March/April 2021

Anemia: A Risk Factor for COVID-19
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 14 No. 2 P. 10

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
Red blood cells (RBCs), also called erythrocytes, are the most abundant type of blood cell. The primary function of RBCs is to transport oxygen to the body’s various organs and deliver carbon dioxide to the lungs. Anemia is a condition that develops when there are insufficient healthy RBCs or when the concentration of hemoglobin (Hgb), the iron-containing oxygen-carrying protein, found in RBCs is too low. As a result of low Hgb concentrations, persons with anemia can experience an inadequate supply of oxygen reaching a number of different organ systems. Organs potentially affected by anemia, along with possible signs and symptoms, include the following:

• eyes (yellowing);
• skin (paleness, yellowing, cold hands and feet);
• respiratory system (shortness of breath);
• muscular system (weakness, lower leg cramps);
• intestinal system (changed stool color);
• central nervous system (increased thirst, headache, anxiety, fatigue, dizziness, and fainting with severe anemia);
• blood vessels (low blood pressure);
• heart (palpitations, rapid and irregular heart rate, and, with severe anemia, chest pain, angina, heart attack); and
• spleen (enlargement).

Pathophysiology of Anemia and Severe COVID-19
Although the exact pathophysiology of anemia and severe COVID-19 isn’t fully understood, several potential mechanisms have been proposed.

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
Previously, concerns with hyperferritinemia (elevated levels of ferritin), specifically in persons with hyperferritinemia syndrome, had been studied. It was found that in 50% of cases patients with high ferritin (major intracellular iron storage protein) levels die.4 Similar trends associating hyperferritinemia with COVID-19 are now being noted.

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
A number of potential biomarkers of anemia and iron metabolism have been pinpointed that may help identify those patients at greatest risk for severe COVID-19 outcomes. These markers include Hgb, ferritin, transferrin, ferritin/transferrin ratio, and RBC distribution width (RDW).

Hgb
In order to help describe a potential association between anemia and more severe COVID-19, researchers conducted a review of 17,200 records. The final meta-analysis included seven studies with a total of 9,912 COVID-19 patients. Six of the studies defined anemia as a Hgb level lower than 13 g/dL, while one study used a cut-off value of Hgb below 11 g/dL to define anemia. The pooled analysis showed persons with anemia to be at significant increased risk of severe COVID-19.6

Ferritin
Another study provides further insight into the potential prognostic value of Hgb and ferritin levels in identifying patients at increased risk of severe COVID-19 outcomes. The researchers utilized six bibliographic databases (searched up to May 5, 2020) which included 56 unique studies with data from 14,044 COVID-19 patients (59 years median age).7 Pooled mean Hgb and ferritin levels in COVID-19 patients across all ages were 13.041 g/dL and 673.91 ng/mL, respectively. Researchers discovered that Hgb levels in these patients decreased with advancing age and that lower Hgb levels were found in a larger percentage of comorbid and critically ill patients.

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

Transferrin
Whereas ferritin is responsible for the storage of iron in cells, the plasma protein known as transferrin combines with ferritin to transport iron through the blood to sites where new blood cells are formed, such as the liver, spleen, and bone marrow. Transferrin levels are often tested to determine the cause of anemia, to examine iron metabolism (for example, in iron deficiency anemia), and to determine the iron-carrying capacity of the blood. Transferrin levels are found to be abnormally high in iron deficiency anemia.

Significant research has been aimed at determining why some persons with COVID-19 develop only mild or no symptoms when infected, while others experience severe, life-threatening forms of the disease. It’s known that severity increases with age and is higher in males than in females, and that severe cases are frequently characterized by increased blood clotting and thrombosis formation. Therefore, a team of researchers combined existing data on gene expression in humans and infected cells to search for molecules involved in blood coagulation that may explain differences seen between females and males and with increased age.8 Out of more than 200 candidate factors, the researchers identified transferrin to be a procoagulant and that it’s increased with age, is higher in males than females, and is higher in SARS-CoV-2–infected cells. This indicates that transferrin may have potential as a biomarker for the early identification of COVID-19 patients at high risk of severe disease.

Ferritin:Transferrin Ratio
In another study, researchers studied the prevalence and predictive value of anemia of inflammation or functional iron deficiency, originating from immune-medicated COVID-19 alterations of iron homeostasis.9 The researchers conducted a retrospective analysis of 259 patients admitted to the hospital for COVID-19. They found that at the time of admission 24.7% were anemic, with the majority of these patients suffering from anemia of inflammation. Anemia was associated with significantly higher in-hospital mortality (odds ratio 3.729) but not an increased frequency of ICU admission or the need for mechanical ventilation. Eighty percent of patients were found to have functional iron deficiency upon admission and experienced more advanced inflammation and significantly longer hospital stays. Of particular importance was that a ferritin:transferrin ratio greater than 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation.

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

RDW
RDW is a blood test that measures the amount of RBC variation in volume and size. The RDW test is commonly done when a complete blood count is ordered. Normal RBCs maintain a standard size of 6 to 8 micrometers in diameter. An elevated RDW results when the average size of RBCs is outside of this normal range and is associated with lower mean RBC volume, indicating problems in RBCs’ ability to effectively transport oxygen to various organs. Elevated RDW is most common when a patient is diagnosed with diseases that directly affect RBCs, with patients presenting symptoms of anemia including numbness, pale skin, and dizziness. Elevated RDW has previously been found to be a risk factor for death from all causes and is associated with significant higher rates of mortality and severe morbidity in patients requiring hospitalization for pneumonia.10

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

Final Thoughts
A number of different biomarkers of anemia and iron metabolism appear to be useful in helping to identifying COVID-19 patients who may be at high risk of severe COVID-19 outcomes. Patients with existing anemia should be made aware of this risk factor, and health care providers should closely monitor for new anemia or worsening of symptoms in those patients suspected of COVID-19.

— 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.

References
1. Global anaemia prevalence and number of individuals affected. World Health Organization website. https://www.who.int/vmnis/anaemia/prevalence/summary/anaemia_data_status_t2/en/. Published 2008.

2. Reade MC, Weissfeld L, Angus DC, Kellum JA, Milbrandt EB. The prevalence of anemia and its association with 90-day mortality in hospitalized community-acquired pneumonia. BMC Pulm Med. 2010;10:15.

3. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10(2):1271.

4. Rosário C, Zandman-Goddard G, Meyron-Holtz EG, D’Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013;11:185.

5. Shoenfeld Y. Corona (COVID-19) time musings: our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmun Rev. 2020;19(6):102538.

6. Hariyanto TI, Kurniawan A. Anemia is associated with severe coronavirus disease 2019 (COVID-19) infection. Transfus Apher Sci. 2020;59(6):102926.

7. Taneri PE, Gómez-Ochoa SA, Llanaj E, et al. Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. medRxiv. 2020;20122267.

8. McLaughlin KM, Bechtel M, Bojkova D, et al. COVID-19–related coagulopathy — is transferrin a missing link? Diagnostics (Basel). 2020;10(8):539.

9. Bellmann-Weiler R, Lanser L, Barket R, et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9(8):2429.

10. Braun E, Kheir J, Mashiach T, Naffaa M, Azzam ZS. Is elevated red cell distribution width a prognostic predictor in adult patients with community acquired pneumonia? BMC Infect Dis. 2014;14:129.

11. Foy BH, Carlson JCT, Reinertsen E, et al. Association of red blood cell distribution width with mortality risk in hospitalized adults with SARS-CoV-2 infection. JAMA Netw Open. 2020;3(9):e2022058.