key: cord-344135-pyibu6rj authors: Zuo, Peiyuan; Tong, Song; Yan, Qi; Cheng, Ling; Li, Yuanyuan; Song, Kaixin; Chen, Yuting; Dai, Yue; Gao, Hongyu; Zhang, Cuntai title: Decreased prealbumin level is associated with increased risk of mortality in hospitalized elderly patients with COVID-19 date: 2020-07-03 journal: Nutrition DOI: 10.1016/j.nut.2020.110930 sha: doc_id: 344135 cord_uid: pyibu6rj Objective: Severe patients tended to have lower serum prealbumin concentration in patients with novel coronavirus (SARS-CoV-2) infected pneumonia (COVID-19). This study was performed to investigate the association of prealbumin at baseline on COVID19-related mortality in elderly patients. Methods: We non-selectively and consecutively collected participants in Tongji Hospital in Wuhan from January 17 to February 17, 2020. Univariate and multivariate logistic regression models were employed to evaluate the correlation between prealbumin and in-hospital outcomes (in-hospital mortality, ICU admission and mechanical ventilation) in elderly COVID-19 patients. Linear trend was performed by entering the median value of each category of prealbumin tertile as continuous variable and was visually confirmed by using generalized additive models. Interaction and stratified analyses were conducted as well. Results: A total of 446 COVID-19 elderly patients were included in the final analyses and the in-hospital mortality was 14.79%. 15.47% patients admitted to intensive care unit and 21.3% patients required mechanical ventilation. Compared with patients in the highest tertile, the prealbumin of patients in the lowest tertile had a 19.09-fold higher risk of death (OR = 20.09; 95% CI, 3.62 to 111.64; P = 0.0006), 25.39-fold higher risk of ICU admission (OR = 26.39; 95% CI, 4.04to 172.39; P = 0.0006) and 1.8-fold higher risk of mechanical ventilation (OR = 2.8; 95% CI, 1.15 to 6.78; P = 0.0227) after adjustment for potential confounders. There was a linear trend correlation between serum prealbumin concentration and risk of in-hospital mortality, ICU admission and mechanical ventilation in elderly patients with COVID-19 infection. Conclusion: Prealbumin is an independent risk factor of the in-hospital mortality for COVID-19 elderly patients. Assessment of prealbumin may help identify high risk elderly individuals with COVID-19. 1. The authors should report mean (or median) day of sample drawing after admission. This is particularly important to assess whether prealbumin levels and inflammatory markers were measured on the same day. Response: It is really true as reviewer said that the time of sample drawing after admission is particularly important to assess whether prealbumin levels and inflammatory markers were measured on the same day. In addition, if the prealbumin blood sample was extracted during the recovery period, it will have impact on the results. In our study, a relatively comprehensive blood test data were obtained from all the patients within 24 hours after admission. Then the blood indexes were monitored according to the change of condition. We only extracted the baseline levels of blood examinations. Considering the Reviewer's suggestion, we calculated the mean day of sample drawing after admission (mean±SD, 0.67 ± 0.65). We added this sentence "The day of sample drawing after admission was 0.67 ± 0.65 day." into the 1st paragraph of the results. 2. The predictive role of prealbumin in COVID-19 patients has been already reported in different publications. The assessment of whether prealbumin in COVID-19 patients is a marker of inflammation or a marker of malnutrition would be of the utmost importance. Unfortunately, the submitted article does not allow to elaborate on this important feature. It is suggested that the authors include the neutrophil-to-lymphocyte ratio in their multivariate analysis. Also, the authors should report the anthropometric variables of the patients (i.e., body weight, food intake changes, weight loss, BMI). Response: It is true as reviewer said that to assess prealbumin in COVID-19 patients is a marker of inflammation or a marker of malnutrition would be of the utmost importance. Malnutrition is associated with inflammation in older hospitalized patients. Aging, frailty, and chronic diseases are associated with impaired immune function and are compounded by immune dysregulation from malnutrition. When immune response is dysregulated, it would result in an excessive inflammation, even death. Therefore, we tend to think that serum prealbumin concentration is a screening marker for both malnutrition and inflammation. Considering the reviewers suggestion, we added neutrophil-to-lymphocyte ratio in our multivariate analysis. The results are as follows: There is no significant statistical difference of BMI and body weight across different groups of prealbumin (tertile). We have added this content in Table 1 . Furthermore, we investigate the correlation between BMI and body weight and in-hospital outcomes. There was a borderline significant association between BMI and risk of mechanical ventilation in the full adjusted model (OR, 1.17; 95% CI, 1.01 to 1.37; P =0.0446). There was no significant association between BMI and body weight with risk of all-cause death and ICU admission. Recent report revealed that overweight was associated with greater risk of severe pneumonia compared with patients of normal weight [1] . In our data, the number of overweight elderly patients is more than those of low-weight and the risk of elderly patients with low-weight may be underestimate. The height measurement of the elderly is often lower than their actual height, and many disabled elderly people are not easy to measure their body weight. Furthermore, in the elderly, the fat mass may be preserved or even increased while with low muscle mass and strength which contribute to higher mortality risk [2] . Therefore, BMI is not an accurate predictor of nutritional status in elderly. The food intake changes, weight loss proposed by the reviewers are very good anthropometric variables measurement indicators, but unfortunately we did not collect these data. It is almost impossible for us to collect the whole baseline anthropometric variables now. We feel sorry for this. We appreciate reviewer's careful work earnestly. Your comments and suggestions improved the quality of our manuscript. We tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the framework of the paper. A clean revised manuscript was attached. We appreciate for Reviewer's warm work earnestly, and hope that the correction will meet with approval. Also, we appreciate for Editors warm work earnestly, and hope that the correction will meet with approval. Once again, thank you very much for your comments and suggestions. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Decreased prealbumin level is associated with increased risk of mortality in hospitalized elderly patients with COVID-19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 Based on recent statistical data of China, among patients who were 65 years and older, the mortality rate was 34.5%, which was significantly higher than that of younger patients at 4.7% 4 . The proportion of deaths over 60 years old accounts for 81% of the total deaths in the national wide, which implicates aged people are more vulnerable to the SARS-CoV-2 5 . Till present there are rare reports in literature focusing on the risk factors for poor outcomes of the elderly patients with COVID-19. Serum prealbumin, known as transthyretin, its levels may be lowered not only by malnutrition, but also by inflammation and aging 6, 7 . Compared to albumin, prealbumin has a shorter half-life, a more rapid rate of hepatic synthesis, and predictable catabolic rate; hence, it may be a more sensitive indicator 8 . However, whether prealbumin could be an independent predictor of mortality in hospitalized COVID-19 elderly patients needs to be further elucidated. The present study aims to describe the clinical characteristics and to investigate whether the prealbumin can serve as a valuable predictor of in-hospital mortality, which might provide evidence for the risk stratification in elderly and help to improve the clinical practice and reduce fatality. We designed this study as a retrospective cohort study design. The elderly patients with COVID-19 who were admitted to Tongji Hospital in Wuhan from January 17 to February 17, 2020 were consecutively included. This study was approved by the Medical Ethics Committee of Tongji Hospital (Approval Number: TJ-IRB20200328), and was complied with the Declaration of Helsinki. The data were anonymous and the study was observational, so the informed consent was not gathered. A flow-diagram illustrating patient selection was described in Data collection of participants was performed using hospital electronic medical record system. Information included medical history, demographic data, physical examination, and hematological, biochemical, radiological and microbiological evaluation results were reviewed. The data collection forms were reviewed independently by 2 researchers (CL and LYY). Blood examinations were assessed at the central laboratory of Tongji Hospital following standard operative procedures. The routine blood test was analyzed using Sysmex XE-2100 hematology analyzer (Sysmex, Kobe, Japan). The Cobas C8000 (Roche, Mannheim, Germany) was used to measure the biochemical parameters. Coagulation tests were detected by STA-R MAX coagulation analyzer (Diagnostica Stago, Saint-Denis, France). Throat swab samples were collected and were tested for SARS-CoV-2 with commercial real-time reverse transcription polymerase chain reaction (RT-PCR) kit from DAAN GENE (Guangzhou, China) 9 . The diagnostic criteria and all clinical procedures in this study followed "Diagnosis and Treatment of Pneumonia Caused by New Coronavirus (Trial version 1 to 7) promulgated by the National Health and Health Commission of China. Summary statistics of baseline characteristics of all patients and stratification by prealbumin tertiles were expressed as frequency and proportion for categorical variables, mean ± standard deviation (SD) (Gaussian distribution) or median (range) (Skewed distribution) for continuous variables, and as percentages for categorical variables. The differences between groups were analyzed using the χ2 (categorical variables), One-Way ANOVA test (normal distribution), or Kruskal-Whallis H test (skewed distribution). We examined the relationship of the prealbumin as categorized into tertiles with the outcomes of all-cause death, ICU admission and mechanical ventilation. Univariate and multivariate logistic regression models were used to evaluate these relationships, then unadjusted and adjusted odds ratio (ORs) and 95% confidence intervals (CIs) were calculated. Model 1 is the minimally-adjusted model with only sociodemographic variables adjusted. Model 2 is the fully-adjusted model with covariates including age, sex, smoking status, history of hypertension, history of coronary heart disease, history of diabetes, history of chronic kidney disease, history of carcinoma, history of chronic liver disease, neutrophil, lymphocyte, prothrombin time, activated partial thromboplastin time, d-dimer, alanine 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 transaminase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, creatinine，C-reactive protein and neutrophil-to-lymphocyte ratio. We calculated odds ratio (ORs) and 95% confidence intervals (CIs). The highest tertile was the reference for prealbumin. We performed test for linear trend by entering the median value of each category of prealbumin tertile as continuous variable to examine the possibility of nonlinearity. To ensure the robustness of our results, we also performed stratified analyses with the prealbumin as a continuous variable for the overall population and stratified by gender, age, hypertension status and coronary heart disease status at baseline. Generalized additive models were used to visually confirm the relationship between prealbumin as continuous variable and the risk of outcomes (all-cause death, ICU admission and mechanical ventilation). Modeling was performed with the statistical software packages R (http://www.R-project.org, The R Foundation) and EmpowerStats (http://www. empowerstats.com, X&Y Solutions, Inc, Boston, MA). P values less than 0.05 (two-sided) were considered statistically significant. In our study, 447 cases were excluded. To avoid selection bias due to missing data, we performed a sensitivity analysis. The results showed that there was no statistical difference between missing group and non-missing group (supplemental table 1). Of 446 elderly inpatients included in the final analysis，the mean age was 72.95 (6.39) years, ranging from 65 years to 95 years, and most patients were male (table 1). The baseline characteristics of these included participants were listed in table1. The day of sample drawing after admission was 0.67 ± 0.65 day. No significant statistical difference in sex, smoking status, body weight, BMI, comorbidity (hypertension, coronary heart disease, chronic kidney disease, cerebral vascular disease, carcinoma, chronic liver disease), symptoms (fever, cough, headache, diarrhea and myalgia/fatigue at admission) were detected across different groups of prealbumin (tertile). When compared with subjects in the highest tertile, those in the lowest tertile were older, more likely to have diabetes medical history, with higher Neutrophil count, lower lymphocyte count, worse coagulation function and liver function. To investigate the correlation between prealbumin and in-hospital outcomes, we constructed three models using univariate and multivariate logistic regression models ( ORs for the association between prealbumin tertiles and in-hospital outcomes. Further adjusting for the baseline levels of blood examinations, including blood routine (neutrophil, lymphocyte， neutrophil-to-lymphocyte ratio), coagulation function (prothrombin time, activated partial thromboplastin time, d-dimer), liver fuction (alanine transaminase, aspartate aminotransferase, total bilirubin), renal function (blood urea nitrogen, creatinine) and infection indicators (C-reactive protein) did not affect the relationships in the fully adjusted models (OR = 20.09; 95% CI, 3.62 to 111.64; P =0.0006 for all-cause death; OR = 26.39; 95% CI, 4.04 to 172.39; P 0.0006 for ICU admission; OR = 2.8; 95% CI, 1.15 to 6.78; P = 0.0227 for mechanical ventilation). Therefore, lower tertile of prealbumin exhibited an increased risk of worse in-hospital outcomes (full adjusted P for trend for all-cause death, ICU admission and mechanical ventilation: P < 0.0001, P <0.0001 and P = 0.0066 respectively). Generalized additive models (Fig 2A through 2C ) were used to visually assess functional relationships between the prealbumin as continuous variate and the risk of in-hospital outcomes. Serum prealbumin was found to have negative linear relationship with the risk of all-cause death, ICU admission and mechanical ventilation. To determine the consistency of the relationship between baseline prealbumin as a continuous variable and in-hospital outcomes, we conducted stratified analyses (Table 3) In this study, we found that lower serum prealbumin significantly associated with an increased risk of worse outcomes and all-cause death during hospitalization. Patients in the lowest tertile of prealbumin were older, and with higher Neutrophil count, lower lymphocyte count, worse coagulation function and liver function compared with subjects in the highest tertile. Then we adjusted relevant covariates including age, sex, smoking status, comorbidities, neutrophil, lymphocyte, coagulation function, liver function, renal function and C-reactive protein to minimize the potential impact of confounding. Compared with crude regression analyses, this association still persisted when adjusting for demographic and clinical variables in the multivariable regression analyses. Moreover, stratified by gender, age, hypertension and diabetes, increased level of serum prealbumin was associated with the decreased risk of all-cause death, ICU admission and mechanical ventilation, which determine the consistency of the relationship between lowest serum prealbumin tertile and the increased risk of worse outcomes in elderly COVID-19 patients. Several previous studies have demonstrated baseline prealbumin change in COVID-19 patients. Decreased level of prealbumin was observed among COVID-19 patients 10 High proportion of severe to critical cases and high fatality rate were observed in the elderly COVID-19 patients, and rapid disease progress was noted in the dead 5 . One possible explanation involves the greater potential of seniors to be in a state of inflammation, nutritional deficiency and other complications. Prealbumin is a globular, non-glycosilated protein, synthesized by the liver, and complexed with a retinol-binding protein, which acts as a transporter of retinol/vitamin A and thyroid hormones 7 . Low plasma prealbumin level has far-back emerged as an earliest laboratory indicator of poor nutritional status 12, 13 . In addition, prealbumin are also associated with inflammation. Previous studies showed that in response to the inflammation, the body responds by synthesizing a large number of cytokines. These include interleukins and tumor necrosis factors that down-regulate, decrease, plasma concentrations of albumin and prealbumin 14, 15 . Therefore, assay of serum prealbumin concentration is recommended by some investigators as a screening marker for both malnutrition and inflammation. Elderly with low plasma prealbumin levels mean that those people are at greater risk of malnutrition and inflammatory conditions, which may lead to poor prognosis. Malnutrition is commonly seen in hospitalized patients in both the developed and developing world, especially among elderly patients. A review of 110 published studies of acute care patients reported that malnutrition incidence ranged from 42-91% of hospitalized elderly 16 . It was found that compared to non-famine regions of India, experiencing famine had significantly higher influenza mortality rates during the 1918 Influenza pandemic 17 . Aging, frailty, and chronic diseases are associated with impaired immune function and are compounded by immune dysregulation from malnutrition. When immune response is dysregulated, it would result in an excessive inflammation, even death. In the current COVID-19 study, it was found that elderly patients have higher levels of white blood cells counts, CRP, inflammatory cytokines and are more likely to experience critical disease than did those younger patients 4, 18 . This retrospective cohort study included 446 elderly COVID-19 patients, until the date of The results of this study have several clinical implications and strengths. A low prealbumin concentration can therefore be regarded primarily as a signal identifying the at-risk elderly patient who would suffer worse outcomes and requires careful assessment and monitoring for whom nutritional support and Inflammation detection may be needed as part of the treatment plan 19 . As observational study was susceptible to various confounders, we adjusted many variables that may affect the relationship between prealbumin and in-hospital outcomes to minimize potential confounding. In addition, we tested the robustness of the results by repeating the analyses in different subgroups of gender, age, history of hypertension and history of diabetes. Our study has some limitations. First, by including patients still in hospital as of J February 17, 2020, the case fatality ratio in our study cannot reflect the true mortality of elderly COVID-19. Second, the record of data may be affected by prehospital medication and the time interval between admission and onset. Third, since all subjects in our study were hospitalized Chinese elderly patients diagnosed with COVID-19, results of this study might not directly be applied to other ethnicities and age groups. In conclusion, this retrospective cohort study revealed that the prealbumin is an independent risk Data are mean ± SD, median (interquartile range), or percentage. BMI, Body mass index; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cerebral vascular disease; CLD, chronic liver disease; PT = prothrombin time; APTT = activated partial thromboplastin time; ALT = alanine transaminase. AST = aspartate transaminase; Hs-cTnI, High-sensitive cardiac ble 1 troponin I. Figure 2 . General additive models demonstrate the relationship between prealbumin as continuous variable and the probability of in-hospital outcomes. Adjusted for age, sex, smoking status, history of hypertension, history of coronary heart disease, history of diabetes, history of chronic kidney disease, history of carcinoma, chronic liver disease, neutrophil, lymphocyte, prothrombin time, activated partial thromboplastin time, d-dimer, alanine transaminase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, creatinine, C-reactive protein and neutrophil-to-lymphocyte ratio. Supplemental Data are mean ± SD, median (interquartile range), or percentage. BMI, Body mass index; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cerebral vascular disease; CLD, chronic liver disease; PT = prothrombin time; APTT = activated partial thromboplastin time; ALT = alanine transaminase. AST = aspartate transaminase; Hs-cTnI, High-sensitive cardiac troponin I. 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Additionally, all of the authors have approved the contents of this paper and have agreed to the Nutrition's submission policies. None of the authors has any potential conflict of interest to disclose. All the authors confirm that there is no Plagiarism or self-plagiarism and fabrication of data.