Anemia: A Risk Factor for COVID-19
Anemia affects an estimated 1.62 billion people worldwide, which corresponds to almost 25% of the world’s population.1 Prior to the emergence of the current COVID-19 pandemic, studies had identified anemia to be common in patients with community-acquired pneumonia and to be associated with a higher 90-day mortality rate.2 The high incidence of anemia worldwide is of particular concern during this global pandemic, as there have been a growing number of case reports that describe anemia as a risk factor for increased severity of COVID-19 and increased mortality.
Heightened awareness of anemia as a risk factor for the development of severe COVID-19 may help health care professionals apply risk stratification efforts to identify patients at greatest risk of severe COVID-19 outcomes, while also helping to better allocate needed hospital resources and guide public health awareness and recommendations.
Overview of Anemia
• eyes (yellowing);
Initially, COVID-19 was widely regarded as an infective-inflammatory disease that mainly affects the lungs. As the pandemic has progressed, it’s become clear that COVID-19 affects not only the lungs but also a number of different organs with different pathways of injury. As noted earlier, Hgb serves as a carrier of oxygen to organs throughout the body. In persons with anemia, low Hgb levels exist and indicate that there’s a disruption in the transportation of oxygen to multiple organs, causing hypoxia, which can then lead to the multiple organ dysfunction that contributes to the severe outcomes commonly seen in severe COVID-19.
One pathophysiological mechanism in anemia and more severe COVID-19 suggests that SARS-CoV-2 (the coronavirus responsible for COVID-19) may worsen anemia in some persons through its interaction with Hgb, specifically through its interaction at CD147, CD26, and other receptors located on erythrocyte and/or blood cell precursors. Through this interaction, SARS-CoV-2 may attack the heme (iron-containing part of Hgb) on the 1-beta chain of Hgb, and subsequently cause hemolysis.3
A second possible pathophysiological mechanism involves the hepcidin-mimetic action of a spike protein found on the surface of SARS-CoV-2 that induces iron deficiency and decreases functioning Hgb while also causing hyperferritinemia (increased circulating and tissue ferritin which is an intracellular protein that stores and releases iron). Hyperferritinemia can give rise to ferroptosis (iron-dependent form of tissue death) along with the release of free toxic heme. Subsequent oxidative stress and lipoperoxidation may then cause an immune overresponse, referred to as macrophage activation syndrome, which then triggers the inflammatory cytokine storm associated with severe outcomes of the disease, including hypoxia and increased coagulation activation.3
Hyperferritinemia — A Closer Look
Normally, ferritin neutralizes the toxic properties of iron and increases its solubility by binding to free ions of the trace element of iron. When iron is in its soluble form, the body is able to expend it as needed for the regulation of cellular oxygen metabolism. Low ferritin levels can lead to lower iron concentrations and iron deficiency anemia, while elevated levels of ferritin indicate the presence of viruses and bacteria in the body. In COVID-19, the high levels of ferritin cause an exaggerated immune (inflammatory) response, with macrophages secreting excessive cytokines (cytokine storm), which is implicated in increased severity and adverse outcomes.
Scientists searching for ways to reduce circulating ferritin levels in COVID-19 have identified a marker called CD163. Studies are underway to identify treatments that can inhibit the synthesis of CD163 and other macrophage signaling molecules using antibodies.5
Biomarkers of Anemia and Iron Metabolism
Furthermore, when comparing moderate cases of COVID-19 vs severe cases, researchers found that those with severe cases had lower pooled mean Hgb [weighted mean difference (WMD) -4.21 (95% confidence interval [CI] -6.63 to -1.78)] and higher ferritin [WMD -730.55 ng/mL (95% CI 413.24 to 1047.85)]. A significant difference in mean ferritin level of 1027.23 ng/mL (95% CI 819.53 to 1,234.94) was found between survivors and nonsurvivors, but not in Hgb levels. The researchers noted that no studies provided information on anemia or other biomarkers of interest and suggested that future studies should explore the impact of iron metabolism and anemia and in the pathophysiology, prognosis, and treatment of COVID-19.7
This study indicates that anemia and alterations of iron homeostasis are highly prevalent in patients with severe COVID-19 disease. The research indicates that iron metabolism markers (ferritin and transferrin) and Hgb can contribute to risk stratification of patients, with initial anemia being associated with increased mortality, whereas alterations of iron homeostasis with a higher ferritin:transferrin ratio reflects more advanced inflammation and is a predictor of subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation. The researchers suggest ferritin:transferrin ratio to be a robust and easily available marker that can be used for risk stratification of patients with SARS-CoV-2 infection upon hospital admission. They also suggested that further studies are needed to investigate probable (direct) effects of changed iron homeostasis on the pathogenesis and severity of COVID-19 infections, as well as the potential for therapeutic interventions by modulating iron availability.9
A recent study involving more than 1,600 COVID-19 patients (admitted between early March and April 2020) treated at four Boston hospitals found that elevated RDW measured at hospital admission and rising RDW during hospitalization were found to be linked to significantly higher death rates from COVID-19.11 An RDW greater than 14.5% at the time of hospital admission for illness due to SARS-CoV-2 infection was associated with an almost three-fold increase in risk for death in the cohort (relative risk [RR] 2.73), with a mortality rate of 31% in these patients, compared with 11% in those with normal RDW. Among patients younger than 50 years, an RDW greater than 14.5% at admission increased the risk for death from COVID-19 more than five-fold (RR 5.25), with a mortality rate of 8% vs 1%, respectively, associated with elevated and normal RDW.
Patients with elevated RDW at admission were more than six times more likely to die within 48 hours of admission. Only nine of 1,175 patients with normal RDW died during the first 48 hours of admission (mortality rate 0.8%) compared with 23 of 479 patients with elevated RDW (mortality rate 4.9%). In addition, RRs for different age groups were significantly different compared with each other, suggesting an effect modification, with an elevated RDW having a larger effect on mortality for younger patients (<70 years) than on older patients. Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. A total of 1,173 patients had normal RDW, and 468 had elevated RDW. Among patients younger than age 50 years, 341 had normal RDW and 65 had elevated RDW.
The relative risk for death associated with elevated RDW compared with normal RDW was 2.73 among the entire cohort, 5.25 among patients younger than 50 years, 2.9 among patients between the ages of 50 and 59 years, 3.96 among patients between the ages of 60 and 69 years, 1.45 among patients who were aged 70 to 79, and 1.59 among patients who were aged 80 or older. Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW didn’t change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%.11
The researchers concluded that RDW is “a routine laboratory test that may be useful in risk stratification of hospitalized patients with COVID-19.”11
— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.
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