-0.910]), lowered requirement of mechanical ventilation (RR 0.59 [0.51-0.69]), decreased requirement of intensive care unit (ICU) (RR 0.62 [0.45-0.86]), lowered length of ICU stay (single-study) and decreased duration of mechanical ventilation (two-studies). In mild to moderate population, steroid treatment was associated with a higher "duration of hospital stay," while no difference was seen in other domains. In patients at risk of progression to "acute respiratory distress syndrome," steroid administration was associated with "reduced requirement of mechanical ventilation" (single-study). Conclusion: This study guides the use of steroid across patients with different severity categories of COVID-19. Among mechanically ventilated patients, steroid therapy may be beneficial in terms of reduced mortality. Among "severe and critical" patients; steroid therapy was associated with lowered mortality, decreased requirement of mechanical ventilation, and ICU. However, no benefit was observed in "mild to moderate" population. To conclude, among properly selected patient populations (based-upon clinical severity and biomarker status), steroid administration may prove beneficial in patients with COVID-19.
Article
The mechanisms of COVID-19-associated coagulopathy (CAC) are complex and differ in many ways from the standard mechanisms of thrombosis in critically ill patients. This review presents the pathogenesis, diagnosis, and comparison of various types of coagulopathy with SAS. During COVID-19 infection, the number of sudden deaths outside the hospital increased. One possible reason is the high incidence of serious thrombotic events in patients with COVID-19. However, the pathogenesis of these life-threatening events is multifactorial and requires independent discussion. Deviations in laboratory studies of the hemostatic system in patients infected with SARS-CoV-2 with a severe course indicate the activation of the blood coagulation system corresponding to sepsis-induced coagulopathy (SIC) or DIC. However, hemostasis disorders in COVID-19 have characteristics that distinguish them from DIC in sepsis. The clinical and laboratory features of CAC overlap with hemophagocytic syndrome, antiphospholipid syndrome, and thrombotic microangiopathy. The review presents data on their similarities and differences. Inadequate diagnosis or inadequate treatment of hypercoagulability may explain the high incidence of unexplained deaths from COVID-19. They can be associated with potentially preventable microvascular and macrovascular thrombosis and subsequent cardiovascular complications, including myocardial injury and infarction, as well as insufficient information content of biomarkers for their assessment. Research to identify the most informative biomarkers for decision-making to intensify anticoagulant prophylaxis in patients with severe COVID-19 is progressing rapidly, with increasing focus on TEG and ROTEM. The review presents changes in CAC during hormone therapy for COVID-19-associated lung damage. Pulse therapy with high doses of GCS has a rapid anti-inflammatory effect, but at the same time increases the level of D-dimer, which increases the risk of venous thrombosis and thromboembolism.
Article
This systematic review focuses on the state-of-the-art pharmacotherapy of immune disorders in the novel coronavirus infection (COVID-19), leading to a cytokine storm and uncontrolled inflammatory response that causes severe tissue damage and multiple organ failure. A lot of theoretical, experimental and clinical data support the need for immunomodulatory (immunosuppressive) therapy for this disease. It should be emphasized that all immunomodulatory drugs for COVID-19 are prescribed off label, and the evidence base of the results of randomized trials is just being accumulated. We review the immunomodulatory therapy for COVID-19 with the following agents: glucocorticoids, hydroxychloroquine and chloro-quine, type 1 interferons, interleukin-6 antagonists (tocilizumab, sarilumab, olokizumab), interleukin-1 p inhibitor canakinumab, tumour necrosis factor inhibitors (infliximab), Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, ruxolitinib), as well as drugs with other mechanisms of action (abatacept, nivolumab, tacrolimus, sirolimus, fingolimod, melphalan, cyclosporine, methotrexate). At the moment, the most reasonable is the use of interleukin-6 receptor inhibitors, intermediate and high dose glucocorticoids, and JAK inhibitors. Based on the latest data from clinical studies, especially the "Solidarity” trial, the use of hydroxychloroquine and chloroquine seems to have insufficient evidence. There are significant pathophysiological overlaps in the development of immunopathology in COVID-19 and in rheumatic diseases, and the strategy of early aggressive immunosuppressive therapy proposed by a number of researchers almost completely coincides with the current strategies for rheumatoid arthritis.
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Background: Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful predictive factor for critical illness caused by COVID-19. Methods: The study prospectively involved 61 patients with COVID-19 infection as a derivation cohort, and 54 patients as a validation cohort. The predictive factor for critical illness was selected using LASSO regression analysis. A nomogram based on non-specific laboratory indicators was built to predict the probability of critical illness. Results: The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent risk factor for critical illness in patients with COVID-19 infection. The NLR had an area under receiver operating characteristic of 0.849 (95% confidence interval [CI], 0.707 to 0.991) in the derivation cohort and 0.867 (95% CI 0.747 to 0.944) in the validation cohort, the calibration curves fitted well, and the decision and clinical impact curves showed that the NLR had high standardized net benefit. In addition, the incidence of critical illness was 9.1% (1/11) for patients aged ≥ 50 and having an NLR < 3.13, and 50% (7/14) patients with age ≥ 50 and NLR ≥ 3.13 were predicted to develop critical illness. Based on the risk stratification of NLR according to age, this study has developed a COVID-19 pneumonia management process. Conclusions: We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary.
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Background Establishing who is at risk from a novel rapidly arising cause of death, and why, requires a new approach to epidemiological research with very large datasets and timely data. Working on behalf of NHS England we therefore set out to deliver a secure and pseudonymised analytics platform inside the data centre of a major primary care electronic health records vendor establishing coverage across detailed primary care records for a substantial proportion of all patients in England. The following results are preliminary. Data sources Primary care electronic health records managed by the electronic health record vendor TPP, pseudonymously linked to patient-level data from the COVID-19 Patient Notification System (CPNS) for death of hospital inpatients with confirmed COVID-19, using the new OpenSAFELY platform. Population 17,425,445 adults. Time period 1st Feb 2020 to 25th April 2020. Primary outcome Death in hospital among people with confirmed COVID-19. Methods Cohort study analysed by Cox-regression to generate hazard ratios: age and sex adjusted, and multiply adjusted for co-variates selected prospectively on the basis of clinical interest and prior findings. Results There were 5683 deaths attributed to COVID-19. In summary after full adjustment, death from COVID-19 was strongly associated with: being male (hazard ratio 1.99, 95%CI 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (HR 2.36 95% CI 2.18-2.56); severe asthma (HR 1.25 CI 1.08-1.44); and various other prior medical conditions. Compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted HR 2.17 95% CI 1.84-2.57; fully adjusted HR 1.71 95% CI 1.44-2.02); with similar findings for Asian people (age-sex adjusted HR 1.95 95% CI 1.73-2.18; fully adjusted HR 1.62 95% CI 1.43-1.82). Conclusions We have quantified a range of clinical risk factors for death from COVID-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. People from Asian and black groups are at markedly increased risk of in-hospital death from COVID-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. Deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. The findings for clinical risk factors are concordant with policies in the UK for protecting those at highest risk. Our OpenSAFELY platform is rapidly adding further NHS patients' records; we will update and extend these results regularly. Keywords COVID-19, risk factors, ethnicity, deprivation, death, informatics.
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Objective To explore the clinical value of immune-inflammatory markers to assess the severity of coronavirus disease 2019 (COVID-19). Methods 127 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study, and classified into non-severe and severe groups. Demographics, symptoms, underlying diseases and laboratory data were collected and assessed for predictive value. Results Of 127 COVID-19 patients, 16 cases (12.60%) were classified into the severe group. High level of interleukin-6 (IL-6), C-reaction protein (CRP) and hypertension were independent risk factors for the severity of COVID-19. The risk model based on IL-6, CRP and hypertension had the highest area under the receiver operator characteristic curve (AUROC). Additionally, the baseline IL-6 was positively correlated with other immune-inflammatory parameters and the dynamic change of IL-6 in the severe cases were parallel to the amelioration of the disease. Conclusion Our study showed that high level of IL-6, CRP and hypertension were independent risk factors for assessing the severity of COVID-19. The risk model established upon IL-6, CRP and hypertension had the highest predictability in this study. Besides, IL-6 played a pivotal role in the severity of COVID-19 and had a potential value for monitoring the process of severe cases.
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Background Several studies have described the clinical characteristics of patients with novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19), indicating severe patients tended to have higher neutrophil to lymphocyte ratio (NLR). Whether baseline NLR could be an independent predictor of in-hospital death in Chinese COVID-19 patients remains to be investigated. Methods A cohort of patients with COVID-19 admitted to the Zhongnan Hospital of Wuhan University from January 1 to February 29 was retrospectively analyzed. The baseline data of laboratory examinations, including NLR were collected. Univariate and multivariate logistic regression models were developed to assess the independent relationship between the baseline NLR and in-hospital all-cause death. A sensitivity analysis was performed by converting NLR from a continuous variable to a categorical variable according to tertile. Interaction and stratified analyses were conducted as well. Results 245 COVID-19 patients were included in the final analyses, and the in-hospital mortality was 13.47%. Multivariate analysis demonstrated that there was 8% higher risk of in-hospital mortality for each unit increase in NLR (Odds ratio [OR] = 1.08; 95% confidence interval [95% CI], 1.01 to 1.14; P = 0.0147). Compared with patients in the lowest tertile, the NLR of patients in the highest tertile had a 15.04-fold higher risk of death (OR = 16.04; 95% CI, 1.14 to 224.95; P = 0.0395) after adjustment for potential confounders. Notably, the fully adjusted OR for mortality was 1.10 in males for each unit increase of NLR (OR = 1.10; 95% CI, 1.02 to 1.19; P = 0.016). Conclusions NLR is an independent risk factor of the in-hospital mortality for COVID-19 patients especially for male. Assessment of NLR may help identify high risk individuals with COVID-19.
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Background and aimsBehçet’s disease (BD) is an auto-immune vasculitis, characterized by episodic inflammation of multiple organs. The neutrophil to lymphocyte ratio (NLR) is used as a marker of inflammation in several diseases nowadays. While nitric oxide (NO) seem to be involved in BD pathogenicity. Our study aims to investigate the NLR as an inflammatory marker of BD activity as well as to evaluate the relationship between the NO production and NLR in Algerian BD patients with different clinical manifestations before and under colchicine + corticosteroid treatment.Methods For this purpose, we evaluated the NLR as the ratio of neutrophil count to lymphocyte count in naïve and treated active BD patients with different clinical manifestations and in inactive ones. Furthermore, we assessed NO production by the Griess’ method in the same patients. Additionally, we evaluated in vivo interferon-γ (IFN-γ) and interleukin-4 (IL-4) levels using ELISA.Results and discussionOur results indicate that the NLR and nitrite levels were higher in naïve active BD patients. Interestingly, this high ratio and NO production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and vascular involvement. Importantly, in treated BD patients NLR was higher in active patients especially in those with mucocutaneous involvement while increased nitrites levels were regardless of the clinical manifestations studied. Both NLR and NO production decreased in these treated active patients. In addition, IL-4 production differed according to the clinical manifestations studied contrary to the IFN-γ production.Conclusion Collectively our results suggest that the NLR is a potential marker of BD activity in Algerian patients, predicting the disease severity. Moreover, the positive relationship between the NLR and NO production is related to an increased risk of mucocutaneous lesions and vascular involvement. Thus, the application of these two accessible tools could be benefit for the clinical prognosis and treatment of BD.
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Background: In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases were a concern. Objectives: To describe the coagulation feature of patients with NCP. Methods: Conventional coagulation results and outcomes of consecutive 183 patients with confirmed NCP in Tongji hospital were retrospectively analysed. Results: The overall mortality was 11.5%, the non-survivors revealed significantly higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (P<0.05). 71.4% of non-survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their hospital stay. Conclusions: The present study shows that abnormal coagulation results, especially markedly elevated D-dimer and FDP are common in deaths with NCP.
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Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.
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Background: Acute pulmonary embolism is a serious medical condition that has a substantial global impact. Inflammation plays a role in the pathophysiology and prognosis of acute pulmonary embolism (APE). The aim of the present study was to investigate the prognostic value of admission parameters for complete blood count (CBC) in APE. Methods: A total of 203 patients who were hospitalized with diagnosed APE were retrospectively enrolled in the study. Clinical data, PESI scores, admission CBC parameters, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were all recorded. The clinical outcomes of study subjects were determined by the reported patient 30-day mortality and long-term mortality. Results: During a median follow-up period of 20 months [interquantile range 17], 34 subjects in the study population (17%) died. NLR and PLR levels were significantly higher in patients who died within the 30 days (n = 14) [9.9 (5.5) vs. 4.5 (4.1), p = 0.01 and 280 (74) vs. 135 (75), p = 0.01, respectively] and during the long-term follow-up (n = 20) [8.4 (2.9) vs. 4.1 (3.8), p = 0.01 and 153 (117) vs. 133 (73), p = 0.03, respectively] when compared to the patients that survived. In Cox regression analysis, age, systolic blood pressure, systolic pulmonary arterial pressure, PESI scores (HR 1.02 95%CI 1.01-1.04, p = 0.01), elevated levels of NLR (HR 1.13 95%CI 1.04-1.23, p = 0.01) and PLR (HR 1.002 95%CI 1.001-1.004, p = 0.01) were independently correlated with total mortality. Conclusions: Admission NLR and PLR may have prognostic value in patients with APE.
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Background: Recently, endogenous glucocorticoid excess has been identified as a risk factor for VTE. Whether exogenous use of glucocorticoids is associated with an increased risk of VTE is unclear. We aimed to quantify the risk of symptomatic pulmonary embolism (PE) in patients using corticosteroids. Methods: A case-control study using the PHARMO Record Linkage System, a Dutch population-based pharmacy registry, was conducted. Cases were 4,495 patients with a first hospital admission for PE between 1998 and 2008. Control subjects were 16,802 sex- and age-matched subjects without a history of PE. International Classification of Diseases codes for hospitalization were used to retrieve information on underlying conditions. Results: The risk of PE was highest in the first 30 days of glucocorticoid exposure (adjusted OR, 5.9; 95% CI, 2.3-3.9) and gradually decreased with increasing duration of use (OR, 1.9; 95% CI, 1.3-2.9) for long-term users (> 1 year). Low-dose glucocorticoid use (prednisolone daily dose equivalent < 5 mg) carried a twofold increased risk of PE (OR, 1.8; 95% CI, 1.3-2.4), whereas a 10-fold increased risk was observed for the highest dose of glucocorticoids (prednisolone > 30 mg) (OR, 9.6; 95% CI, 4.3-20.5). Stratification for both duration and dose of glucocorticoid showed the highest risk of PE in recently started users compared with long-term users at the time of PE, irrespective of the dose. Conclusion: Patients treated with oral glucocorticoids may be at an increased risk of PE, especially during the first month of exposure. This hypothesis requires confirmation in future studies.
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Preliminary evidence has suggested the role of inflammation in development and prognosis of cardiovascular diseases and cancers. Most of the prognostic studies failed to account for the effects of co-morbid conditions as these might have raised the systemic inflammation. We used neutrophil lymphocyte ratio (NLR) as a measure of systemic inflammation and investigated its association with prevalent chronic conditions. Present study is a cross sectional study conducted on population of Karachi, Pakistan. A detailed questionnaire about the demographic details of all subjects was filled and an informed consent obtained for blood sampling. Multinomial regression analyses were carried out to investigate the relationship between NLR and prevalent chronic conditions. 1070 apparently healthy individuals participated in the study. Proportion of individuals with hypertension was higher in middle and highest tertile of NLR as compared to the lowest tertile (18.2% & 16.1% compared to 11.8%). Individuals with hypertension were 43% (RRR = 1.43, 95% CI 0.94-2.20) and 66% (RRR = 1.69, 95% CI 1.09-2.54) more likely to be in the middle and highest tertile of NLR respectively compared to the baseline group. Similarly, individuals with diabetes mellitus were 53% (RRR = 1.53, 95% CI 0.93-2.51) and 65% (RRR = 1.65, 95% CI 1.01-2.71) more likely to be in the middle or highest tertile of NLR as compared to the baseline NLR group. Systemic inflammation measured by NLR has a significant association with prevalent chronic conditions. Future research is needed to investigate this relationship with longitudinal data to establish the temporal association between these variables.
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Glucocorticoids hypersensitivity may be involved in the development of abdominal obesity and insulin resistance. Eight normal weight and eight obese women received on two occasions a 3-h intravenous infusion of saline or hydrocortisone (HC) (1.5 microg x kg(-1) x min(-1)). Plasma cortisol, insulin, and glucose levels were measured every 30 min from time(-30) (min) (time(-30)) to time(240). Free fatty acids, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were measured at time(-30), time(180), and time(240). At time(240), subjects underwent an insulin tolerance test to obtain an index of insulin sensitivity (K(ITT)). Mean(30-240) cortisol level was similar in control and obese women after saline (74 +/- 16 vs. 75 +/- 20 microg/l) and HC (235 +/- 17 vs. 245 +/- 47 microg/l). The effect of HC on mean(180-240) insulin, mean(180-240) insulin resistance obtained by homeostasis model assessment (HOMA-IR), and K(ITT) was significant in obese (11.4 +/- 2.0 vs. 8.2 +/- 1.3 mU/l, P < 0.05; 2.37 +/- 0.5 vs. 1.64 +/- 0.3, P < 0.05; 2.81 +/- 0.9 vs. 3.32 +/- 1.02%/min, P < 0.05) but not in control women (3.9 +/- 0.6 vs. 2.8 +/- 0.5 mU/l; 0.78 +/- 0.1 vs. 0.49 +/- 0.1; 4.36 +/- 1.1 vs. 4.37 +/- 1.2%/min). In the whole population, the quantity of visceral fat, estimated by computerized tomography scan, was correlated with the increment of plasma insulin and HOMA-IR during HC infusion [Delta mean(30-240) insulin (r = 0.61, P < 0.05), Delta mean(30-240) HOMA-IR (r = 0.66, P < 0.01)]. The increase of PAI-1 between time(180) and time(240) after HC was higher in obese women (+25%) than in controls (+12%) (P < 0.05), whereas no differential effect between groups was observed for free fatty acids or adiponectin. A moderate hypercortisolism, equivalent to that induced by a mild stress, has more pronounced consequences on insulin sensitivity in abdominally obese women than in controls. These deleterious effects are correlated with the amount of visceral fat.
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The treatment of atypical pneumonia, subsequently termed severe acute respiratory syndrome (SARS), is controversial, and the efficacy of corticosteroid therapy is unknown. We have evaluated the clinical and radiographic outcomes of 72 patients with probable SARS (median age 37 years, 30 M), who received ribavirin and different steroid regimens in two regional hospitals. Chest radiographs were scored according to the percentage of lung field involved. Seventeen patients initially received pulse steroid (PS) (methylprednisolone > or =500 mg/day) and 55 patients initially received nonpulse steroid (NPS) (methylprednisolone <500 mg/day) therapy. The cumulative steroid dosage; intensive care unit admission, mechanical ventilation, and mortality rates; and hematologic and biochemical parameters were similar in both groups after 21 days. However, patients in the PS group had less oxygen requirement, better radiographic outcome, and less likelihood of requiring rescue PS therapy than their counterparts. There was no significant difference between the two groups in hemolytic anemia, severe secondary infections, or hematemesis, but patients in the PS group had less hyperglycaemia. Initial use of pulse methylprednisolone therapy appears to be a more efficacious and an equally safe steroid regimen when compared with regimens with lower dosage and should be considered as the preferred steroid regimen in the treatment of SARS, pending data from future randomized controlled trials.
Article
Background Accumulating evidence proposed JAK inhibitors as therapeutic targets warranting rapid investigation. Objective This study evaluated the efficacy and safety of ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor, for COVID-19. Methods We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe COVID-19. Results Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus SoC treatment (22 patients) or placebo based on SoC treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in intervention group and 21 patients in control group were included in the study. Treatment with ruxolitinib plus SoC was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed CT improvement at D14 compared with 13 (61.9%) patients from the control group (P = 0.0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at D28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. Conclusions Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population. This trial is registered at www.chictr.org.cn as ChiCTR-OPN-2000029580.
Article
Background Coronavirus disease 2019 (COVID-19) predisposes patients to a prothrombotic state with demonstrated microvascular involvement. The degree of hypercoagulability appears to correlate with outcomes, however optimal criteria to assess for the highest risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography (TEG) measurements of coagulation would correlate with thromboembolic events. Methods Patients admitted to an intensive care unit with COVID-19 diagnoses that had TEG analyses performed were studied. Conventional coagulation assays, D-dimer levels, and viscoelastic parameters were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new onset renal failure. Results Forty-four patients with COVID-19 were included in the analysis. Derangements in coagulation laboratory values including elevated D-Dimer, fibrinogen, PT, and PTT were confirmed; viscoelastic parameters showed an elevated maximum amplitude and low lysis at 30 minutes. A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted VTE with an AUROC of .742 (p=0.021). A D-Dimer cutoff of 2600 ng/ml predicted need for dialysis with an AUROC of .779 (p=0.005). Overall, patients with no lysis of clot at 30 minutes and a D-Dimer of greater than 2600 ng/ml had a rate of VTE of 50% compared to 0% for patients with neither risk factor (p=0.008) and had a hemodialysis rate of 80% compared to 14% (p=0.004). Conclusions Fibrinolysis shutdown, as evidenced by elevated D-Dimer and complete failure of clot lysis at 30 minutes on thromboelastography, predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19. Further clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.
Article
Background: Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses. Methods: We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects. Results: In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia. Interpretation: Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.
Article
We performed a meta-analysis to determine safety and efficacy of corticosteroids in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. We searched PubMed, Web of Science, Medline, WanFang Chinese database, and ZhiWang Chinese database using Boolean operators and search terms covering SARS-CoV-2, SARS-CoV, OR MERS-CoV AND corticosteroids to find appropriate studies. Review Manager 5.3 was used to analyze results of meta-analysis. Observational studies were analyzed for quality using the modified Newcastle–Ottawa scale and randomized clinical trials, using the Jadad scale. Subjects were divided into those with severe-only and other (severe and not severe) cohorts based on published criteria. Efficacy endpoints studied included mortality, hospitalization duration, rates of intensive care unit (ICU) admission, use of mechanical ventilation, and a composite endpoint (death, ICU admission, or mechanical ventilation). We included 11 reports including 10 cohort studies and 1 randomized clinical trial involving 5249 subjects (2003–2020). Two discussed the association of corticosteroids and virus clearing and 10 explored how corticosteroids impacted mortality, hospitalization duration, use of mechanical ventilation, and a composite endpoint. Corticosteroid use was associated with delayed virus clearing with a mean difference (MD) = 3.78 days (95% confidence Interval [CI] = 1.16, 6.41 days; I2 = 0%). There was no significant reduction in deaths with relative Risk Ratio (RR) = 1.07 (90% CI = 0.81; 1.42; I2 = 80%). Hospitalization duration was prolonged and use of mechanical ventilation increased. In conclusion, corticosteroid use in subjects with SARS-CoV-2, SARS-CoV, and MERS-CoV infections delayed virus clearing and did not convincingly improve survival, reduce hospitalization duration or ICU admission rate and/or use of mechanical ventilation. There were several adverse effects. Because of a preponderance of observational studies in the dataset and selection and publication biases our conclusions, especially regarding SARS-CoV-2, need confirmation in a randomized clinical trial. In the interim we suggest caution using corticosteroids in persons with COVID-19.
Article
Background The outbreak of the coronavirus disease 2019 (Covid‐19) shows a global spreading trend. Early and effective predictors of clinical outcomes is urgent needed to improve management of Covid‐19 patients. Objective The aim of the present study was to evaluate whether elevated D‐dimer levels could predict mortality in patients with Covid‐19. Methods Patients with laboratory confirmed Covid‐19 were retrospective enrolled in Wuhan Asia General Hospital from January 12, 2020 to March 15, 2020. D‐dimer levels on admission, and death events were collected to calculate the optimum cutoff using receiver operating characteristic curve. According to the cutoff, the subjects were divided into two groups. Then the in‐hospital mortality between two groups were compared to assess the predictive value of D‐dimer level. Results A total of 343 eligible patients were enrolled in the study. The optimum cutoff value of D‐dimer to predict in‐hospital mortality was 2.0 µg/ml with a sensitivity of 92.3% and a specificity of 83.3%. There were 67 patients with D‐dimer≥2.0 µg/ml, and 267 patients with D‐dimer <2.0 µg/ml on admission. 13 deaths occurred during hospitalization. Patients with D‐dimer levels≥2.0 µg/ml had a higher incidence of mortality when comparing to those who with D‐dimer levels < 2.0 µg/ml (12/67 vs 1/267, P<0.001, HR:51.5, 95%CI:12.9‐206.7). Conclusions D‐dimer on admission greater than 2.0µg/mL (fourfold increase) could effectively predict in‐hospital mortality in patients with Covid‐19, which indicated D‐dimer could be an early and helpful marker to improve management of Covid‐19 patients.
Article
COVID-19, caused by the SARS-CoV-2 virus, has become pandemic. With sharply rising infection rates, patient groups characterized by an enhanced infection risk will be challenged by the virus. In this context, patients with chronic immune-mediated inflammatory diseases are of particular interest, as these diseases are characterized by an intrinsic immune dysfunction leading to inflammation that may enhance risk for severe infection. Immune-mediated inflammatory diseases are often treated with cytokine blocking therapy. This comment discusses whether such therapies may pose a risk — or even a benefit — in the context of the current COVID-19 pandemic.
Article
Aim To accumulate evidence that indicates the key role played by virus-triggered inflammation in the 2019-novel coronavirus disease (COVID-19) which emerged in Wuhan City and rapidly spread throughout China. Methods Age, neutrophil(NEU)-to-lymphocyte (LYM) ratio (NLR), lymphocyte-to-monocyte(MON) ratio, platelet-to-lymphocyte ratio(PLR), and C-reactive protein(CRP) of 93 patients with laboratory confirmed COVID-19 were investigated and compared. The receiver operating characteristic curve was applied to determine the thresholds for five bio-markers, and their prognostic values were assessed via the Kaplan–Meier curve and multivariate COX regression models. Results The median age was 46.4 years old, and 37cases were females. A total of 26.8% of patients had been to Wuhan, and 73.1% had contacted with people from Wuhan. Fever (83.8%) and cough (70.9%) were the two most common symptoms. Elevated NLR and age were significantly associated with illness severity. The binary logistic analysis identified elevated NLR (hazard risk [HR] 2.46, 95% confidence interval [CI] 1.98–4.57) and age (HR 2.52, 95% CI 1.65–4.83) as independent factors for poor clinical outcome of COVID-19. NLR exhibited the largest area under the curve at 0.841, with the highest specificity (63.6%) and sensitivity (88%). Conclusions Elevated age and NLR can be considered independent biomarkers for indicating poor clinical outcomes.
Article
Since March 11, 2020, the World Health Organization (WHO) defined Coronavirus disease 2019 (COVID‐19) as a pandemic, with a series of confirmed cases that currently exceeded 300,000 people worldwide and with approximately 14,500 deaths. Accumulated evidence suggests that a subgroup of patients with severe COVID‐19 could have a dysregulation of the immune response that allows the development of viral hyperinflammation. Thus, all patients with severe COVID‐19 should be screened for hyperinflammation using laboratory parameters in order to improve mortality. Neutrophil‐to‐Lymphocyte ratio (NLR) and Lymphocyte‐to‐C‐reactive protein ratio (LCR) are established inflammation markers that reflect systemic inflammatory response, and both are available in almost all laboratories. In this study, a meta‐analysis was performed to investigate whether NLR and LCR values can help predict clinical severity in patients with COVID‐19.
Article
The novel corona virus infection (now classified as COVID‐19), first identified in December 2019 in Wuhan, China, has contributed to significant mortality in several countries with the number of infected cases increasing exponentially worldwide.¹ The majority of the most severely ill patients initially present with single organ failure (i.e. respiratory insufficiency) but some of them progress to more systemic disease and multiple organ dysfunction. One of the most significant poor prognostic features in those patients is the development of coagulopathy.² In patients who develop sepsis from various infectious agents, development of coagulopathy is one of the key and persistent features which is associated with poor outcomes.³ In this context, the role of International Society of Thrombosis and Haemostasis (ISTH) would be crucial in guiding health care professionals how to manage the coagulopathy of COVID‐19. A simple and easily follow‐able algorithm for the management of COVID‐19 coagulopathy would currently be useful in both the well‐resourced and less‐resourced settings as a guide in managing this complication. This pragmatic statement should clearly be considered as an interim guidance since the clinical experience of managing this pandemic is increasing. The authors are certain that this statement will be modified with developing knowledge and therapeutics in managing COVID‐19. The aim of this guidance document is to provide a risk stratification at admission for a COVID‐19 patient and management of coagulopathy which may develop in some of these patients, based on easily available laboratory parameters.
Article
Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/L (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/L could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
Article
An 80-year-old woman with rheumatoid arthritis presented with chest pain. Clinical examination revealed new-onset paroxysmal atrial fibrillation with symptomatic sinus pauses and worsening mitral regurgitation, which were both resistant to conventional therapies. Based on her skin lesions, an increase in pleural and pericardial effusion, possible myocardial involvement, and a positive finding for immune complex testing, rheumatoid vasculitis was diagnosed. Subsequent glucocorticoid therapy suppressed systemic inflammation, resulting in structural, functional, and electrical reverse remodeling of the left atrium with complete remission of atrial arrhythmias and also an improvement of mitral regurgitation. This case highlights the importance of evaluating the underlying disease activity in a case of de novo paroxysmal atrial fibrillation associated with systemic autoimmune disease.
Article
Objective The neutrophil lymphocyte ratio (NLR) has been shown to be highly prognostic across many tumour types, and predictive of treatment outcome in advanced prostate cancer, and has been postulated to be an indirect measure of tumour inflammation. We evaluated the impact of low dose steroids on NLR in men suffering from castration-resistant prostate cancer (CRPC). Patients and methods The NLR was evaluated in a prospective randomized phase II trial comparing prednisolone 5mg twice-daily and dexamethasone 0.5mg daily administered to 75 chemotherapy and abiraterone/enzalutamide-naïve CRPC patients. NLR was examined at baseline (BL), after 6- and 12-weeks of corticosteroid treatment; associations with >50% PSA response, duration of response (PSA progression-free interval) and overall survival (OS) were tested using logistic regression and cox-regression analysis. Results The median NLR for all evaluable patients was 2.6 at BL; 2.9 at 6-weeks; and 4.0 at 12-weeks. Following low-dose corticosteroid initiation, 46 patients had a decline in PSA with 24 confirmed responders. BL-NLR (log10) associated with a PSA response (odds ratio=34.6, 95% confidence interval [CI]=2.0-589.1, P=0.014), and with the extent of the PSA decline (P=0.009). A favourable BL-NLR (<median) associated with a 5.5-fold higher odds of a PSA>50% response (95% CI=1.3-23.9; P=0.02). Higher BL-NLR (log10) associated with a shorter time to PSA progression (hazard ratio [HR] of 9.5, 95% CI=2.3-39.9; P=0.002). In MVA BL-NLR as a discrete variable was independently associated with PSA progression (HR of 3.5, 95% CI 1.5-8.1; P=0.003). NLR at 6-weeks also associated with duration of benefit; in the favourable NLR category time to PSA progression was 10.8 months, for those converting to an unfavourable (>median) category 4.5 months, and for those remaining in a unfavourable category only 1.5 months (95% CI 0.5-2.5; P=0.003). OS was 33.1 months (95% CI 24.2-42.0) and 21.9 months (95% CI 19.3-24.4) for those with an favourable and unfavourable BL-NLR, respectively. Conclusion Treatment-naïve CRPC patients with a high BL or on-treatment NLR appear not to benefit from low-dose corticosteroids. The immunological implications of an unfavourable NLR, and whether corticosteroids may drive prostate cancer progression in patients harbouring a high NLR, warrant further study.
Article
Objectives: To explore the performance of the neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation that predicts prognosis of several diseases, in a cohort of elderly adults with community-acquired pneumonia (CAP). Design: Prospective clinical study from January 2014 to July 2016. Setting: Unit of Internal Medicine, University of Catania, Catania, Italy. Participants: Elderly adults admitted for CAP (N = 195). Measurements: Clinical diagnosis of CAP was defined as the presence of a new infiltrate on plain chest radiography or chest computed tomography associated with one or more suggestive clinical features such as dyspnea, hypo- or hyperthermia, cough, sputum production, tachypnea (respiration rate >20 breaths per minute), altered breath sounds on physical examination, hypoxemia (partial pressure of oxygen <60 mmHg), leukocytosis (white blood cell count >10,000/μL). Clinical examination, traditional tests such as Pneumonia Severity Index (PSI); Confusion, Urea, Respiratory rate, Blood pressure, aged 65 and older (CURB-65), and NLR were evaluated at admission. The accuracy and predictive value for 30-day mortality of traditional scores and NLR were compared. Results: NLR predicted 30-day mortality (P < .001) and performed better than PSI (P < .05), CURB-65, C-reactive protein, and white blood cell count (P < .001) to predict prognosis. No deaths occurred in participants with a NLR of less than 11.12. Thirty-day mortality was 30% in those with a NLR between 11.12% and 13.4% and 50% in those with a NLR between 13.4 and 28.3. All participants with a NLR greater than 28.3 died within 30 days. Conclusions: These results would encourage early discharge of individuals with a NLR of less than 11.12, short-term in-hospital care for those with a NLR between 11.12 and 13.4, middle-term hospitalization for those with a NLR between 13.4 and 28.3, and admission to a respiratory intensive care unit for those with a NLR greater than 28.3.
Article
Background: Corticosteroids have been associated with an increased risk of venous thromboembolism in patients treated for inflammatory diseases. It is unclear whether the thrombotic risk is induced by the inflammation of the underlying inflammatory diseases or whether corticosteroids are prothrombotic as well. Considering the widespread use of corticosteroids in clinical practise, it is critical to know whether corticosteroids enhance coagulation. Objective: To investigate whether a 10-day prednisolone burst therapy activates hemostasis in healthy individuals. Methods: Healthy subjects received either 0.5 mg kg(-1) day(-1) of oral prednisolone or placebo. Venous blood was collected at baseline, day 1 and day 10 and tested for thrombin-antithrombin complexes (TATc), D-dimer, plasmin-alpha2-antiplasmin complexes (PAPc), plasminogen-activator inhibitor type-1 (PAI-1), von Willebrand factor (VWF) and thrombin generation (peak thrombin, velocity index and endogenous thrombin potential [ETP]). Results: Fifteen subjects received prednisolone and 16 placebo (median age 29 vs. 22 years, female subjects 33% vs. 56%, respectively). Peak thrombin and velocity index were higher in the placebo group at baseline. After 10 days of treatment, peak thrombin, velocity index, PAI-1 and VWF increased in the oral prednisolone group as compared with the placebo group (15.8 [SD 16.3] vs. -0.1 [SD 16.1], 41.2 [SD 41.3] vs. -2.3 [SD 42.7], 18.0 [IQR 8.0-37.0] vs. 0.5 [IQR -18.5-13.0], 4.0 [IQR -1.0-12.0] vs. 0.0 [IQR -2.5-1.5], respectively). No changes were observed for TATc, ETP, PAPc and D-dimer. Conclusions: Oral prednisolone induces a procoagulant state in healthy subjects, suggesting that corticosteroid treatment may increase the thromboembolic risk in patients with inflammatory diseases.
Article
Acute pulmonary embolism (PE) is a serious clinical condition characterised by a high mortality rate. Previous studies showed that leukocytosis was associated with recurrences of venous thromboemboli, major bleeding and increased mortality. The aim of the present study was to investigate the prognostic value of neutrophil to lymphocyte ratio (NLR) in patients with acute PE during short term follow-up. A total of 640 patients were screened by I26 code of ICD-9 and 359 patients were included as cases of confirmed acute PE. Admission blood counts and clinical data were obtained from medical charts. The predictors of 30-day mortality were examined. Fifty-one out of 359 patients (14.2%) included in the study died during 30 days follow-up. In multivariate Cox regression analysis systolic blood pressure (HR:0.97 (0.94-0.99 CI95%), p=0.019), diabetes mellitus (HR:3.3 (1.30-8.39 CI95%), p=0.012), CK-MB(HR:1.03 (1.01-1.06 CI95%), p=0.024) and NLR (HR:1.03 (1.01-1.06 CI95%), p=0.008) were predictors of 30-day mortality. An optimal cut-off value of NLR was determined as 9.2 by using ROC curve. Hazards ratio of NLR>9.2 was found to be 3.60 (1.44-9.18 CI95%, p=0.006). NLR>9.2 had a sensitivity, specificity, negative predictive value, and positive predictive value of 68.6%, 80.5%, 93.9% and 36.5%, respectively. NLR on hospital admission may be a predictor of 30-day mortality in acute PE. Since complete blood count is a part of the routine laboratory investigation in the most hospitalised patients use and preliminary promising results of this study, NLR should be investigated in future prospective randomised trials regarding prognostic value in acute PE.
Article
Importance Excess endogenous cortisol has been linked to venous thromboembolism (VTE) risk, but whether this relationship applies to exogenous glucocorticoids remains uncertain. Because the prevalence of glucocorticoid use and the incidence of VTE are high, an increased risk of VTE associated with glucocorticoid use would have important implications. Background To examine the association between glucocorticoid use and VTE. Design Population-based case-control study using nationwide databases. Setting Denmark (population 5.6 million). Participants We identified 38 765 VTE cases diagnosed from January 1, 2005, through December 31, 2011, and 387 650 population controls included through risk-set sampling and matched by birth year and sex. The VTE diagnosis date for the case was the index date for cases and matched controls. Exposure We classified individuals who filled their most recent glucocorticoid prescription 90 days or less, 91 to 365 days, and more than 365 days before the index date as present, recent, and former users, respectively. Present users were subdivided into new (first-ever prescription 90 days or less before the index date) and continuing users (others). Main Outcomes and Measures We used conditional logistic regression adjusted for VTE risk factors to estimate incidence rate ratios (IRRs) and 95% CIs for glucocorticoid users vs nonusers. Results Systemic glucocorticoids increased VTE risk among present (adjusted IRR, 2.31; 95% CI, 2.18-2.45), new (3.06; 2.77-3.38), continuing (2.02; 1.88-2.17), and recent (1.18; 1.10-1.26) users but not among former users (0.94; 0.90-0.99). The adjusted IRR increased from 1.00 (95% CI, 0.93-1.07) for a prednisolone-equivalent cumulative dose of 10 mg or less to 1.98 (1.78-2.20) for more than 1000 to 2000 mg, and to 1.60 (1.49-1.71) for doses higher than 2000 mg. New use of inhaled (adjusted IRR, 2.21; 95% CI, 1.72-2.86) and intestinal-acting (2.17; 1.27-3.71) glucocorticoids also increased VTE risk. Conclusions and Relevance The risk of VTE is increased among glucocorticoid users. Although residual confounding may partly explain this finding, we consider a biological mechanism likely because the association followed a clear temporal gradient, persisted after adjustment for indicators of severity of underlying disease, and existed also for noninflammatory conditions. Hence, our observations merit clinical attention.
Article
To review the current literature on glucocorticoid-induced hyperglycemia and provide a strategy for its treatment. We undertook an electronic (MEDLINE) and a library review of the existing pertinent literature published from 1950 to March 2009. Glucocorticoid-induced hyperglycemia is common in patients with and without diabetes. The odds ratio for new-onset diabetes mellitus in patients treated with glucocorticoids ranges from approximately 1.5 to 2.5. Total glucocorticoid dose and duration of therapy are strong predictors of diabetes induction. Other risk factors include age and body mass index. Failure to treat glucocorticoid-induced hyperglycemia is related to the presumed short duration of administration of glucocorticoid treatment and the emphasis on fasting plasma glucose only. Understanding the pharmacodynamics of glucocorticoids can lead to increased recognition and improved treatment of the condition. Recent demonstrations that even shortterm elevations in blood glucose level may be associated with adverse sequelae argue for greater attention to the condition. Glucocorticoid-induced hyperglycemia is an important clinical finding that, if recognized, can be effectively treated. We propose a relatively simple schema for the proactive management of corticosteroid-induced hyperglycemia that has been effective and easily adaptable to both the inpatient and the outpatient setting.
Article
Severe acute respiratory syndrome (SARS), now known to be caused by a coronavirus, probably originated in Guangdong province in southern China in late 2002. The first major outbreak occurred in Guangzhou, the capital of Guangdong, between January and March 2003. This study reviews the clinical presentation, laboratory findings and response to four different treatment protocols. Case notes and laboratory findings were analysed and outcome measures were collected prospectively. The SARS outbreak in Guangdong province and the outbreak in Guangzhou associated with hospitals in the city are described, documenting clinical and laboratory features in a cohort of 190 patients randomly allocated to four treatment regimens. Patients were infected by close contact in either family or health-care settings, particularly following procedures likely to generate aerosols of respiratory secretions (e.g. administration of nebulized drugs and bronchoscopy). The earliest symptom was a high fever followed, in most patients, by dyspnoea, cough and myalgia, with 24 % of patients complaining of diarrhoea. The most frequent chest X-ray changes were patchy consolidation with progression to bilateral bronchopneumonia over 5-10 days. Thirty-six cases developed adult respiratory distress syndrome (ARDS), of whom 11 died. There was no response to antibiotics. The best response (no deaths) was seen in the group of 60 patients receiving early high-dose steroids and nasal CPAP (continuous airway positive pressure) ventilation; the other three treatment groups had significant mortality. Cross-infection to medical and nursing staff was completely prevented in one hospital by rigid adherence to barrier precautions during contact with infected patients. The use of rapid case identification and quarantine has controlled the outbreak in Guangzhou, in which more than 350 patients have been infected. Early administration of high-dose steroids and CPAP ventilation appears to offer the best supportive treatment with a reduced mortality compared with other treatment regimens.
Article
It is well known that glucocorticoids induce insulin resistance, but the exact time scale in humans is not well known. The aim of the study was to determine the time scale of effects of pharmacologic doses of glucocorticoids on insulin sensitivity. Subjects were treated with repeated methylprednisolone infusions and oral prednisone for Graves' orbitopathy. Insulin sensitivity was determined using euglycemic hyperinsulinemic clamp (EHGC) before, during the first glucocorticoid infusion and after 2 months of treatment. EHGC started 2 h after the start of the glucocorticoid infusion, and lasted for 2 h. In another group of patients, insulin sensitivity was determined by short insulin tolerance test (SITT) before and during the first glucocorticoid infusion. SITT started 15 min after the start of the glucocorticoid infusion and lasted for 15 min. Ten subjects were included in each protocol. All were euthyroid during the study period. Four hours after the start of the glucocorticoid infusion significant reduction of insulin sensitivity was observed, which did not change for a further 2 months of glucocorticoid treatment [before 7.82 (95% confidence interval (CI) 5.35-10.29), first infusion, 4.93 (95% CI 2.99-6.87), after 2 months 5.36 (95%CI 3.91-6.81) mg/kg/min]. No significant change in insulin sensitivity occurred during the first 30 min of glucocorticoid infusion [before 139.7 (95%CI 94.1-185.3), during 146.7 (95%CI 106.3-187.1) mumol/l/min]. In humans, glucocorticoid- induced insulin resistance develops quickly, in about 4 h, and does not change during further glucocorticoid treatment.
Cytokine storm intervention in the early stages of COVID-19 pneumonia
  • X Sun
  • T Wang
  • D Cai
  • Z Hu
  • J Chen
  • H Liao
Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine & Growth Factor Reviews. 2020;53:38-42. DOI: 10.1016/j.cytogfr.2020.04.002
Therapeutic management of patients with COVID-19: a systematic review. Infection Prevention in Practice. 2020;100061
  • M Tobaiqy
  • M Qashqary
  • S Al-Dahery
  • A Mujallad
  • A A Hershan
  • M A Kamal
Tobaiqy M, Qashqary M, Al-Dahery S, Mujallad A, Hershan AA, Kamal MA et al. Therapeutic management of patients with COVID-19: a systematic review. Infection Prevention in Practice. 2020;100061. [Epub ahead of print]. DOI: 10.1016/j.infpip.2020.100061
Effective treatment of severe COVID-19 patients with tocilizumab
  • X Xu
  • M Han
  • T Li
  • W Sun
  • D Wang
  • B Fu
Xu X, Han M, Li T, Sun W, Wang D, Fu B et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences. 2020;117(20):10970-5. DOI: 10.1073/ pnas.2005615117
Canakinumab in a subgroup of patients with COV-ID-19. The Lancet Rheumatology
  • C Ucciferri
  • A Auricchio
  • Di Nicola
  • M Potere
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