key: cord-0897284-eh6qiv4d
authors: Oh, Seung Mi; Skendelas, John P.; Macdonald, Eric; Bergamini, Michael; Goel, Swati; Choi, Jaeun; Segal, Kathryn R.; Vivek, Kumar; Nair, Singh; Leff, Jonathan
title: On-admission anemia predicts mortality in COVID-19 patients: A single center, retrospective cohort study
date: 2021-03-29
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2021.03.083
sha: 094100c3c93359a07f66ddd80a8c5c68e475ae4a
doc_id: 897284
cord_uid: eh6qiv4d

OBJECTIVES: We investigated the impact of anemia based on admission hemoglobin (Hb) level as a prognostic risk factor for severe outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: A single-center, retrospective cohort study was conducted from a random sample of 733 adult patients (age ≥ 18 years) obtained from a total of 4356 laboratory confirmed SARS-CoV-2 cases who presented to the Emergency Department of Montefiore Medical Center between March–June 2020. The primary outcome was a composite endpoint of in-hospital severe outcomes of COVID-19. A secondary outcome was in-hospital all-cause mortality. RESULTS: Among the 733 patients included in our final analysis, 438 patients (59.8%) presented with anemia. 105 patients (14.3%) had mild, and 333 patients (45.5%) had moderate-severe anemia. Overall, 437 patients (59.6%) had a composite endpoint of severe outcomes. On-admission anemia was an independent risk factor for all-cause mortality, (Odds Ratio 1.52, 95% CI [1.01–2.30], p = 0.046) but not for composite severe outcomes. However, moderate-severe anemia (Hb < 11 g/dL) on admission was independently associated with both severe outcomes (OR1.53, 95% CI [1.05–2.23], p = 0.028) and mortality (OR 1.67, 95% CI [1.09–2.56], p = 0.019) during hospitalization. CONCLUSION: Anemia on admission was independently associated with increased odds of all-cause mortality in patients hospitalized with COVID-19. Furthermore, moderate-severe anemia (Hb <11 g/dL) was an independent risk factor for severe COVID-19 outcomes. Moving forward, COVID-19 patient management and risk stratification may benefit from addressing anemia on admission.

population 12 , little information regarding anemia as a risk factor for respiratory infection outcomes was available in the adult literature. However, anemia on admission has been implicated as a possible risk factor for severe COVID-19 outcomes, albeit without consistency 3, 5, 13, 14 . In a recently published study, anemia was associated with higher rates of mortality in COVID-19 patients who displayed signs of immune-mediated alteration of iron homeostasis 15 .

Furthermore, reduction in hemoglobin has been observed in critically ill patients 16, 17 , but the relationship between anemia and severe illness of COVID-19 remains poorly understood, with no studies looking at pre-existing history of anemia or iron deficiency anemia 18 .

In this study, we investigated anemia based on admission hemoglobin level as a prognostic risk factor for severe COVID-19 outcomes in hospitalized patients. Additionally, we evaluated the association between increasing severities of anemia, anemia as a comorbidity, and reduction in hemoglobin levels during hospitalization with severe COVID-19 outcomes.

Investigation of its association with severe cases of COVID-19 was warranted since anemia is a preventable and modifiable factor.

We conducted a retrospective study of COVID-19 patients, confirmed by positive nasopharyngeal RT-PCR test for SARS-CoV-2, diagnosed at the Montefiore Health System from March 12 -June 15, 2020. From a total of 4356 identified COVID-confirmed patients who presented to the ED, we used arbitrary cutoffs of Hb values (9g/dL and 13g/dL) to divide patients and randomly sampled 250 patients from each group for a total of 750 patients. Sample size was determined from a preliminary study to compare inpatient admission rates between J o u r n a l P r e -p r o o f Journal Pre-proof groups based on Hb cutoff values. We then used the WHO classification (Hb <12g/dL for females, <13g/dL for males) to identify patients who presented with anemia on admission and subclassified those cases of anemia as mild (Hb 11-12.9g/dL in men and .9g/dL in women) or moderate-severe (Hb < 11g/dL) 19 . The data were obtained using Clinical Looking Glass (CLG), an electronic data support software used at Montefiore, and through manual review of electronic medical records.

We collected data on baseline demographics, clinical comorbidities, laboratory values pertaining to anemia and inflammation, in-hospital complications, clinical outcomes, and interventions given during the hospital course such as the use of vasopressors, invasive mechanical ventilation (IMV), hemodialysis, transfusions, and admission to the intensive care unit (ICU).

Our primary outcome was a composite endpoint of severe COVID-19 outcomes among the different anemia cohorts. We defined the composite endpoint as the occurrence of any events such as death, prolonged mechanical ventilation, acute hypoxic respiratory failure, and sepsis based on the WHO COVID-19 management guidelines 20 during the hospitalization. In brief, acute hypoxic respiratory failure was defined as clinical signs of pneumonia plus severe respiratory distress or O2 saturation < 90% on room air. Sepsis was defined as acute lifethreatening signs of organ dysfunction caused by a documented infection, and a clinical diagnosis of sepsis or septic shock in the medical notes. Secondary outcome was all-cause mortality. Hospitalization was defined as admission to the hospital for at least 24 consecutive hours or death in the emergency department within 24 hours of presentation.

We report demographic and clinical characteristics as frequencies and percentages for categorical variables and as means and standard deviations for continuous variables. Sampling weights were utilized to take into account the change of classification for the post-stratified random samples on statistical tests. We used Chi-squared tests and T-test or the one-way analysis of variance (ANOVA) for categorical and continuous variables, respectively, to compare between patients with and without severe outcomes and between anemia statuses on admission.

Log transformation was applied for non-normally distributed continuous variables. We employed multivariable logistic regression to evaluate the association of anemia on admission with each outcomea composite endpoint of severe events (primary outcome) and all-cause mortality (secondary outcome)while adjusting for potential confounding factors. Variables with p-value <0.1 on bivariate analysis or established clinical significance were included: age, sex, diabetes mellitus, hypertension, hyperlipidemia, heart disease, chronic kidney disease, levels of AST and platelet. For anemia on admission, binary anemia status and categorical anemia severity were each used in multivariable models. Odds ratios (ORs) with associated 95% confidence intervals (CIs) were estimated for effects of variables on each outcome. In addition, we performed two subgroup analyses for patients with no anemia on admission and patients with ferritin values prior to admission to investigate the associations of becoming anemic during hospitalization and pre-existing iron deficiency anemia with the composite endpoint of severe outcome. All tests of statistical significance were two-sided, and p-values <0.05 were considered statistically significant. Data were analyzed using Stata (16.1, StataCorp LLC, College Station, TX).

J o u r n a l P r e -p r o o f Journal Pre-proof From a total of 4356 patients with RT-PCR-confirmed SARS-CoV2 infections who presented to the emergency department, anemia was identified in 1887 (43.3%) patients. Among the randomly sampled 750 patients, 14 patients were excluded because they were discharged from the ED in less than 24 hours. One patient remained admitted at the end of the data collection period and was excluded from analysis. Two patients with no prior medical records admitted with altered mental status were also excluded. We report the findings from a final cohort of 733 patients.

Baseline demographics and clinical characteristics are depicted in Table 1 . The mean age was 65 (±16) years, with 372 (50.8%) men. Hypertension (76.3%) was the most common comorbidity, followed by hyperlipidemia (49.9%), diabetes mellitus (48.7%), and chronic kidney disease (37.0%). Baseline laboratory parameters were elevated for ferritin, D-dimer, and CRP.

Overall, 219 (29.9%) patients died during hospitalization, and 437 (59.6%) reached the composite endpoint of severe outcomes (Figure 1) .

Patients with severe outcomes were older (p <0.001, Table 1 ) with a higher rate of preexisting comorbidities such as hyperlipidemia (p=0.009), heart failure (p=0.003), and chronic kidney disease (p=0.031) but did not have a higher rate of history of anemia. Supplementary Table S1 depicts complications and management during hospitalization. More patients with severe outcomes received transfusion (p< 0.001), and the rates of all complications were higher in patients with severe outcomes (p < 0.003). Serum chemistry values showed significantly elevated acute phase reactants such as ferritin, D-dimer, and CRP (p <0.001, Table 1 ). Indices of functional impairment of major organs such as AST and creatinine were also significantly elevated in the severe outcome group (p <0.001). Based on admitting hemoglobin values, more J o u r n a l P r e -p r o o f Journal Pre-proof patients in the severe outcome group met the diagnostic criteria for anemia on admission (63.2% vs. 54.7%, p=0.038).

In our cohort, 438 (59.8%) of patients had hemoglobin levels corresponding to anemia diagnosis on admission. As shown in Table 2 , patients with anemia on admission were older, more likely female, and had significantly higher rates of comorbidities, including chronic kidney disease (49.1% vs. 19.3%, p <0.001), heart failure (21.0% vs. 8.5%, p<0.001), and cancer (25.3% vs. 11.5%, p<0.001). Not all patients with the comorbidity of anemia in the past presented with anemia on admission (248/304, 81.6%).

Anemia was mild in 105 (14.3%) patients and moderate-severe in 333 (45.5%) patients.

Overall, rates of comorbidities were lowest in the no anemia group compared to each cohort of anemia severity, except for COPD (8.1% in no anemia, 6.7% in mild anemia, and 17.2% in moderate-severe anemia). The rate of prior history of anemia increased with anemia severity (19% vs. 34.3% vs. 63.7%, p<0.001). With increasing severities of anemia on admission, patients showed elevated inflammatory markers such as D-dimer (p<0.001) and presented with lower albumin and higher creatinine on admission (p<0.001, Supplementary Table S2) .

Patients who presented with anemia on admission had a longer length of stay (p=0.001, Supplementary Table S2 ) and a significantly higher rate of complications such as sepsis (43.4% vs. 31.5%, p=0.015) and hemodialysis (23.0% vs. 7.1%, p <0.001). Accordingly, anemic patients had significantly higher rates of mortality (33.6% vs. 24.4%, p=0.017) and severe outcomes (63.0% vs. 54.6%, p=0.038). When comparing different anemia severities, rates of adverse events such as prolonged stay, hypotension, and hemodialysis increased significantly with anemia severity (Figure 2a, b) . However, the mild anemia group had highest rate of hypoxia J o u r n a l P r e -p r o o f Journal Pre-proof (55.6% in no anemia, 58.7% in mild anemia, and 56.2% in moderate-severe anemia) and acute respiratory failure (45.1% vs. 49.5% vs. 40.2%) than no anemia and moderate-severe anemia groups. Overall, although rates of mortality and severe composite outcomes increased with increasing anemia severity, the differences were not significant.

Tables 3 depicts the results of the multivariable logistic regression analysis for severe outcomes. After controlling for confounders, anemia on admission was not predictive of severe outcomes (Model I), but moderate-severe anemia was significantly associated with increased odds of severe outcomes (OR 1.532, CI [1.048-2.230], p=0.028, Model II). In the multivariable analysis for morality ( 

Our single-center, retrospective study of 733 patients admitted with SARS-CoV2 in the greater New York City area showed that anemia on admission is predictive of higher rate of mortality in hospitalized patients with COVID-19, but was not significant for having severe outcomes during hospitalization. However, moderate-severe anemia on admission was independently associated with both mortality and severe outcomes in COVID-19 patients. We additionally found that anemia acquired during the course of hospitalization was independently associated with severe COVID-19 outcomes.

Our findings on the associations between anemia and death were similar to the findings from a recent study by Bellmann et al., who also reported anemia on admission as an independent predictor of mortality in 259 patients with COVID-19 (OR 3.729, CI[1.02-11.75], p=0.001) but no association with functional iron deficiency 15 . Another recent study by Tao et al. reported anemia as an independent risk factor for severe COVID-19 in 222 patients (OR 3.47, [1.02-11.75], p=0.046) 18 , which differs from our findings, but their definition of severe cases had a higher cutoff of O2 saturation. Whereas both studies included all patients admitted with COVID-19, we report results from a cohort of patient population with higher prevalence of onadmission anemia (43.3% vs. 24.7%, 35.6%). Our sample size is larger than the total patients included in either study, and our patient population was more heterogenous, with a higher comorbidity burden than either study.

Hemoglobin concentration is one of the most important markers of oxygen-carrying capacity in the blood. In the setting of respiratory compromise and increased oxygen demand in a hyper-metabolic state such as COVID-19, anemia can further reduce oxygen delivery to peripheral tissues. That SARS-CoV-2 directly infects cells expressing the ACE-2 enzyme has been observed in organs throughout the body 22 hypothesized that viral entry through receptors located on erythrocytes may induce hemolysis, resulting in hemolytic anemia 17 . Anemia may be a result of severe infection due to alteration of iron homeostasis by the innate immune system, implicated by the pathological value of ferritin observed in severe COVID-19 cases. The innate immune system reduces iron's bioavailability by pro-inflammatory cytokine pathways that upregulate hepcidin, an iron regulatory protein that blocks iron release from macrophages. This leads to decreased intestinal iron absorption and cellular sequestration of iron in macrophages, 24 and an upregulation of cytosolic ferritin, which stores iron to prevent iron-mediated free radical damage 25 . The net result of decreased iron availability, elevated ferritin and hindered erythropoiesis may explain the association between severe COVID-19 and moderate-severe anemia. In COVID-19, marked hyperferritinemia has been reported with the development of cytokine storm characterized by significantly elevated IL-6, CRP, and other inflammatory markers in critically ill patients 26 27,28 . Our data also suggest that patients with severe outcomes had significantly elevated levels of acute-phase reactants, suggesting a state of inflammation. While our data suggest that being anemic in the ED alone is Our study has several limitations. First, this study was conducted using the data from one integrated-delivery health system in New York; hence our results may have limited generalizability. However, as anemia is a global condition with higher prevalence in developing countries, our findings may have potential implications. Secondly, the study was performed during the peak of the pandemic, in which contactless interviews and shortened notes were the norm and limited the amount of information from chart review. Similarly, not all laboratory studies were performed on all patients, and values were missing in laboratory parameters. Lastly, our main limitation was that we could not separate acute from chronic anemia, and did not account for the etiology of anemia including hemoglobinopathies and sickle cell disease, which J o u r n a l P r e -p r o o f limits our interpretation. Nonetheless, our study suggests that moderate-severe anemia on admission regardless of its etiology poses as a risk for severe outcomes in COVID-19.

Future research would benefit from an inclusion/exclusion criteria of laboratory values to help distinguish anemia by etiology and strengthen the multivariable regression analysis.

Furthermore, a thorough look at all treatments including medications could further control for the differences in outcomes.

Anemia is a global disease associated with the prognosis of many clinical diseases, including diseases with respiratory compromises, such as COVID-19. We report that anemia on admission and particularly moderate-severe anemia was independently associated with all-cause mortality in patients hospitalized with COVID-19. Moderate-severe anemia was also predictive of severe outcomes in COVID-19 patients. Anemia on admission and changing hemoglobin levels throughout hospitalization may help further guide risk stratification and management of patients hospitalized with COVID-19. Additional studies addressing more inclusion of laboratory values and treatments received by patients should be the focus of future studies. Model I: Adjusted model for the association between anemia and all-cause mortality, Model II: Adjusted model for the association between different severities of anemia and all-cause mortality. 1 Adjusted Odds Ratio. *Variables with 20% or more missing values were not included in the multivariable model due to too many missing values. **ALT was not included in multivariable models because of the high correlation with AST which appeared to be the highest predictive variable in bivariate analysis. ***Creatinine was not included in multivariable models because of the high correlation with CKD which appeared to be the highest predictive variable in bivariate analysis. Total subgroup n = 295, a subset of sample who did not have anemic hemoglobin levels on admission. 1 Adjusted Odds Ratio. *Variables with 20% or missing values were not included in the multivariable model: ferritin, D-dimer, CRP due to too many missing values. **Chronic Kidney Disease was not included in multivariable models because of the high correlation with creatinine which appeared to be the highest predictive variable in bivariate analysis. *** ALT was not included in multivariable models because of the high correlation with AST which appeared to be the highest predictive variable in bivariate analysis. Representation of prevalence of disease outcomes in total sample cohort. ICU admission signifies admission to the traditional Intensive Care Units, and may not reflect the true prevalence for need of intensive cares since patients admitted to make-shift ICUs and higher level care floors could not be accurately counted. Hypotension was defined as systolic blood pressure <100 and diastolic blood pressure <60, or a mention of hypotension in the physician notes. AKI was defined as an elevation in creatinine by ≥ 0.3 mg/dL within 48 hours or increase in serum creatinine to ≥ 1.5 times baseline, or urine volume <0.5mL/kg/hour for six hours according to the KDIGO guidelines 30 Moderate-severe anemia patient group was significantly more likely to receive hemodialysis than the other two groups. No statistically significant differences were observed in the rates of mechanical ventilation, ICU admission, or vasopressor use. However, ICU admission rate may not reflect the true prevalence for need of intensive cares since patients admitted to make-shift ICUs and higher-level care floors could not be accurately counted. b) Prevalence of clinical outcomes and diagnoses among patients without anemia and with different severities of anemia. *Chi square p <0.05. Error bars are of standard errors calculated based on sample statistics. Moderate-Severe anemia group had significantly higher rates of prolonged stay, sepsis/septic shock, and death compared to the other two groups. The rate of acute hypoxic respiratory failure was highest in the mild anemia group, and lowest in the moderate-severe anemia group. Although lacking statistical significance, the rate of composite severe outcomes increases with anemia severity. 

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We thank our colleagues Giuseppe Fiorcia and Jasmine Kim for their contribution to data extraction.