Hematology

On-admission anemia predicts mortality in COVID-19 patients: A single center, retrospective cohort study

a b s t r a c t

Objectives: We investigated the impact of anemia based on admission hemoglobin 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 hospital- ization.

Conclusion: Anemia on admission was independently associated with increased odds of all-cause mortality in pa- tients 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.

(C) 2021

  1. Introduction

Since its discovery in December 2019 in Wuhan, China, the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has rapidly evolved into a global pandemic with over 100 million confirmed cases worldwide and total deaths exceeding 2 million as of March 2021 [1]. Despite much progress that has been made over the past year to combat the pandemic including vaccinations which began in January 2021, ef- forts to respond to and understand the virus continue as reports of new coronavirus variants have emerged across the globe [2], posing a

* Corresponding author at: Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

E-mail address: [email protected] (S.M. Oh).

challenge for healthcare providers to predict the outcomes in COVID- 19 patients.

Older age, male sex, and multiple comorbid conditions, including hy- pertension, diabetes, hypercholesterolemia, cardiovascular disease, and kidney disease have been associated with mortality and critical out- comes of COVID-19 [3-6]. Anemia is a global health concern affecting over 1.6 billion people, approximately 24.8% of the world’s population, and is often associated with common medical conditions and critical ill- ness [7,8]. Anemia has been identified as a significant risk factor for mor- tality and hospitalization in several diseases, such as heart failure, chronic obstructive pulmonary disease, and myocardial infarction [9- 11]. While Iron deficiency anemia has been reported as a risk factor for lower respiratory tract infection in the pediatric population [12], lit- tle information regarding anemia as a risk factor for respiratory infec- tion outcomes was available in the adult literature. However, anemia

https://doi.org/10.1016/j.ajem.2021.03.083

0735-6757/(C) 2021

on admission has been implicated as a possible risk factor for severe COVID-19 outcomes, albeit without consistency [3,5,13,14]. In a re- cently published study, anemia was associated with higher rates of mor- tality in COVID-19 patients who displayed signs of immune-mediated alteration of iron homeostasis [15]. Furthermore, reduction in hemoglo- bin has been observed in critically ill patients [16,17], but the relation- ship 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 hemoglo-

bin 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 modifi- able factor.

  1. Methods
    1. Study design and data collection

We conducted a retrospective study of COVID-19 patients, con- firmed by positive nasopharyngeal rt-PCR test for SARS-CoV-2, diag- nosed 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 (9 g/dL and 13 g/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 groups based on Hb cutoff values. We then used the WHO classification (Hb <12 g/dL for females, <13 g/dL for males) to identify patients who presented with anemia on admission and subclassified those cases of anemia as mild (Hb 11-12.9 g/dL in men and 11-11.9 g/dL in women) or moderate-severe (Hb < 11 g/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 , hemodialysis, transfusions, and admission to the in- tensive care unit (ICU).

    1. Definitions and outcomes

Our primary outcome was a composite endpoint of severe COVID-19 outcomes among the different anemia cohorts. We defined the compos- ite 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 sat- uration < 90% on room air. Sepsis was defined as acute life-threatening signs of organ dysfunction caused by a documented infection, and a clin- ical diagnosis of sepsis or septic shock in the medical notes. Secondary outcome was all-cause mortality. Hospitalization was defined as admis- sion to the hospital for at least 24 consecutive hours or death in the emergency department within 24 h of presentation.

    1. Statistical analysis

We report demographic and clinical characteristics as frequencies and percentages for categorical variables and as means and standard de- viations for continuous variables. Sampling weights were utilized to

take into account the change of classification for the post-stratified ran- dom samples on statistical tests. We used Chi-squared tests and t-test or the one-way analysis of variance (ANOVA) for categorical and continu- ous variables, respectively, to compare between patients with and with- out 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 outcome – a compos- ite endpoint of severe events (primary outcome) and all-cause mortal- ity (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, hyper- tension, 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 addi- tion, we performed two subgroup analyses for patients with no anemia on admission and patients with ferritin values prior to admission to in- vestigate 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).

  1. Results

From a total of 4356 patients with RT-PCR-confirmed SARS-CoV2 in- fections 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 h. 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.

    1. Baseline demographics, clinical characters, and outcomes

Baseline demographics and clinical characteristics are depicted in Table 1. The mean age was 65 (+-16) years, with 372 (50.8%) men. Hy- pertension (76.3%) was the most common comorbidity, followed by hy- perlipidemia (49.9%), diabetes mellitus (48.7%), and chronic kidney disease (37.0%). Baseline laboratory parameters were elevated for ferri- tin, D-dimer, and CRP. Overall, 219 (29.9%) patients died during hospi- talization, and 437 (59.6%) reached the composite endpoint of severe outcomes (Fig. 1).

Patients with severe outcomes were older (p < 0.001, Table 1) witha higher rate of pre-existing 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. Supplemen- tary Table S1 depicts complications and management during hospitali- zation. 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 signifi- cantly elevated acute phase reactants such as ferritin, D-dimer, and CRP (p < 0.001, Table 1). Indices of functional impairment of major or- gans such as AST and creatinine were also significantly elevated in the severe outcome group (p < 0.001). Based on admitting hemoglobin values, more patients in the severe outcome group met the diagnostic criteria for anemia on admission (63.2% vs. 54.7%, p = 0.038).

    1. Comparisons between anemia status on admission

In our cohort, 438 (59.8%) of patients had hemoglobin levels corre- sponding to anemia diagnosis on admission. As shown in Table 2,

Table 1

Demographic and clinical characteristics by severe outcome status.?

All patients N = 733

No Severe Outcomes N = 296 (40.4%)

Severe Outcomes N = 437 (59.6%)

P-value (n1)

Mean (SD) or n (%)

Mean (SD) or n (%)

Mean (SD) or n (%)

Demographics

Age (mean)

65 (+-16)

62 (+-17)

67 (+-15)

<0.001

Sex, Male (%)

372 (50.8)

146 (39.2)

226 (60.8)

0.324

Race or Ethnic Group

0.77

White

72 (9.8)

29 (9.8)

43 (9.8)

Hispanic or Latino

260 (35.5)

109 (36.8)

151 (34.6)

Black or African American

280 (38.2)

109 (36.8)

171 (39.1)

Asian

22 (3.0)

7 (2.4)

15 (3.4)

Other2

99 (13.5)

42 (14.2)

57 (13.0)

Body Mass Index (kg/m2)

29.39 (+- 7.81)

28.51 (+-7.61)

29.03 (+-7.94)

0.598 (n=693)

Comorbidities and risk factors

Comorbidities

Anemia3

304 (41.5)

114 (38.5)

190 (43.5)

0.125

Diabetes Mellitus

357 (48.7)

130 (43.9)

227 (51.9)

0.078

Hypertension

559 (76.3)

211 (71.3)

348 (79.6)

0.008

Hyperlipidemia

366 (49.9)

130 (43.9)

236 (54.0)

0.009

Coronary Artery Disease

202 (27.6)

73 (24.7)

129 (29.5)

0.165

Heart Failure

117 (16.0)

32 (10.8)

85 (19.5)

0.003

Asthma

112 (15.3)

42 (14.2)

70 (16.0)

0.309

COPD

88 (12.0)

31 (10.5)

57 (13.0)

0.317

Chronic Kidney Disease

271 (37.0)

94 (31.9)

177 (40.6)

0.031

Cancer

145 (19.8)

56 (18.9)

89 (20.4)

0.359

Immunosuppressed

83 (11.3)

32 (10.8)

51 (11.7)

0.368

Current/Former smoker

235 (38.9)

81 (32.8)

154 (43.1)

0.029

Laboratory Parameters

Hemoglobin (g/dL)

11.15 (+-2.94)

11.22 (+-2.99)

11.10 (+-2.91)

0.658

Hgb min (g/dL)

9.53 (+-2.81)

9.98 (+-2.91)

9.23 (+-2.70)

<0.001 (n=728)

Hgb Max (g/dL)

11.85 (+-2.57)

11.95 (+-2.50

11.79 (+-2.62)

0.671 (n=728)

Ferritin (ng/mL)

1716 (+-4713)

1043 (+-1339)

2142 (+-5891)

<0.001 (n=573)

Transferrin (mg/dL)

153.87 (+-57.50)

156.60 (+-59.98)

151.93 (+-54.23)

0.301 (n=125)

Ferritin/Transferrin

13.78 (+-31.07)

9.00 (+-10.51)

17.19 (+-39.45)

0.729 (n=125)

D-dimer (ug/mL)

4.22 (+-5.33)

2.75 (+-3.61)

5.21(+-6.03)

<0.001 (n=586)

MCV (fL)

89.71 (+-8.44)

88.49 (+-8.25)

90.53 (+-8.48)

0. 003

WBC (k/uL)

9.32 (+-9.13)

8.91 (+-10.96)

9.77 (+-7.66)

0.002 (n=730)

IL-6 (pg/mL)

149.44 (+-242.11)

40.76 (+-33.65)

195.63 (+-276.34)

0. 027 (n=57)

CRP (ug/mL)

13.24 (+-10.77)

8.26 (+-7.79)

16.68 (+-11.19)

<0.001 (n=541)

Platelet (k/uL)

245.84 (+-130.61)

252.64 (+-129.08)

241.25 (+-131.57)

0.676 (n=730)

Albumin (g/dL)

3.58 (+-0.61)

3.71 (+-0.58)

3.48 (+-0.61)

<0.001 (n=712)

ALT (U/L)

48.19 (+-140.26)

37.46 (+-61.68)

55.39 (+-173.87)

0.013 (n=712)

AST (U/L)

68.23 (+-179.75)

49.07 (+-55.45)

81.31 (+-227.82)

<0.001 (n=700)

Creatinine (mg/dL)

2.51 (+-3.06)

2.12 (+-2.50)

2.77 (+-3.37)

<0.001 (n=730)

Anemia on Admission

438 (59.8)

162 (54.7)

276 (63.2)

0.038

Length of Stay**

Mean (days)

11 (+-13)

7 (+-7)

16 (+-16)

<0.001 (n=502)

Prolonged stay (>11 days)

129 (17.6)

40 (13.8)

89 (42.0)

< 0.001 (n=502)

*All raw sample values are reported. P-values applied with sampling weights are reported. 1n reports counts of available values and frequencies reported. If no n is written, n = 733, whole sample.2Other category includes all patients who either declined to answer, fit in to none of the categories, or information was unavailable.3Comorbidities and risk factors Anemia is information on any medical history or prior diagnosis of Anemia, regardless of current admission hemoglobin status.

**Length of stay excludes patients who died during hospital stay. Abbreviations: ED: Emergency Department, DM: Diabetes Mellitus, HTN: Hypertension, HLD: Hyperlipidemia, CAD: Coronary Artery Disease, CHF: Chronic Heart failure CKD: Chronic Kidney Disease, COPD: Chronic Obstructive Pulmonary Disease.

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 admis- sion (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, ex- cept 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 increas- ing severities of anemia on admission, patients showed elevated inflam- matory markers such as D-dimer (p < 0.001) and presented with lower albumin and higher creatinine on admission (p < 0.001, Supplemen- tary Table S2).

Patients who presented with anemia on admission had a longer length of stay (p = 0.001, Supplementary Table S2) and a signifi- cantly 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). Ac- cordingly, anemic patients had significantly higher rates of mortal- ity (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 (Fig. 2a, b). However, the mild anemia group had highest rate of hypoxia (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 differ- ences were not significant.

Overall Outcomes

Invasive Mechnical Ventilation

ICU admission Hypotension Vasopressor Hemodialysis Transfusion

Complications

AKI DVT/PE

Acute hypoxic respiratory failure

Sepsis/Septic Shock

Death Severe Outcomes

59.6%

22.5%

16.2%

39.7%

26.1%

16.5%

30.6%

44.9%

5.7%

38.6%

43.5%

29.9%

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0%

Prevalence (%) among total sample

Fig. 1. Prevalence of clinical outcomes in our total sample cohort. 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 h or increase in serum creatinine to >=1.5 times baseline, or urine volume < 0.5 mL/kg/h for six hours according to the KDIGO guidelines [30]. DVT/PE: Deep Vein Thrombosis/Pulmonary Embolism, ICU: Intensive Care Unit, AKI: Acute Kidney Injury.

    1. Independent risk factors for death and severe outcomes

Tables 3 depicts the results of the multivariable logistic regres- sion 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 (Table 4), anemia on admission remained an independent risk factor for mortality (OR 1.523, CI [1.008-2.303], p = 0.046, Model I). Fur- ther analysis showed that moderate-severe anemia was significantly associated with increased risk of death in COVID-19 patients (OR 1.671, CI [1.090-2.563], p = 0.019, Model II).

In our subgroup analysis of patients who were not anemic on ad- mission, becoming anemic during the hospitalization was significantly

associated with an increase in the risk of having severe COVID-19 outcomes (OR 1.737, CI [1.033-2.922] p = 0.037, Table 5) after adjusting for confounders. Another subgroup analysis of patients with ferritin values prior to admission demonstrated that pre- existing iron deficiency anemia [21] was not significantly associated with severe outcomes of COVID-19 in an unadjusted regression anal- ysis (Supplementary Table S3).

  1. Discussion

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 pa- tients with COVID-19, but was not significant for having severe out- comes during hospitalization. However, moderate-severe anemia on

Table 2

Demographics and patient characteristics by anemia status on admission (no anemia, mild, and moderate-severe anemia)

No Anemia

N = 295 (40.2)

Anemia

N = 438 (59.8)

P-value+

Mild

N = 105 (14.3)

Mod-Severe

N = 333 (45.5)

P-value? (n1)

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

Or n (%)

Or n (%)

Or n (%)

Or n (%)

Demographics

Age (years)

63 (+-16)

66 (+-16)

0.009

67 (+-15)

66 (+-16)

0.032

Sex, Male

163 (55.3)

209 (47.7)

0.045

54 (51.4)

155 (46.5)

0.018

BMI (kg/m2)

30.59 (+-7.80)

27.69 (+-7.61)

<0.001

28.65 (+-7.02)

27.39 (+-7.78)

<0.001(n = 693)

Comorbidities

Anemia

56 (19.0)

248 (56.5)

<0.001

36 (34.3)

212 (63.7)

<0.001

Iron supplementation

27 (9.2)

160 (36.5)

<0.001

20 (19.0)

140 (42.0)

<0.001

DM

114 (38.6)

243 (55.5)

<0.001

57 (54.3)

186 (55.9)

<0.001

HTN

199 (67.5)

360 (82.2)

<0.001

86 (81.9)

274 (82.3)

<0.001

HLD

138 (46.8)

228 (52.1)

0.317

51 (48.6)

177 (53.2)

0.410

CAD

55 (18.6)

147 (33.6)

<0.001

36 (34.3)

111 (33.4)

<0.001

HF

25 (8.5)

92 (21.0)

<0.001

25 (8.5)

20 (19.0)

<0.001

Asthma

34 (11.5)

78 (17.8)

0.058

18 (17.1)

60 (18.1)

0.115

COPD

24 (8.1)

64 (14.6)

0.085

7 (6.7)

57 (17.2)

0.011

CKD

57 (19.3)

214 (49.1)

<0.001

38 (36.2)

176 (53.2)

<0.001

Cancer

34 (11.5)

111 (25.3)

<0.001

18 (17.1)

93 (27.9)

<0.001

Immunosuppressed

9 (3.1)

74 (17.0)

<0.001

12 (11.4)

62 (18.7)

<0.001

Clinical Outcomes

Length of Stay*

9 (+-12)

12 (+-13)

0.012

10 (+-10)

12 (+-13)

0.001 (n = 502)

Prolonged Stay*

40 (18.2)

89 (31.6)

0.022

14 (20.6)

75 (35.0)

0.005 (n = 502)

Transfusion

19 (6.4)

205 (46.8)

<0.001

16 (15.2)

189 (56.8)

<0.001

1n reports counts of available values and frequencies reported. If no n is written, n = 733, whole sample. Abbreviations: ED: Emergency Department, DM: Diabetes Mellitus, HTN: Hyper-

tension, HLD: Hyperlipidemia, CAD: Coronary Artery Disease, HF: Heart failure CKD: Chronic Kidney Disease, COPD: Chronic Obstructive Pulmonary Disease, PE/DVT: Pulmonary Embo- lism/Deep Vein Thrombosis. +: P- value for the test comparing anemia vs. no anemia. ?: P-value for the test comparing three categories of no anemia, mild, and moderate-severe anemia.

(a)

35%

Proportion of Patients who received intervention (%)

30%

25%

20%

15%

10%

5%

0%

clinical interventions

No Anemia Mild Anemia Moderate-Severe Anemia

(b)

80

Proportion of Patients with Outcome (%)

70

60

50

40

30

20

10

0

Clinical Outcomes

No Anemia Mild Anemia Moderate-Severe Anemia

Invasive Mechanical Ventilation

ICU admission Vasopressor Hemodialysis*

Length of Stay >10 days*

Sepsis/Septic Shock*

Hypoxia Acute Hypoxic Respiratory Failure

Death* Composite severe outcome

Fig. 2. a) Prevalence of Clinical interventions among patients without anemia and different severities of anemia. *Chi-square p < 0.05. Error bars are of standard errors calculated based on sample statistics. 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.

admission was independently associated with both mortality and severe outcomes in COVID-19 patients. We additionally found that ane- mia 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]. An- other 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

Table 3

Logistic regression models of the composite endpoint of severe outcomes

Unadjusted Model Adjusted Model I Adjusted Model II

OR

95% CI

P-value

aOR1

95% CI

P-value

aOR1

95% CI

P-value

Demographics Age > 65

1.989

1.427-2.772

<0.001

1.715

1.171-2.510

0.006

1.727

1.180-2.528

0.005

BMI

1.006

0.984-1.028

0.601

Male Sex

1.179

0.850-1.635

0.325

1.271

0.897-1.801

0.176

1.287

0.908-1.824

0.156

Comorbidities DM

1.346

0.967-1.873

0.078

1.050

0.709-1.555

0.807

1.053

0.711-1.559

0.796

HTN

1.654

1.137-2.408

0.009

1.129

0.693-1.840

0.627

1.121

0.694-1.842

0.622

HLD

1.556

1.119-2.165

0.009

1.373

0.935-2.015

0.105

1.370

0.933-2.011

0.109

Heart Disease

1.443

1.009-2.063

0.044

0.952

0.626-1.448

0.818

0.953

0.626-1.451

0.822

Asthma

1.274

0.798-2.032

0.310

COPD

1.314

0.768-2.249

0.318

Kidney Disease

1.472

1.035-2.093

0.031

1.122

0.740-1.700

0.588

1.101

0.724-1.674

0.652

Cancer

1.221

0.797-1.870

0.360

Lab Findings Hemoglobin

0.988

0.937-1.041

0.645

Ferritin*

1.000

1.000-1.000

0.001

D-dimer*

1.134

1.077-1.194

<0.001

WBC

1.047

0.990-1.107

0.107

CRP*

1.096

1.066-1.128

<0.001

Platelet

0.999

0.998-1.001

0.392

ALT**

1.003

0.999-1.007

0.096

AST

1.006

1.003-1.010

0.001

1.007

1.002-1.011

0.002

1.007

1.002-1.011

0.002

Creatinine***

1.087

1.011-1.170

0.025

Classifications

Anemia (on admission) vs. none

1.411

1.019-1.954

0.038

1.403

0.969-2.032

0.073

Anemia Severity Mild vs. none

1.383

0.872-2.200

0.168

1.297

0.792-2.125

0.301

Mod-Sev vs. none

1.441

1.045-1.985

0.026

1.532

1.048-2.230

0.028

Model I: Adjusted model for the association between anemia and composite endpoint of severe outcomes. Model II: Adjusted model for the association between different severities of anemia and composite endpoint of severe outcomes.1Adjusted Odds Ratio. *Variables with 20% or 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.

Table 4

Logistic regression models of mortality outcome

Unadjusted Model Adjusted Model I Adjusted Model II

Demographics

Age > 65

OR 2.790

95% CI

1.914-4.065

P-value

<0.001

aOR1 2.277

95% CI

1.481-3.501

P-value

<0.001

aOR1 2.295

95% CI

1.492-3.529

P-value

<0.001

BMI

0.986

0.962-1.012

0.293

Male Sex

1.311

0.920-1.870

0.134

1.535

1.029-2.288

0.036

1.557

1.044-2.323

0.030

Comorbidities DM

1.266

0.887-1.808

0.194

0.856

0.565-1.299

0.465

0.860

0.567-1.303

0.476

HTN

2.738

1.720-4.358

<0.001

2.157

1.181-3.939

0.012

2.163

1.187-3.942

0.012

HLD

1.643

1.148-2.351

0.007

1.392

0.924-2.097

0.113

1.390

0.922-2.095

0.116

Heart disease

1.458

1.003-2.120

0.048

0.677

0.429-1.069

0.094

0.676

0.428-1.069

0.094

Asthma

1.156

0.715-1.868

0.554

COPD

1.338

0.778-2.302

0.292

CKD

1.889

1.309-2.725

0.001

1.257

0.801-1.974

0.320

1.234

0.784-1.942

0.364

Cancer

1.298

0.833-2.024

0.250

Lab Findings Hemoglobin

0.972

0.914-1.034

0.365

Ferritin*

1.000

1.000-1.000

<0.001

D-dimer*

1.142

1.101-1.185

<0.001

WBC

1.027

0.986-1.070

0.199

CRP*

1.080

1.058-1.103

<0.001

Platelet

0.998

0.006-0.999

0.006

0.997

0.995-0.999

0.005

0.997

0.995-0.999

0.005

ALT**

1.001

1.000-1.003

0.095

AST

1.004

1.000-1.008

0.048

1.004

1.000-1.008

0.033

1.004

1.000-1.008

0.033

Creatinine***

1.091

1.025-1.161

0.006

Classifications

Anemia (on admission) vs. none

1.541

1.079-2.200

0.017

1.523

1.008-2.303

0.046

Anemia Severity Mild vs. none

1.496

0.913-2.451

0.011

1.406

0.823-2.404

0.212

Mod-Sev vs. none

1.587

1.118-2.253

0.010

1.671

1.090-2.563

0.019

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.1Adjusted 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 mul- tivariable 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.

cohort of patient population with higher prevalence of on-admission 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 com- promise 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 en- zyme has been observed in organs throughout the body [22], leading to significant complications such as septic shock and multiple organ dys- function [5,23] as they may reduce the availability of ACE-2 receptors and thus prevent vasodilation, further compounding peripheral tissue ischemia. Indeed, a meta-analysis by Taneri et al. showed that Severity of disease and prognosis of patients with COVID-19 may depend on lower Hb levels as severe cases had significantly lower hemoglobin levels [13], a possible explanation for why anemic patients have higher rate of mortality and severe adverse events.

In addition, our subgroup analysis demonstrated that anemia ac- quired during hospitalization was independently associated with severe COVID-19 outcomes. Patients infected with COVID-19 may develop ane- mia through several possible mechanisms. Cavezzi et al. 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 ob- served in severe COVID-19 cases. The innate immune system reduces iron’s bioavailability by pro-inflammatory cytokine pathways that up- regulate 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 upregu- lation of cytosolic ferritin, which stores iron to prevent iron-mediated free radical damage [25]. The net result of decreased iron availability, el- evated 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 [26-28]. Our data also suggest that patients with severe outcomes had significantly ele- vated levels of acute-phase reactants, suggesting a state of inflamma- tion. While our data suggest that being anemic in the ED alone is inconclusive to predicting severe outcomes of COVID-19, it seems war- ranted to assess whether moderate-severe anemia could be used as a reliable measure to help guide clinical management of COVID-19.

Our findings may have implications in guiding the management of COVID-19 patients hospitalized with or without anemia. Based on our study results, the timing of anemia and the severity of anemia could offer additional insights into COVID-19 patients’ treatment. In the case of COVID-19 infection with mild anemia on presentation, O2 supple- mentation, in addition to General practice guidelines, may suffice. How- ever, if the patients are moderate-severely anemic in the ED or become newly anemic during hospitalization, the use of steroids may prevent further deterioration, in addition to Standard care using iron or blood transfusions. However, the current WHO and NIH guidelines based on the RECOVERY trial have a conditional recommendation against cortico- steroids in patients with a mild course of COVID-19 [29]. Given our find- ings, early detection of anemic hemoglobin levels and their severity could be beneficial in considering the use of systemic steroids before Disease progression.

Our study has several limitations. First, this study was conducted using the data from one integrated- delivery health system in New

Declaration of interest“>Table 5

Subgroup Analysis: Logistic Regression analysis of the composite endpoint of severe out- comes in patients with no anemia on admission who later become anemic

Unadjusted Model Adjusted Model I

OR

95% CI

P-value

aOR1

95% CI

P-value

Demographics Age > 65

2.361

1.470-3.791

<0.001

2.792

1.527-5.103

0.001

BMI

1.000

0.970-1.031

0.993

Male Sex

1.349

0.847-2.147

0.207

1.479

0.847-2.585

0.168

Comorbidities DM

1.236

0.768-1.991

0.382

1.120

0.624-2.010

0.704

HTN

1.397

0.854-2.286

0.182

0.876

0.450-1.704

0.695

HLD

1.497

0.939-2.387

0.089

1.243

0.688-2.246

0.469

Heart Disease

1.328

0.764-2.309

0.313

0.888

0.441-1.786

0.738

Asthma

1.160

0.559-2.406

0.689

COPD

1.661

0.684-4.031

0.261

1.272

0.414-3.910

0.673

Kidney Disease**

1.616

0.883-2.956

0.119

Cancer

1.330

0.636-2.781

0.448

Lab Findings Ferritin*

1.000

1.000-1.000

0.017

D-dimer*

1.135

1.062-1.212

<0.001

WBC

1.152

1.080-1.229

<0.001

1.139

1.061-1.222

<0.001

CRP*

1.108

1.062-1.156

<0.001

Platelet

1.000

0.998-1.002

0.913

ALT***

1.004

0.999-1.009

0.091

AST

1.008

1.002-1.014

0.005

1.007

1.001-1.013

0.015

Creatinine

1.325

0.995-1.764

0.054

1.132

0.934-1.372

0.204

Classifications Becoming anemic

1.693

1.062-2.701

0.027

1.737

1.033-2.922

0.037

vs. none

Total subgroup n = 295, a subset of sample who did not have anemic hemoglobin levels on admission.1Adjusted Odds Ratio. *Variables with 20% or missing values were not in- cluded 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 bivar- iate analysis. *** ALT was not included in multivariable models because of the high corre- lation with AST which appeared to be the highest predictive variable in bivariate analysis.

York; hence our results may have limited generalizability. However, as anemia is a global condition with higher prevalence in developing coun- tries, 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 ane- mia including hemoglobinopathies and Sickle cell disease, which 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 differ- ences in outcomes.

  1. Conclusion

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 hos- pitalization 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.

Sources of support

None.

Declaration of Interest

None.

Acknowledgement

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

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2021.03.083.

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