cord-000522-d498qj2b	2002	Five topics were selected that have been shown in randomized, controlled trials to reduce mortality: limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, early goal-directed therapy, use of drotrecogin alfa (activated), use of moderate doses of steroids, and tight control of blood sugar. The present article provides guidelines from experts in the field on optimal patient selection and timing for each intervention, and provides advice on how to integrate new therapies into ICU practice, including protocol development, so that mortality rates from this disease process can be reduced. The interventions discussed encompassed low tidal volume in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) (Edward Abraham), early goal-directed therapy (EGDT) (Emanuel Rivers), drotrecogin alfa (activated) (Gordon Bernard), moderate-dose corticosteroids (Djillali Annane), and tight control of blood sugar (Greet Van den Berghe).
cord-001050-lq9tp20z	2013	title: Severe leukopenia in Staphylococcus aureus-necrotizing, community-acquired pneumonia: risk factors and impact on survival BACKGROUND: Necrotizing pneumonia attributed to Panton-Valentine leukocidin-positive Staphylococcus aureus has mainly been reported in otherwise healthy children and young adults, with a high mortality rate. The objectives of this study were to define the characteristics of patients with severe leukopenia at 48-h hospitalization and to update our data regarding mortality predicting factors in a larger population than we had previously described. Multivariate analysis indicated that the factors associated with severe leukopenia were influenza-like illness (adjusted odds ratio (aOR) 4.45, 95% CI (95% confidence interval) 1.67-11.88, P=0.003), airway bleeding (aOR 4.53, 95% CI 1.85-11.13, P=0.001) and age over 30 years (aOR 2.69, 95% CI 1.08-6.68, P=0.033). Severe community-acquired pneumonia caused by Panton-Valentine leukocidin-positive Staphylococcus aureus: first reported case in the United Kingdom Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin
cord-001322-7xmxcm35	2014	Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe. A number of more recent, larger studies have focussed on identifying patients with CAP at increased risk of severe sepsis and death, as well as those who may require ventilator or vasopressor support [3, [24] [25] [26] . The aim of the study reported here was to define the clinical characteristics, microbiological aetiology, outcomes and independent risk factors for mortality in a large, contemporary cohort of patients with severe CAP admitted to ICUs across Europe. The British Thoracic Society Research Committee and The Public HealthLaboratory Service: The aetiology, management and outcome of severe community-acquired pneumonia on the intensive care unit A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit
cord-002227-x1ddi8wg	2016	In the process of nursing children with severe pneumonia, intensive care was provided, including condition assessment and diagnosis, close observation of disease, keeping the airway unblocked, rational oxygen therapy, prevention and treatment of respiratory and circulatory failure, support of vital organs, complications, and health education. As a result, severe pneumonia produces corresponding clinical symptoms, such as respiratory failure, heart failure, toxic encephalopathy and intestinal paralysis, which endanger the lives of children in the short term, and is the first cause of death of pediatric inpatients (6, 7) . Type I respiratory failure also refers to the coexistence of hypoxemia and hypercapnia, impairment of ventilatory function and gas exchange functions, severe lung lesion, obstruction of trachea and bronchia caused by sticky secretions, blood change of PaO 2 <60 mmHg, and PaCO 2 >50 mmHg. Main clinical manifestations of children patients with type I pneumonia with respiratory failure include, poor mental state or dysphoria, polypnea, cyanosis of lips, dyspnea, nasal flaring and three depression signs.
cord-002757-upwe0cpj	2017	The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. In developing countries where polio is still endemic and oral polio vaccine is essential for eradicating the disease, it is of utmost importance that all PIDD patients and family members should not receive live oral polio (OPV) because of the reported prolonged excretion of the virus for months and even years [24] . As for host factors, although severe and fatal cases have been described in healthy immunocompetent hosts [129, 130] , there is evidence to suggest that children under the age of 10 [130] and immunocompromised hosts either secondary to hematologic malignancies, immunosuppressant treatment for organ transplantation, or HIV infection are at a greater risk to develop more severe disease with higher case fatality rates [131, 132] .
cord-004949-icsey27p	2014	The objective of this study was to compare systemic and local cytokine profiles and neutrophil responses in patients with severe versus non-severe community-acquired pneumonia (CAP). Compared to non-severe CAP patients, the severe CAP group showed higher plasma levels of proand anti-inflammatory cytokines but in contrast, lower sputum concentrations of pro-inflammatory cytokines. The objectives of this study were to characterize and contrast the lung and systemic cytokine profiles as well as blood neutrophil responses in patients with severe versus non-severe CAP at the time of hospital admission. In order to compare results of the plasma cytokines and neutrophil functional assays from CAP patients with those of healthy individuals, blood samples were also obtained from a control group (n=12) of healthy adult donors (approved by the University of Louisville′s IRB #191.06). Generally, patients in the severe CAP group showed a pattern with median plasma concentrations of both pro-and anti-inflammatory cytokines that were higher in comparison with the non-severe CAP group and the healthy control group.
cord-005646-xhx9pzhj	1996	Aims and methods The aim of both a prospective and retrospective survey conducted in German pediatric intensive care units in 1993 was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ARDS patients who were treated in the tt~ee year period from 1991 to 1993.All patients had acute bilateral alveolar infiltration of noncardiogenic origin and a pO2~iO2 ratio < 150mmHg. The influence of sex, underlying disease and single organ failure was analyzed using the Fischer''s exact test, the influence of additional organ failure on mortality was tested with the Cochran-Mantel-Haenszet statistics.
cord-006448-elfroq6f	2007	We report a case of severe adenovirus pneumonia in a young immunocompetent male who presented with sudden onset respiratory distress that progressed rapidly to respiratory failure and made a successful recovery on supportive measures. Systematic review of the literature identified 14 cases of severe adenovirus pneumonia (defined as respiratory failure requiring ventilatory support at any point during the course of illness) in otherwise healthy immunocompetent adults both in epidemic and community settings. We report a case of severe adenovirus pneumonia in a previously healthy immunocompetent male who presented to us with rapidly developing respiratory failure and made a successful recovery on supportive measures. We defined severe adenovirus pneumonia if associated with respiratory failure requiring ventilatory support at any point during the course of illness and immunocompetent adults as individuals with no acquired or congenital immunodeficiency state with or without associated premorbid conditions.
cord-007786-cu831tl7	2019	We suggest that in patients with hypotensive shock, fluid bolus therapy (30 mL/kg) with isotonic crystalloids be commenced (ungraded) and, if available, early initiation of vasopressor medication (ungraded) Timing of enteral feeding in cerebral malaria We suggest not to use a strategy of permissive hypercapnia to achieve ventilation with low tidal volumes in patients with cerebral malaria, because of the high incidence of brain swelling in these patients (ungraded) Fluid management in severe dengue We recommend not to use prophylactic platelet transfusion for thrombocytopenia in the absence of active bleeding complications or other risk factors (uncontrolled arterial hypertension, recent stroke, head trauma or surgery, continuation of an anticoagulant treatment, existing hemorrhagic diathesis) (1B) acidosis [14, 15] , and transpulmonary thermodilution-guided rapid fluid resuscitation resulted in pulmonary edema in 8/28 (29%) patients [15] . There are several randomized clinical trials comparing crystalloid with colloid fluid management for the treatment of patients with severe dengue and compensated shock.
cord-016057-efc6msf4	2005	In a confidential inquiry into malaria deaths in an area of South Africa with limited tertiary care facilities, major contributing factors were delays in diagnosis and initiation of adequate therapy, failure to administer the correct antimalarial at the correct dosage and frequency, inadequate monitoring of severity indicators in complicated cases, and the suboptimal management of complications (6). Some patients with severe malaria may have a negative smear due to sequestration of parasitised red blood cells, and a decision to treat with antimalarial chemotherapy should be considered if the index of suspicion is very high. The choice of chemotherapy for malaria is dependent on the severity of disease, the known or suspected resistance pattern of the parasite in the area where the malaria infection was acquired, the species of parasite, and patient profile (age, pregnancy, comorbidity, allergies, and medications, including any antimalarials recently administered). Acute renal failure in patients with severe falciparum malaria
cord-017715-99ri6x0y	2015	2. The patient has been to or lived in areas reported with infectious SARS patients and patients suffering from secondary infections 2 weeks before the disease onset, who also have abovementioned clinical symptoms, not high peripheral blood white cell count and pulmonary shadows on chest X-ray fi lms. 3. The patient has been to or lived in areas reported with infectious SARS patients and patients suffering from secondary infections 2 weeks before the disease onset, who also have abovementioned clinical symptoms, pulmonary shadows on chest X-ray fi lms, and no obvious response to anti-infectious treatment. If the foci could not be absorbed for a long term in SARS recovery phase or patients still have symptoms but normal chest presentations, CT scan need to be carried out for further observation as it can better visualize the subtle pulmonary interstitial changes, such as lung interlobular septum thickening, intralobular septum thickening, subpleural linear shadow, and small ground-glassdensity lesion and regional and segmental bronchiectasis, and therefore is helpful for clinical diagnosis of pulmonary interstitial fi brosis.
cord-017758-zfudssm9	2017	These include new phleboviruses of the Bunyaviridae family, exemplified by severe fever with thrombocytopenia syndrome virus [SFTSV] recognized in China in 2010, and the Heartland virus, a closely related but distinct virus, presenting with similar clinical features and discovered in Missouri in 2012. Other newly recognized tickborne infections include a novel spirochete of the relapsing fever group, Borrelia miyamotoi, first reported to cause human infection in Russia in 2011 and subsequently discovered to cause clinical disease in the Netherlands, Japan, and the United States, with transmission by the black-legged deer tick Ixodes scapularis. Transmission of SFTSV is considered mainly from tick bites, but there is also evidence from multiple reports that the virus can be transmitted from human to human by direct contact with blood of infected patients [67] [68] [69] [70] [71] . Severe fever with thrombocytopenia syndrome virus in ticks collected from humans, South Korea
cord-017870-5fu4uswq	2010	Studies of outcome of patients with falciparum malaria in the intensive care unit (ICU) commonly report that markers of severity of illness (such as the SAPS or APACHE II score), shock, acidosis, coma, pulmonary edema and coagulation disorders are indicators of poor outcome [21] . On the other hand studies have suggested that HIV infection may be significantly associated with the development of severe and complicated malaria [24] , being associated with a high parasite burden with the associated risk that this may potentially lead to poor malaria control and a greater chance for the development of resistance to anti-malarial agents [26] . Studies in children recovering from cerebral malaria have shown neurological sequelae in approximately 10 % or more of cases and these occur especially with infections that were complicated by hypoglycemia [3, 7] .
cord-018764-02l423mk	2007	The influence of inflammatory cytokines on cellular function offers a molecular framework to explain the multiple clinical syndromes that are observed during acute malarial illness, and provides a fresh avenue of investigation for adjunct therapies to ameliorate the malarial disease process. The presence of hyperlactataemia, hypoglycaemia, and metabolic acidosis, all three consistent with a patient being forced to rely on anaerobic glycolysis for energy production, have provided a consensus that hypoxia is central to disease pathogenesis in falciparum malaria. Another inflammatory cytokine, macrophage inhibitory factor (MIF) that is increased in malaria, and induced by TNF, has been shown to cause dyserythropoiesis in in vitro studies on bone marrow cells [95, 96] . Although the sepsis world now discusses several origins for the lactate increase, including inflammation-induced mitochondrial dysfunction [97] , in falciparum malaria it is still generally attributed to a reduced oxygen supply, mostly through microvascular occlusion by sequestered parasitised erythrocytes [121] .
cord-023169-obupqcua	2013	The severe illness, characterized by febrile illness with jaundice, acute renal injury and bleeding, is recognized as Weil''s disease, though many different local names have been used such as Fort Bragg, mud, swamp and sugar cane fevers. Complications such as cholestatic jaundice, aseptic meningitis, acute renal injury, haemorrhage especially in the lung and myocarditis can occur and lead to a fatal outcome. 24 Complications such as jaundice, acute renal injury, haemorrhage, especially pulmonary haemorrhage, aseptic meningitis, myocarditis, shock, occur early during the course of illness. Acute pancreatitis has been reported rarely, although serum amylase may be raised in up to 60% of patients with severe disease due to renal impairment. Nowadays, the term ''Weil''s syndrome'' usually refers to the extremely severe form of leptospirosis, characterized by the combination of jaundice, renal dysfunction, and haemorrhagic diathesis, especially pulmonary haemorrhage. Acute febrile illness accompanied by jaundice and renal failure should always include leptospirosis in the differential diagnosis.
cord-026031-hnf5vayd	2009	Fresh whole blood Coagulopathy with active hemorrhage (disseminated intravascular coagulation, thrombocytopenia; massive acute hemorrhage; no stored blood available) Stored whole blood Massive acute or ongoing hemorrhage; hypovolemic shock caused by hemorrhage that is unresponsive to conventional crystalloid and colloid fluid therapy; unavailability of equipment required to prepare blood components Packed red blood cells Nonregenerative anemia, immune-mediated hemolytic anemia, correction of anemia before surgery, acute or chronic blood loss Fresh frozen plasma Factor depletion associated with active hemorrhage (congenital: von Willebrand''s factor, hemophilia A, hemophilia B; acquired: vitamin K antagonist, rodenticide intoxication, DIC); acute or chronic hypoproteinemia (burns, wound exudates, body cavity effusion; hepatic, renal, or gastrointestinal loss); colostrum replacement in neonates Frozen plasma Acute plasma or protein loss; chronic hypoproteinemia; (contains stable colostrum replacement in neonates; hemophilia B and clotting factors) selected clotting factor deficiencies Platelet-rich plasma* Thrombocytopenia with active hemorrhage (immune-mediated thrombocytopenia, DIC); platelet function abnormality (congenital: thrombasthenia in Bassett hounds; acquired: NSAIDs, other drugs) Cryoprecipitate
cord-026653-094bk0t0	2020	This review will evaluate reports of allergic and substance-specific infusion reactions (IR), injection-site reactions (ISR), hypersensitivity reactions (HSR), urticaria, and anaphylaxis caused by BSs. The most common indications for the use of biologics in lung diseases are allergic and severe uncontrolled asthma. The Australian Public Assessment report and the FDA label did not observe an increase in the incidence of severe immunological and anaphylactic reactions related to the use of nintedanib [25, 26] . According to the recent BCCA Drug Manual, it was reported that HSR including anaphylaxis can develop in ≤ 1 % (severe < 1 %), IRs in 1 % (severe ≤ 1 %), and immune-mediated rash in 8-18 % ( severe ≤ 1 %) of patients [58] . The FDA''s 2019 label reported infusion-related reactions in 11-24 % of patients (placebo 7-18.0 %), acute urticaria in 1-2 %, acute HSRs in 1.5 %, pruritus in 4 %, and serious IRs and anaphylaxis in < 1 % [159] .
cord-030369-4dn02a35	2019	Once pulmonary infection is present, the disease condition will likely deteriorate, directly causing death; (3) a majority of infections are nosocomial infection, and pathogens are usually resistant to common antibiotics, making therapy challenging; (4) the pathogens causing infection are diverse but mainly Gram-negative bacteria, although the incidence of Gram-positive and fungal infections is increasing; (5) infection is closely related to the prognosis for liver failure patients. Although their clinical manifestation differ significantly, the "coexistence of acute and chronic failures" is shared by failures of all those organs; (2) CLF classification has been generally recognized at home and abroad, and the necessity of classification are further proved by the difference between CLF and the other three types; (3) CLF cases are relatively large in proportion (nearly 30%), which is still increasing (since the proportion of ALF/SALF are lowering); (4) Complications of CLF are common and are found in various forms, with bad prognosis; (5) In CLF patients with correlation to HBV, virus replication are commonly found, which is closely related to decompensation.
cord-032181-gmcugd8h	2019	3. Hepatorenal syndrome, which is characterized by renal failure, hemodynamic changes in arterial circulation and abnormalities in the endogenous vascular system, is a common clinical complication of end-stage liver disease, and one of the important indicators for the prognosis of patients with severe hepatitis. The latest report indicated that basic laboratory examinations for coagulation function testing in common use at present, such as PT, APTT, international normalized ratio (INR) etc., have little correlation with occurrence of gastrointestinal bleeding in these patients, thereby revealing the importance to search and pay close attention to those complicating disease upregulating bleeding risk, such as bacterial infection, renal failure, hemodynamic change after portal hypertension, dysfunction of endotheliocyte as well as macrophagocyte and so on [107] .
cord-033833-woref5g8	2020	title: A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. Exclusion criteria include one or more of the following: allergy to pyridostigmine; pregnancy or breastfeeding status; concomitant autoimmune disease; diagnosed immunodeficiencies (including HIV infection); need for mechanical ventilation, admission to the ICU, or meeting criteria for septic shock before providing signed, informed consent; inability to receive orally or enterally administered drugs; use of immunosuppressants or immune-modulators (including chemotherapy and corticosteroids) in the preceding 28-day period unless recommended by the treatment medical team as part of the therapeutic approach for SARS-CoV-2 infection; and participation in clinical trials of any kind in the previous 28 days.
cord-035020-mhs7yext	2020	title: Platelet-to-lymphocyte ratio, a novel biomarker to predict the severity of COVID-19 patients: A systematic review and meta-analysis Research articles comparing the PLR value on admission in adult patients with COVID-19 with varying degrees of severity were included in the analysis. Therefore, this systematic review aims to review the prognostic value of PLR levels on admission to determine the severity and mortality of COVID-19 patients. We included cohort studies evaluating the difference in PLR levels on admission in adults (>18 years old) with confirmed COVID-19 (diagnosed using RT-PCR) categorized based on disease severity (severe and non-severe patients), and/or mortality (survivor and non-survivor). Our meta-analysis, which included a total of 998 COVID-19 patients, showed that high PLR value was associated with severe COVID-19. Six out of the seven included studies demonstrated similar results with increased PLR on admission found in severe cases of COVID-19 compared to those with mild or moderate diseases.
cord-253077-61fmul8c	2020	Lastly, Nonhuman primate (NHP) studies and patient data on SARS-CoV-1 have also shown that virus spike-specific IgG responses can exacerbate acute lung injury due to repolarization of alveolar macrophages into pro-inflammatory phenotypes and enhanced recruitment of inflammatory monocyte via CCL2 and IL-8 (Clay et al., 2012; Liu et al., 2019) . Collectively, these data suggest that cross-talk with monocytes might impair NK cell recognition and killing of SARS-CoV-2infected cells, and antibodies targeting IL-6 and TNF-signaling may benefit enhanced NK cell functions in COVID-19 patients ( Figure 2 ). However, these CD4 T cells lacked phenotypic markers of activation and were specific for C-terminal S protein epitopes that are highly similar to endemic human coronaviruses, suggesting that crossreactive CD4 memory T cells in some populations (e.g., children and younger patients that experience a higher incidence of hCoV infections) may be recruited into an amplified primary SARS-CoV-2-specific response (Braun et al., 2020) .
cord-253502-v2hh3w3r	2004	authors: Leung, C.W.; Chiu, W.K. title: Clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (SARS) in children [5] [6] [7] [8] [9] [10] [11] Superspreading events including a major hospital outbreak, in-flight transmission on board commercial PAEDIATRIC RESPIRATORY REVIEWS (2004) Summary Children are susceptible to infection by SARS-associated coronavirus (SARS-CoV) but the clinical picture of SARS is milder than in adults.
cord-254419-qw83atrx	2020	This narrative review aims to summarize the current available evidence on the interplay between hypercoagulability, thrombo-inflammation, and pulmonary microvascular thrombosis in COVID-19 infection resulting in respiratory failure and how this information can be used to design clinical trials to optimize patient outcomes. ACE2 angiotensin-converting enzyme 2, CRP C-reactive protein, ESR erythrocyte sedimentation rate, LDH lactate dehydrogenase, NETS neutrophil extracellular traps, SARS-COV-2 severe acute respiratory syndrome coronavirus 2, TMPRSS2 transmembrane protease serine 2 shown to be at higher risk of worse outcomes [13] [14] [15] (Fig. 2) . CHD chronic heart disease, CLD chronic lung disease, CKD chronic kidney disease, DOACS direct oral anticoagulants, FDPs fibrinogen degradation products, HTN hypertension, IFN interferon, JAK Janus kinase, LDH lactate dehydrogenase, LMWH low molecular weight heparin, NSAIDS nonsteroidal anti-inflammatory drugs, PT prothrombin time, TNF tumor necrosis factor, VW Ag Von Willebrand antigen and microvascular thrombosis appears to be responsible for the clinical picture that leads to progressive multi-organ failure in a small percentage of patients, ultimately causing fatalities.
cord-254809-o454k6ae	2020	Third, according to an analysis of nearly 45,000 confirmed cases, 19% of patients with COVID-19 have been identified as severe cases and critically ill cases, involving severe pneumonia and metabolic disorders, developing into acute respiratory distress syndrome (ARDS), multiple organ dysfunctions (MODS), and even septic shock and death (9, 12) . In this study, we investigated mild cases and severe cases infected with SARS-CoV-2, as well as healthy young children and adults. Our study suggests that monocytes, neutrophils, and T-lymphocytes are associated with the onset and progress of COVID-19 infection, and immunopathogenesis was involved in ARDS, metabolic disorders, and MODS in severe cases. We collected the data of patients with COVID-19, including the clinical records, laboratory results and chest computed tomography (CT) scan images of mild and severe cases in the hospital. Extremely high levels of circulating lymphocytes and monocytes would benefit to fight against SARS-CoV-2 infection, which might be associated with the low morbidity of COVID-19 in young children.
cord-255174-h1izji2g	2020	It is very important to analyse the clinical characteristics of COVID-19 in international regions and identify risk factors to reduce the incidence of severe and critical illness in the early stage. In this letter, we present discrepancies of patients with different disease severities and risk factors for severe COVID-19 by comparing and analysing epidemiological and clinical data of 167 confirmed patients in Anhui, China. There are still no specific therapies for COVID-19(1); nevertheless, assessing risk factors and symptomatic treatment in the early stage of the disease can improve the prognosis. The similarities and differences between severe and non-severe patients in this letter suggested that elderly patients with multiple comorbidities, hypoxia, decreased CD4 and CD8 cell counts and increased levels of CRP and IL-6 are all closely associated with disease severity and prognosis, which should be assessed seriously during diagnosis and treatment. MDT consultation and artificial liver therapy are very effective methods for severe patients with COVID-19.
cord-255490-gyq6cpc9	2020	Restrospective analysis of clinical data of 85 patients infected with SARS‐CoV‐2, including gender, age, comorbidities, symptoms, blood routine, clotting profile, biochemical examination, albumin, myocardial enzyme profile, inflammatory markers, and chest CT. Severe patients often develop dyspnea and/or hypoxemia one week after onset, and may even rapidly progress to acute respiratory distress syndrome (ARDS), septic shock, hard-to-correct metabolic acidosis, bleeding and coagulation dysfunction, and multiple organ failure 2 . The clinical data of 85 patients diagnosed by COVID-19 were collected, including 39 common patients in department of infectious diseases from January 10, 2020 to February 15, 2020 and 46 severe and critical patients in intensive care unit (ICU) from January 10, 2020 to February 28, 2020. In addition, in terms of comorbidities, compared with common patients, the proportion of severe and critical patients with hypertension (13.0% vs 41.0%, p=0.003) and coronary heart disease (2.2% vs 20.5%, p=0.017) were higher.
cord-257344-d13at1y5	2020	Patients with predisposing diseases are highly prone to COVID-19 and manifesting severe infection especially with organ function damage such as acute respiratory distress syndrome, acute kidney injury, septic shock, ventilator-associated pneumonia, and death. Patients with underlying diseases are highly prone to present with severe infection especially with organ function damage such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), septic shock, and ventilator-associated pneumonia (VAP) 10, 13 . Results of another systematic review and meta-analysis on 53 randomized clinical trials on administration of hydroxychloroquine in COVID-19 management revealed that hydroxychloroquine administration (case group) was significantly associated with higher incidence of total adverse effects in comparison to placebo or no treatment (control group) in overall population of patients with COVID-19 45 . Almost all of the potential drugs in COVID-19 treatment containing chloroquine, hydroxychloroquine, ribavirin, and lopinavir/ritonavir have hepatic metabolism.
cord-258307-nsdhvc8w	2011	The most recent and perhaps most fearsome emerging infections are the appearance of West Nile virus encephalitis in New York City in 1999 and its rapid spread westward 6 ; inhalation anthrax, deriving from use of Bacillus anthracis spores as a biologic weapon against the US civilian population in 2001 7 ; the global outbreak of severe acute respiratory syndrome (SARS) in 2003 8 ; and the looming threat of pandemic influenza, especially global disease caused by the highly virulent avian subtype A (H5N1). If it is not, the effort will not have been wasted because it is likely that all the planning and resource allocation will prove invaluable for controlling the spread of natural emerging pathogens, such as SARS-CoV or a new strain of influenza virus, which are probably far more likely to pose a serious threat to human and animal health in the United States and worldwide.
cord-260238-2p209g2p	2004	Severe acute respiratory syndrome (SARS) was caused by a previously unrecognized animal coronavirus that exploited opportunities provided by ''wet markets'' in southern China to adapt to become a virus readily transmissible between humans. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS CoV) in SARS patients: implications for pathogenesis and virus transmission pathways Characterization of severe acute respiratory syndrome-associated coronavirus (SARS CoV) spike glycoprotein-mediated viral entry Severe acute respiratory syndrome associated coronavirus (SARS CoV) infection inhibition using spike protein heptad repeat-derived peptides Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAB to S1 protein that blocks receptor association
cord-261633-r4qlbnc5	2014	The impact of -defensin-2 on the inflammatory response (e.g., the level of ICAM-1 expression), the severity of lung injury, and the sepsis outcome (7-day survival rate) were observed and evaluated. Previous studies showed that single nucleotide polymorphism (SNP) of -defensin-1 gene (DEFB1) correlates with chronic obstructive pulmonary disease, asthma, genetic allergy, HIV infection, and pseudomonas species infection in oral mucosa [38] [39] [40] [41] [42] . Distribution of alleles, gene types, and haplotypes associating with these loci were studied and compared between septic patients and controls, as well as between survivals and victims of severe sepsis. The authors found that patients with high copy number of DEFA1/DEFA3 were predisposed to severe sepsis and tended to have lower level of plasma HNP1-3 as well as cytokines such as TNF-, IL-6, and IL-10.
cord-263031-cco2vh0f	2020	We discuss immunological and clinical considerations for patients on biologic agents (biologicals)targeting the type 2 inflammatory response due to difficult-to-treat allergic diseases in the context of COVID-19. In other coronavirus infections such as severe acute respiratory syndrome (SARS), type I IFN are critical for the initiation of immune response and virus clearance. In line with a paucity of mechanistic data on COVID-19 in the context of type 2 inflammation, knowledge on the disease course in patients treated with biologicals targeting type 2 inflammation due to severe asthma or other atopic diseases, such as CSU, AD and CRSwNP, is scarce to absent. In the past years, new biological therapies for severe asthma, atopic dermatitis (AD), chronicrhinosinusitis with nasal polyps (CRSwNP) and chronic spontaneous urticaria (CSU) have been developed targeting different aspects of the type 2 immune response.
cord-270533-s2d3q4ob	2004	Severe acute respiratory syndrome (SARS), a newly emerged infectious disease of humans in the 21st century, appeared in Guangdong Province in Southern China in November 2002 and spread to 26 countries on five continents along international air travel routes, causing large scale outbreaks in Hong Kong, Singapore and Toronto in early 2003. This novel CoV has satisfied Koch''s postulates for causation by its consistent isolation from SARS patients, viral isolation, reproduction of disease in non-human primates after inoculation and the presence of specific antibody response against the virus in both patients and experimentally infected primates 8 . Indeed, sporadic reemergence of cases have been reported in Guangdong Province as well as from research laboratories Summary Severe acute respiratory syndrome (SARS) is a new infectious disease of the 21st century that has pandemic potential. The high morbidity and mortality of this potentially pandemic infection demands a rapid research response to develop effective antiviral treatment and vaccine.
cord-274802-7ioiwsd8	2020	Proteomic and transcriptomic studies on bronchoalveolar lavage (BAL) samples from COVID-19 patients have also revealed considerable insights into the expression of SARS-CoV-2 receptors, co-receptors, immune responses, as well as risk factors for severe disease e.g. age and co-morbidities. Furthermore, treatment with a recombinant C5a antibody on 2 male COVID-19 patients aged 54 and 67 years showed significant benefit in suppressing complement hyperactivation, which contributes to the excessive immune response causing aggravated inflammatory lung injury, a hallmark of SARS-CoV-2 pathogenesis and lethality (242) . Consistent with endothelial injury, the significantly elevated levels of von Willebrand factor found in the patient with severe COVID-19 has led to the idea that the infection of the ACE2 expressing endothelium by SARS-CoV-2 induces injury and activates the complement , which sets up a feedback loop that maintains a state of inflammation (243, (268) (269) (270) . Initial clinical studies in China involving 100 SARS-CoV-2 infected patients, who were treated with Chloroquine, showed amelioration of pneumonia, shortened disease progression, increased resolution of lung lesions on CT, and a better virus-negative conversion (313, 314) .
cord-275154-vwnpred5	2009	Conclusions While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. Conclusions While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. To determine if host immune responses play a potential role in the evolution of mild or severe nvH1N1 illness we performed an analysis of systemic chemokine and cytokine levels in serum from severe and mild nvH1N1 patients shortly following the onset of symptoms.
cord-275506-3t5gf66c	2020	[45] A retrospective study of COVID-19 patients admitted to ICU identified DVT in 25% with advanced age, lower lymphocyte counts and elevated D-dimers being significant risk factors. [63] Currently, the evidence base for the clinical management of COVID-19 is mostly limited to case series and other relatively small observational studies of hospitalised patients. Similar to findings in SARS patients, [64] lymphopenia is the most commonly reported hematological abnormality in COVID-19 and recent data shows that it can be predictive of disease severity. The use of convalescent plasma may, in addition, provide neutralising antibodies against SARS-CoV-2 and a small-scale clinical trial has reported modest but encouraging results in severely-ill but not in critical COVID-19 patients. In view of the increased thrombotic risk associated with COVID-19, prophylactic anticoagulation with low Accepted Article molecular weight heparin is recommended for all hospitalised patients with the disease and clinical trials are needed to investigate the role of more intensive anticoagulation and other experimental therapies.
cord-277217-jh4qmoso	2013	35 The study, which analyzes only early childhood disease, reports that 99% of influenza-related cases of severe ALRI among children younger than 5 years occur in low-and middle-income countries, and that 13% of all ALRI in this age group are associated with influenza virus infection. The vast majority of severe illness occurs in low-and middle-income countries, 42 yet there are currently little clinical data or evidence-based management guidelines to improve hospital care for patients in these settings. 66, 67 Hospital care is often delivered by nurses and non-specialist doctors who may have limited time, resources, training, and access to information to manage severely ill patients, 67,68 particularly during a public health emergency like the 2009 influenza pandemic. Several recent global initiatives have developed guidelines for the syndromic management of severe influenza and other severe illness in resource-limited settings.
cord-277347-5innqoip	2020	title: A cohort study of 223 patients explores the clinical risk factors for the severity diagnosis of COVID-19 METHODS: In this retrospective study, the clinical characteristics, laboratory findings, treatment and outcome data were collected and analyzed from 223 COVID-19 patients stratified into 125 non-severe patients and 98 severe patients. For the diagnosis markers, we found that the levels of D-dimer, C-reactive protein (CRP), lactate dehydrogenase (LDH), procalcitonin (PCT) were significantly higher in severe group compared with the non-severe group on admission (D-Dimer: 87.3% vs. The laboratory findings on admission were shown in Table 1 Table 2 is the summary of case studies (4, 5, 9, 10) examining the association between clinical characters and COVID-19 in the meta-analysis, dividing into two subtypes: severe and non-severe patients. Figure shows the association between elevated risk factors and severity of COVID-19 in the meta-analysis: CRP (A), LDH (B), PCT(C) and D-dimer (D).
cord-278013-0d6o5w8z	2020	We analyzed the epidemiological dataset of confirmed cases with COVID-19 in Japan as of 28 February 2020 and estimated the number of severe and non-severe cases, accounting for under-ascertainment. The ascertainment rate of non-severe cases was estimated at 0.44 (95% confidence interval: 0.37, 0.50), indicating that unbiased number of non-cases would be more than twice the reported count. Considering that reported cases are usually dominated by non-severe 11 cases, the adjusted total number of cases is also about a double of observed count. Here f a denotes the ratio of non-severe to 1 severe reported case of age group a, as estimated from age-specific severity and 2 incidence rate ratio in China (Guan et al., 2020 , Novel, 2020 . The ascertainment rate of non-severe cases, k, was estimated at 0.44 (95% 10 confidence interval (CI): 0.37, 0.50). The present study estimated the ascertainment-adjusted number of cases in 19 Japan, using age-specific severe fraction of cases.
cord-278477-9a7gmzz3	2020	Aims This study aimed to assess whether body mass index (BMI), fasting plasma glucose (FPG) levels, blood pressure (BP), and kidney function were associated with the risk of severe disease or death in patients with COVID-19. To examine the association between baseline health status and the risk of severe disease in patients with COVID-19, we performed a case-control study, using data from the nationwide registry of COVID-19 cases and from the biennial health checkup database in South Korea. In the present study based on a nationwide COVID-19 registry combined with an independent regular health checkup data, the effect of FPG levels and eGFR on the risk of severe or fatal COVID-19 varied between sex and age groups. In our retrospective study using a nationwide health checkup database, high FPG levels and low eGFR were significantly associated with the risk of severe COVID-19 (including fatal illness among women.
cord-285557-my16g91c	2004	This strengthened the case for the novel coronavirus being the cause of SARS, but only after it had been shown to cause a similar illness in artificially infected macaques could it be regarded as fulfilling all four of Koch''s postulates ; World Health Organisation Multicentre Collaborative Networks for Severe Acute Respiratory Syndrome Diagnosis, 2003) . Nevertheless, and despite considerable progress in this field, much remains to be done until laboratory tests become a useful tool for the management of SARS cases (World Health Organization Multicentre Collaborative Network for Severe Acute Respiratory Syndrome Diagnosis, 2003) . An enzyme-linked immunosorbent assay (ELISA) was developed that detects antibodies in the serum of SARS patients and reliably yields positive results at around day 21 after the onset of illness (World Health Organization Multicentre Collaborative Network for Severe Acute Respiratory Syndrome Diagnosis, 2003).
cord-286683-mettlmhz	2020	Interestingly, the increased amounts of proinflammatory cytokines in serum associated with pulmonary inflammation and extensive lung damage described both in SARS [59] and MERS diseases [60] were also reported in the early study of 41 patients with COVID-19 in Wuhan [41] . A recently published case report of a patient with mild-to-moderate COVID-19 revealed the presence of an increased activated CD4+ T cells and CD8+ T cells, antibody-secreting cells (ASCs), follicular helper T cells (TFH cells), and anti-SARS-CoV-2 IgM and IgG antibodies, suggesting that both cellular and humoral responses are important in containing the virus and inhibiting severe pathology [82] . Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: Retrospective case series
cord-286799-q9p5kg65	2020	The subsequent analysis with single-factor and multivariate logistic regression methods indicated that 17 factors on admission differed significantly between mild and severe groups but that only comorbidity with underlying diseases, increased respiratory rate (>24/min), elevated C-reactive protein (CRP >10 mg/L), and lactate dehydrogenase (LDH >250 U/L) were independently associated with the later disease development. Finally, we evaluated their prognostic values with receiver operating characteristic curve (ROC) analysis and found that the above four factors could not confidently predict the occurrence of severe pneumonia individually, though a combination of fast respiratory rate and elevated LDH significantly increased the predictive confidence (AUC = 0.944, sensitivity = 0.941, and specificity = 0.902). Finally, we evaluated their prognostic values with receiver operating characteristic curve (ROC) analysis and found that the above four factors could not confidently predict the occurrence of severe pneumonia individually, though a combination of fast respiratory rate and elevated LDH significantly increased the predictive confidence (AUC = 0.944, sensitivity = 0.941, and specificity = 0.902).
cord-286843-8qh1pblc	2018	Univariate and multivariate logistic regression showed that serum procalcitonin, APACHE II severity score and mixed viral-bacterial infection were associated with increased risk of hospital mortality. Postulated prohibitive factors against the routine performance of viral diagnostics tests in patients with severe CAP may include a lack of clear clinical guidelines, perceived low cost-effectiveness and the paucity of effective anti-viral therapies for respiratory viruses other than influenza. Our primary hypothesis was that respiratory viruses were important causative pathogens in severe CAP and was associated with increased mortality when present with bacterial pathogens in mixed viral-bacterial co-infections. performed a prospective observational study on physician practices in the use of respiratory virus diagnostics demonstrating that despite clinical guideline recommendations on testing of respiratory viruses during influenza season, less than half of patients admitted to the intensive care unit with pneumonia were tested for viral pathogens [14] .
cord-287872-i6cahnxd	2020	Severe respiratory COVID-19 and hospitalized COVID-19 were genetically correlated with 127 and 174 phenotypes, respectively, after multiple testing correction ( Figure 1A ). With 188 traits genetically correlated with either COVID-19 outcome after multiple testing correction (Table S3) , we tested for causality among UKB, severe respiratory COVID-19, hospitalized COVID-19. After multiple testing correction we detected 24 and 42 latent causal genetic relationships with severe respiratory COVID-19 and hospitalized COVID-19, respectively (Table S4) . After multiple testing correction there were no significant differences between genetic causality proportions estimated for severe respiratory COVID-19 and hospitalized COVID-19. Phenome-wide assessment of 14 COVID-19 liability loci (across three severity outcomes: severe respiratory, hospitalized COVID-19, and all COVID-19) identified 439 significant (FDR q<0.05, Figure 1C ) out of 7,221 phenotypes across six ancestries (Table S5) .
cord-294700-pb5k21da	2020	Although the majority of SARS-CoV-2 infections in pediatric populations result in minimal or mild COVID-19 in the acute phase of infection, a small subset of children develop severe and even critical disease in this phase with concomitant inflammation that may benefit from immunomodulation. The framework presented herein offers an approach to decision-making regarding immunomodulatory therapy for severe or critical pediatric COVID-19 and is informed by currently available data, while awaiting results of placebo-controlled randomized clinical trials. Given the lack of available results from randomized-controlled trials of immunomodulatory therapy in children with COVID-19, the risk-benefit ratio for most pediatric patients points toward supportive care as the key management strategy. In the absence of such opportunity, and recognizing that definitive evidence is lacking, consideration for use of immunomodulatory agents in cases of SARS-CoV-2 infection with clinical and biochemical evidence of cytokine storm physiology (e.g., features of secondary HLH) should be limited to patients with clear evidence of critical COVID-19 disease and risk for multi-organ failure.
cord-296605-p67twx7a	2004	title: Management of Critically Ill Patients with Severe Acute Respiratory Syndrome (SARS) Most SARS patients would require high flow oxygen supplementation, 20–30% required intensive care unit (ICU) or high dependency care, and 13–26% developed acute respiratory distress syndrome (ARDS). The management of critically ill SARS patients requires timely institution of pharmacotherapy where applicable and supportive treatment (oxygen therapy, noninvasive and invasive ventilation). More than onethird of all the SARS patients required high flow oxygen therapy [4] , 20-30% required intensive care unit (ICU) admission or high dependency care, and 13-26% developed acute respiratory distress syndrome (ARDS) [5, 6] . Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China Evaluation of non-invasive positive pressure ventilation in treatment for patients with severe acute respiratory syndrome Clinical observation of non-invasive positive pressure ventilation (NIPPV) in the treatment of severe acute respiratory syndrome (SARS)
cord-297323-l3f12hg4	2020	Like many viruses, SARS‐CoV‐2 has evolved strategies to circumvent innate immune detection including low CpG levels in the genome, glycosylation to shield essential elements including the receptor binding domain, RNA shielding and generation of viral proteins that actively impede anti‐viral interferon responses. These subsequently induce expression of type I IFNs (IFNα/β) and interferon stimulated genes (ISGs) [figure 2] many of which have potent antiviral activities, as well as other proinflammatory mediators e.g. cytokines, chemokines and antimicrobial peptides that are essential to initiate the host innate and adaptive immune response. Likewise, viral load, obesity, gender, race, blood groups and comorbidities have all been reported to influence the response to SARS-CoV-2 infection, [ Table 4 ; (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) (112) ] although few studies have fully examined the extent to which subversion and activation of innate immune components contribute to susceptibility in these cases. Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection
cord-299093-zp07aqpm	2020	Thus, evasion of IFN signaling by SARS-CoV-2 and impaired IFN production in J o u r n a l P r e -p r o o f human peripheral blood immune cells might contribute to the productive viral replication, transmission, and severe pathogenesis during COVID-19, although further testing is warranted to fully dissect these putative evasion pathways [95] . For instance, Krt18-hACE2 and betaactin-hACE2-transgenic mice rapidly succumb to SARS-CoV-2 infection with lung infiltration of inflammatory immune cells inducing severe pulmonary disease, accompanied by evident thrombosis and anosmia, which partially recapitulate human COVID-19 [114] [115] . Furthermore, upon viral challenge, lymphocytes have expanded in rhesus macaque models around 5 dpi with complementary B-cell responses against SARS-CoV-2 Spike appearing 10-15 dpi in blood samples [125] ; expansion of these adaptive immune compartments was analogous to those observed in COVID-19 patients [37, 125, [132] [133] [134] .
cord-299150-1noy0z88	2020	However, clinical trials of agents tested for severe COVID19 may not necessarily test for mortality outcomes as the primary endpoint, as was highlighted in the press release of the recent remdesivir trial. Since drugs improving mortality in severe COVID-19 is the most important endpoint to achieve both from clinical and public policy standpoint, we evaluated the type of primary endpoints currently being assessed in randomized controlled trials (RCTs) in severe COVID19. Our analysis found that only 6/19 (30%) ongoing phase III RCT in severe COVID19 have mortality as the standalone primary endpoint or a part of composite endpoint. Given that mortality is as high as 25% in severe COVID19 who need ICU care and average time to death is 3-6 days [2, 3] , the number of mortality events needed and follow-up time do not pose an impediment for analysis of mortality as the primary endpoint.
cord-300559-vuuxthx2	2020	Logistic regression analysis showed that male, high body mass index (especially obesity), elevated fasting blood glucose and urinary protein positive are all risk factors for severe young COVID‐19 patients. The analysis showed that a high body mass index (especially obesity), an elevated FBG level, an elevated LDH level, and urinary protein positivity were all risk factors for severe COVID-19 in these young patients. A recently published study from China also showed that in metabolic-associated fatty liver disease patients, obesity can increase the risk for severe COVID-19 by about 6-fold [22] . Notably, in the present study, all of the severely or critically ill COVID-19 patients were males, an observation which may also be related to the distribution of obesity in China. Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease
cord-302115-r39ser2c	2020	We propose here the first model, explaining how the outcome of first, crucial 10‐15 days after infection, hangs on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, Mannose Binding Lectin ). The delayed and strong adaptive immune response (high affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm) leading to complications often requiring intensive therapy and being, in some patients, fatal. All rights reserved We focused on humoral components and, in particular on natural antibodies and MBL, to ascertain whether these players of the innate immunity fit all the epidemiological and clinical pre-conditions presented in the last three months by SARS-CoV-2. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for Accepted Article This article is protected by copyright.
cord-302166-tah3jdw0	2020	We suggest that these patients may become critically ill because of monogenic inborn errors that disrupt protective immunity to SARS-CoV-2. We suggest that these patients may become critically ill because of monogenic inborn errors that disrupt protective immunity to SARS-CoV-2. Studies since 1996 have identified a number of monogenic inborn errors of immunity (IEIs) underlying life-threatening infectious diseases, including specific viral diseases, in previously healthy patients 1,3-6 . The search for monogenic IEIs conferring predisposition to severe COVID-19 in previously healthy children and young or even middle-aged adults should therefore involve the genome-wide, agnostic testing of genetic hypotheses (see also COVID Human Genetic Effort) 10 . The discovery of monogenic IEIs to SARS-CoV-2 should help unravel the mechanistic basis of the immunopathogenesis of severe COVID-19 in young, previously healthy individuals. A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection
cord-303196-ltmu3ncu	2016	title: Severe maternal morbidity due to respiratory disease and impact of 2009 H1N1 influenza A pandemic in Brazil: results from a national multicenter cross-sectional study BACKGROUND: The aim of this study was to assess the burden of respiratory disease, considering the influenza A pandemic season (H1N1pdm09), within the Brazilian Network for Surveillance of Severe Maternal Morbidity, and factors associated with worse maternal outcome. In each group, PLTC (less severe cases) and Severe Maternal Outcome (SMO: MNM + MD) cases were compared to evaluate the factors potentially associated with more severe disease, including delay in obstetric care, also using the Prevalence Ratios plus their respective 95 % CI adjusted for the design effect of cluster sampling. Our study presents the burden of severe respiratory diseases among cases of severe maternal morbidity and results of the 2009 H1N1 influenza pandemic, considering 27 referral maternity hospitals in Brazil.
cord-305223-go75cs6r	2020	title: Clinical Characteristics of Patients with Severe Pneumonia Caused by the SARS-CoV-2 in Wuhan, China OBJECTIVES: The aim of this study was to explore the clinical characteristics and risk factors of severe pneumonia caused by the SARS-CoV-2 in Wuhan, China. SPSS was used for data analysis to explore the clinical characteristics and risk factors of patients with severe pneumonia caused by SARS-CoV-2. Statistical analysis showed that advanced age, increased D-Dimer, and decreased lymphocytes were characteristics of the patients with severe pneumonia. Severe pneumonia usually progresses rapidly, and many clinical indicators can change in a short time, especially lymphocyte count, D-Dimer and serum albumin values, and chest CT manifestations. The result suggests that advanced age, lymphocyte decline, and D-dimer elevation are independent risk factors for patients with severe COVID-19. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China
cord-305583-p2jp5fiq	2016	Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. There are now three main therapeutic options for the treatment of uncomplicated falciparum malaria in adults in the UK: artemisinin combination therapy (ACT), oral atovaquoneeproguanil or quinine plus doxycycline (or quinine plus clindamycin in certain circumstances) (see Box 4 for details of doses). 52 In line with the WHO guidelines, we recommend that IV artesunate should be used preferentially over quinine as the drug of choice for treatment of severe falciparum malaria in children (grade 1A).
cord-308169-a0ft6wdy	2013	A recently published consensus statement on severe asthma broadened the concept of ''difficult asthma'' to reflect the situation in less developed countries, where access to medications and appropriate care is a major issue, by defining three different patient groups including un(der)treated symptomatic patients, patients with low treatment adherence or unconventional therapies, and those remaining symptomatic despite high doses of anti-asthmatic therapies (13, 14) . Other similar initiatives included the EU-sponsored Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium that has published a consensus-based systematic algorithm approach to differentiate between ''problematic'', ''difficult'' and ''severe refractory'' asthma in the evaluation of patients with chronic severe asthma symptoms for use in clinical research and specialized care (73) . These treatment options for patients with severe asthma who remain symptomatic despite adhering to standard medical care include novel anti-inflammatory drugs that have been shown in preliminary studies to be effective in treating airway inflammation in asthma and so warrant further investigation (32, (83) (84) (85) (86) , and other novel approaches such as bronchial thermoplasty (87) .
cord-312486-rumqopg0	2020	The question is whether ACE2 expression levels are pertinent to SARS-CoV-2 infection only in the tissues relevant to viral entry and the lungs as its major target, [44, 45] or, given that COVID-19 in its severe form is a systemic disease with multi-organ disfunction [46, 47] , ACE2 expression levels may be important in multiple organs and tissues other than those of the respiratory system. However, the activation of multiple complement pathways, dysregulated neutrophil responses, endothelial injury, and hypercoagulability appear to be interlinked with SARS-CoV-2 infection and instead serve to drive the severity of the disease [91] . Regarding SLE, the prototypic systemic autoimmune disease, a group of investigators suggested that inherent epigenetic dysregulation causing hypomethylation and overexpression of ACE2, the functional receptor for SARS-CoV-2, might facilitate viral J o u r n a l P r e -p r o o f entry, viremia, and increased likelihood of cytokine storm in such patients [153] .
cord-316928-ivwz7jxi	2020	Considerable concern has emerged for the potential harm in the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) in COVID-19 patients, given that ACEIs and ARBs may increase the expression of ACE2 receptors that represent the way for coronavirus 2 to entry into the cell and cause severe acute respiratory syndrome. Partly to help solving this issue, we undertook a prospective study aimed at assessing the clinical characteristics, with particular emphasis on the type of antihypertensive medication, of all consecutive patients presenting at the Emergency Department of a Community Hospital in Gavardo, in the neighborhood of Brescia in Lombardia (Italy), and found to be positive for SARS-CoV-2 infection. In conclusion, we studied prospectively a cohort of consecutive Emergency Department patients found to have COVID-19 and were able to assess the relationship between ACEI and ARB use and the severity of the disease.
cord-317058-anvmj4li	2020	Multivariate logistic analysis indicated that patients aged ≥63 years (odds ratio = 41.0; 95% CI: 2.8, 592.4), with an absolute lymphocyte value of ≤1.02×10(9)/L (odds ratio = 6.1; 95% CI = 1.5, 25.2) and a C-reactive protein level of ≥65.08mg/L (odds ratio = 8.9; 95% CI = 1.0, 74.2) were at a higher risk of severe illness. Our study indicates that age, the absolute lymphocyte count at initial visit, and CRP may be used as predictors during the early stage of diagnosis in patients who are at risk of developing severe COVID-19. Although this study has some limitations, including a small sample size, few variables included in the multivariate analysis, a retrospective cohort design, and limited data collected from medical records, the results of our study indicate that older age, a decreased lymphocyte count on admission, and an increased concentration of serum CRP could serve as early warning signs in patients who are at risk of developing severe COVID-19.
cord-318319-efqf5e1i	2020	The lymphocyte count after ciclesonide treatment in the non-severe pneumonia group was significantly higher (p = 0. Many patients with coronavirus infection disease 2019(COVID-19) are subclinical, and it has been reported that people are J o u r n a l P r e -p r o o f contagious even when asymptomatic [1, 2] , which means preventing the spread of SARS-CoV-2 is challenging [3] . Risk factors of severe pneumonia include age, comorbidities, smoking, reduced lymphocyte count, elevated ferritin levels, and elevated C-reactive protein (CRP) levels [4] [5] [6] [7] [8] [9] . In addition, we examined whether ciclesonide could prevent the development of severe COVID-19 among patients with these predictors. Moreover, the lymphocyte count after ciclesonide therapy in the non-severe pneumonia group was significantly higher (p=0.0156) compared to before treatment (mean 6.14 days, SD 2.17) (Figure 3b ).
cord-322229-a7sz6e3c	2020	The current study represents the mental health survey conducted on the students of South India after the completion of one month quarantine period of the COVID-19 outbreak. Conclusion: In India during the outbreak of COVID-19, an alarming number of students were found to have an impact on mental health due to the outbreak and were observed to have higher levels of stress, anxiety, and depression. This study represents probably the first mental health survey conducted in the students of South Indiaafter the one month quarantine period of the COVID-19 outbreak. After the country''s outbreak of COVID-19, the government of India declared public health emergency of National concern, 26 % of respondents reported severe to extremely severe depressive symptoms; 31.5 % of respondents reported severe to extremely severe anxiety symptoms,and 19 % reported severe to extremely severe stress levels.
cord-324840-ug5a9wx6	2013	In a cohort of critically ill pediatric patients, Fidler and coworkers observed that MBL levels less than 1000 ng/mL, consistent with MBL-2 gene exon 1 polymorphisms, significantly increased the risk of developing systemic inflammatory response syndrome (SIRS) and progression to severe sepsis/septic shock [32] . The association between the deficiency of this protein and worse outcome during severe systemic infections (i.e., evolution to refractory septic shock) may be also related to the significant interaction between complement activation, inflammatory cytokines'' "storm", and coagulation cascade. Hence MBL, due to its pivotal role in the crosstalking among complement activation, coagulation, and systemic inflammation, may represent a key point for the understanding of the development of systemic severe infections, as interestingly investigated in animal models and clinical studies involving patients with severe sepsis/septic shock.
cord-325170-50oy9qqy	2020	Specifically, we employed a deep learning-based model to effectively mine the complementary information in static clinical data and serial quantitative chest CT sequence. The differences of clinical and laboratory data and imaging features between the patient with and without severe/critical progression were compared using Chi-square test, Fisher''s exact test, independent t test and paired t test. With the worldwide outbreak of COVID-19, early prediction and early aggressive treatment of mild patients at high risk of malignant progression to severe/critical stage are important ways to reduce mortality. We also demonstrated that our method can effectively fuse these two complementary data and handle time-series information in the quantitative chest CT sequence, which achieved an AUC of 0.954 (95% CI Although lots of clinical, laboratory, and imaging parameters varied significantly between patients with and without severe/critical progression, seven predictive All rights reserved. In conclusion, the deep learning-based method using clinical and quantitative CT data to predict malignant progression to severe/critical stage.
cord-328384-jzfr2t3p	2020	We performed a systematic review and meta-analysis to assess the risk factors associated with poor clinical outcomes among patients with COVID-19. We performed a systematic review and meta-analysis to evaluate potential risk factors that might influence the severity of COVID-19. Studies were included in this review if they met the following inclusion criteria: (1) assessed the clinical manifestations and laboratory findings of patients with mild to severe COVID-19; The studies included in this systematic review also suggest that the levels of D-dimer were significantly higher in patients with severe COVID-19. Our data suggest that elevated levels of urea and creatinine, and not chronic kidney disease, were associated with severe COVID-19, which indicates that acute inflammation might be caused by SARS-CoV-2 infection. These data suggest that it cannot be determined clearly whether the elevated levels of liver enzymes in patients with severe COVID-19 are caused by direct infection or by drug-induced liver injury.
cord-331519-ye4dtna5	2020	Conclusions: A combination of demographic and clinical features on admission is strongly associated with progression to severe disease or death in a US cohort of COVID-19 patients. In a sub-group analysis of patients < 60 years of age, we identified male sex (aHR 1.7;95%CI 1.11-2.58), BMI (aHR 1.25 per 5-unit increase; 95%CI 1.14-1.37), CCI (aHR 1.27; 95%CI 1.1-1.46) and respiratory rate (aHR 1.16 per increase of 1 over 18; 95%CI 1.13-1.2) as significantly associated with severe illness or death ( Table 2, Table S5 ). Our study provides valuable insight into the disease trajectories of hospitalized COVID-19 patients in the US and the risk factors associated with severe outcomes. In conclusion, we identified several important demographic and simple to assess factors associated with severe COVID-19 outcomes including age, nursing home status, BMI, D-dimer, troponin, ALC and respiratory rate.
cord-332298-ig1j5z07	2020	In the last few years, the terminology has further evolved with the term equine asthma (EA) now being recommended to describe horses with chronic respiratory signs ranging in severity from mild to severe that were previously referred as inflammatory airway disease and recurrent airway obstruction, respectively (3) . The future development of new portable and sensitive devices for measuring the lung function of horses (forced oscillation or flow interruption techniques), or the discovery of blood biomarkers for EA would help not only to facilitate the diagnosis of mild and moderate forms of EA in clinical practice, but also to possibly identify new phenotypes for these conditions. Qualitative data were gathered through semi-structured focus group discussions designed to capture current practices and opinions relating to the diagnosis and treatment of lower airway inflammation, as well as familiarity with and views on the most recent ACVIM consensus statement (3), in which the term "mild-moderate equine asthma" was recommended.
cord-332480-3uodkrkp	2020	Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. 13, 14, 16, 17 Of note, similar to severely ill COVID-19 cases, elevated serum levels of IL-6, TNF-α and IFN-γ have been consistently observed in cytokine release syndrome (CRS) that is common in the patients receiving T cell-engaging immunotherapies (bispecific antibody constructs or chimeric antigen receptor (CAR) T cell therapies). A randomized Phase 1b/2, double-blind, placebo-controlled clinical trial is currently recruiting patients to investigate the therapeutic efficacy of a humanized anti-GM-CSF IgG1 monoclonal antibody TJ003234 in severely ill COVID-19 patients (NCT04341116). 68 Similarly, treatment of ten severely ill COVID-19 patients with 200 mL of convalescent plasma containing viral neutralizing antibody titers more than 1:640 (A dilution of plasma that neutralized 100 TCID 50 (50% tissue-culture-infective dose) of SARS-CoV-2) led to reduced CRP levels, undetectable viremia and improved clinical symptoms.
cord-334564-bqh9jkds	2020	Since COVID-19 is associated with increased levels of pro-inflammatory cytokines (8) , an immune signature shared with several psychiatric disorders, we propose how the relationship between SARS-CoV-2/host can possibly impair interactions between the immune, nervous and endocrine systems, leading to psychiatric symptoms. Several studies have demonstrated psychiatric manifestations in patients with MERS or SARS during the acute phase, such as increased stress levels, impaired memory, symptoms of depression, anxiety, PTSD, psychoses, and suicidal behavior (28) (29) (30) (31) (32) (33) . If the increase in cytokine levels and the manifestation of psychiatric symptoms are related to the severity of the symptoms of SARS-CoV infection, the "cytokine storm" might also be related to the "mental health thunderstorms" seen in patients with COVID-19? Similar to possible mechanisms involved in the impacts of SARS-CoV-2 infection on mental health, social isolation may also be associated with dysfunctional psycho-neuroendocrine-immune interactions, which in turn can contribute to the development or the worsening of psychiatric disturbances (Figure 2) .
cord-334735-up81jotp	2003	Severe acute respiratory syndrome (SARS) is a viral disease, observed primarily in Southern China in November 2002, with variable flu-like symptoms and pneumonia, in approx. Weitere Fälle wurden aus Vietnam, Singapur und den USA (hier mation about a new syndrome by the end of February 2003, after the first cases outside the Republic of China had been observed. Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong Identification of a novel coronavirus in patients with severe acute respiratory syndrome Guideline on management of severe acute respiratory syndrome (SARS) A novel coronavirus associated with severe acute respiratory syndrome SARS: imaging of severe acute respiratory syndrome Coronavirus as possible cause of severe acute respiratory syndrome A cluster of cases of severe acute respiratory syndrome in Hong Kong Severe acute respiratory syndrome (SARS): infection control Dieses Prinzip ist bei den Neuraminidaseinhibitoren zur Therapie der Influenza bekannt und klinisch umgesetzt [7, 9, 21] .
cord-335061-wn8u7u9y	2020	This model is found effective to identify severe COVID-19 cases on admission, with a sensitivity of 84.6%, a specificity of 84.6%, and an accuracy of 100% to predict the disease progression toward rapid deterioration. In light of this unmet need in efficient triage of COVID-19 cases, the study is sought to 56 develop and validate a learning-based model that evaluates patients'' priority of being 57 admitted to hospital care due to their appearance or susceptibility toward severe 58 COVID-19. As this study was sought to identify 86 the hospitalization priority according to the prehospital assessment of severe COVID-19 87 risk, only clinical data obtained on admission were used to evaluate the importance of 88 clinical variables in identification of severe or potentially severe cases. To assess the 358 effectiveness of models in early prediction of severe progressions, patients who were 359 presented with non-severe symptom on admission but developed severe disease during 360 hospitalization were enrolled as an external testing set for analysis.
cord-337137-0ey40gzw	2005	Published by John Wiley & Sons, Ltd. Severe acute respiratory syndrome (SARS) is a new viral disease caused by a novel coronavirus, SARS-CoV ( Figure 1 ) [1, 2] . Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases Detection of severe acute respiratory syndrome-associated coronavirus in pneumocytes of the lung Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan Retroviruses pseudotyped with the severe acute respiratory syndrome coronavirus spike protein efficiently infect cells expressing angiotensin-converting enzyme 2 The severe acute respiratory syndrome coronavirus 3a protein up-regulates expression of fibrinogen in lung epithelial cells Autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome (SARS)-associated coronavirus infection
cord-337599-dyxfsojh	2020	Under such circumstances, drug repurposing has emerged as a realistic and effective strategy to counter the virus menace in the short run, and several antiviral and antimalarial medicines are currently in different stages of clinical trials. Researchers are also experimenting with nutrients, vitamins, monoclonal antibodies, and convalescent plasma as immunity boosters against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This report presents a critical analysis of the global clinical trial landscape for COVID-19 with an emphasis on the therapeutic agents and vaccines currently being tested at pandemic speed. 166 The Institute of Biotechnology, AMMS, China, registered a randomized, double-blind, 167 placebo-controlled Phase-II clinical trial of recombinant novel coronavirus (2019-nCOV) 168 vaccine (adenovirus vector) in healthy adults aged 18 and above on April 10, 2020, (Table1, 169 Entry 6). Clinical study for safety and efficacy of Favipiravir in the treatment of novel 924 coronavirus pneumonia (COVID-19) Genentech Announces FDA Approval of Clinical Trial for Actemra to Treat 1093 Hospitalized Patients with Severe COVID-19 Pneumonia
cord-339266-glmshsh6	2020	Objectives:To describe the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with co-morbid neurological symptoms. Conclusions:Patients with COVID-19 with co-morbid neurological diseases had an advanced age, a high rate of severe illness, and a high mortality rate. Clinical case studies of COVID-19 showed that elderly patients and patients with co-morbid neurological diseases had a high rate of severe and critical illness and a high rate of mortality. 13, 14 To the best of our knowledge, except for a few case reports, there has been no clinical analysis of patients with neurological diseases and co-morbid COVID-19. In summary, patients with COVID-19 with co-morbid neurological diseases had an advanced age, a high rate of severe illness, and a high mortality rate. Patients with COVID-19 with co-morbid neurological diseases had an advanced age, a high rate of severe illness, and a high mortality rate.
cord-345371-pjbviagq	2020	The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. Here, we review the recently published literature on the pharmacological treatments used so far and/or undergoing evaluation in clinical trials, with focus on the biochemical mechanisms of action of repurposed or investigational drugs, classified as agents directly targeting the virus ( Figure 1 and Table 1 ) and those used to treat the respiratory distress and inflammation associated with the cytokine release syndrome ( Figure 2 and Table 2 ).
cord-346539-kxnrf5g5	2020	This paper answers pressing questions, formulated by young clinicians and scientists, on SARS‐CoV‐2, COVID‐19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. The first cases of the coronavirus disease 2019 (COVID19) , caused by the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), were reported in China in December 2019 1 and rapidly led to pandemic. 40, 41 A seroconversion study in COVID-19 patients has found and association between disease severity and SARS-CoV-2-specific IgA levels. Mesenchymal stem cell therapy may potentiate the low IFN-I and -III levels and moderate IFN-stimulated gene response reported in SARS-CoV-2-infected ferrets and COVID-19 patients. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial
cord-347058-kejcwlng	2020	AIMS: This study aimed to make a comparison between the clinical laboratory-related factors, complete blood count (CBC) indices, cytokines, and lymphocyte subsets in order to distinguish severe coronavirus disease 2019 (COVID-19) cases from the non-severe ones. Our meta-analyses with random-effect models showed a significant decrease in lymphocytes, monocyte, CD4+ T cells, CD8+ T cells, CD3 cells, CD19 cells, and natural killer (NK) cells and an increase in the white blood cell (WBC), neutrophils, neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP)/hs-CRP, erythrocyte sedimentation rate (ESR), ferritin, procalcitonin (PCT), and serum amyloid A (SAA), interleukin-2 (IL-2), IL-2R, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) in the severe group compared to the non-severe group. In this new pandemic pneumonia, the levels of CRP and ESR significantly increased in severe cases compared to non-severe COVID-19 patients [31, 45] , which greatly coincides with those found in the present systematic review and meta-analysis.
cord-349558-vof63qat	2020	Exclusion criteria included: [1] studies of exclusively paediatric or pregnant patients, due to the varying presentation of COVID-19 in these groups, [2] insufficient data on symptoms/comorbidities on admission in either severe or non-severe disease groups (or ICU and non-ICU All rights reserved. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Table 1 shows details of all included studies including reported findings pertaining to symptoms and comorbidities related to disease severity or ICU admission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Tables 3 and 4 show the odds ratios, 95% confidence intervals and p-values for the individual symptoms and comorbidities that were investigated in at least three of the included studies, for both severe disease and ICU admission, respectively.
cord-350492-1s6wtj25	2020	On these bases, we aimed to review the similarities between severe COVID-19 and diseases included in hyperferritinemic syndrome, from a pathogenic, clinical, and therapeutic point of view, thus proposing new insights to improve the management of those patients. In addition, it has been shown that increased amounts of pro-inflammatory cytokines, including IL-1β, IL-6, IL-12, IFN-γ, IP-10, and MCP1, were associated with pulmonary inflammation and extensive lung damage in SARS patients (25) , thus suggesting a further pathogenic loop in inducing the cytokine storm. The final result is the uncontrolled proliferation of activated immune cells, the massive production of pro-inflammatory mediators, and the development of cytokine storm syndrome, either in severe COVID-19 or SJIA. Considering the lack of efficacy of antiviral therapy for severe coronavirus infection, it is reasonable to postulate the clinical usefulness of specific immunomodulatory therapies (Figure 1) , as observed for other diseases included in hyperferritinemic syndrome such as intravenous immunoglobulins (IVIGs) and tocilizumab, the humanized monoclonal antibody against IL-6 receptor (7).