key: cord-0730595-xm1la1nm authors: Maguire, D.; McMillan, D. title: The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts date: 2021-02-06 journal: nan DOI: 10.1101/2021.02.04.21250932 sha: 6d98b491e4ebe800551b900de5cb2eb57fdd5f4e doc_id: 730595 cord_uid: xm1la1nm Background: In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts. Methods: Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17th March 2020 - 1st May 2020) and (cohort 2: 18th May 2020 - 6th July 2020) were examined for routine clinical, laboratory and clinical outcome data. Results: Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). Over the 2 cohorts, age >70 (p<0.001), male gender (p<0.05), hypertension (p<0.01), heart failure (p<0.05), cognitive impairment (p<0.001), frailty (p<0.001), COPD (p<0.05), delirium (p<0.001), elevated peri-operative Glasgow Prognostic Score (p<0.001), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.01); and the 4C score were associated with 30-day mortality. When compared with the 4C score, greater frailty (OR 10.2, 95% C.I. 3.4 to 30.6, p<0.01) and low albumin (OR 5.6, 95% C.I. 2.0 to 15.6, p<0.01) were strongly independently associated with 30-day mortality. Conclusion: In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19. Article summary: In two consecutive cohorts of patients with COVID-19 infection admitted to two urban teaching hospitals in Glasgow, UK, there were variations in a number of clinicopathological characteristics despite similar mortality (23 and 22%). In these two cohorts, in a multivariate analysis that included the 4C mortality score, clinical frailty score >3, low serum albumin concentration (<35 g/L), high neutrophil-lymphocyte ratio (>5), and abnormal serum sodium concentration (<133/>145 mmol/L) remained independently associated with 30-day mortality. shown to have prognostic value (4) (5) (6) . In particular, the 4C mortality score was developed in 100 more than 55,000 patients with COVID-19 and measured the systemic inflammatory 101 response using C-reactive protein (6) . Other measures of the systemic inflammatory response 102 such as the neutrophil lymphocyte ratio (NLR) have also been shown to have prognostic 103 value (7) . Moreover, the systemic inflammatory response has been shown to be a useful 104 therapeutic target in patients with COVID-19 (8) (9) (10) . However, to date, as there have been CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. E l e c t r o n i c p a t i e n t r e c o r d s f o r p a t i e n t s w h o w e r e a d m i t t e d t o t w o l a r g e c i t y t e a c h i n g 116 h o s p i t a l s ( G l a s g o w R o y a l I n f i r m a r y ( G R I ) a n d t h e Q u e e n E l i z a b e t h U n i v e r s i t y H o s p i t a l 117 As per routine clinical practice in the Emergency Department (ED) and Acute Assessment 134 Unit (AAU) in both hospitals, patients were scored on the National Early Warning Score 135 (NEWS) at presentation to triage. NEWS is a validated score of severity of physiological 136 derangement that allocates a score (0-3) to six clinical parameters (pulse rate, blood pressure, 137 respiratory rate, oxygen saturations, requirement for supplemental oxygen and level of 138 responsiveness (alert (A), responding to verbal (V), painful (P) stimuli and unresponsive (U) 139 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 6, 2021. ; https://doi.org/10.1101/2021.02.04.21250932 doi: medRxiv preprint AVPU scale)) (11) . NEWS determines the triage category and level of immediate treatment 140 that is required at the time of presentation, and the interval to re-administering the NEWS 141 scoring tool according to the score achieved (i.e. the severity of physiological derangement). 142 NEWS >4 and >7 are considered to indicate moderately severe and severe physiological 143 derangement respectively. 144 The 4C Mortality Score is a validated prognostic score that predicts in-hospital mortality 146 among patients with COVID-19 who are admitted to a general hospital setting in the U.K. 147 (6) . It includes eight variables that are readily available at initial hospital assessment: age, 148 sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of 149 consciousness, urea level, and C-reactive protein (score range 0-21 points) (see Table 1 ). CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 6, 2021. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. T a b l e 1 * C o m o r b i d i t i e s w e r e d e f i n e d b y u s i n g C h a r l s o n c o m o r b i d i t y i n d e x , w i t h t h e 168 a d d i t i o n o f c l i n i c i a n d e f i n e d o b e s i t y 169 170 In the present study, age was grouped as less than Frailty was assessed using the Clinical Frailty Scale (CFS) (12, 13) . The CFS is a validated 177 measure of clinical frailty that has been shown to have prognostic value (13) . The CFS 178 includes items such as comorbidity, cognitive impairment and disability while also 179 incorporating functional interpretation of physical frailty according to level of dependence in 180 living circumstances (12) . In the present study, living circumstances were classified as: 181 independent; living at home with support from family member / paid carer or sheltered 182 accommodation; care home; or dependent living in a nursing home. 183 Admission serum C-reactive protein (CRP), albumin concentrations and differential blood 184 cell counts were categorised using local reference intervals. Neutrophil-lymphocyte ratio 185 (NLR) and the peri-operative Glasgow Prognostic Score (poGPS) were calculated as outlined 186 in Tables 2 and 3 (14) (15) (16) . The NLR and poGPS are validated prognostic scoring systems that 187 have been used in a variety of clinical settings. They both utilise two components, 188 neutrophils/ lymphocytes and C-reactive protein/ albumin respectively, that are routinely 189 measured in patients admitted to the general hospital setting. For this study, each scoring 190 system had 3 divisions indicating mild, moderate and severe systemic inflammatory response 191 respectively (17) . 192 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; https://doi.org/10.1101/2021.02.04.21250932 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; Details of the recruitment of patients for cohort 1 (n=243) have been previously described 235 (5) . In cohort 2, of the 356 patients who were confirmed to have COVID-19 infection by 236 PCR test, 278 patients fulfilled the criteria for inclusion with age, sex, BMI. Seventeen 237 patients were re-admitted and these were excluded from the analysis at second admission 238 leaving 261 patients to be included in the analysis. 239 240 Comparison of the demographical and clinicopathological characteristics of the two cohorts 241 are shown in Table 4 . Compared with cohort 1, cohort 2 were older (p<0.001), more likely to 242 be female (p<0.05) and have less independent living circumstances (p<0.001). With reference 243 to previous medical history, compared with cohort 1, cohort 2 had hypertension and heart 244 failure (both p<0.05), had chronic renal failure (p<0.001), had cognitive impairment and 245 previous delirium (both p<0.01), were less frail (p<0.001) and had less asthma (p<0.01). 246 With reference to diagnostic criteria, compared with cohort 1, cohort 2 were more likely to be 247 PCR positive and CXR negative (both p<0.001). With reference to laboratory results, 248 compared with cohort 1, cohort 2 had low albumin (p<0.001), low haemoglobin (p<0.001), 249 low haematocrit (p<0.05), lower MCV (0.05), abnormal sodium (p<0.01), elevated creatinine 250 (p<0.01), elevated alkaline phosphatase (p<0.001). 30-day mortality was similar between the 251 cohorts (23% and 22%). 252 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. The relationship between demographic and clinicopathological characteristics and 30-day 257 mortality in the two combined cohorts is shown in . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. To determine which admission parameters were independently associated with 30-day 267 mortality, those factors identified in Table 5 as significant and not in the 4C mortality score 268 were also entered into a binary logistic regression analysis ( CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. The results of the present study show that, in 2 consecutive cohorts, there was a variation in 2 the admission demographic and clinicopathological characteristics. In particular, the latter 3 cohort were older, had more cardiovascular and renal disease and greater derangement of 4 their laboratory data. Despite this, 30-day mortality was similar between the cohorts. In both 5 cohorts the 4C score, which incorporates age, sex, comorbidity, respiratory, renal and brain 6 function and a measure of the activation of the systemic inflammatory response, had 7 prognostic value. In addition, when compared directly with the 4C mortality score a number 8 of other factors had independent prognostic value, in particular clinical frailty and a low 9 albumin. Taken together, the present results would suggest that the relationship between 10 clinicopathological factors and short-term mortality in patients with COVID-19 may vary 11 with time. Also, that there are other important factors in short term mortality of patients with 12 COVID-19, not captured by the 4C mortality score and such factors may improve the 13 prognostic value of the 4C score. Therefore, there is a need for further work to determine 14 independent prognostic value of clinicopathological factors in patients presenting with 15 COVID-19. 16 17 The basis of the strong prognostic value of the clinical frailty scale and low albumin, 18 independent of the 4C mortality score in these patients, is not clear. However, COVID-19 19 patients with a clinical frailty score >3 may be considered vulnerable and frail and this entity 20 (the ability to care for themselves and its relationship with mortality) may not be captured 21 directly by the 4C score. In particular, the present results may indicate that having COVID-22 19 induced cytokine storm in a frail patient is a life threatening event (18). Similarly, with 23 reference to a low serum albumin concentration, a cytokine storm would increase the 24 likelihood of mortality. In the case of a low albumin it is clear that this may reflect both an 25 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 6, 2021. ; https://doi.org/10.1101/2021.02.04.21250932 doi: medRxiv preprint ongoing systemic inflammatory response and also poor nutritional status (19). It may be that 26 the strong prognostic value of frailty also reflects poor nutritional status since a systemic 27 inflammatory response occurring against a background of low metabolic reserves is likely to 28 lead to cellular and organ dysfunction. If this was the case, then it might be expected that 29 frail and hypoalbuminaemic patients would benefit most from treatment with anti-30 inflammatory agents and nutritional supplementation. Therefore, it may be important to also 31 consider nutritional risk in patients with COVID-19. Irrespective, it would be important to 32 consider frailty and a low albumin in the assessment of patients with COVID-19 (20). The present study has a number of limitations. The sample size is relatively small and 43 therefore subject to limitations such as sample bias. However, the clinicopathological data 44 collected was comprehensive across two cohorts, included factors validated in large cohorts 45 of patients with COVID-19 and therefore allowed direct comparison of these factors. 46 47 48 49 50 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 6, 2021. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted February 6, 2021. ; https://doi.org/10.1101/2021.02.04.21250932 doi: medRxiv preprint In the two consecutive cohorts there were variations in a number of clinicopathological 52 characteristics despite similar mortality NLR>3, abnormal serum sodium concentration (<133 / >146 mmol/L), clinical frailty 54 score >3 and low serum albumin concentration (<30 g/L) were independently associated with 55 30-day mortality in patients admitted to hospital with COVID-19 infection • COVID-19 (SARS-CoV-2 infection) References 1. 2020. 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