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Metrics details. Demographic, comorbidity and laboratory determinants of death and of ICU admission were explored in all Danish hospitalised patients. National health registries were used to identify all hospitalized patients with a COVID diagnosis. We obtained demographics, Charlson Comorbidity Index CCIand laboratory on admission and explored prognostic factors for death using multivariate Cox proportional hazard regression and competing risk survival analysis. The seven-day cumulative incidence of ICU admission was lower for females 7. Males presented with more pronounced laboratory abnormalities on admission.

Advanced age, male sex, comorbidity, higher levels of systemic inflammation and cell-turnover were independent factors for mortality.

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Age was the strongest predictor for death, moderate to high level of comorbidity were associated with a nearly two-fold increase in mortality. Mortality was ificantly higher in males after surviving the first week. Peer Review reports. Starting on March 13th, Denmark introduced comprehensive lockdown measures, as one of the first European countries, and four weeks later the country gradually reopened. Despite variations reported across countries, emerging evidence consistently indicates that older men with multiple comorbidities have poorer COVIDrelated outcomes [ 123 ].

To date, studies from Denmark focusing on the overall epidemiological characteristics during the early phase of the epidemic [ 45 ] and the association with several cardiovascular outcomes have been made publicly available [ 6 ]. Differences in laboratory markers of newly admitted SARS-CoV-2 positive cases and their association to severe outcomes have been reported from studies [ 378910 Denmark text sex contacts, 11121314151617 ], but remain unexplored in Denmark and other Scandinavian populations.

We present a complete nationwide observational study with comprehensive clinical and laboratory parameters during the first five months of the COVID epidemic in Denmark.

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The aim was to study demographic, comorbidity and laboratory determinants of death and ICU admission in Denmark. All residents of Denmark have free access to health care. Using the Danish National Patient Register DNPRwhich contains detailed information on all hospital contacts nationwide, we identified all individuals in the entire population of 5.

Patients without a unique personal registration PRN in Denmark were not present. When admissions were less than one hour apart, the patient was considered to be hospitalised the period in between as well, thus counting towards the h hospital stay. We extracted information from the following specific registries: 1 The CRS [ 20 ], which comprise date of birth, sex, vital status, date of death, emigration, area of residence; 2 The DNPR [ 21 ], which includes dates of admission and discharge, admitting departments, and all primary and secondary discharge diagnoses and procedure codes from hospital contacts; 3 Register of Laboratory for Research RLRR [ 19 ], which contains nationwide laboratory information except Midtjylland Region, population 1.

Subsequent analyses were performed on pseudo anonymized data. Age, sex, underlying medical conditions, and laboratory parameters were included in the analysis. If a measurement was repeated within this period, we used Denmark text sex contacts average. Baseline characteristics are presented as medians with interquartile range IQR for continuous variables, and s and percentages for categorical variables.

Covariates included age, sex, CCI and laboratory parameters when available.

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Interaction between covariates where examined. Cumulative incidence rates of ICU admission were analysed with competing risk survival analysis Aalen Johansen estimator with death as a competing event using Grays test for statistical ificance. Laboratory parameters underwent additional univariate analysis for differences between subgroups, using t-test for statistical ificance. The analyses were stratified by sex, and primary and secondary outcomes.

Statistical ificance level was set at 0. All tests of ificance were two-sided. We identified hospital contacts with a COVID diagnosis, of these were hospitalised, and met our inclusion criteria. On admission, In total, Stratified univariate analyses of laboratory parameters at the time of hospitalisation revealed ificant sex differences in levels of C-reactive protein CRPferritin, lymphocyte and platelet counts, lactate dehydrogenase LDHcreatinine, urea, and blood glucose.

Males presented with more pronounced laboratory abnormalities on admission, compared to females, but differences were less pronounced in the subgroups of patients who later required ICU admission or those who died Table 2. Patients who needed ICU admission or died, had more marked derangement of all the above test Table 3. During follow-up, The day mortality among patients admitted to an ICU was The day KM survival rate was This was lower for males than for females Patients with higher CCI index had lower day survival rates with The effect of the level of CCI was more pronounced in patients of older age Fig.

Kaplan-Meier curves illustrating day survival. A Sex. B Sex and age. C Charlson comorbidity index modified by Quan and sex. D Charlson comorbidity index modified by Quan and age-group. Among all hospitalised patients included in the study, The cumulative incidence rate of ICU admission during the first week after hospitalisation was There was no difference on CCI with In the multivariate analyses Fig. Conditional upon surviving the first week, the underlying comorbidity level, increasing age and male sex were all independently associated with death during day 8— Patients who died during the first 7-days after admission were excluded from the analyses of 8 to day mortality.

Where noted, the biometrics were entered on the log2 scale. Reference: normal value; CI: confidence interval; HR: hazard ratio. ICU admission was required in Advanced age, high levels of systemic inflammation CRP, Denmark text sex contacts, D-dimerhigh cell turnover LDHazotaemia ureakidney function creatinineand haemato-lymphoid reaction lymphopenia, neutrophilia, thrombocytopenia were independently associated with death within the first week of admission.

Patients who later required ICU admission had higher markers of inflammation, cell-turnover and metabolic dysregulation. Our findings are in line with the ly reported effects of age, male sex, and level of comorbidities on both mortality and the need for ICU admission [ 1371724 ]. In contrast to reports [ 1216 ], a remarkably high proportion nearly two thirds of patients had low levels of comorbidity preceding the COVID admission.

Having a moderate to high level of comorbidity was associated with a nearly two-fold increase in mortality. Males and females had similar mortality rates during the first week of admission, but likelihood for death ificantly diverged towards an increased fatality rate among males after surviving the first week for all analysed strata. The reasons behind these differences in early and late mortality are not clear, but probably multifactorial.

Sex differences in thromboembolic events could be a residual confounder of clinical relevance which may explain a difference between 7-day and day mortality for males and females. From a clinical point of view, it is reasonable to assume, that the immediate time after hospitalization may be more critical where sex differences play less of a role and the acute state of the infection is more relevant.

Thereafter other factors may become relevant as the acute threat subsides. The acute phase may be more pronounced at time of hospital admission and is stronger reflected in the baseline laboratory findings but become less relevant for the final outcome. In line with findings, patients who were at highest risk of ICU admission were males with higher CRP, LDH and blood glucose among others, indicating higher levels of inflammation, cell-turnover and metabolic dysregulation [ 371415 ].

Sex Denmark text sex contacts in laboratory parameters were markedly less pronounced in the subgroup of patients who presented with more severe outcomes, including ICU admission and death.

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Differences in the degree of inflammatory response between males and females could be a field for future research. Abnormal coagulation parameters on admission, including D-dimer, were associated with a higher risk of death but not ICU admission Table 3 as shown in other studies [ 717 ]. This could be related to a low of events among patients where the test was taken. Since Danish health care registries are independently recorded and complete [ 192021 ], the risk of selection bias and loss to follow-up was minimal.

However, we acknowledge potential differences in referral patterns during the epidemic. In comparison to studies from Denmark [ 56 ] we found a higher mortality. However, we report outcomes in a selected group of patients namely those in need of hospitalisation and therefore presenting with a more severe clinical course. The diagnosis of COVID and several other variables have not yet undergone full internal validation to date. In our survival analysis, loss to follow-up in relation to the primary outcome mortality could cause informative censoring. However, as borders were closed during most of the study period, we consider this problem minimal.

Also, we did not have access to vital parameters blood pressure, oxygen saturation etc. Although speculative, the massive lock-down, and organisational changes with extraordinary resources allocated could in part explain the possible lower median hospital duration compared to other studies [ 25 ].

Moreover, information on the actual viral load and shredding could be an indicator for the state of infection at hospitalisation but was not available in the registers at the time of this study. Sex differences in care-seeking behaviour with males presenting with a more advanced stage of disease is also a possibility.

Studies of diseases and conditions that may develop rapidly with fatal outcome can be susceptible to Neyman bias, which arises when a gap in time occurs between exposure and selection of study participants [ 26 ]. We addressed this bias by using the first admission date to the hospital as the start of follow-up rather than the date of diagnosis. Regarding missing data, we argue that laboratory parameters are missing in a systematic, non-random fashion as blood samples were taken only when a healthcare worker deemed it appropriate based on a clinical judgment.

The adjusted hazard ratios should thus be interpreted as prognostic factors for a highly selected population for which laboratory parameters were relevant for clinical reasons [ 27 ]. The majority of cases have been seen in the capital region www.

We had admitted patients from this region who did not have laboratory registered due to the lack of synchronization with data from this region. Moreover, patients in the Capital Region Copenhagen have missing laboratory. In the initial phase of the epidemic, all patients in the Capital Region with a positive SARS-CoV-2 test were admitted regardless of severity of the disease.

We argue that although the laboratory pertain to a group of patients with severe symptoms, they may well be indicative of factors of importance in the clinical follow-up and outcome of severely ill COVID patients. We chose to use baseline laboratorial values at admission and their effect on outcome, since important clinical decisions on observation and management often are made at this time. We therefore did not analyse the trend dynamics of Denmark text sex contacts covariates used or the Denmark text sex contacts of higher values during the course of admission, which would require other regression modelling and is a different research question altogether beyond the scope of the present article.

Not all individuals had laboratory for all of the parameters upon admission whereby adjusting missing values with interpolation methods on such a highly selected population were not deemed appropriate. Thus, we choose to report on the laboratory findings individually adjusting only for age, sex and CCI. Our analysis show that adjusted for pre-existing factors, several of the laboratory findings are related to increased mortality risk. However, we acknowledge that the baseline laboratory markers are different from other pre-existing determinants, and therefore could be directly on the causal pathway to more severe clinical disease or death.

Including both may have resulted in an underestimate of the importance of laboratory values and may partially mask the indirect influence of more distal factors like sex. The laboratory cut-off parameters for the multivariate analysis were arbitrary selected by the investigators. This could perhaps have resulted in an underestimation of the association between some laboratory parameters and outcomes.

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We have therefore included detailed stratified description of the in Tables 2 and 3, and the multivariate analysis should be interpreted in this context. Finally, the generalizability of our to other settings would be limited due to organizational and capacity differences between health systems in different countries, particularly regarding the definitions of ICU admissions. Among hospitalised patients during the first wave of COVID in Denmark, advanced age, male sex, chronic comorbidities, and selected clinical and laboratory parameters were all independently associated with higher risk of severe COVID related outcomes.

Males presented with more pronounced laboratory abnormalities at hospital Denmark text sex contacts. Males and females had comparable mortality during the first week of admission, but the likelihood for death was ificantly higher for males after the first week. ICU admitted patients had higher markers of inflammation, cell-turnover, and metabolic dysregulation.

Identification of such factors can be used for planning strategies targeting specific high-risk individuals. Characterization and clinical course of patients with coronavirus disease in New York: retrospective case series. Factors associated with hospital admission and critical illness among people with coronavirus disease in New York City: prospective cohort study. Int J Epidemiol. Association between male sex and outcomes of Coronavirus Disease Covid - a Danish nationwide, register-based study.

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Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in Wuhan, China. J Thromb Haemost.

Denmark text sex contacts

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