Italian patients with hemoglobinopathies exhibit a 5‐fold increase in age‐standardized lethality due to SARS‐CoV‐2 infection
Authors: Filomena Longo, Barbara Gianesin, Vincenzo Voi, Irene Motta, Valeria Maria Pinto, Andrea Piolatto, Anna Spasiano, Giovan Battista Ruffo, Maria Rita Gamberini, Susanna Barella, Raffaella Mariani, Carmelo Fidone, Rosamaria Rosso, Maddalena Casale, Domenico Roberti, Chiara Dal Zotto, Angelantonio Vitucci, Federico Bonetti, Lorella Pitrolo, Micol Quaresima, Michela Ribersani, Alessandra Quota, Francesco Arcioni, Saveria Campisi, Antonella Massa, Elisa De Michele, Roberto Lisi, Maurizio Miano, Sabrina Bagnato, Massimo Gentile, Valentina Carrai, Maria Caterina Putti, Marilena Serra, Carmen Gaglioti, Margerita Migone De Amicis, Giovanna Graziadei, Anna De Giovanni, Paolo Ricchi, Manuela Balocco, Sabrina Quintino, Zelia Borsellino, Monica Fortini, Anna Rita Denotti, Immacolata Tartaglione, Andrea Beccaria, Marco Marziali, Aurelio Maggio, Silverio Perrotta, Alberto Piperno, Aldo Filosa, Maria Domenica Cappellini, Lucia De Franceschi, Antonio Piga, Gian Luca Forni
Journal: American Journal of Hematology (2021)

Since the beginning of the COVID-19 pandemic, concerns have been expressed worldwide for patients with hemoglobinopathies and their vulnerability to SARS-CoV-2 infection. Data from Lebanon confirmed a role of underlying comorbidities on COVID-19 severity, but no deaths among a cohort of thalassemia patients.1 Patients with sickle cell disease (SCD) displayed a broad range of severity after SARS-CoV-2 infection, spanning from a favorable outcome unless pre-existing comorbidities (UK cohort)2 to high case mortality in US.3 History of pain, heart, lung, and renal comorbidities was identified as risk factors of worse COVID-19 outcomes by the US SECURE-SCD Registry.4 While Italy experienced a death rate in the general population among the highest in the world, preliminary data from the first wave of the pandemic showed a lower than expected number of infected thalassemia patients (updated up to April 10, 2020), likely due to earlier and more vigilant self-isolation compared to the general population.5 To explore the vulnerability to SARS-CoV-2 infection, the Italian Society for Thalassemia and Hemoglobinopathies (SITE) designed a study to compare the prevalence and mortality of COVID-19 in individuals with hemoglobinopathies and the general Italian population (EMO AER COVID-19 study). The study was approved by Institutional Review Board authorities, registered on clinicaltrials.gov (NCT04746066), and was performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Designed to gather data from multiple healthcare providers in Italy, it allowed for collecting relevant demographics and clinical data on a dedicated electronic Case Report Form (eCRF) (available at https://covid19.site-italia.org) by each participating center. We enrolled patients with transfusion-dependent thalassemia (TDT), nontransfusion-dependent thalassemia (NTDT), and sickle cell disease (SCD) referred to participating centers and diagnosed with SARS-CoV-2 infection in the study period March 6, 2020 to April 7, 2021. SARS-CoV-2 infection was confirmed by either a positive swab of the upper or lower respiratory tract or serology. Patients with less than 15 days of follow-up from either the onset of symptoms or a SARS-CoV-2 positive test were excluded. Twenty-nine centers from 13 Italian Regions participated in the EMO AER COVID-19 study. These centers regularly provide care for approximately 6200 patients with hemoglobinopathies (3400 TDT, 1500 NTDT, 1300 SCD), representing 65% of the Italian population affected by these pathologies. Therefore, this sample is highly representative of Italian patients with hemoglobinopathies followed by an organized and widespread national network, providing both high coverage and high definition of data. During the 398-day study period, a total of 345 SARS-CoV-2 infections were recorded (overall, prevalence 5.5%): 230 cases among TDT (prevalence 6.8%), 50 among NTDT (prevalence 3.3%), and 65 among SCD patients (prevalence 5.0%). In the SCD group, 49% of patients were β-Thal/HbS. Diagnosis of COVID-19 was confirmed by a positive swab in 91% of the cases and by the presence of serum IgG in 9% of the cases. Among reported cases, 52% were female. The median age at the infection was 41 years (IQR: 29–48, range: 0.75–85), with 10% of patients being pediatric (median age: 8 years, IQR: 4–11). Seventy-four percent of patients had at least one comorbidity at the time of infection. The most common were: splenectomy or functional asplenia (50%), iron overload (23%), liver disease (19%), heart disease (16%), and diabetes (8%). ABO blood groups were distributed as follows: 50% were O, 33% were A, 15% were B, and 2% of patients were AB. We observed a broad spectrum of COVID-19 severity, ranging from no symptoms (83/345, 24%) to severe manifestations (66/345, 19%) and death (7/345, 2%). The most common symptoms were fever (157/345, 46%), cough (145/345, 42%), fatigue and diffuse pain (119/345, 34%), and anosmia and ageusia (104/345, 30%). Severe symptoms, such as difficulty breathing or thoracic pain, affected 62/345 (18%) of patients; 55/345 (16%) had pneumonia; and 1 patient experienced pulmonary thromboembolism. Overall, 68 (20%) patients required hospitalization, 15 (8 TDT, 2 NTDT, 5 SCD) in high-intensity care units (ICU). Nine out of 68, all with pneumonia (1 TDT, 1 NTDT, and 7 SCD), required additional or ad hoc blood transfusions due to acute hemoglobin drop. The median hospitalization time was 11 days (IQR: 5–21, range: 1–102 days, information available for 46 patients). Seven patients experienced fatal COVID-19 during the period of observation: 4 TDT (46/M, 48/M, 49/M, 56/F), 1 NTDT (45/M), 2 SCD (57/M, 57/F), both with the diagnosis of β-Thal/HbS. One TDT patient (57/F) and two patients (1 SCD, 52/M; 1 TDT, 57/F) died after the conclusion of the analysis and were not included in this survey. The overall lethality rate was 2.0%. The age-standardized lethality ratio (SLR) was then calculated as the ratio between the observed and the expected number of deaths, based on the age-specific rates in the Italian-COVID population. The resulting SLR was 4.8 (±3.5, 95% CI). All the fatal episodes were observed starting from November 2020. For hospital admission, age was a risk factor in TDT (OR = 1.03; CI: 1–1.1; p = .04) and NTDT (OR = 1.05; CI: 1–1.1; p = .04), but not in SCD. In TDT only, the presence of underlying lung or heart disease increased the risk to be admitted to the hospital (OR = 4.5, CI = 1.1–19.3, p = .04; OR = 2.9, CI = 1.0–8.0, p = .04). For the SCD group, chronic liver disease was associated with a higher risk of hospital admission (OR = 7.5, CI: 1.1–53.5, p = .04). For ICU admission and mortality, the presence of previous pulmonary disease was a risk factor only for TDT (OR = 5.6, CI: 1.2–25.1, p = .03; OR = 26.6; CI: 2.3–311.4; p = .01, respectively). According to our results, the prevalence of COVID-19 in hemoglobinopathies in Italy was similar to the general population (5.5% vs. 6.2%) in the first 13 months of the pandemic. Considering the known underestimation of SARS-CoV-2 prevalence in the Italian population and the greater reliability of the same estimation in our strictly monitored patients, we speculate that the risk of infection in hemoglobinopathies was actually reduced. This hypothetical difference should be explained by the effectiveness of early recommendations from dedicated healthcare providers and the prudent attitude of the chronic patients in front of risk, as already reported from expert centers in other countries.6 The estimation of lethality is complex: 95.6% of the confirmed COVID-19 deaths in the Italian population have occurred in subjects in ages 60 or greater and 86.2% of the deaths in ages 70 or greater. Lethality rates for COVID-19 infected patients were 26.7% for ages 90 years or greater, 19.8% for ages 80–89 years, 9.4% for ages 70–79 years, and 2.7% for ages 60–69 years. Our study population is significantly younger in age overall, with only 1.4% subjects infected above 70 years of age, reflecting the age-distribution of the hemoglobinopathies in Italy. The proper comparator for our population is the segment of the Italian population younger than 60 years of age, which experienced 5% of the total COVID-19 deaths, with lethality rates varying from <0.1% (age 20–29 years) to 0.6% (age 50–59 years). While no significant differences were observed in patients aged 0–30s, significantly higher lethality was observed in subjects aged 40–49 and 50–59 years, where all fatal cases were registered. Assuming for hemoglobinopathies the same lethality rates of Italians with comparable age, the number of observed deaths in hemoglobinopathies is approximately 5-fold the expected one (Figure 1). All deaths occurred in patients in the fourth to fifth decades of life, mostly obese, splenectomized, and with numerous comorbidities. Surprisingly, none of them (except one for which no recent clinical data are available) had a significant iron overload. Both deaths in the SCD group occurred in patients with β0-Thal/HbS, while there were no fatal events among patients with homozygous HbS, in agreement with the local genotype distribution that is characterized by a high prevalence of older Caucasian β-Thal/HbS patients (homozygous HbS are more frequent among younger patients). Age was a risk factor for hospital admission due to SARS-CoV-2 infection in both TDT and NTDT, but not in SCD. Other risk factors were the presence of underlying comorbidities at the time of infection, particularly chronic lung, heart, or liver disease. In addition, chronic lung disease was a significant risk factor for ICU admission or mortality (in TDT only). The main limitations of this work are represented by the evaluation of indirect outcomes of COVID-19 severity; in addition, not all the Italian centers taking care of these patients were involved in the study. However, the data presented here include the large majority of known patients affected by hemoglobinopathies in Italy. Another limitation of our study is the inability to consider the effects of early vaccination in this at risk cohort compared with the general population. Our data clearly indicate that patients affected by hemoglobinopathies have up to a five times higher likelihood of suffering lethal SARS-CoV-2. Thus, these patients should be referred to specific and expert healthcare providers. Future studies should monitor the long-term effect of COVID-19 in patients with hemoglobinopathies. More relevantly, the effectiveness of vaccines should be evaluated in these patients to address the presence of any possible difference with the general population. The authors would like to thank ALT (Associazione per la Lotta alla Talassemia R. Vullo—Ferrara) and Dott. Giacomo Siri, PhD, Biostatistician of Galliera Hospital. No conflict of interest to declare.