Infections are one of the leading causes of morbidity and mortality in patients with hemoglobinopathies, described in β-thalassemia as the second most common cause of death, preceded by cardiac failure and hepatic disease [9]. The immune system status of these patients has not always been thoroughly investigated. Still, undoubtedly the well-known increased susceptibility of patients with thalassemia to infections reveals an underlying immune system dysfunction. Indeed, several immune abnormalities have been described in β-thalassemic patients, both quantitative and functional, involving various components of the innate and adaptive immune response. Specifically, the T-lymphocyte compartment is characterized by an increased number and activity of suppressor T-cells (CD8) with a concomitant reduction of proliferative activity of helper T-cells (CD4), presenting a decreased CD4/CD8 ratio.
Moreover, a defective Natural Killer (NK) cell function is reported, with more B-lymphocytes with increased activity but reduced differentiation. These patients suffer from impaired immunoglobulin secretion with high levels of IgG, IgM, and IgA; abnormalities in chemotaxis and defective phagocytosis in neutrophils and macrophages; finally, suppressed activities of the complement system, with reduced levels of C3 and C4. All these anomalies have been attributed to the disease and therapeutic interventions [10, 11]. Iron overload due to the physiopathology of the disease itself and the frequent and chronic need for blood transfusions has been implicated as the principal immunodeficiency factor in β-thalassemia. Free iron leads to numerous complications, such as heart failure, liver damage, and endocrine abnormalities, interfering with the immune balance and favoring the survival of infectious organisms [12]. Interestingly, immune system abnormalities that have been described in conditions characterized by iron overload as hemochromatosis include decreased phagocytosis by the monocyte–macrophage system, alterations in T-lymphocyte subsets, with an enhancement of CD8 and suppression of CD4, impairment of immunoglobulin secretion and suppression of complement system function [13–15].
Moreover, hypertransfusion regimens applied to thalassemia major patients lead to continuous allo-antigenic stimulation, significantly impairing the immune balance [16, 17]. Besides direct exposure to the risk of transfusion-transmitted infections, multiple transfusions have been associated with autoimmune hemolysis, T- and B-lymphocyte alterations, disruption in the pattern of cytokine production, and modification of monocyte-macrophage functions [18].
On the other side, splenectomy (currently reserved for patients with marked symptoms related to hypersplenism) and hypo-functional spleen as a disease complication play a significant role in immune system modifications (with a significantly high absolute lymphocytic count and low level of IgM memory B cells), leading to an increased risk to complicated infections in thalassemia [19–23]. In March 2020, the World Health Organization (WHO) declared the pandemic outbreak caused by Sars-CoV-2, with elderly and debilitated subjects identified as patients at higher risk. Hemoglobinopathy patients are more susceptible to virus infection than the general population, with an increased risk of a severe course, given the immunocompromised state and the many comorbidities they usually present [24].
In SCD, increased vulnerability to SARS-CoV-2 infection is likely due to compromised immunity resulting from impaired spleen function, systemic vasculopathy, hypercoagulability, and elevated risk of thrombosis, and patients with thalassemia often present multi-organ damage because of their immune dysfunction, iron overload, chronic anemia and hypoxemia [25]. An important role can also be performed by altered tissue oxygen transport, iron metabolism, and elevated levels of oxidative stress [26]. Another relevant aspect of SARS-CoV-2 infection in hemoglobinopathies, especially SCD and thalassemia, is that patients are usually treated with hydroxyurea, a cytotoxic agent with possible immunocompromising effects, potentially worsening the outcome of the SARS-CoV-2 disease in these patients [27].
Despite these data, an early study of a small cohort of SARS-CoV-2-positive patients with thalassemia in northern Italy showed relatively mild to moderate clinical courses when compared to the general population, with all infected thalassemia patients cured [28], differing by was observed in Iran on a similar series with different severity and mortality [29].
In December 2020, the advent of RNA vaccines triggering an immune response by delivering a protein that produces antibodies to the SARS-CoV-2 virus completely changed our approach to this type of infection and the outcome of patients, especially in the setting of immunocompromised hematological subjects. Evidence to date has shown that the effectiveness of the two vaccines in preventing infection by the SARS-CoV-2 virus ranges from 94–95% [30]. In the setting of hematological patients, we previously studied and reported the risk of vaccine exacerbating an underline coagulative disorder (i.e., hemophilia or thrombotic thrombocytopenic purpura [31, 32]). It’s known the role of the disrupted immune system and the previous or concomitant therapy in not allowing an adequate antibody response to administering the vaccine [33–37].
Starting from this evidence, patients suffering from hemoglobinopathies were promptly vaccinated. A priority vaccination program was developed in our Center for patients with hemoglobinopathy, who were vaccinated as early as possible, as suggested by national and international recommendations.
Moreover, during the SARS-CoV-2 emergency, our management strategy included supportive transfusion therapy even during the patient's positivity period. For this purpose, an area with suitable characteristics for the isolation and safety of the patient has been identified, with medical and nursing staff equipped with adequate PPE.
However, we observed that, except for 8 cases with a reduction > 0.5 g/dL, the patient's Hb values did not significantly reduce compared to the basic during the positivity days. So subsequently, we decided to postpone the transfusion of blood components until the patient becomes negative if the hemoglobin at the blood count check, always performed in dedicated areas and safety for the patient and staff, showed values ≥9.5 g/dL.
Our study confirms these data in a relatively large series of patients, showing that the underlying immunological alterations in patients affected by hemoglobinopathies do not significantly impair response to SARS-CoV-2 vaccination, preferring this prophylaxis in place of different strategies, such as tixagevimab-cilgavimab [38, 39].
We finally demonstrated through an extended follow-up, allowing the transfusion regimen to be slightly delayed for each patient without significant risks thanks to the absence of any drop in hemoglobin value, conversely to the data reported before the vaccine era [40].