key: cord-0978773-1phcwzet authors: Del Sole, Francesco; Farcomeni, Alessio; Loffredo, Lorenzo; Carnevale, Roberto; Menichelli, Danilo; Vicario, Tommasa; Pignatelli, Pasquale; Pastori, Daniele title: Features of severe COVID‐19: a systematic review and meta‐analysis date: 2020-08-09 journal: Eur J Clin Invest DOI: 10.1111/eci.13378 sha: 475ebd475869443481a7552bf9220a0db12b0ae2 doc_id: 978773 cord_uid: 1phcwzet INTRODUCTION: To systematically review clinical and biochemical characteristics associated with the severity of the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐related disease (COVID‐19). MATERIALS AND METHODS: Systematic review of observational studies from PubMed, ISI Web of Science, SCOPUS and Cochrane databases including people affected by COVID‐19 and reporting data according to the severity of the disease. Data were combined with odds ratio (OR) and metanalysed. Severe COVID‐19 was defined by acute respiratory distress syndrome, intensive care unit admission and death. RESULTS: We included 12 studies with 2,794 patients, of whom 596 (21.33%) had severe disease. A slightly higher age was found in severe versus non‐severe disease. We found that prevalent cerebrovascular disease (Odds Ratio [OR] 3.66, 95% Confidence Interval [CI] 1.73‐7.72), chronic obstructive pulmonary disease (OR: 2.39, 95%CI 1.10‐5.19), prevalent cardiovascular disease (OR: 2.84, 95%CI 1.59‐5.10), diabetes (OR: 2.78, 95%CI 2.09‐3.72), hypertension (OR: 2.24, 95%CI 1.63‐3.08), smoking (OR: 1.54, 95%CI 1.07‐2.22), and male sex (OR: 1.22, 95%CI 1.01‐1.49) were associated with severe disease. Furthermore, increased procalcitonin (OR: 8.21, 95%CI 4.48‐15.07), increased D‐Dimer (OR: 5.67, 95%CI 1.45‐22.16) and thrombocytopenia (OR: 3.61, 95%CI 2.62‐4.97) predicted severe infection. DISCUSSION: Characteristics associated with the severity of SARS‐CoV‐2 infection may help to guide the early identification and management of patients with poor outcomes. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a serious public health emergency in Eastern Countries as well as in Europe and US, causing the new pandemic with increasingly numbers of infected people and deaths. The clinical presentation of SARS-CoV-2 related disease (COVID-19) is highly variable, ranging from asymptomatic/paucisymptomatic patients to acute respiratory distress syndrome (ARDS) and sepsis, with patients needing admission to intensive care unit (ICU) and mechanical ventilation [1] . Thus, SARS-CoV-2 infection primarily affects the lungs, but may cause a systemic involvement leading to sepsis and multi organ failure [2] . For this reason, the management of COVID-19 patients may differ, ranging from patients potentially being cured at home to those transferred to hospital for more intensive treatment. Of note, even in patients admitted to the hospital, there may be a lag phase between illness onset and disease complications [3] [4] [5] , and it is still unclear if it is possible to early identify patients who will need mechanical ventilation or ICU admission. This issue is of clinical relevance as early identification of COVID-19 patients at risk of experiencing more severe complications may prompt to treatment diversification. As clinical and laboratory characteristics associated with severe SARS-CoV-2 infection are not completely clarified, we performed a systematic review and meta-analysis of the data so far reported in SARS-CoV-2 infected patients to identify clinical and laboratory variables associated with a high risk ARDS, ICU or poor survival. The following variables were included in the analysis: age, male sex, prevalent cerebrovascular disease, chronic obstructive pulmonary disease (COPD), prevalent cardiovascular disease, diabetes, hypertension, cancer, smoking, increased procalcitonin, increased D-Dimer, thrombocytopenia, prothrombin time (PT), and activated activated partial thromboplastin time (aPTT). Definition of comorbidities were based on medical records review. Increased D-Dimer was defined ≥0,5 mg/L (µg/mL) by Guan This article is protected by copyright. All rights reserved that used a lower cut-off (≥0,05 ng/ml). Thrombocytopenia was generally defined as platelet count < 100 x10 9 decided. Studies not including a control group and animal studies were excluded. Case reports, editorials, commentaries, letters, review articles, guidelines were also excluded from the analysis. The outcome for each study was set as the odds ratio (OR) and was computed based on reported counts of severe patients, for each risk factor. A continuity correction of 0.5 was also used. The standard error of the log-hazard ratio was also computed directly based on these counts, which This article is protected by copyright. All rights reserved were available for all studies, and used to compute 95% confidence intervals. For continuous variables, the outcome was set as the proportion of severe patients in the study, and the variable was summarized through the overall median. The I 2 -statistic was quantified to measure heterogeneity. For categorical predictors the DerSimonian and Laird random-effects model was used when an I2>25% was observed; fixed-effects methods otherwise. Forest plots summarized the results. For continuous predictors a similar criterion was used to compare random and fixed effects meta-regressions. Bubble plots were used to summarize the results. All analyses were done using the R (R Development Core Team) software version 3.5.1. A p-value <0.05 was considered statistically significant. We included 12 studies with 2,794 patients with SARS-CoV-2 infection. The weighted median age of this population was 50 years ( Patients with severe disease had a slightly higher age compared to non-severe ones ( Table 1 ). In the severe group, 38.1% were women and 61.9 % were men. Among men, the proportion of those presenting with severe disease was 22.4% (range 15.7%-60.0%). A lower percentage of severity was found in women, which was 17.9% (range 5.9%-64.7%). A metanalysis of the OR of each variable (Figures 1-2) showed that the strongest factors associated with a severe SARS-CoV-2 infection were in decreasing order, prevalent This article is protected by copyright. All rights reserved cerebrovascular disease (OR: 3.66), chronic obstructive pulmonary disease Table 2) . For the laboratory variables, the study by Tang This article is protected by copyright. All rights reserved Our pooled analysis on a large sample of patients with SARS-CoV-2 infection showed that the strongest factors associated with severe COVID-19 were cerebrovascular disease, COPD, prevalent cardiovascular disease, diabetes, increased procalcitonin, increased D-Dimer, and thrombocytopenia. The prevalence of cardiovascular risk factors reported in our analysis is similar to that reported in another recent review including >50,000 patients on this topic [7] . Prior cardiovascular disease and coexistence of risk factors such as diabetes were more associated with poor outcomes suggesting that atherosclerosis and its complications predispose to worse outcomes. Such association may be explained by the fact that cardiac damage is a frequent complication of SARS-CoV-2 as shown in patients needing ICU in whom troponin elevation may be detected up to approximately 40% of patients [8] . Thus, a recent analysis showed that patients with SARS-CoV-2 infection admitted with elevated troponin levels had worse outcomes compared to those with normal levels [9] . compared to those with non-severe disease. Studies including elderly and very elderly patients are needed to better investigate this association. 17β-estradiol and progesterone, which may play a role as immunomodulators in the host response to the viral infection [10] . In addition, there is evidence that some X-linked genes, Among the laboratory variables, elevated procalcitonin and D-dimer and low platelet count were more frequently observed in patients with severe disease. Elevated D-dimer and low platelet count may be suggestive of systemic clotting activation with secondary fibrinolysis and platelet consumption. This finding confirms a pro-thrombotic phenotype of SARS-CoV-2 infection, which This article is protected by copyright. All rights reserved is associated with the severity of the disease [13] . At this regard, a study including 449 patients with severe SARS-CoV-2 infection showed that patients with sepsis-induced coagulopathy treated with low molecular weight heparin (LMWH) had a lower 28-day mortality than non-users (32.8% vs 52.4%, p=0.017) [14] . Based on this, the ISTH recommended that all SARS-CoV-2 infections should be treated with prophylactic doses of low-molecular weight heparin to lower the thrombotic risk [15] . Further study is, however, necessary to stablish if this approach is effective and may be useful for all SARS-CoV-2 patients or only for those at risk of severe disease. Finally, we found a significant association between the severity of COVID-19 and serum levels of procalcitonin, a marker of systemic inflammation and sepsis severity, suggesting that systemic sepsis, probably related to bacterial sovra-infection, may complicate the clinical course of SARS-CoV-2 infection [16] . The clinical relevance of our findings relies on the evidence that there is a latency between SARS-CoV-2 first clinical presentation and development of complications; thus, previous studies reported a median time from illness onset to hospitalisation of 7-11 days [3, 4] , to ICU admission of 9 days [5] and to the development of ARDS of 8 days [4] , indicating that there may be a relatively long period between infection-related symptoms onset and occurrence of severe complications. Interestingly, non-survivor patients or those with ARDS had a higher latency period, suggesting that a delay in the care may lead to poorer outcomes [4, 5] . Thus, early identification of variables associated with poor outcomes may be useful to plan more appropriate preventive therapy to reduce the risk of ARDS and ICU and eventually improve survival and also to optimize the allocation of healthcare resources, which may be very limited in some countries. This article is protected by copyright. All rights reserved conferred by each single comorbidity, we cannot exclude that the concomitant presence of multiple conditions may further include the risk of severe disease. In conclusion, data of this meta-analysis shows that comorbidities such as COPD, prior cardiovascular disease and diabetes are associated with SARS-CoV-2 severity. The association between these clinical characteristics and COVID-19 severity may allow a better risk stratification in this patients' population. This article is protected by copyright. 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