Mediterranean Journal of Hematology and Infectious Diseases Original Article Preliminary Data on COVID-19 in Patients with Hemoglobinopathies: A Multicentre ICET-A Study Vincenzo de Sanctis1, Duran Canatan2, Joan Lluis Vives Corrons3, Mehran Karimi4, Shahina Daar5, Christos Kattamis6 and Ashraf T. Soliman7, (Steering Committee); Yasser Wali8, Salam Alkindi5, Valeh Huseynov9, Afag Nasibova9, Tarık Onur Tiryaki10, Melike Sezgin Evim11, Adalet Meral Gunes11, Zeynep Karakas12, Soteroula Christou13, Saveria Campisi14, Tahereh Zarei4, Doaa Khater15, Yesim Oymak16, Valeriya Kaleva17, Denka Stoyanova18, Atanas Banchev18, Maria Concetta Galati19, Mohamed A Yassin20, Shruti Kakar21, Myrto Skafida22, Yurdanur Kilinc23 (Participants); Saif Alyaarubi24, Narmin Verdiyevas9, Iva Stoeva25, Giuseppe Raiola26, Demetris Mariannis27, Leopoldo Ruggiero28, Salvatore Di Maio29 (Collaborators). 1 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy, 2 Antalya Genetic Diseases Diagnostic Center, Antalya, Turkey, 3 Red Blood Cell, and Haematopoietic Disorders Unit, Institute for Leukaemia Research Josep Carreras (IJC) and University of Barcelona, Catalonia, Spain. ENERCA Coordinator, 4 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, 5 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman, 6 First Department of Paediatrics, National Kapodistrian University of Athens, Athens, Greece, 7 Pediatrics and Endocrinology Department of Pediatrics, Hamad Medical Center, Doha, Qatar and Department of Pediatrics, University of Alexandria, Alexandria, Egypt (Steering Committee); 8 Paediatric Hematology Unit, Child Health Department, College of Medicine, Sultan Qaboos University Oman and Department of Paediatrics, Faculty of Medicine, Alexandria University, Egypt, 9 Center of Thalassemia, Baku, Azerbaijan, 10 İstanbul University, Faculty of Medicine, Department of Hematology, İstanbul, Turkey, 11 Uludag University, Medical Faculty, Dept. of Pediatric Hematology, Bursa, Turkey, 12 Istanbul University, Istanbul Faculty of Medicine, Pediatric Hematology / Oncology, Istanbul, Turkey, 13 Archibishop Makarios III Hospital, Thalassaemia Clinic, Nicosia, Cyprus, 14 UOSD Thalassemia, Umberto I° Hospital, Siracusa, Italy, 15 Department of Pediatric Endocrinology Alexandria University, Egypt and Department of Pediatrics, Sultan Qaboos University, Oman, Qatar, 16 Dr. Behcet Uz Children's Hospital, Izmir, Turkey, 17 Expert Center for Coagulopathies and Rare Anemias, Varna, Bulgaria, 18 Pediatric Hematoncology, University Hospital "Tzaritza Giovanna – ISUL," Sofia, Bulgaria, 19 Pediatric Haematoncology, Pugliese-Ciaccio Hospital, Catanzaro, Italy, 20 Hematology Section, National Center for Cancer Care and Research, Hamad Medical Corporation, (HMC), Doha, Qatar, 21 Pediatric Hematology Oncology, Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, India, 22 First Department of Paediatrics, National Kapodistrian University of Athens, Athens, Greece, 23 Pediatric Hematology Department, Çukurova University, Adana, Turkey, 24 Pediatric Endocrinology Unit, Child Health Department, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman, 25 Paediatric Endocrinologist, Head "Screening and Functional Endocrine Diagnostics" University Paediatric Hospital, Sofia, Bulgaria, 26 Department of Paediatrics, Pugliese-Ciaccio Hospital, Catanzaro, Italy, 27 Royal Lancaster Infirmary, Lancaster, UK, www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 1 / 9 28 Pediatrician, Lecce, Italy, 29 Emeritus Director in Pediatrics, "Santobono-Pausilipon" Children's Hospital, Naples, Italy. Competing interests: The authors declare no conflict of Interest. Abstract. Objectives: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings, and outcomes of COVID-19 in patients with transfusion-dependent β thalassemia major (TM), β-thalassemia intermedia (TI) and sickle cell disease (SCD). Design: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies, participated in the survey. Main outcome data: Clinical, laboratory, and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. Results: A total of 13 patients, 7 with TM, 3 with TI, and 3 with SCD, with confirmed COVID-19, were identified in 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. Six patients had pneumonia, and 4 needed oxygen therapy. Increased C -reactive protein (6/10), high serum lactate dehydrogenase (LDH; 6/10), and erythrocyte sedimentation rate (ESR; 6/10) were the most common laboratory findings. 6/10 patients had an exacerbation of anemia (2 with SCD). In the majority of patients, the course of COVID-19 was moderate (6/10) and severe in 3/10 patients. A 30-year-old female with TM, developed a critical SARS-CoV-2 infection, followed by death in an Intensive Care Unit. In one Center (Oman), the majority of suspected cases were observed in patients with SCD between the age of 21 and 40 years. A rapid clinical improvement of tachypnea/dyspnea and oxygen saturation was observed, after red blood cell exchange transfusion, in a young girl with SCD and worsening of anemia (Hb level from 9.2 g/dl to 6.1g/dl). Conclusions: The data presented in this survey permit an early assessment of the clinical characteristics of COVID 19 in different countries. 70% of symptomatic patients with COVID- 19 required hospitalization. The presence of associated co-morbidities can aggravate the severity of COVID- 19, leading to a poorer prognosis irrespective of age. Keywords: COVID-19; SARS-CoV-2; β-thalassemia; Sickle cell disease; Patients' characteristics; Clinical course; Risk factors. Citation: de Sanctis V., Canatan D., Corrons J.L.V., Karimi M., Daar S., Kattamis C., Soliman A.T, Wali Y., Alkindi S., Huseynov V., Nasibova A., Tiryaki T. O., Evim M.S., Gunes A.M., Karakas Z., Christou S., Campisi S., Zarei T., Khater D., Oymak Y., Kaleva V., Stoyanova D., Banchev A., Galati M. C., Yassin M.A., Kakar S., Skafida M., Kilinc Y., Alyaarubi S., Verdiyevas N., Stoeva I., Raiola G., Mariannis D., Ruggiero L., Di Maio S. Preliminary data on COVID-19 in patients with hemoglobinopathies: a multicentre icet-a study. Mediterr J Hematol Infect Dis 2020, 12(1): e2020046, DOI: http://dx.doi.org/10.4084/MJHID.2020.046 Published: July 1, 2020 Received: May 30, 2020 Accepted: June 14, 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Correspondence to: Vincenzo De Sanctis MD, Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, 44121 Ferrara, Italy. Tel: +39 0532 770243. E-mail: vdesanctis@libero.it Introduction. The recent COVID-19 outbreak has with COVID-19 (44,672 laboratory-confirmed, 16,186 been deemed a global health emergency. From Dec 31, suspected, and 10,567 clinically diagnosed), reported 2019, to May 20, 2020, 4,861,456 cases of COVID-19 that the clinical severity was mild in 81.4%, severe in (in accordance with the applied case definitions and 13.9%, and critical in 4.7%. Most patients were testing strategies in the affected countries), and between 30 to 79 years of age (87%), 1% were less 322,483 deaths were reported than 9 years, 1% between 10 and 19 years and 3% (https://www.ecdc.europa.eu/en/geographical- were 80 and above years.3 distribution-2019-ncov-cases). Subjects at higher risk for severe illness are: adults The clinical presentation of COVID-19 disease is > 60 years, patients with chronic diseases [heart, lungs, quite variable.1,2 A study from the Chinese Center for and end-stage renal disease neuromuscular disorders, Disease Control and Prevention on 72,314 patients sickle cell disease (SCD), cirrhosis and diabetes], www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 2 / 9 immunocompromised patients, pregnant women or Definitions of confirmed COVID-19 and close contact. those immediately postpartum (<2 weeks), and patients A patient was classified as confirmed COVID-19 in the who reside in nursing homes or long-term care presence of laboratory confirmation of COVID-19 facilities (https://www.england.nhs.uk/coronavirus/wp infection, documented by at least one nasal/pharyngeal content/uploads/ sites; Updated:11 April 2020). swab specimen positive for SARS-CoV-2 nucleic acid In subjects with SCD, this is probably due to testing (NAT) using reverse-transcriptase polymerase- impaired immunity resulting from impaired function of chain-reaction (RT-PCR) technology,14 irrespective of the spleen, systemic vasculopathy that predisposes to clinical signs and symptoms, according to the end-organ dysfunction, and an increased risk of European Centre for Disease Prevention and Control as thrombosis. Patients with thalassemias could have of Mar 2, 2020. Close contact definition was based on multiple organ impairment due to iron overload and the current WHO available information.10 chronic anemia (chronic hypoxemia) of the heart, lungs (pulmonary artery hypertension), liver and endocrine Data collection. The collected data included: glands. Both groups of patients have been considered demographic data, medical history, exposure history, vulnerable to COVID-19 and at potentially higher risk underlying comorbidities, symptoms, signs, laboratory for severe complications compared to the general findings, chest X-ray and/or computed tomography young population (especially in the older age group).4 (CT) scans, treatment schedules, and outcomes. The Moreover, coexistent immune system impairment in disease onset was defined as the day when the first patients with thalassemia also predisposes to more symptoms appeared before the first medical severe COVID-19 disease.4 However, there is limited contact/examination. Time (in days) from the onset of information available on COVID-19 infection in disease to hospital discharge was also recorded. patients with hemoglobinopathies.4-9 Laboratory data included: complete blood cell count We report the preliminary results of an International (CBC), C-reactive protein (CRP), erythrocyte Multicentre Study (IMS), promoted by the sedimentation rate (ESR), liver enzymes and serum International Network of Clinicians for creatinine, D-dimer, levels of procalcitonin, serum Endocrinopathies in Thalassemia and Adolescence lactate dehydrogenase (LDH), and serum ferritin levels. Medicine (ICET-A). The survey aimed to investigate the COVID-19 retrospectively in patients with Clinical and diagnostic classification. Patients with a hemoglobinopathies, namely β-thalassemias (TM and nasal/pharyngeal swab specimen positive for SARS- TI) and SCD, followed in 17 Centers from 10 CoV-2, fever, respiratory symptoms, and radiologic countries. changes consistent with diffuse pneumonitis were defined as having pneumonic COVID-19. Positive Survey Design and Participants patients, with fever and respiratory symptoms without Questionnaire development. A. First step radiologic changes, were defined as having non- In April 2020, the Coordinator of the ICET-A pneumonic COVID-19. Positive patients, without fever (VDS) with DC and JLVC designed and promoted a and respiratory symptoms, were defined as survey questionnaire to collect, as a primary aim, data asymptomatic. Furthermore, according to the latest on confirmed COVID-19 in patients with recommendations of the National Health Commission hemoglobinopathies and as a secondary aim, the of the People's Republic of China14 and WHO,10 numbers of suspected or probable COVID-19 cases,10 COVID-19 disease was classified into four types: mild, without performing the test, registered from Jan 1, moderate, severe and critical. Type 1 mild: mild 2020, to 7th June 2020. clinical symptoms without pneumonia at chest For a uniform collection of data, the diagnosis of β- computed tomography; Type 2 moderate: fever and thalassemias was based on the definitions proposed by other respiratory symptoms with pneumonia seen at Kattamis et al.11 in TM patients, Karimi et al.12 in TI imaging; Type 3 severe: respiratory distress (≥ 30 cases, and by Quinn13 for the diagnosis of SCD. breaths per min), hypoxia (oxygen saturation: ≤ 93%), Before the distribution to the ICET-A members, the or abnormal results of blood gas analysis; and type 4 questionnaire was revised and discussed with the critical: respiratory failure requiring mechanical ICET-A Board (SD, CK, and MK). ventilation, shock, or other organ(s) failure requiring A. Second step. The final questionnaire was sent by intensive care unit monitoring and treatment. mail to 12 Thalassemia Centers of the ICET-A Network. Study approval. Ethical approval and informed patient Each ICET-A member was free to distribute the or guardian consent were obtained in accordance with questionnaire to other Thalassemia Centers within their local institutional requirements and with Good Clinical own country. The deadline for returning the requested Practice and the Declaration of Helsinki principles for data was fixed to 7th June 2020. ethical research, and its later amendments. www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 3 / 9 Data presentation. Descriptive statistics of the The mean serum ferritin level in 12/13 patients was participants' baseline characteristics are provided as 1,428±1,538 ng/ml. Four patients with thalassemia had mean and standard deviation (SD) for continuous been splenectomised; 4 had endocrine complications: 3 variables and frequency and percentages for categorical had insulin-dependent diabetes mellitus (2 with TM variables. A detailed description of confirmed COVID- and in 1 with TI), and one hypogonadal female patient 19 patients is also provided. had a history of renal disease with hypertension. One patient had arrhythmia (Table 2). Results. A total of 17 Centers, 5 from Turkey, 3 from Three asymptomatic patients had laboratory- Italy, 2 from Bulgaria, and 1 each from Azerbaijan, confirmed positive results for SARS-CoV-2 (based on Cyprus, Greece, India, Iran, Oman, and Qatar, nucleic acid testing of pharyngeal swab samples). All following 9,499 patients with hemoglobinopathies (β- had had close contact with an infected family member thalassemias and SCD), participated in the survey. The or community exposure. These patients remained distribution by age groups, sex, and type of asymptomatic throughout quarantine and clinical hemoglobinopathy are listed in table 1. The largest monitoring. group of patients with TM and TI was reported in In symptomatic patients, the mean interval between Azerbaijan (TM:1,304; TI:605) and for SCD in Oman symptoms onset and first medical evaluation was 5.0 ± (SCD: 2,000). 3.4 days (range: 3–14). A total of 13 patients with confirmed COVID-19 by Fever was present in 8 out of 10 (80%) symptomatic RT-PCR, 7 with TM, 3 with TI, and 3 with SCD, were patients (peak 38.1°C-39.5°C). Other common signs retrospectively identified from 6 Centers (Azerbaijan, and symptoms were: cough (70%), headache (60%), Cyprus, Iran, Italy, Turkey, and Oman) (Table 2). The fatigue (60%), gastrointestinal symptoms (diarrhea overall mean age of patients was 33.7±12.3 years /vomiting/abdominal pain; 50%), tachypnea/dyspnea (range:13-66); 9 (69.2%) were females. (40%), sore throat (40%), anosmia/hyposmia (40%), The general characteristics of patients with conjunctivitis (30%), rhinorrhea (20%) and myalgia thalassemias, SCD, and confirmed COVID- 19 are (10%). Back and chest pain were reported in a patient reported in table 3. None of them were overweight. with SCD. Six patients had pneumonia (unilateral in 3, Table 1. Total number of patients with hemoglobinopathies enrolled in the ICET-A survey. Hemoglobinopathy Age group 1 Age group 2 Age group 3 < 21 yrs 21-40 yrs > 40 yrs 1. Thalassemia major (TM) 2,659 1,598 705 No. males /. females; total 1,007/937; 1,944 (*) 680/801;1,481 (*) 302/342;644 (*) Age range = = 41-69 2. Thalassemia intermedia (TI) 530 577 182 No. males /. females; total 295/231;526 (*) 258/273;531 (*) 87/94;181 (*) Age range = = 41-87 3. Sickle cell disease (SCD) 1,309 1,677 262 No. males/ females; total 587/480;1,067 (*) 624/598;1,222 (*) 97/145;242 (*) Age range = = 40-70 (*) Data not fully available. Table 2. Number of confirmed COVID- 19 in patients with hemoglobinopathies reported from 6 countries in comparison to the number of patients in the general population, updated to 8 th June 2020 (https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases). Countries and Number of patients with number of hemoglobinopathies: Number (%) of confirmed Covid-19 positive cases Number of Covid-19 in patients with hemoglobinopathies positive cases in participating Centers TM - TI and SCD general population Italy (3 Centers) 306 - 79 – 37 1 TM (F - 34 yrs) (0.3 %) 234,998 Turkey (5 Centers) 658 -164 -335 1 TM (M - 22 yrs); 1 TM asymptomatic (F - 30 yrs) (0.3 %) 170,132 Azerbaijan (1 Center) 1,304 - 605 -124 2 TM asymptomatic (1 F - 29 yrs and 1M - 31 yrs) (0.15 %) 7,553 Iran (1 Center) 720 - 311- 0 3 TM (F - 30, 31 and 38 yrs) (0.41 %) 1 TI (F- 66 yrs) (0.32 %) 171,789 Cyprus (1 Center) 247- 44 – 28 1 TM (M - 46 yrs) (0.4%) 964 Oman (1 Center) 300 - 44 – 2,000 3 SCD (2 F -13 and 43 yrs, and 1 M -26 yrs) (0.15%) 16,882 Legend. TM:Thalassemia major; TI: Thalassemia intermedia; SCD: Sickle cell disease; M: males; F: females. www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 4 / 9 Table 3. General characteristics in thalassemic and SCD patients with confirmed COVID-19.. Clinical and laboratory variables Thalassemias Sickle cell anemia Total number (10) (3) Clinical phenotype: TM and/ TI 8 /2 3 severe Gender male (M) / female (F) 3 /7 1/2 Age in yrs mean SD ( range) 35.7±11.7 (22-66) 27.3 ±12.2 ( 13-43) Blood group 5: A+; 4: B+; 1: AB+ 2: 0 +; 1: NR Household or community exposure 4/10 1/10 Hospitalization in symptomatic patients 5/7 2/3 Isolation and follow-up at home 4/10 1/3 Splenectomy 4/10 1/3 Functional hyposplenism Last serum ferritin level mean+SD 1,653 ± 1,592 2/3: 289 and 316 (ng/ml, range) (Range: 225-5,960) 1/3:NA Body mass index (Kg/m2) 19.39 ± 3.5 1/3 (17.8) LIC: MRI T2* (mg Fe/g d.w.) Mild: 3/10; Moderate 2/10; Severe 3/10 NA HCV Ab + 3/10 = HCV-RNA + = 1/3 (treated) Cardiac complications 1/10 (Arrythmia) 2/3: NR Myocardial T2* (ms) 6/10 >20 ms; 1/10: 16 ms 3/3: NA Chronic kidney disease before Covid-19 1/10 (Nephropathy and hypertension) 1/3 Respiratory disease before Covid-19 0/10 1/3 (Asthma) Pulmonary hypertension 0/10 0/3 Endocrine complications 3/10: IDDM; 1/10 HH; 1/10 HT 0/3 Iron chelation therapy and other treatments DFO: 3/10; DFP: 1/10; DFX: 6/10; DFO-DFX: 1/10; HU: 4/10 HU:3/3 Legend = TM: β-thalassemia major; TI: β-thalassemia intermedia; NA: Not available: LIC: liver iron concentration, was classified as mild (LIC > 3 and < 7), moderate (LIC > 7 and < 14) and severe (LIC > 14 mg/g/d.w.); HCV Ab: hepatitis C antibodies; Myocardial T2* value: normal >20 ms, mild to moderate iron overload:10 -20 ms and severe : <10 ms; DFO: desferrioxamine; DFP: deferiprone; DFX: deferasirox; HU: hydroxyurea; IDDM: Insulin Dependent Diabetes mellitus; HH: Hypogonadotropic Hypogonadism; HT: primary hypothyroidism. bilateral in 2, and multiple opacities in 1 patient), and moxifloxacin (3 patients), were given to 5 of 6 patients four needed oxygen therapy, and four patients (2 with with TM. Low molecular weight heparin and antiviral SCD) had non-pneumonic COVID-19. drugs (2 and 1 out of 10 patients, respectively) were In the majority of patients (6), the course of less commonly used. A rapid clinical improvement of COVID-19 was defined as moderate, and severe in 3. tachypnea/dyspnea and oxygen saturation was Oxygen saturation of ≤ 93% was documented in 3 observed, after red blood cell exchange transfusion, in patients. One of them, a 30-year-old female with TM a 13-year-old girl with SCD and COVID-19. At developed critical type 4 COVID-19, according to the hospital admission, she presented with high fever, National Health Commission of the People's Republic cough, worsening of anemia (decreased Hb level from of China14 and WHO,10 characterized by progressive 9.2 g/dl to 6.1g/dl) and elevated D-Dimers). respiratory and renal insufficiency, followed by death None of the SCD patients received in an Intensive Care Unit. hydroxychloroquine or convalescence plasma Increased C-reactive protein (6/10), high LDH transfusion. (6/10), high ESR (6/10), and high D-dimers, in 4 out of The average time from the onset of disease to 5 tested patients, were the most common laboratory hospital discharge was 12.8 ±5.4 days. findings. Six patients with confirmed COVID-19 (1 Seven Centers did not report cases of suspected or with SCD) had a reduction of hemoglobin levels, three probable COVID-19, and 5 Centers did not respond patients had lymphopenia (low absolute number of with the requested information. One Center reported lymphocytes), and 1 SCD patient had detailed information (data are presented in Table 4). thrombocytopenia. The majority of cases were observed in patients with Experimental treatments for SARS-CoV-2 infection, SCD, between 21- 40 years (5.5%). including hydroxychloroquine (2.5 mg/kg twice daily; 2 patients), azithromycin (10 mg/kg once Discussion. People of all ages are susceptible to daily)/clarithromycin (7.5 mg/kg twice daily) or SARS- CoV-19 infection. Clinical manifestations of www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 5 / 9 Table 4. Number of suspected or probable COVID- 19 in patients with hemoglobinopathies in Oman. Age group Age group Age group Group of patients and demographic data < 20 yrs 21-40 yrs > 40 yrs Total (Total no.) (Total no.) (Total no.) and % 1. Thalassemia major (TM) - No. 120 170 10 300 No. of males and No. females 50/70 60/110 5/5 = Age range = = 41-47 = WHO - Suspected Covid 19 -M/F 3/2 1/0 0/0 6 (2.0%) WHO - Probable Covid 19 - M/F 1/0 0/0 0/0 1 (0.3%) 2. Thalassemia intermedia (TI) - No. 28 10 6 44 No. of males and No. females 14/14 4/6 5/1 = Age range 5-20 21-28 41-43 = WHO - Suspected Covid 19 - M/F 0 0 0 0 WHO - Probable Covid 19 - M/F 0 0 0 0 3. Sickle cell disease (SCD) - No. 800 1,000 200 2,000 No. of males and No. females 430/370 510/490 80/120 = Age range = = 40-61 = WHO - Suspected Covid 19 - M/F 10/21 20/30 2/3 86 (4.3%) WHO - Probable Covid 19- M/F 2/0 3/2 0/1 8 (0.4%) SARS-CoV-19 infection range from asymptomatic to and 2 TI) of COVID-19 were detected. Seventeen severe pneumonia and respiratory failure. Severe patients (73.9%) had mild to moderate symptoms and disease can lead to death. Hospitalization rates are recovered, while six patients died (26.1%, 2 TM, and 4 higher for people of advanced age (> 60 years). TI). More than 60% of all patients had at least one Although age and comorbidities have been described as comorbidity, and 80% were splenectomised. The the main determinants of disease progression towards prevalence of COVID-19 in thalassemia patients was severe respiratory distress, the high diversity in clinical less than the general population, but the mortality rate severity among patients could suggest a possible role was significantly higher, also taking into consideration of the host genetic background contributing to the the lower age.15 Therefore, these findings provide observed inter-individual clinical variability associated further objective evidence to take into account the with COVID-19 in black and ethnic minority people. comprehensive risk assessment and prognosis among Up to 7th June 2020, the impact of COVID-19 in thalassemic patients with COVID-19. thalassaemic or SCD patients had only been The clinicopathological features, management, and preliminarily evaluated in different countries.3-9,15 outcomes of 10 SCD patients (8 male and 2 female), A study of a small cohort of patients with with COVID-19 infection (6 with confirmed COVID- thalassemia from Northern Italy, which was the 19 and 4 with suggestive clinical, laboratory and epicenter for coronavirus COVID-19 in Europe, radiological features, but a negative swab) with a mean showed relatively mild to moderate COVID-19 disease age of 36 years, were reported by McCloskey et al. 5 A in 11 patients (10 with TM and 1 with TI) compared to 57-year-old patient with several pre-existing the general population with all infected thalassemia comorbidities including severe neurological patients recovered.9 The mean age of this cohort of the impairment as a result of a previous stroke, died. thalassemic patients was 44 ± 11 years (range 31-61 Another patient with chronic kidney disease (CKD) years), and 55% (6/11) were females. One patient, with stage III developed significant deterioration of renal severe symptoms, required ventilation with continuous function and required temporary peritoneal dialysis, but positive airway pressure (CPAP). All patients had otherwise had a full recovery, as did the remaining associated comorbidities, and 70% were patients.5 splenectomised. The likely source of infection was To our knowledge, this is the first preliminary found in 64% of cases, while the clinical course ranged multicenter study evaluating the COVID-19 in patients from 10 to 29 days.9 with hemoglobinopathies, namely β-thalassemias and A multicenter, retrospective, cross-sectional study SCD. Approximately 90% of COVID-19 cases are was obtained across all comprehensive thalassemia associated with household or community exposure, and centers in Iran, from January to Apr 29, 2020. All 10% are associated with travel.1,2 In the present survey suspected and confirmed COVID-19 cases from a total the likely source of infection was detected in only 5/13 of 15,950 TM and 2,400 TI patients were evaluated (38.4%) of patients. Fifteen confirmed cases (12 TM and 3 TI; mean age A recent review of data from 59,254 patients from 36.1 ± 12.1; range 22-66 years). Moreover, eight 11 countries has shown a positive association between symptomatic suspected β-thalassemia patients (6 TM male sex and a higher mortality rate.16 Although adult www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 6 / 9 men are more susceptible to COVID-19 infection and if they develop fever. Medical consideration should be adult females produce more robust inflammatory given to the presence of superimposed infection, responses as compared to men,17 10 out of 13 of particularly with encapsulated pathogens.25,26 patients (76.9%) in our survey were females. Therefore, In patients with SCD, hypoxia, dehydration, or further studies are needed to elucidate this particular acidosis due to respiratory infection may trigger a gender aspect of COVID-19 in hemoglobinopathies. vaso-occlusive and hemolytic crisis and acute chest Asymptomatic infection at the time of laboratory syndrome (ACS), with a high risk of thrombosis in confirmation has been reported in many settings.18,19 pulmonary arteries.27 Thus, measures to prevent and Some of these cases developed symptoms at a later treat ACS early in the event of viral infection, require stage of infection; the proportion of these cases has not particular alertness by physicians treating infected yet thoroughly evaluated.20 There are also reports of patients.28 patients remaining asymptomatic throughout Another relevant aspect for COVID-19 infection in quarantine, as observed in our patients. hemoglobinopathies, mainly SCD and TI, relates to Four of our patients (2 with SCD) had non- current therapy with hydroxycarbamide (hydroxyurea), pneumonic COVID-19, 6 had pneumonic COVID-19, a cytotoxic agent, with possible immune-compromising and five patients, in addition to fever and cough, had effects contributing to an adverse outcome of these gastrointestinal symptoms, such as diarrhea, vomiting patients.28 Risk stratification recommendations for and/or abdominal pain. children and adults hospitalized with COVID are In the majority of patients (90%) worldwide, the available from the American Society of Hematology outcome of COVID-19 infection has been defined as a (https://hematology.org/covid-19/covid-19-and-vte- mild or moderate disease, but severe, and especially anticoagulation). critical cases are accompanied by a high mortality rate. The current study has some limitations. First, only Current knowledge has shown that the mortality rate is 13 patients with confirmed COVID-19 infection were high in people with chronic underlying diseases.21,22 identified. However, the data presented in this study Blood groups were known in 12 of our 13 permit an early assessment of the clinical confirmed COVID-19 patients: 5 were blood group A characteristics of COVID-19 in different countries. (41.6%), 33.3% blood group B, 16.6% blood group 0, Second, though the sample of patients with COVID-19 and 8.3% blood group AB. Therefore, it is plausible was small, we observed a prevalence of females versus that different blood groups might vary in their males. These data contrast with the reduced susceptibility to COVID-19, as reported by Zhao et susceptibility of females, probably linked to the X al.23 However, more evidence is needed to confirm this chromosome and sex hormones, which play an observation, taking into consideration the specific important role in innate and adaptive immunity.29 distribution of blood groups among populations. Nevertheless, this is a preliminary report of a rapidly Furthermore, in patients with hemoglobinopathies, evolving condition, as the parameters discussed here several factors may be associated directly or indirectly are changing quickly with time. Third, our survey with the triggering of a severe outcome of the COVID- included mainly young adult patients with an age range 19.3-6 Both intravascular and extravascular hemolysis between 20 and 40 years. Lastly, the number of can occur in thalassemia patients. Clinicians should, reported COVID-19 cases has certainly underestimated therefore, closely monitor blood counts of thalassemia the real burden of disease, given the widespread patients with COVID-19, and caution should be unavailability and accuracy of tests, and also the maintained towards the possibility of exacerbated significant proportion of infected persons, who develop hemolytic anemia in the setting of acute viral infection. asymptomatic or mild unidentified forms of the disease, Moreover, there is a significant concern that the remain undiagnosed. The high number of suspected or overlap of lung disease from COVID-19 with acute probable COVID-19 in patients with SCD sustain this chest syndrome (ACS) may result in increased hypothesis. Therefore, we should be careful when complications among individuals with SCD. 24 measuring the prevalence of confirmed COVID-19, Splenectomy is a common therapeutic intervention acknowledging that the rate will be likely higher once in β-thalassemias, while many SCD patients have a the denominator is adjusted to the correct number of hypo-functional spleen. Splenectomy was reported in individuals who acquired the infection. 6/13 of our patients with thalassemias. Based on the knowledge of the immunological Conclusions. It is reasonable to say that few cases of functions of the spleen, there is no evidence that COVID-19 have so far been reported in thalassemias asplenic/hyposplenic patients are at higher risk of and SCD patients in the literature. Is this due to a lack having severe COVID-19 infection. of testing or a real lack of infection/susceptibility? In Nevertheless, since fever could indicate bacterial as our survey, a total of only 13 patients with confirmed well as viral infection, all patients should be instructed COVID-19 were identified in 17 Centers, from 10 to seek medical advice by contacting their clinical team countries, following 9,499 patients with www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020046 Pag. 7 / 9 hemoglobinopathies. However, our provisional data aggravate the severity of infection, leading to death. should be interpreted cautiously because only 20% of Automated exchange transfusion improved the patients with thalassemias and 8.7% of SCD patients outcome of COVID-19 respiratory failure in a young were in the higher age group (> 40 years) for SARS- girl with SCD. In the forthcoming weeks, we will CoV-2 infection. 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