PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/jmv.27011
AUTHOR CONTRIBUTIONS
All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Rapp, Tremblay, Mascarenhas, Taioli, Ghaffari. Acquisition, analysis, or interpretation of data, drafting of the manuscript, Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Rapp, Alpert, Lieberman‐Cribbin. Supervision: Mascarenhas, Taioli, Ghaffari.
To the Editor,
We have read with great interest the meta‐analysis that examined the impact of increased red cell distribution width (RDW) and coronavirus disease 2019 (COVID‐19) outcomes, conducted by Lee and colleagues, and recently published in the Journal of Medical Virology. The authors concluded that elevations in RDW were associated with adverse COVID‐19 outcomes. 1 However, as a large subset of hospitalized COVID‐19 patients are anemic (over 30% in our own study), 2 the impact of elevation of RDW independent of anemia in COVID‐19 remains to be clarified. 1 , 3 , 4 Here we have analyzed a large population of COVID‐19 patients and addressed whether the impact of RDW on mortality in this cohort is related to their anemia.
Patients ≥18 years who were diagnosed with COVID‐19 at the Mount Sinai Health System between March 1 and April 1, 2020 and had a complete blood count at presentation (n = 2562) were selected to assess the association between RDW and mortality. Anemia was defined by WHO criteria (hemoglobin levels <13 g/dL for males and less than 12 g/dl for females) and an elevated RDW was defined as greater than 15%. Comorbidities were assessed using the Charlson comorbidity index (CCI). As patients did not have uniform follow up time, multivariable Cox proportional hazards regression models, stratified by presence of anemia, were performed to assess the association of RDW with mechanical ventilation and mortality independent of the effects of age, sex, race, and CCI. All analyses were performed using SAS software, v9.4 (SAS Institute). This study was approved by the Program for Protection of Human Subjects of the Icahn School of Medicine at Mount Sinai.
Among 2562 patients with COVID‐19 for whom complete blood count was obtained, 501 patients (19.6%) had an elevated RDW at the time of diagnosis (Table 1). At univariate analysis, elevated RDW was statistically significantly associated with mechanical ventilation (p = .0109) and mortality (p < .0001). We found that elevated RDW was statistically significantly associated with higher risk of both being placed on a ventilator (adjusted hazards ratio [HRadj]: 1.66, 95% confidence interval [CI]: 1.19–2.32) and mortality (HRadj: 1.60, 95% CI: 1.18–2.15)in non‐anemic patients, but there was no association in anemic patients (Table 2). These associations were independent of the effects of age, sex, race, and CCI. There was a statistically significant interaction between anemia and RDW when the associations with mechanical ventilation (p = .02) and mortality (p = .01) were studied.
Table 1.
Baseline characteristics of patients (N = 2562)
| Variable | N (%) |
|---|---|
| Sex | |
| Male | 1458 (56.9) |
| Female | 1104 (43.1) |
| Race | |
| Non‐Hispanic white | 632 (24.7) |
| Hispanic and/or nonwhite | 1930 (75.3) |
| Age (years) | |
| <52 | 628 (24.5) |
| 52−63 | 605 (23.6) |
| 64–75 | 707 (27.6) |
| >75 | 622 (24.3) |
| Red blood cell distribution width (%) | |
| >15 | 501 (19.6) |
| ≤15 | 2061 (80.4) |
| Anemia (hemoglobin < 12 g/dl, females; <13 g/dl, males) | |
| Yes | 792 (30.9) |
| No | 1770 (69.1) |
| Variable | Mean (SD) |
| Charlson comorbidity index | 1.71 (2.09) |
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
Table 2.
Predictors of being placed on mechanical ventilation and mortality among COVID‐19 positive patients according to anemia status
| Non‐anemic patients (n = 1770) | ||
|---|---|---|
| Variable | Mechanical ventilation HR adj a (95% CI) | Mortality HR adj a (95% CI) |
| RDW (%) >15 versus ≤15 | 1.66 (1.19–2.32) | 1.60 (1.18–2.15) |
| Female versus male | 0.65 (0.52–0.82) | 0.69 (0.55–0.85) |
| Non‐Hispanic white versus Hispanic and/or nonwhite | 0.73 (0.56–0.95) | 0.90 (0.71–1.14) |
| Age (years) | ||
| <52 | 1.0 (Ref) | 1.0 (Ref) |
| ≥52–63 | 1.91 (1.39–2.67) | 1.93 (1.25–2.98) |
| 64–75 | 2.46 (1.77–3.42) | 3.42 (2.29–5.13) |
| >75 | 1.81 (1.23–2.65) | 6.63 (4.41–9.96) |
| Charlson comorbidity index | 0.97 (0.91–1.04) | 1.03 (0.98–1.09) |
| Anemic patients (n = 792) | ||
| RDW (%) >15 versus ≤15 | 0.91 (0.66–1.25) | 0.96 (0.74–1.25) |
| Female versus male | 0.99 (0.72–1.36) | 0.76 (0.58–0.99) |
| Non‐Hispanic white versus Hispanic and/or nonwhite | 1.08 (0.76–1.54) | 1.23 (0.94–1.62) |
| Age (years) | ||
| <52 | 1.0 (Ref) | 1.0 (Ref) |
| ≥ 52–63 | 1.37 (0.76–2.46) | 4.94 (2.22–11.03) |
| 64–75 | 2.31 (1.37–3.91) | 6.88 (3.17–14.97) |
| >75 | 1.48 (0.86–2.57) | 10.10 (4.67–21.76) |
| Charlson comorbidity index | 1.02 (0.95–1.09) | 1.07 (1.01–1.12) |
Note: The High RDW*Anemia interaction term was statistically significant for both mechanical ventilation (p = .02) and mortality (p = .01).
Abbreviations: CI, confidence interval; COVID‐19, coronavirus disease 2019; HRadj, adjusted odds ratio; RDW, red cell distribution width; Ref, reference.
Adjusted for all variables listed.
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
Previous studies have found that elevations in RDW are predictive of mortality in numerous settings, 5 , 6 as it may serve as an early indicator of physiological stress via reductions in erythropoietic output. 7 To address the value of RDW elevations in the context of anemia, in this study of a large sample of COVID‐19 patients, unlike the previously referenced studies, 1 , 3 , 4 we stratified our large sample of patients according to their hemoglobin levels and included patients that were not hospitalized. We confirmed that RDW elevation is independently predictive of morbidity and mortality in COVID‐19. In addition, for the first time we show that the elevated RDW association with mortality and mechanical ventilation is present exclusively in non‐anemic patients. The underlying mechanism implicated in this association is speculative. Considering the tight association of elevated RDW with anemia and the fact that anemia is an independent predictor of disease severity, the predictive value of RDW may not surpass that of anemia and only be exposed in non‐anemic patients. Therefore, we propose that RDW be considered by clinicians, especially in non‐anemic patients, when risk‐stratifying COVID‐19 patients.
CONFLICT OF INTERESTS
The authors delcare that there are no conflict of interests.
ACKNOWLEDGMENTS
The authors would like to thank Members of the Hematology and Medical Oncology Fellowship and Institute for Translational Epidemiology at Mount Sinai Health System especially Drs. Leonard Naymagon, Maaike van Gerwen, Mathilda Alsen, Santiago Thibaud, Alaina Kessler, Sangeetha Venugopal, Iman Makki, Qian Qin, Sirish Dharmapuri, Tomi Jun, Sheena Bhalla, Shana Berwick, and Jonathan Feld for their work and assistance in creating the clinical database. This study was in part supported by 5P30CA196521‐05 to EM and R01HL136255 to SG.
Joseph L. Rap and Douglas Tremblay contributed equally to this work.
Contributor Information
John Mascarenhas, Email: john.mascarenhas@mssm.edu.
Emanuela Taioli, Email: emanuela.taioli@mountsinai.org.
Saghi Ghaffari, Email: saghi.ghaffari@mssm.edu.
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