Effects of Beta-Thalassemia on COVID-19 Outcomes

Abstract

Beta-thalassemia is a hemoglobinopathy caused by mutations in the beta-globin chain. This disrupts hemoglobin production and can potentially result in severe anemia. There has been a rise in COVID-19 cases over the last 2 years, with a predominant effect on the respiratory and vascular systems of the body. Since beta-thalassemia is the most common inherited single-gene disorder in the world, investigating the impact of COVID-19 on these patients is important. Some theories suggest that patients with beta-thalassemia will be more susceptible to COVID-19 and have worse outcomes due to their underlying comorbid conditions. However, majority of the literature found that beta-thalassemia is protective against COVID-19. This could be because SARS-CoV-2 proteins can attack the beta chain of normal hemoglobin, resulting in impaired oxygen transfer and increased ferritinemia. Thus, in hemoglobinopathies with beta-chain defects and low hepcidin levels, susceptibility to COVID-19 infection is potentially decreased. Higher levels of Hemoglobin F in thalassemia patients may also be protective against viral infections. Surprisingly, most studies and case reports focus on patients with beta-thalassemia major. There is yet much to learn about the outcomes of patients with thalassemia minor and other hemoglobinopathies.

1. Introduction

Thalassemias are a group of autosomal recessive blood disorders caused by variations in alpha or beta globin genes that disrupt hemoglobin production and lead to ineffective erythropoiesis and hemolysis [1]. Given that hemoglobin serves as the oxygen-carrying component of red blood cells (RBCs), inadequate production can cause severe anemia and other life-threatening complications requiring frequent blood transfusions to maintain hemoglobin levels. Individuals affected by these disorders can start presenting with symptoms early in childhood and last for their entire lifetime.

Hemoglobin is made up of two chains: alpha-globin and beta-globin chains. Alpha thalassemia is generally caused by alpha-globin gene deletion that results in either reduced or absent alpha-globin production. Since the alpha-globin gene has four alleles, disease severity is dependent on the number of deleted alleles. One deletion can be clinically silent, whereas four deletions can be incompatible with life and lead to hydrops fetalis [1]. Beta thalassemia is generally caused by beta-globin gene point mutations that are classified based on the zygosity of the gene mutation. A heterozygous mutation will result in one defective and one normal gene allowing for some production of the beta-globin chains. This is the mildest form of beta-thalassemia. A homozygous mutation will result in two defective genes causing a total absence of beta-globin chains. This mutation can lead to moderate to severe symptoms. Since the alpha and beta-globin chains are insoluble alone, they can precipitate and lead to damage to RBC membranes and intravascular hemolysis [1].

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached the entire globe over the last 2 years and resulted in millions of deaths. It primarily targets the respiratory and vascular systems of the body. Since beta-thalassemia is the most common inherited single-gene disorder in the world and can affect the oxygen-carrying capacity of the body, investigating the impact of COVID-19 on these patients is important given the limited research data currently available [2].

2. Classifications of beta-thalassemia

The disease burden of beta-thalassemia depends on the zygosity of the beta-globin chain gene mutation. There are three main types of beta-thalassemia: beta-thalassemia major, beta-thalassemia intermedia, and beta-thalassemia minor [3].

2.1 Beta-thalassemia major

Individuals who are homozygous for the beta-globin chain mutation are classified as having beta-thalassemia major and completely lack beta chains. The manifestations of beta-thalassemia major are much more severe than beta-thalassemia minor and can result in jaundice, growth retardation, hepatosplenomegaly, endocrine abnormalities, and severe anemia. Symptoms begin at the age of 6 months when fetal hemoglobin is completely replaced by defective globin chains that accumulate and damage RBC membranes. Patients at this stage may present with failure to thrive and require lifelong blood transfusion and iron chelation therapy [3]. The classic clinical picture of beta-thalassemia major is primarily seen in underdeveloped countries where long-term transfusion facilities are not widely available. Patients who are inadequately treated for beta-thalassemia major commonly present with brown pigmentation of the skin, poor musculature, genu valgum, development of masses from extramedullary hematopoiesis, and skeletal changes in the long bones of the legs and craniofacial structures due to expansion of the bone marrow. Individuals not receiving regular transfusion therapy may die from high-out cardiac failure. Adequate maintenance of a minimum hemoglobin level between 9.0 and 10.5 g/dl ineffective erythropoiesis can be inhibited and regular growth and development can occur up to 10–12 years [3]. However, the complications of iron overload from repeated transfusions may manifest in children with growth retardation and failure of sexual maturation and in adults with liver fibrosis and cirrhosis, endocrine dysfunction resulting in diabetes mellitus and parathyroid insufficiency, and cardiac disease including dilated cardiomyopathy and arrhythmias. Hence, adequate iron chelation therapy is necessary as well. In the early 2000s, 50% of beta-thalassemia major patients died before the age of 35 due to all these complications. With the advent of new developments of noninvasive methods to measure organ iron levels and chelation therapy, the prognosis of beta thalassemia major has greatly improved [1, 2, 3].

2.2 Beta-thalassemia intermedia

Patients with beta-thalassemia intermedia can present much later in life than those with beta-thalassemia major. They have milder anemia symptoms and may still require transfusions but much less frequent, if at all. They can remain asymptomatic until adulthood, during which they may develop clinical features such as pallor, jaundice, cholelithiasis, hepatosplenomegaly, extramedullary masses of hyperplastic erythroid marrow, osteopenia, osteoporosis, and thrombotic complications. Patients can present with cardiac manifestations as well, including high-cardiac output and pulmonary hypertension with preserved systolic function [3]. Pseudoxanthoma elasticum, a disease caused by the accumulation of calcium deposits in elastic fibers in the skin, eyes, and blood vessels, is also common among beta-thalassemia intermedia patients [3]. Although the rate of iron loading is slower in these patients, similar complications can still occur if proper iron chelation therapy is not administered [1, 2, 3].

2.3 Beta-thalassemia minor

Heterozygotes of the beta-globin chain mutation are classified as having beta-thalassemia minor in which beta chains are being produced to a lesser degree than normal. Patients are generally asymptomatic or have mild anemia symptoms [1, 2, 3].

3. Epidemiology of beta-thalassemia

Beta-thalassemia is most prevalent in the Mediterranean and Middle East populations but is also common in regions of Southeast Asia. It has been less prevalent in regions of Northern Europe and North America. It is reported that 80–90 million people are carriers of this disease, making up about 1.5% of the global population [4]. According to a report published by the World Health Organization in 2008, more than 40,000 infants are born with beta-thalassemia annually, the majority of whom are transfusion-dependent. Roughly 205,000 newborns with beta-thalassemia are born in Southeast Asia, 10,000 in the Eastern Mediterranean region, 1000 in Europe, and 350 in North, Central, and South America. Thailand alone has close to 4000 new cases of beta-thalassemia annually. Only a few European countries have reported incidences of beta-thalassemia major, including Belgium which reported 1 in 25,000 neonates being born with beta-thalassemia, and 1 in 113,000 neonates in France between 2005 and 2008. In the United States, an incidence of 1 in 55,000 newborns was reported in California [4]. The high prevalence of beta-thalassemia in certain regions can be explained by multiple factors. There is a higher carrier rate and a cultural preference for consanguineous marriages in the Middle East. Increases in rates of migration from areas with a higher prevalence of beta-thalassemia to non-endemic areas have led to a higher prevalence of the disease in some European and Northern American regions. Also, with the improvement of health resources and access to blood transfusion centers, and adequate iron chelation therapy, survival rates have increased significantly, adding to the prevalence of beta-thalassemia [3, 4].

Comprehensive prevention programs have been put in place in endemic areas of beta-thalassemia, with a focus on public education, genetic counseling, population screening, and prenatal diagnostic testing. The Greek National Registry for Hemoglobinopathies reported a lower incidence of beta-thalassemia compared to what was expected based on the prevalence of carriers in the population [4]. Similar trends have been noted in Iran and Iraq as well, suggesting that thalassemia these programs have been effective in reducing the prevalence of the disease in some regions.

4. Beta-globin gene mutations causing beta-thalassemia

The beta-globin chain is encoded by a structural gene on chromosome 11 that is clustered with five other beta-like genes including ε(HBE), Gγ (HBG2), Aγ (HBG1), δ (HBD), and β (HBB) [5]. These genes are arranged on the chromosome based on the order of their developmental expression and are dependent on local promotor sequences and upstream control regions which bind to various erythroid-specific transcription factors (e.g. GATA-1, GATA-2, NF-E2, KLF1) and co-factors (e.g. FOG, p300). The controlled gene expression leads to the production of specific hemoglobin tetramers including embryonic (Hb Gower-1 (ζ2ε2), Hb Gower-2 (α2ε2), and Hb Portland (ζ2β2)), fetal (α2γ2), and adult (HbA, α2β2 and HbA2, α2δ2). Each is produced at a distinct stage of development, allowing for the process of hemoglobin switching to occur between the embryonic, fetal, and adult stages of life [5].

Fetal hemoglobin (HbF) is the primary hemoglobin from birth till about 6 months of age. Since it is made up of two alpha and two gamma chains and no beta chains, the manifestations of beta-thalassemia are not seen until after 6 months. When HbF levels drop and make up less than 5% of the total hemoglobin content of the body, it is replaced with adult hemoglobin (HbA), which is made up of two alpha and two beta chains. Since beta chain production is disrupted in beta-thalassemia, symptoms begin during this time. Hydroxyurea is an agent that upregulates gamma-globin gene production leading to increased HbF production. Though this therapy is widely used in sickle cell disease, its efficiency in beta-thalassemia is still being investigated [5, 6, 7].

There have been more than 300 beta-thalassemia alleles reported in the literature. However, only about 40 account for more than 90% of beta-thalassemia worldwide likely because only a few mutations are common in endemic regions. Downregulation of the beta-globin chain can be caused by a variety of molecular changes such as point mutations, small deletions limited to the beta-globin genes, or even extensive deletions of this region. However, most mutations are non-deletional. They may be single-base substitutions and small insertions or deletions of only a few bases within the gene. These mutations can lead to downregulation of the beta-globin gene throughout all stages of gene expression including transcription of the gene from DNA into mRNA to translation of the mRNA into a functional protein [5, 6]. Very rarely do larger deletions in the beta-globin gene result in beta-thalassemia. There are 18 deletions specifically on the beta-globin gene that have been found to cause beta-thalassemia. They range from 25 base pairs to about 6000 base pairs [5].

5. Pathophysiology of beta-thalassemia

Hemoglobin A is a tetrameter made up of two heterodimers each consisting of one alpha and one beta globin chain, attached to a heme moiety in the center. A balanced production these chains is crucial and tightly regulated. Once the globin chains combine, they are highly soluble in RBCs. However, if left unbound, these globin chains are highly insoluble and can accumulate in the blood. In beta-thalassemia, excess alpha-globin chains begin aggregating as soon as they accumulate in erythroid precursors and precipitate adjacent to the RBC membrane in early marrow erythroid precursors. This disrupts proper membrane assembly and can accelerate apoptosis [8, 9, 10, 11].

5.1 Effects of beta-thalassemia on red blood cells

In normal physiology, hemoglobin in RBCs is oxidized to methemoglobin and subsequently reduced back to native hemoglobin. However, in patients with beta-thalassemia, the unpaired alpha chains attached to a heme moiety are more susceptible to oxidation and proteolysis, leading to the formation of hemichromes. These hemichromes can generate reactive oxygen species that in turn oxidize adjacent RBC membrane proteins and lipids. This can cause damage to the membrane by affecting the globin chains that bind to the membrane and directly altering cytoskeletal and integral membrane proteins [8, 9, 10, 11].

Normal RBC precursors undergo cytoskeletal and membrane assembly via spectrin, band 4.1, band 3, and several other proteins. The asymmetry of the phospholipid bilayer that naturally exists between the inner and outer leaflets of the membrane is disrupted with oxidative damage and results in a disorderly and discontinuous pattern of membrane protein incorporation, especially in the regions with alpha chain aggregates [12]. There is also a lack of membrane stability caused by an oxidative injury that hinders the ability and inability to handle sheer stress [13]. All these changes are responsible for the abnormal maturation of RBCs in beta-thalassemia. Although the use of proteases may be used to treat membrane damage caused by an accumulation of globin chains by directly attacking and partially destroying the chains, they do not aid in their elimination from the body [14].

Beta-thalassemia can also affect the hydration of RBCs and result in their dehydration. This may be due to excessive activation of the potassium-chloride cotransport system, which is responsible for controlling potassium chloride loss in the body. Excessive activation results in the loss of these ions, leading to the loss of water as well. The resultant dehydration can cause a high mean cell hemoglobin concentration and a dense appearance on peripheral blood smears [13]. The flexible nature of RBCs allows for them to travel through the capillary circulation and the reticuloendothelial system lined by phagocytic cells lie within the spleen, liver, and lungs. The dehydration of RBCs caused by beta-thalassemia can affect this essential property and cause a delay in RBC passage and increased engulfment by macrophages [13, 15].

5.2 Causes of anemia in beta-thalassemia

Ineffective erythropoiesis refers to a decrease in the production of RBCs due to the destruction of maturing erythroblasts from either apoptosis or hemolysis. In patients with thalassemia, ineffective erythropoiesis leads to the expansion of the erythroid progenitor cell population and acceleration of differentiation, and mature arrest at the polychromatophilic erythroblast stage [16].

Some causes of ineffective erythropoiesis include apoptosis of erythroid precursors. Studies have shown that a possible mechanism for this apoptosis in beta-thalassemia patients involves the sequestration of heat shock proteins by free alpha-globin chains contained within the cytoplasm of precursor RBCs. These heat shock proteins are generally expressed in response to stress and play an important role in the stabilization of the cell [17]. The caspase and cytochrome proteins, which regulate apoptosis, were also found to be abnormally phosphorylated in the bone marrow erythroblasts of some beta-thalassemia patients [18]. Apoptosis of cells can result in the movement of phosphatidylserine from the inner to the outer leaflet of RBC membranes, which serves as a signal for the removal of the cell by macrophages in the reticuloendothelial system [19].

Adverse consequences of ineffective erythropoiesis can arise at peripheral locations and result in extramedullary hematopoiesis, which is the production of RBCs outside of the bone marrow. This process is driven by a rise in erythropoietin levels and can manifest with the expansion of bone marrow cavities that can distort long bone, head, and facial bones that are not common sites of erythropoiesis. Ineffective erythropoiesis can also result in increased iron absorption, which is accompanied by its own set of complications.

Hemolysis can also lead to anemia in beta-thalassemia patients and can shorten the lifespan of the RBC by a third. This hemolysis is caused by the aggregation and oxidation of RBC membranes, resulting in mechanical property changes such as increased rigidity and dehydration that inhibit their smooth passage within the reticuloendothelial system and allow more time for macrophages to phagocytose the cells. Studies show that patients who have undergone splenectomies are more likely to be observed with unstable and deformed RBCs [20, 21, 22].

6. COVID-19

In late 2019, the first cases of mysterious pneumonia of unspecified origin were seen in Wuhan, the capital of Hubei province, China. Later, it would be confirmed that these cases were caused by the coronavirus disease 2019 (COVID-19). This pathogen belongs to the enveloped RNA beta coronavirus family. Due to its similarities with the original severe acute respiratory syndrome coronavirus (SARS-CoV-2) and Middle East Respiratory Syndrome (MERS) viruses, it was named SARS-CoV-2. Over the past 2–3 years, a staggering number of studies have explored the epidemiology and clinical presentation of COVID-19. However, there remains much to be learned regarding how the virus impacts the respiratory system both in the short and long term and how it affects those with chronic conditions such as hemoglobinopathies. Taking a macroscopic view, data classifies the presentation of the disease as mild, severe, or critical [23, 24]. A common symptom that is independently associated with in-hospital mortality is the severity of hypoxemia; this symptom has been described as a potentially important predictor of whether a patient requires intensive care.

6.1 Pathophysiology of hypoxemia in COVID-19

Arterial hypoxemia, an early sequela of COVID-19 infection, is caused mainly due to a V/Q mismatch. Continued blood flow to non-ventilated alveoli increased the P(A-a) O2 gradient. Infection also causes interstitial edema, particularly in structures with elastic properties responsible for withstanding stress and strain. This edema can lead to the appearance of ground-glass opacities and consolidation on chest X-ray or computerized tomographic imaging. Additionally, the edema causes loss of surfactant and increased superimposed pressure on lung parenchyma, eventually leading to alveolar collapse. While this occurs, a moderate amount of cardiac output continues to perfuse these collapsed areas, causing intrapulmonary shunting. The body’s response to this is increased effort of breathing and use of accessory muscles, causing a rise in tidal volume, and subsequently, negative inspiratory intrathoracic pressure. Inflammation also causes increased lung permeability, which when combined with the increase in negative intrathoracic pressure, leads to progressive edema, alveolar flooding, and effusions. Over time, this causes a severe decline in the quality of oxygenation and increases shunt fraction which is difficult to correct by increasing FiO2 [25].

While useful, clinicians should take caution when using oxygen saturation measured by pulse oximetry (SpO2) to detect hypoxemia. Tachypnea and hyperpnea due to infection, as described above, cause respiratory alkalosis and subsequent drop in PaCO2. This leads to a left shift in the oxyhemoglobin dissociation curve. Increased affinity of hemoglobin for oxygen during these periods can result in a paradoxical finding of preserved SpO2 during states of low PaO2 [25, 26, 27]. Another theory for the left-ward shift of the oxy-hemoglobin curve in COVID-19 was put forth by Rapozzi et al. Their hypothesis states that serum heme levels increase in COVID-19 infection, along with harmful iron ions (Fe3+) which cause inflammation and cell death. However, the interaction of the virus and abnormal heme groups remains to be studied. The apparently increased oxygen affinity of hemoglobin leads to lower tissue perfusion and extremity ischemia in patients with normal hemoglobin structure. However, for patients with thalassemias or sickle cell disease that may be on HbF treatment, the changes in the oxy-hemoglobin curve may shed light on if having hemoglobinopathies is protective or not against infection [26].

Further exploration of how COVID-19 affects erythrocytes and hemoglobin was done by the group. They propose that viral protein ORF8 and a surface glycoprotein of COVID-19 damaged the 1-beta chain of deoxyhemoglobin via docking with porphyrin and lead to the release of iron-free porphyrins. This interaction is intriguing. If it can be proven in vitro settings, this apparent interaction could explain cases where having beta-thalassemia has been shown to be protective against COVID- 19 infections. An absence of a beta-hemoglobin chain would leave the virus unable to negatively affect the oxygen binding capacity of existing hemoglobin chains, especially in patients that have increased HbF due to hydroxyurea therapies [26].

6.2 COVID-19 and beta-thalassemia

Multiple studies have been conducted to study the relationship between beta-thalassemia and COVID-19 infection. These studies have been piloted by groups mainly from countries where thalassemias have a higher prevalence, such as the Mediterranean and Middle Eastern nations. Researchers from these nations posit two hypotheses regarding the susceptibility of beta-thalassemia patients to COVID-19. One theory states that patients with beta-thalassemia may be more susceptible to COVID-19 infection and have worse outcomes due to chronic conditions such as heart disease, liver disease, iron overload, adrenal insufficiency, diabetes, and splenectomy. Being in a prolonged state of oxidative stress can lead to immunosuppression and thus worsen the body’s innate ability to combat infection. A latent effect of beta-thalassemia is the need for ongoing medical treatment and attention that these patients need. Frequent visits to hospitals or medical centers for blood transfusion and complication management increase these patients’ exposure to COVID-19. A second theory, however, proposes a different possibility. It suggests that patients who are heterozygous for beta-thalassemia may have immunity against COVID-19 infection. This is in part because beta-thalassemia patients have a higher concentration of HbF, which possesses a unique tetramer structure. The exact protective potential of HbF in COVID-19 infection remains to be studied [27].

Figure 1 is a hypothetical representation of the interaction between the SARS-CoV-2 virus and the erythrocytes infected [28]. The internalization process is the virus is dependent on TMPRSS2, a serine protease, and angiotensin-converting enzyme type 2 (ACE-2), which allow entry of the virus into the cell. Once in the cell, the infection would activate metabolic processes that would result in oxidative stress. This negatively affects erythrocytes and would cause their destruction. The release of Fe²⁺ from damaged erythrocytes would further propel the metabolic reactions leading to oxidative stress. Remnants of alpha and beta hemoglobin chains would also be released into the intercellular space [28].

Figure 1.

SARS-CoV-2 entry into host cell and resultant erythrocyte damage.

6.2.1 Review of published studies

A study from Iran describes 43 patients with beta-thalassemia from the ages of 9–67 years who contracted COVID-19. These patients were both transfusion-dependent and transfusion-independent. Results showed that transfusion-independent patients had a higher mortality rate (27.3%) than patients who were receiving regular transfusions (4.71%). Patients in the transfusion-independent category were found to be in a persistent chronic anemic state with hypercoagulability. Additionally, micro thrombosis made these patients more likely to develop pulmonary artery hypertension and heart failure. However, overall, the study found that the prevalence of COVID-19 infections in the beta-thalassemia population was lower than in the general population. Another report from the same group describes that in 48 patients with beta-thalassemia from ages 9–67, 8 (16.7%) died from COVID-19. Compared to the general population, while patients with beta-thalassemia had a lower prevalence of COVID-19 infection, those that did contract the disease had higher mortality [29, 30].

An Italian group studied individuals with thalassemia who contracted COVID-19 and had 15 days of follow-up from symptom onset of positive SARS-CoV2 positivity. They collected data on 11 patients, mainly centered in northern Italy. Patients ranged from ages 31–61 years with a majority being female. Ten patients were transfusion-dependent, and one was not. Eight of these patients were splenectomized and all patients had thalassemia-associated comorbidities. Six of the patients were hospitalized with mild-moderate upper respiratory symptoms but did not require mechanical ventilation. Three patients were asymptomatic. One patient developed severe symptoms of high fever, agranulocytosis, and lymphopenia. This patient also required intensive ventilation support with continuous positive airway pressure. Of the six hospitalized patients, the clinical course ranged from 10 to 29 days. Splenectomy was not found to affect the clinical course of any of the patients. One surprising finding was the apparent lack of severe acute respiratory syndrome in the patients, as well as a lack of signs of cytokine storm or death given the mean age and comorbidities of the patient population. From their preliminary data, the research team concluded that thalassemia did not increase the severity of COVID-19 disease progression [31].

A French study showed that most of the cases of COVID-19 and thalassemia had a favorable outcome in France. The study proposed that this was most likely due to the rarity of the most severe hemochromatosis-related complications such as diabetes, heart failure, cirrhosis, or iron overload in transfusion-dependent patients. However, the study also reported that patients with signs of iron overload detectable via MRI had an increased risk of thromboembolism events, particularly renal or hematological side effects [32].

Most recently, a systematic review meta-analysis of three papers from France in July 2022 described the susceptibility of beta-thalassemia carriers and COVID-19 susceptibility. Based on their findings and after conducting statistical analysis the study found that beta-thalassemia patients were less susceptible to COVID-19 but had higher mortality if infected when compared to the general population. Those that had an ICU course that did not result in death tended to have a shorter ICU stay when compared to patients with no hemoglobinopathies. While the sample size of this systematic review was small, it shows interesting evidence to further showcase the potential protective effects of beta-thalassemia in COVID-19 infections [33].

6.2.2 Review of case reports

A multitude of case reports showcasing the outcomes of COVID-19 infection in patients with hemoglobinopathies has been published. From Indonesia, four beta-thalassemia pediatric patients developed mild COVID-19 infection with one developing thrombosis supported by elevated D-dimer [34]. In Italy, a 59-year-old woman who was transfusion-dependent developed a mild COVID-19 infection [35]. In Pakistan, two patients developed a mild infection as well, with one of the patients having a prior splenectomy [36]. Most case reports describe the infection progression in pediatric patients, while also reporting benign infection courses for all patients.

6.2.3 Summary of findings

Almost universally, the presented studies highlight the relatively young population of patients with COVID-19 and thalassemia had a favorable outcome probably due to the rarity of the most severe hemochromatosis complications. Specific risks related to both thalassemia-related co-morbidities and long-term treatments should be considered. No clear-cut separation between the direct effect of thalassemia on hemoglobin structure and the effect of systemic comorbidities on COVID-19 outcomes has been established.

SARS-CoV-2 proteins can attack the beta chain of hemoglobin, resulting in impaired oxygen transfer and increased ferritinemia. Thus, in hemoglobinopathies with beta chain defects and low hepcidin levels, susceptibility to COVID-19 infection might decrease. Higher levels of HbF in thalassemia patients may be protective against viral infections; the anti-parasitic effect of HbF has been well-documented in areas where malaria is endemic. Studies have attributed lower COVID-19-related mortality in tropical countries where there is a higher prevalence of thalassemias/sickle cell disease due to the increased use of hydroxyurea which induces HbF production. This theory supports the pursuit of clinical studies analyzing the role of HbF-inducing therapies as treatment for COVID-19. Hydroxyurea is a medication used in patients with thalassemia intermedia. Its anti-inflammatory function, antiviral effect, and induction of HbF levels might suggest the benefit of hydroxyurea against the severe forms of COVID-19 [37, 38].

Splenectomy is a common therapeutic intervention in thalassemias, but it might increase the risk of coagulopathy and cytokine storms. However, there is no evidence that splenectomy increases the risk of severe COVID-19 in asplenic/hyposplenic patients [39]. High ferritin levels might be a negative prognostic factor in patients with COVID-19, and iron chelation might be beneficial against COVID-19 [40]. Patients with hemoglobinopathies, including those with thalassemias, are at increased risk of developing severe complications of COVID-19. Lifestyle and nutrition controls are important in controlling their infection, and vitamin D supplementation is beneficial against viral and bacterial infections. Two trace elements, zinc, and selenium are involved in the immune system’s integrity and are necessary for beta-thalassemia patients during the COVID-19 pandemic.

6.2.4 Socio-economic factors affecting patients with beta-thalassemia

Most infants born with beta-thalassemia are in Southeast Asia and the Middle East. Nations in these geographical locations are still developing standardized and accessible healthcare for their citizens. While patient education and screening measures have been taken and some countries, such as Iran and Greece, have reported a lower incidence of thalassemias, there remains a stark asymmetry in access to proper healthcare in developing nations when compared to nations of the European Union and North America. As a result, it is possible that many patients who suffer from hemoglobinopathies may not have access to or be educated about when to seek healthcare. This results in lower data from clinical sources for studies such as those listed above. Additionally, due to the small sample size of the studies listed above, the power of each outcome is low. While some of the results reported are seen as significant after statistical analysis, it is not possible to generalize these findings without further inquiry. The potential protective nature of thalassemias in COVID-19 infection may not be relevant if patients who do contract the disease have higher mortality when compared to the general population [41].

6.3 Vaccines for patients with beta-thalassemia

While exact SARS-CoV-2 vaccination rates among patients with thalassemias are difficult to ascertain, vaccination is imperative in this community. The efficiency of the humoral response to the new vaccines against SARS-CoV-2 is currently a topic of great scientific relevance. The importance of vaccination in vulnerable patients is highlighted by the increased mortality rates in patients with hemoglobinopathies that contract COVID-19. A recent study by Anastasia et al. describes the humoral immune system response to the Comirnaty vaccine in beta-thalassemia major patients. In the study, beta thalassemia major patients were boosted with BNT162b2, an mRNA vaccine, produced by Pfizer-Biontech. Sixty-seven patients met the inclusion criteria. Blood samples were collected from participants after receiving two doses of the vaccine. Antibody titers were measured against the receptor binding domain (RBD) in the S1 subunit of the Spike protein by using a quantitative Elecsys anti-SARS-CoV-2 ROCHE automated system. The study observed that 73.3% of splenectomized transfusion-dependent thalassemia patients showed anti-S ab titers in the second quartile, while non-splenectomized transfusion-dependent thalassemia patients had anti-S ab titers below 800 BAU/mL.

One month after administration of the second vaccine dose, there were no notable side effects in the patients. The production of immunoglobulin levels was robust in asplenic patients, arising several issues concerning the unusual humoral immune response in this vulnerable population. The group suggests that after splenectomy, memory B cells are deficient in patients. The role of humoral immunity then falls on perilymphatic tissue and bone marrow. The group suggests that this paradoxical increase in antibody titers in splenectomized patients may be due to unknown interactions between a novel mRNA vaccine and pathways in the immune system yet to be elucidated [42].

7. Conclusion

In conclusion, the current literature supports the conclusion that beta-thalassemia is protective against COVID-19. Surprisingly, most studies and case reports focus on patients with beta-thalassemia major. There is yet much to learn about the outcomes of patients with thalassemia minor and other hemoglobinopathies. The relative protective factors of beta-thalassemia major may not be present in other manifestations of the disease. Due to the limited patient population and lack of resources in nations where thalassemia is more common, it is possible a widescale study is not feasible. A lack of evidence-based medicine for such patients is glaring in the age of modern medicine. Leaders and researchers in hematology should focus efforts on expanding the current data available by controlled testing using in vitro samples. A keen understanding of the interactions between COVID-19 and abnormal hemoglobin chains is needed to better treat this vulnerable patient population.

Conflict of interest

The authors declare no conflict of interest.