Relationship between Selective IgA Deficiency and COVID-19 Prognosis.

Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic.

commentary: COVID-19 and Obesity: Exploring Biologic Vulnerabilities, Structural Disparities, and Weight Stigma

Diagnoses of coronavirus disease 2019 (COVID-19) from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were first reported in December 2019. Since its emergence from the Chinese province of Wuhan, the World Health Organization (WHO) has announced 162 million confirmed cases of the SARS-CoV-2 infection worldwide, and reported roughly 3.3 million deaths as of May 16, 2021.1 Stratified by country, the United States leads with nearly 33 million confirmed COVID-19 cases, followed by India, Brazil, France, Turkey, and Russia.2 Structural firefighters perform essential public safety work and have continued that work despite the challenges of COVID-19. Career firefighters typically have long work schedules (24 or 48 hours on duty followed by multiple days off) and eat and sleep at the station as part of a team/shift. Firefighters respond to multiple hazards which include fires and rescues. In many localities, firefighters are dual trained as emergency medical service (EMS) personnel and provide emergency medical care. Because of their close living quarters and contact with the public, including rendering patient care and transporting patients, it is likely that firefighters are at an increased risk of infection with SARS-CoV-2. The fire service is aware of the risk of infection and has quickly adopted the increased use of personal protective equipment (PPE) and modified policies and procedures aimed at reducing the risk to firefighters.3,4 However, very little attention has been paid to occupational risks that may increase the severity of COVID-19 or to the potential long-term consequences of COVID-19 that may pose specific concerns for firefighters. The purpose of this review is to 1) outline the pathogeneses of COVID-19, 2) explore clinical and mechanistic links between COVID-19 and cardiovascular disease, 3) review known risk factors for COVID-19 complications and their prevalence among firefighters, and 4) consider steps that can be taken to better understand the long-term consequences of COVID-19 in the fire service. The review is limited to occupational factors for structural firefighters and does not cover wildland firefighters, although we acknowledge that COVID-19 may also present special concerns for wildland firefighters. PATHOGENESIS OF COVID-19 The SARS-CoV-2 virus enters the body predominantly via the lungs, and often results in pronounced respiratory symptoms. Thus COVID-19 was initially described as a respiratory disease. Indeed, respiratory failure from acute respiratory distress syndrome has been shown to be leading cause of COVID-19 induced mortality.5 A study by Guan et al6 reported that the majority of COVID-19 related consequences feature pneumonia and acute respiratory distress, which is consistent with other analyses suggesting that about 40% of COVID-19 patients develop acute respiratory distress syndrome, and 20% of these syndromes are severe.7 Wang et al8 showed that 61% of the individuals that required intensive care due to COVID-19 developed acute respiratory distress syndrome. COVID-19 not only lead to respiratory symptoms, but also underlying respiratory conditions increase the likelihood of experiencing severe symptoms. Meta-analyses revealed that the odds of severe COVID-19 infection were 5.69 times higher if individuals who have a history of chronic obstructive pulmonary disease.9 The virus requires the cooperation of two key proteins, TMPRSS2, and angiotensinogen converting enzyme 2 (ACE2) to infiltrate the body via the lung pneumocytes. TMPRSS2 is a key cellular regulator of coronavirus spike protein (S protein), with the S1 domain of the S protein responsible for receptor binding and the S2 domain controlling membrane fusion. Thus, coronavirus requires the binding of the S1 region to a cell surface receptor followed by the S2 subunit mediated fusion of the viral and cellular membranes in order to enter its host.10 This process requires S protein priming, or cleavage, by host proteases at the S1and S2 domains of the virus. This process has been described as a principle step for the cellular entry of SARS-CoV-2.11 Following S protein cleavage, Sars-CoV-2 binds to and enters lung cells via the enzyme ACE2, which is highly expressed in alveolar type 2 cells.12 Dissimilar to the original SARS-CoV, it has been suggested that SARS-CoV-2 may have a higher affinity to ACE2 positive cells in the upper respiratory tract, exacerbating its potent and detrimental effects.11 ACE2 is a membranous protein and importantly, an inactivator of angiotensin II (AngII). The binding of SARS-CoV-2 to ACE2 in lung cells promotes the endocytosis of the ACE2-SARS-CoV-2 complex, resulting in a reduction of membrane ACE2 abundance and an increase in serum AngII.12 Thus, SARS-CoV-2's affinity for ACE2 could explain its downstream effects on vascular parameters, including alterations in systolic and diastolic blood pressures, as elevated plasma AngII can increase blood pressure via aldosterone-mediated vasoconstriction and sodium and water retention on the kidneys.13 Furthermore, increased plasma AngII is associated with increased risks of myocardial infarction and left ventricular hypertrophy.13 In addition, SARS-CoV-2 promotes inflammation via the AT1R.12 The AngII-AT1R axis activates pro-inflammatory transcription factors NF-kB and STAT3, upregulating pro-inflammatory cytokines such as TNFa and IL-6 family cytokines,12,14 possibly leading to vascular inflammation and disease. Furthermore, recent studies suggest that the Sars-CoV-2 protein ORF3a encourages an aggressive inflammatory response via NF-κB activation, chemokine secretion, Golgi fragmentation, ER stress, and cell death.15 ORF3a can also inhibit type I interferon (type I IFN) signaling, downregulate major histocompatibility complex (MHC) class I expression, and reduce CD8+ cytotoxic T cell activity. Specifically, Siu et al15 demonstrated that ORF3a encourages the binding of TRAF3 to cytoplasmic portions of TNF receptors, promoting ubiquitination, and processing of p105 to p50. P50 is generated by TRAF3 ubiquitin-ligase ubiquitination of p150 and 26S proteasome-mediated removal of p105C terminal sequences. P50 then binds to RelA, RelB, or C-Rel subunits to produce functional NF-κB, a transcription factor essential for pro-IL-1β expression. The prevalence of pro-IL-1β transcripts is a requirement for NLRP3 inflammasome activation. Therefore, ORF3a-mediated p105 processing into p50 can help activate the NLRP3 inflammasome and lead to a robust inflammatory response.15 Siu et al further demonstrated ORF3a's ability to induce ASC polyubiquitination via a TRAF3 ubiquitin-ligase.15 ASC is the adapter complex of the NLRP3 inflammasome, and polyubiquitination of ASC provides a nondegradative signal necessary for ASC activation, caspase-1 activation, and mature IL-1β protein formation.15 Ultimately, the studies mentioned above illustrate how COVID-19 can target the cardiovascular system through its mode of entry and lead to vascular inflammation and dysfunction via upregulation of pro-inflammatory signaling. COVID-19 AND CARDIOVASCULAR DISEASE Although SARS-CoV-2 was first described as a respiratory disease, cardiac tissue and blood vessels express ACE2 receptors and appear to be particularly prone to COVID-19 infection.14 The heart, an ACE2 expressing tissue, was studied during the Toronto SARS outbreak (SARS-CoV), and investigators found evidence of SARS-CoV RNA in 35% of autopsied hearts.16 COVID-19 acts in a similar manner to the previous SARS-CoV, indicating that individuals with cardiovascular disease (CVD) are more prone to severe complications of SARS-CoV-2 compared to healthy individuals. Initial research on CVD-induced complications of COVID-19 was conducted in China. Wang et al investigated the association between biomarkers of CVD and the exacerbation of COVID-19 in hospitalized patients and found that cardiac injury, defined as either elevated high-sensitivity cardiac troponin I (hs-cTnI) or ECG/echocardiographic abnormalities, was present in 7.2% of the patients.8,17,19 The study also found that 22% of COVID-19 patients in ICU had biomarkers of cardiac injury.8,17 Zhou et al reported that hs-cTnI levels were at or greater than the 99th percentile upper reference limit in 46% of non-survivors, compared to only 1% of survivors who had levels this high.17,18 Thus, it has become apparent that COVID-19 can have severe cardiovascular consequences. Ultimately, it is also becoming clear that the presence of CVD, or CVD risk factors, can increase the likelihood of severe complications of COVID-19. The observational study by Zhou et al described above, also reported that 8% of patients (13% of non-survivors) had been diagnosed with CVD and 38% (48% of non-survivors) had been diagnosed with hypertension.17,18 Furthermore, Wang et al found that comorbidity of COVID-19 and CVD was prevalent in 15% (25% requiring ICU care) of patients analyzed, and Guan et al reported that 2.5% (9% among those with intubation or death) of COVID-19 patients also suffered from coronary artery disease.10,11,14 Chen et al demonstrated that in a cohort of 99 COVID-19 infected individuals at the Wuhan Jinyintan Hospital, 40% had some manifestation of cardiovascular or cerebrovascular disease.19 Other researchers have also reported on the higher prevalence of hypertension among COVID-19 patients; one study that although reports 15% of COVID patients had hypertension, 36% of those who needed intubation or suffered death had hypertension. Another study reported 31% of patients with COVID-19 had hypertension; however, 58% of patients requiring ICU care had hypertension.6,8 These findings demonstrate a clinical link between COVID-19 and CVD. EFFECT OF COVID-19 ON CARDIOVASCULAR SYSTEM Following the COVID-19 outbreak, researchers have begun to investigate the mechanisms associating COVID-19 and CVD. Emerging evidence strongly suggests the SARS-CoV-2 infection decreases myocardial functioning. Previous research has demonstrated that SARS-CoV, resembling both the structure and function of SARS-CoV-2, perturbates myocardial functioning.20 Recent research analyzing the cardiac manifestations of the SARS-CoV-2 infection found that the most common cardiac abnormality (39% of patients at baseline) was right ventricular dilation and dysfunction, followed by left ventricular diastolic and systolic dysfunction (16% and 10% of patients at baseline, respectively).21 In this study, 20% of these patients had clinical deterioration, with 60% of them having right ventricle deterioration and 25% having left ventricle systolic and diastolic deterioration.20 Thus, it appears that COVID-19, similar to other severe hypoxic respiratory illnesses, impairs cardiac function mostly by a right ventricular pressure overload state. Myocardial injury involves a pronounced escalation in pro-inflammatory cytokine secretions, which is commonly seen in COVID-19 patients. Specifically, research has found that patients suffering from COVID-19 had an upregulation of the pro-inflammatory cytokines IL1B, IFNγ, IP10, and MCP1. Individuals in ICU admission for COVID-19 had higher concentrations of the cytokines GCSF, IP10, MCP1, MIP1A, and TNFα than those not in ICU.22 An increase in these molecules due to COVID-19 severity can lead to an activation and dysregulation of T helper cells.22 Imbalances in (type 1 and type 2) T helper cells can lead to respiratory dysfunction, hypoxemia, and myocardial injury.20 Interestingly, Huang et al noticed that type 2 T-helper cell cytokines (IL4 and IL10), that suppress inflammation, were upregulated during infection of SARS-CoV-2.20 A study of competitive athletes recovering from COVID-19 found that 15% (4/26) had cardiovascular magnetic resonance findings suggestive of myocarditis despite only 2 of the 4 participants with findings suggestive of myocarditis having had COVID-19 symptoms.23 Acute thrombotic events are another major complication in individuals fighting the SARS-CoV-2 infection. Blood hypercoagulability has been shown to be common among hospitalized COVID-19 patients.24 Elevated D-Dimer levels, associated with thrombus formation and breakdown, are also reported in COVID-19 patients, worsening over the course of the disease.24 A review by Terpos et al elegantly describes how thrombus degradation products including PT and aPT are consistently upregulated in individuals requiring ICU admission.24 COVID-19 has also been shown to induce acute pulmonary embolisms in certain individuals,24–27 and one study found that 30% of COVID-19 patients had acute pulmonary embolus, measured by a CT coronary angiogram.28 This rate of pulmonary embolus is higher than what is usually seen in critically ill patients without COVID-19 (1.3%).28 Ultimately, COVID-19 patients are at higher risk for thromboembolic events, leading to adverse cardiovascular health risks. The endothelium plays key roles in regulating blood flow, maintaining hemostatic balance, and in immune response. Emerging evidence suggests that a vascular disease process contributes to COVID-19 pathogenesis.29 Several studies have begun to elucidate the role of endothelial dysfunction with COVID-19. Epithelial dysfunction, specifically pulmonary endothelial damage, is a common manifestation observed in patients infected with SARS Cov-2 virus and other coronaviruses.26 Endothelium damage due to COVID-19 is thought to occur by multiple mechanisms, including: a dysregulated immune response, enhanced vascular permeability, and exacerbated presence of pulmonary edemas.26,30 Varga et al31 demonstrated endothelial cell dysfunction in vital organs of individuals after becoming infected with COVID-19. These authors presented convincing evidence to indicate that the SARS CoV-2 virus has direct effects on endothelial cells, possibly due to the fact that ACE2 is also widely expressed on endothelial cells in multiple organs.14 Thus, it appears that recruitment of immune cells and pro-inflammatory cytokines due to ubiquitous expression of ACE2 can result in extensive endothelial dysfunction and cellular apoptosis. THE EFFECTS OF OBESITY ON CARDIOVASCULAR HEALTH AND COVID-19 Obesity has been recognized as an important predictor of CVD risk and adverse cardiorespiratory outcomes. Genetic and clinical experiments have found that that obesity is causally related to many disease states including hypertension, diabetes mellitus type 2, coronary heart disease, stroke, atrial fibrillation, renal disease, and heart failure.32 Others have reported that around 75% of hypertension can be attributed to obesity.33 It is clear that this obesity-induced hypertension leads to renal dysfunction due to an increased sympathetic nervous state and upregulated renin–angiotensin system.33 Obesity has effects on the infection and exacerbation of the SARS-CoV-2 infection. Sattar et al propose that obesity and ectopic fat deposition might reduce both optimal cardiorespiratory and immune response mechanisms, two major factors that can lead to severe manifestations of COVID-19.32 Several studies have reported on an association between obesity and COVID-19. Hamer et al reported a two-fold risk ratio of being infected with COVID-19 for obese individuals compared to normal weight individuals.34 These risk ratios were adjusted for age, sex, and mutually for each lifestyle, and physical inactivity. Furthermore, obesity was identified as the risk factor that contributed greatly to the prediction of COVID-19 infection risk. Finally, Hamer et al calculated a Population Attributable Fraction (PAF), which corresponds to the prevalence of risk factors in a population and the strength of its association with an outcome (COVID-19).34 The PAF used adjusted effect estimates on lifestyle factors (smoking, physical inactivity, overweight, and obesity) and COVID-19 and found that the total PAF for the three unhealthy lifestyle factors was 51.4%.34 Specifically, overweight and obesity had a PAF of 29.5%, smoking had a PAF of 13.3%, and physical inactivity had a PAF of 8.6%. Overall, it has become quite clear through both mechanistic and clinical research that there is a powerful effect of obesity on COVID-19 infection and severity. POTENTIAL RELATIONSHIPS BETWEEN FIREFIGHTERS AND COVID-19 As discussed through this paper, there is a strong relationship between both pulmonary disease, CVD and COVID-19. While initial research has focused on risk factors that place individuals at increased risk for COVID-19 complications, this section details ways that occupational exposures and cardiovascular risk factors that are known to be prevalent among firefighters, might make firefighters an occupational group that is at high risk of developing COVID-19 complications and for whom the long-term effects of COVID-19 infection might be particularly problematic. As summarized in Tables 1 and 2 and discussed in the following section, there are multiple factors that are known to exacerbate the rate of infection or severity of infection with SARS-CoV-2 and that are occupationally associated with firefighting. TABLE 1 - Association Between Medical Conditions of COVID-19 and Firefighting Medical Conditions COVID-19 Research Fire Service Research 1. Pulmonary disease • Significantly associated with a severe COVID-19 infection (OR 5.69, 95% CI: 2.49–13.00)9• 30% of studied COVID-19 patients developed acute respiratory distress syndrome,28 61% of studied COVID-19 patients developed acute respiratory distress syndrome,7,8,28 with approximately 20% of these cases being severe8 • Decrements in respiratory function were two-to-four-times greater in firefighters than general population35• Pulmonary function is associated with frequency of fire exposure36• Those who transitioned to less active assignments might not be protected from pulmonary disease88 2. Cardiovascular disease • 15–40% of patients had some manifestation of cardiovascular or cerebrovascular disease7,8,19 • Firefighters with other comorbidities demonstrated unfavorable CVD and cardiorespiratory fitness profiles70 COVID-19, coronavirus disease 2019; CVD, cardiovascular disease. TABLE 2 - Association Between Risk Factors of COVID-19 and Firefighting Risk Factors COVID-19 Research Fire Service Research 1. Age • Significant association of older age (≥65 years) and risk of COVID-19 mortality• Ranging from an OR of 3.76 (95% CI: 1.15–17.39; P = 0.023) to 4.59 (95% CI: 2.61–8.04; P < 0.001)57,58 • 9% of the entire US firefighting cohort is 60 years of age or older55 2. Sex • Males have made up as much as 60.3–70% of patients hospitalized with the SARS-CoV-2 infection• Prostatic diseases are associated with elevations in COVID-19 induced cardiac injury (OR 1.505, 95% CI; P = 0.046)60• In males, each standard deviation increase in free androgen escalates risk of severe COVID-19 manifestations (OR 1.22, 95% CI: 1.03–1.45; P = 0.024)60 • 96% of the US fire service is comprised of men, and more than half of US metropolitan departments have no women firefighters55,62 3. Hypertension • 56.6% of New York City area COVID-19 patients had hypertension59• Significant associate of COVID-19 mortality (pooled OR 2.70, 95% CI: 1.40–5.24; P = 0.003)57 • Up to 30% of the entire fire service have hypertension63,72• 46% of males and 29% of females firefighters had blood pressure the of 1 or 2 58% of firefighters and of firefighters have Obesity • been as the one of COVID-19 obese individuals are at greater risk for severe COVID-19 • of firefighters = were as either overweight or of overweight and obese firefighters may the US Cardiovascular • troponin is associated with COVID-19 mortality risk (OR 95% CI: P < cardiac injury in 7.2% of patients, and in 22% of ICU of patients had right ventricular dilation and dysfunction, had left ventricular diastolic dysfunction, 10% had systolic • Acute of decreases can induce ventricular and of myocardial and blood and • increased ACE2 and TMPRSS2 in alveolar type 2 cells and • Decrements in were more than the rate in were related to frequency of fire but not to age, smoking or Firefighters who a during fire a times greater rate of compared to COVID-19, coronavirus disease 2019; vital Pulmonary from recent study indicate that in the respiratory function of firefighters years) was two-to-four-times greater than the in the general reports with findings and also that the of pulmonary function in firefighters is associated with the frequency of fire of fires are more potent of than previous on their occupational firefighters appear to be at an increased risk of pulmonary is less evidence that firefighting leads to increased pulmonary disease, but this is a pulmonary disease is associated with increased risk for developing a severe COVID-19 infection. Pulmonary Risk and the acute and long-term effects of and is a in the fire service. have that and can reduce firefighters in 1 by lung function often to Furthermore, et demonstrated an of in firefighters following a of with 30% of the cohort having a in of Other studies have shown that the in which firefighters for and of can cause decreases in and vital as as in serum cell protein and serum studies the effects of long-term and on health have been the results are A study conducted on firefighters from the fire showed that in the and were not associated with of firefighting in active and that the protective respiratory equipment used by the fire service to be the detrimental effects of enhanced and In addition, a review of studies from to that the of and on health is and limited by of and that firefighters in pulmonary However, a study by et found that the in were more than the rate and was related to frequency of fire but not to age, smoking or et further showed that active firefighters a greater in compared to those who had or firefighters who a during fire a times greater rate of compared to Other studies have shown that with respiratory use in et showed that after years of there was a 10% in the of firefighters who to the World Thus, there is but not evidence that to and can both and pulmonary function in firefighters, use of respiratory protective equipment in the fire service. As pulmonary function is a robust to COVID-19 infection and severe COVID-19 Recent evidence also demonstrated that to can increase both ACE2 and TMPRSS2 in alveolar type 2 cells and due to firefighting might have a direct effect on COVID-19 but further research is Cardiovascular Risk Age cardiovascular health is by the prevalence of cardiovascular risk factors which can include age, sex, hypertension, and from that 9% of US firefighters are 60 years of age or Although a this of the fire service might have a more pronounced risk of COVID-19 infection than the general A recent observational study reported that age is one of the leading risk factors for infection and death due to Other studies have confirmed this that older individuals (≥65 years) have from to times higher risk of COVID-19 Cardiovascular Risk Sex suggests that males are more to a COVID-19 infection than with one study from the New York City area that males made up of the patients hospitalized with the SARS-CoV-2 A study in found that males made up of the patients on in the males were more in COVID-19 patients than in The in and COVID-19 infection is thought to be due to levels of between males and Specifically, TMPRSS2 expression has been shown to be by and androgen receptor which is a requirement for the transcription of et reported that related to androgen increased the odds of having troponin T levels induced cardiac by the et also found that free androgen associated with COVID-19 and severity in males, but not in among males who were for COVID-19, each standard deviation increase in free androgen increased the odds of a positive COVID-19 as as severe COVID-19 by The fire service is et reported that to of the US fire service is comprised of and more than half of US metropolitan departments have no women firefighters. Other that of firefighters and of firefighters are an occupational group by is most likely to be by the SARS-CoV-2, as higher androgen levels are found in Cardiovascular Risk Hypertension Hypertension is a risk factor of COVID-19 and CVD that is known to have a high prevalence the US fire service. Hypertension is reported to be one of the most common comorbidities related to COVID-19 infection. In et al found that hypertension was present in 56.6% of hospitalized COVID-19 patients the New York City A these that chronic hypertension, with other cardiovascular were more among patients than survivors (48% also suggests that hypertension is associated with COVID-19 and that individuals as have higher odds of from COVID-19 than a Research that approximately 20% to 30% of the entire fire service have recent study found that 46% of firefighters and 29% of females had blood pressure the of 1 or 2 Cardiovascular Risk Obesity As discussed obesity has been found to increase the risk of a COVID-19 infection. there is a high prevalence of obesity in the US fire service. have shown that obesity was present in of COVID-19 hospitalized Interestingly, work by et al a between age and body Thus, with pronounced obesity are at an increased risk of being infected with SARS-CoV-2. This is for the US fire as obesity is a major CVD risk factor found in firefighters. Obesity has also been found to increase the risk of coronary heart disease and links the mechanisms of vascular alterations to cardiac suggests that firefighters with high have vascular function and are at a greater risk for

Citation:McSharry D, Lam MT, Malhotra AT. OSA as a probable risk factor for severe COVID-19. J Clin Sleep Med. 2020;16(9):1649.

Peer Reviewed

Coronavirus disease 2019 (COVID-19) can lead to serious illness and death, and thus, it is particularly important to predict the severity and prognosis of COVID-19. The Sequential Organ Failure Assessment (SOFA) score has been used to predict the clinical outcomes of patients with multiple organ failure requiring intensive care. Therefore, we retrospectively analyzed the clinical characteristics, risk factors, and relationship between the SOFA score and the prognosis of COVID-19 patients.We retrospectively included all patients ≥18 years old who were diagnosed with COVID-19 in the laboratory continuously admitted to Jingzhou Central Hospital from January 16, 2020 to March 23, 2020. The demographic, clinical manifestations, complications, laboratory results, and clinical outcomes of patients infected with the severe acute respiratory syndrome coronavirus-2 were collected and analyzed. Clinical variables were compared between patients with mild and severe COVID-19. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for severe COVID-19. The Cox proportional hazards model was used to analyze risk factors for hospital-related death. Survival analysis was performed by the Kaplan–Meier method, and survival differences were assessed by the log-rank test. Receiver operating characteristic (ROC) curves of the SOFA score in different situations were drawn, and the area under the ROC curve was calculated.A total of 117 patients with confirmed diagnoses of COVID-19 were retrospectively analyzed, of which 108 patients were discharged and 9 patients died. The median age of the patients was 50.0 years old (interquartile range [IQR], 35.5–62.0). 63 patients had comorbidities, of which hypertension (27.4%) was the most frequent comorbidities, followed by diabetes (8.5%), stroke (4.3%), coronary heart disease (3.4%), and chronic liver disease (3.4%). The most common symptoms upon admission were fever (82.9%) and dry cough (70.1%). Regression analysis showed that high SOFA scores, advanced age, and hypertension were associated with severe COVID-19. The median SOFA score of all patients was 2 (IQR, 1–3). Patients with severe COVID-19 exhibited a significantly higher SOFA score than patients with mild COVID-19 (3 [IQR, 2–4] vs 1 [IQR, 0–1]; P < .001). The SOFA score can better identify severe COVID-19, with an odds ratio of 5.851 (95% CI: 3.044–11.245; P < .001). The area under the ROC curve (AUC) was used to evaluate the diagnostic accuracy of the SOFA score in predicting severe COVID-19 (cutoff value = 2; AUC = 0.908 [95% CI: 0.857–0.960]; sensitivity: 85.20%; specificity: 80.40%) and the risk of death in COVID-19 patients (cutoff value = 5; AUC = 0.995 [95% CI: 0.985–1.000]; sensitivity: 100.00%; specificity: 95.40%). Regarding the 60-day mortality rates of patients in the 2 groups classified by the optimal cutoff value of the SOFA score (5), patients in the high SOFA score group (SOFA score ≥5) had a significantly greater risk of death than those in the low SOFA score group (SOFA score < 5).The SOFA score could be used to evaluate the severity and 60-day mortality of COVID-19. The SOFA score may be an independent risk factor for in-hospital death.

Outcome of very high-risk patients treated by Sotrovimab for mild-to-moderate COVID-19 Omicron, a prospective cohort study (the ANRS 0003S COCOPREV study)

Metabolic biomarkers measured from single blood test can identify apparently healthy people at high susceptibility for developing severe pneumonia, and may also be useful for preventive COVID-19 screening.

Increased liver fibrosis scores (LFS), such as fibrosis-4 index (FIB-4) or non-alcoholic fatty liver disease fibrosis score (NFS), and fatty liver are known risk factors for severe coronavirus disease 2019 (COVID-19). The purpose of this study was to identify the best scores, which predict the prognosis of COVID-19. Participants comprised consecutive Japanese COVID-19 patients admitted to our hospital between February 14, 2020, and April 14, 2021. Multivariate logistic regression analysis was performed to evaluate the relationships between LFS (FIB-4, NFS, aspartate aminotransferase-to-platelet ratio index [APRI], BARD score, and hepatic steatosis index [HSI]) or fatty liver on computed tomography (CT), and severity of COVID-19. Of the 415 patients (mean age, 59 years), 177 patients (42.7%) needed oxygen therapy, 90 patients (21.7%) worsened to severe COVID-19, and 45 patients (10.8%) died during admission. Multivariate logistic regression analysis showed that increased FIB-4 and NFS were risk factors for death, severe COVID-19, and oxygen demand; that increased BARD was a risk factor for severe COVID-19 and oxygen demand; and that increased APRI and HSI were not risk factors for any status of COVID-19. Furthermore, increased NFS or BARD and fatty liver were independent risk factors for severe COVID-19 and oxygen demand. This study showed that FIB-4 and NFS were the best liver fibrosis scores that predicted worse prognosis for COVID-19, and that increased NFS or BARD and fatty liver evident on CT represented independent risk factors for severe COVID-19 and oxygen demand.

Prevalence of obesity among adult inpatients with COVID-19 in France

Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic

Air pollution, racial disparities, and COVID-19 mortality

The ‘third wave’: impending cognitive and functional decline in COVID-19 survivors

Dear Editor, The understanding of the cytokine storm mechanism(s) and its profile are crucial to developing effective therapeutic interventions in COVID-19. In this line, cytokine storm blockers and immune-host modulators are currently being applied in severely ill COVID-19 patients to cope with the overwhelming inflammation. However, most of the current reports highlighted different elevated cytokine patterns among severely ill COVID-19 patients, suggesting that more care should be taken before immunosuppressive therapy by cytokine blockers in COVID-19. Here, we summarize the more common cytokine profiles and cytokine-targeted therapy approaches that have been reported for severe COVID-19 patients. Finally, we underscore the urgent need to identify a precise cytokine panel before the administration of selective immunosuppressive therapy. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS?CoV-2) with the symptoms including fever, dry cough and shortness of breath [1, 2]. Most COVID-19 patients will develop mild to moderate symptoms, while some infected people may face to hyper-inflammation induced by massive cytokines/chemokines production, called as cytokine storm, which may lead to fatal pneumonia and acute respiratory distress syndrome [1, 2]. Although, there is no specific antiviral therapy for COVID-19, understanding of cytokine storm mechanism in this disease can help to speculate possible therapeutic interventions [3]. Current reports have presented different cytokine profiles in patients with severe COVID-19 [1, 4-9]. For example, the higher levels of interleukin (IL)-2, IL-7, IL-10, tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10; CXCL10), MCP-1 (CCL2) and MIP-1A (CCL3), but not IL-6, have been first shown in intensive care unit (ICU) patients compared to non-ICU patients [1]. Subsequent studies revealed the contribution of other cytokines, including IL-1?, IL-1ra, IL-2R, IL-6, IL-8 (CXCL8), IL-17, interferon (IFN)-? and GM-CSF (granulocyte-macrophage colony-stimulating factor), during severe COVID-19 infections [4, 5, 8, 9]. Figure 1 displays the protein-protein interaction between these cytokines/chemokines. In most existing reports, the elevated levels of several cytokines/chemokine (ie., IL-6, IL-10, IFN-?, TNF and IP-10), have been greater emphasized in severely ill (ICU) COVID-19 patients than mild to moderate (non-ICU) group [1, 4-7]. Involvement of the T helper 2 cytokine IL-10, that suppresses inflammation, is a prominent feature of all reports, and an imbalance and/or exhaustion of T cells may be also involved. [1, 10]. Several approaches, including global targeting of the inflammation or neutralizing a single key inflammatory mediator, are being employed to cope with cytokine storm in COVID-19. Among key cytokines, IL-6 has attracted high levels of interest and antibodies that block the IL-6 receptor (tocilizumab and sarilumab) are currently under phase 2/3 clinical trials for the potential treatment of COVID-19 [2]. Targeting IFN-? is another promising approach, which has been highlighted by launching a clinical trial for JAK–STAT inhibitor (ruxolitinib) for controlling COVID-19 severity. [11] TNF acts upstream of IL-6 and anti-TNF therapies previously revealed protective effects in lethal SARS-CoV infection [12]. Several TNF-blocking antibodies (eg., adalimumab, etanercept, and golimumab) are successfully used to treat inflammatory diseases, and these therapies have been urgently recommended for the hospitalized COVID-19 patients [13]. IL-10 is likely upregulated to counter overwhelming infection during SARS-CoV-2 infection, but it may be also involved in the infiltration of inflammatory cells and lung fibrosis [14]. IL-10 blocking, alone or in combination with programmed cell death protein 1 (PD-1), is promising for reinvigorating exhausted T cells and may control COVID-19 pathogenesis [10]. Despite the benefits, there are still disadvantages, such as the development of chronic inflammatory disorders, thus more experimental studies should be done to clarify whether overactivation or ablation of IL-10 could be helpful for severe COVID-19. In some countries, including Iran and Turkey, tocilizumab is a recommended therapeutic strategy for ICU patients with severe COVID-19 [15]. However, it should be note that the elevated IL-6 levels, in common with other cytokines such as TNF, have no specific pattern in all severe COVID-19 patients, so that their levels were not associated with the disease severity in some patients [1, 4, 5]. Therefore, as patients with severe COVID-19 represent the differential cytokine patterns, more care should be taken before immunosuppressive therapy by cytokine blockers in COVID-19. This is important that the doctors evaluate a cytokine panel, at least including IL-6, IFN-?, and TNF-?, to precisely identify the needs of each patient before administration of selective immunosuppressive therapy. Obviously, a combination of immunosuppressive therapy with antiviral therapies that diminish virus titer should be also into account. Declaration of interests The authors declare no conflict of interest. Keywords: Covid-19 , SARS-CoV-2 , cytokine storm

Personal View: Low-Dose Lung Radiotherapy Should be Evaluated as a Treatment for Severe COVID-19 Lung Disease