Akhavan Tavakoli, M.

Azarkeivan, A.

Bazrafshan, A.

De Sanctis, V.

Haghpanah, S.

Karimi, M.

Shirkavand, A.

Zahedi, Z.

Zarei, T.

eprints Iran University of Medical Sciences

findings provide further evidence for a high prevalence of VTEin critically ill patients with SARS-CoV-2 infection. These find-ings are important for identifying a high risk group for adverseoutcomes and to raise clinicians’ awareness of VTE riskamongst critically ill COVID-19 patients.AcknowledgementsWe would like to acknowledge all of the front-line workersat the University of Colorado Anschutz Medical Campus.Author contributionsJAH and SEJ collected and analysed the data. JAH, ELB, andSEJ designed this research study and wrote this manuscript.Joseph A. HippensteelEllen L. BurnhamSarah E. JolleyDivision of Pulmonary Sciences and Critical Care Medicine, Universityof Colorado Anschutz Medical Campus, Aurora, CO, USA.E-mail: joseph.hippensteel@cuanschutz.eduFirst published online 24 June 2020doi: 10.1111/bjh.16908References1. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology inWuhan China: themystery and themiracle. JMed Virol. 2020;92(4):401–2.2. Zhu Na, Zhang D, Wang W, Li X, Yang Bo, Song J, et al. A novel coron-avirus from patients with pneumonia in China, 2019. N Engl J Med.2020;382(8):727–33.3. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, David-son KW, et al. Presenting characteristics, comorbidities, and outcomesamong 5700 patients hospitalized with COVID-19 in the New York cityarea. JAMA. 2020;323(20):2052–9.4. Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance onrecognition and management of coagulopathy in COVID-19: a comment.J Thromb Haemost. 2020. Online ahead of print. https://doi.org/10.1111/jth.148605. Klok, FA, Kruip MJHA, van der Meer NJM, Arbous MS, GommersDAMPJ, Kant KM, et al. Incidence of thrombotic complications in criti-cally ill ICU patients with COVID-19. Thrombosis Research. 2020;191:145–147. http://dx.doi.org/10.1016/j.thromres.2020.04.0136. Klok FA, Kruip M, van der Meer N, Arbous MS, Gommers D, Kant KM,et al. Confirmation of the high cumulative incidence of thrombotic com-plications in critically ill ICU patients with COVID-19: an updated analy-sis. Thromb Res. 2020;3848(20):148–50.7. Middeldorp, S, Coppens, M, van Haaps, TF, Foppen, M, Vlaar, AP,M€uller, MCA, et al. Incidence of venous thromboembolism in hospitalizedpatients with COVID-19. J Thromb Haemost. 2020.8. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial throm-boembolic complications in COVID-19 patients admitted to an academichospital in Milan, Italy. Thromb Res. 2020;191:9–14. Online ahead ofprint. https://doi.org/10.1111/jth.148889. Llitjos J-F, Leclerc M, Chochois C, Monsallier J-M, Ramakers M, AuvrayM, Merouani K. High incidence of venous thromboembolic events in anti-coagulated severe COVID-19 patients. J Thromb Haemost. 2020. Onlineahead of print. https://doi.org/10.1111/jth.1486910. Connors JM, Levy JH. COVID-19 and its implications for thrombo-sis and anticoagulation. Blood. 2020; blood.2020006000.135 23:2033–2040.11. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic orthromboembolic disease: implications for prevention, antithrombotic ther-apy, and follow-up. J Am Coll Cardiol. 2020; S0735-1097(20)35008-7.7523:2950–2973.12. Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous throm-boembolism. Am J Med. 2005;118:978–80.13. Stein PD, Goldman J, Matta F, Yaekoub AY. Diabetes mellitus and risk ofvenous thromboembolism. Am J Med Sci. 2009;337:259–64.14. Cheng Y-J, Liu Z-H, Yao F-J, Zeng W-T, Zheng D-D, Dong Y-G,et al. Current and former smoking and risk for venous thromboem-bolism: a systematic review and meta-analysis. PLoS Medicine. 2013;10(9):e1001515.15. Wichmann D, Sperhake J-P, L€utgehetmann M, et al. Autopsy findings andvenous thromboembolism in patients with COVID-19: a prospective cohortstudy. Ann Intern Med. 2020; M20-2003. Online ahead of print. https://doi.org/10.7326/M20-2003Prevalence and mortality in b-thalassaemias due to outbreakof novel coronavirus disease (COVID-19): the nationwideIranian experienceIn late December 2019, an ongoing outbreak of severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) infectionthat was termed Coronavirus Disease 2019 (COVID-19), wasreported in Wuhan, China.1A total of 3 018 681 patients have been reported globallyand 92 584 confirmed cases have been documented in Iran,until April 29th, 2020. The death toll from the COVID-19 out-break at that time was 207 973 worldwide, and 5877 in Iran.Transfusion-dependent and non-transfusion-dependentthalassaemia (TDT and NTDT) patients may have coexistentcomorbidities due to iron overload2,3 that can expose themto a potentially higher risk of complications attributable toCOVID-19, compared to the normal population.4Limited data about frequency and outcomes of infectedCOVID-19 patients with thalassaemia are currently availablein the literature. In this study, the primary aim was toCorrespondenceª 2020 British Society for Haematology and John Wiley & Sons Ltd e137British Journal of Haematology, 2020, 190, e126–e156determine the prevalence, severity and mortality rate ofCOVID-19 in patients with TDT and NTDT living in Iran.Moreover, we evaluated the associated risk factors in thisvulnerable group of patients.A multicentre, retrospective, cross-sectional study wasobtained across all comprehensive thalassaemia centres inIran, from January to 29 April 2020. All suspected and con-firmed COVID-19 cases from a total of 15 950 TDT (regulartransfusion every 2–4 weeks) and 2 400 NTDT patients regis-tered by the Iranian Ministry of Health (MOH) were evalu-ated.Epidemiological data, demographics, clinical characteristics(type of thalassaemia, splenectomy status, and associatedcomplications), laboratory, imaging, and outcome data werecollected by analyzing patients’ electronic medical records.A coronavirus test was performed based on the Berlin pro-tocol by the real-time reverse-transcription polymerase chainreaction (RT-PCR).5Clinical and imaging manifestations for diagnosis of sus-pected cases were: fever, shortness of breath, fatigue, drycough, and chest computed tomography scan suggestive ofSARS-CoV-2 pneumonia infection.All patients were classified as mild, moderate, severe, andcritically ill according to the guidance issued by the NationalHealth Commission of China (accessed February, 2020).6Hydroxychloroquine combined with lopinavir/ritonavir oratazanavir were the suggested treatment regimens accordingto guidelines issued by the Iranian MOH.The study protocol was approved by the Ethical Commit-tee of Shiraz University of Medical Sciences (Code:1399.228).The patients or their legal guardians signed a consent formto protect the confidentiality and their identity.Qualitative and quantitative variables were comparedusing Fisher’s exact test and the Mann–Whitney test respec-tively between the two groups of confirmed COVID-19 caseswith the outcomes of recovery or death. COVID-19 preva-lence and mortality rate were calculated in confirmed casesand compared, by the chi-square test, with those reported inthe general Iranian population. A P value <005 was consid-ered statistically significant.Fifteen confirmed cases (12 TDT and 3 NTDT) and eightsymptomatic b-thalassaemia patients (6 TDT and 2 NTDT)suspected of being infected with COVID-19 without per-forming the test, were detected in a total of 18 350 Iranianb-thalassaemia patients.Detailed data of confirmed cases are presented in Table SI.Clinical characteristics and laboratory data of confirmed andsuspected COVID-19 cases are summarized in Table I below.Almost all the thalassaemia patients with COVID-19 werefrom Northern and Southern Iran as well as the central part,which were the epicentres for COVID-19 disease.Seventeen patients (739%) had mild to moderate symp-toms and recovered, while six patients died (261%, twoTDT and four NTDT). More than 60% of all patients had atleast one comorbidity (Table I).The clinical and laboratory data were compared in RT-PCR positive b-thalassaemia patients who recovered versusthose who deceased (Table II).The two groups were comparable in nearly all variablesexcept for the thalassaemia type. Moreover, major underlyingdiseases including diabetes, heart disease, hypertension, andpulmonary artery hypertension showed a significantly higherfrequency in the deceased group compared to the recoveredgroup (100% vs. 273%; P = 0026). Eighty per cent of ourpatients with confirmed COVID-19 were splenectomized butsplenectomy was not significantly associated with the fataloutcome (II).The prevalence of confirmed COVID-19 was 1101/10 000in the general population compared to 817/10 000 inpatients with b-thalassaemia up to 29 April 2020(P = 0246). On the other hand, at the same date, the mor-tality rate was significantly higher in patients with b-thalas-saemia (266%) compared to the general population (634%)(P = 0001).According to a COVID-19 webinar presented by the Euro-pean Hematology Association, 51 patients with TDT andCOVID-19 have been reported from nine countries (https://ehaweb.org/COVID-19/webinars.session 3; 16 April 2020).Most of them presented mild to moderate respiratory symp-toms (46 out of 51) and three out of five hospitalizedpatients died.A small cohort study from Northern Italy, which was theepicentre for COVID-19 in Europe, experienced relativelymild to moderate COVID-19 disease (11 cases: 10 with TDTand one with NTDT) compared to the general populationand all infected thalassaemia patients recovered despite all ofthem having associated comorbidities.7Our survey is the first nationwide investigation that sys-tematically evaluated the prevalence of COVID-19, the pres-ence of comorbidities and the prognosis in patients withTDT and NTDT in Iran.Most of our patients showed mild to moderate disease, asreported in Italy, but six cases developed severe symptomscontributing to the patients’ mortality while no deaths werereported in Italian patients with thalassaemias.7The significantly higher mortality rate in COVID-19 tha-lassaemic patients compared to the general Iranian popula-tion may be attributed to the presence of additional riskfactors in patients with thalassaemias.4Moreover, a significantly higher frequency of major under-lying diseases in the deceased group compared to the recov-ery group emphasizes the importance of adherence to ironchelation regiment in thalassaemia patients.No cases of paediatric or adolescent thalassaemia withCOVID-19 were observed in our study, which was similarto fewer children being infected by COVID-19 in the generalpopulation.8One observational study reported subjects with blood groupA were at higher risk while subjects with blood group O wereassociated with a lower risk for SARS-CoV-2 infection.9 OurCorrespondencee138 ª 2020 British Society for Haematology and John Wiley & Sons LtdBritish Journal of Haematology, 2020, 190, e126–e156Table I. Summary of clinical characteristics and laboratory data of confirmed and suspected COVID-19 cases in patients with b-thalassaemias.Parameters COVID-19 (RT-PCR positive; n = 15) Suspected COVID-19 (n = 8)Age (year), mean  SD, min–max 361  121, 22–66 396  903, 30–54Sex (m/f) 7/8 7/1Thalassaemia type (n, %) = =TDT 12 (80) 6 (75)NTDT 3 (20) 2 (25)Splenectomy (yes) (n, %) 12 (80) 4 (571)Serum ferritin (ng/ml)Mean  SD 1725  2245 2847  3189Median (min–max) 830 (225–8200) 2000 (545–9556)(n, %) = =≤2000 11(786) 4 (571)>2000 3 (214) 3 (429)Haemoglobin (g/l), mean  SD 89  68 84  144White blood cell count (per µl), mean  SD 15 885  11 579 22 914  15 830Platelet count (per µl), mean  SD 530 820  289 787 514 428  213 550Heart or liver iron overload (moderate and severe) (n, %) 5 (333) 3 (375)Hydroxycarbamide (yes) (n, %) 3 (20) 4 (50)Comorbidities (yes) (n, %) 12 (80%) 5 (625)Major underlying disease* 7 (467) 4 (50)Symptoms (N, %) = =Fever 10 (667) 3 (375)Cough 9 (60) 2 (25)Dyspnoea 4 (266) 2 (25)Rhinorrhoea and sneezing 1 (66) NRSinusitis 1 (66) NRMyalgia NR 1 (125)Diarrhoea NR 1 (125)Anosmia and hearing loss 1 (66) NRWeakness in lower extremities 1 (66) NRCondition = =Recovered 11 (733) 6 (75)Death 4 (266) 2 (25)RT-PCR, reverse-transcription polymerase chain reaction; TDT, transfusion-dependent b-thalassaemia; NTDT, non-transfusion-dependent b-tha-lassaemia; NR, not reported.*Heart disease, diabetes, pulmonary artery hypertension, and hypertension.Table II. Comparison of demographic and clinical characteristics between confirmed COVID-19 cases in patients with b-thalassaemias based ondisease outcome.RecoveredN = 11DeadN = 4 P valueAge (year), Median (min–max) 36 (22–66) 325 (30–60) 0949Sex (m) (n, %) 5 (455) 2(50) >0999Thalassaemia type (TDT) (n, %) 11 (100) 1(25) 0009Splenectomy (yes) (n, %) 9 (818) 3 (75) >0999Haemoglobin (g/l) median (min–max) 87 (79–97) 95 (82–99) 0226Serum ferritin (ng/ml) >2000 (n, %) 3 (273) 0 >0999White blood cell count (per µl), median (min–max) 12 300 (63–31 900) 12 000 (3775–34 360) >0999Platelet count (per µl), median (min–max) 589 500 (840–848 000) 582 500 (147 000–965 000) 0808Hydroxycarbamide (yes) (n, %) 1 (91) 2 (50) 0154Heart or liver iron overload (moderate and severe) (n, %) 4 (364) 1 (25) >0999Comorbidities (n, %) 8 (727) 4 (100) 0516Major underlying disease* (n, %) 3 (273) 4 (100) 0026*Heart disease, Diabetes, pulmonary artery hypertension, and hypertension.Correspondenceª 2020 British Society for Haematology and John Wiley & Sons Ltd e139British Journal of Haematology, 2020, 190, e126–e156study showed a low frequency of blood group O among con-firmed COVID-19 cases (13%, two out of 15).In conclusion, our study showed a low number of b-tha-lassaemia patients with COVID-19 that most of them devel-oped mild to moderate disease and recovered but havingmultiple comorbidities predisposed these patients to have asevere disease and a significantly higher risk of mortalitycompared to cases in the general population infected withCOVID-19. These findings provide objective evidence whichfurther variables should be taken into account in the com-prehensive risk assessment and prognosis of thalassaemicpatients with COVID-19.AcknowledgementsWe express our appreciation to thalassaemia patients andsincere condolences to the families who have lost thalas-saemic patients with COVID-19 disease. We would like toexpress our appreciation to the Iranian Thalassemia Society,all Iranian thalassaemia centres, doctors, and nurses for theirvery kind cooperation and help in data collection. We alsothank Herand Zargarian for English editing.Funding informationShiraz University of Medical Sciences and the Iranian Tha-lassemia Society supported the research.Author contributionsMK made substantial contributions to the study concept,design of the protocol, and in drafting the manuscript. SH per-formed the statistical analysis and participated in drafting themanuscript. AA, ZZ, MA, AS, and AB were responsible fordata collection and confirmation. TZ participated in draftingthe manuscript. VDS participated in preparation of the proto-col survey and in drafting and revising the manuscript.Conflicts of interestThe authors declare to have no potential conflicts of interestregarding the present work.Mehran Karimi1Sezaneh Haghpanah1Azita Azarkeivan2Zohreh Zahedi1Tahereh Zarei1Maryam Akhavan Tavakoli3Asghar Bazrafshan1Afshan Shirkavand4Vincezo De Sanctis51Hematology Research Center, Shiraz University of Medical Sciences,Shiraz, 2Zafar Adult Thalassemia Clinic, Blood Transfusion ResearchCenter, High Institute for Research and Education in TransfusionMedicine, 3Anatomy Sciences Department, Iran University of MedicalSciences, 4Medical Physicist, Pardis Noor Medical Imaging Center,Tehran, Iran and 5Pediatric and Adolescent Outpatient Clinic,Quisisana Hospital, Ferrara, Italy.E-mail: mkarimi820@gmail.comFirst published online 30 June 2020doi: 10.1111/bjh.16911Supporting InformationAdditional supporting information may be found online inthe Supporting Information section at the end of the article.Table SI. Data of confirmed COVID-19 in patients withb-thalassaemias.References1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirusfrom patients with pneumonia in China, 2019. N Engl J Med.2020;382:727–33.2. Karimi M, Cohan N, De Sanctis V, Mallat NS, Taher A. Guidelines fordiagnosis and management of Beta-thalassemia intermedia. Pediatr HematolOncol. 2014;31:583–96.3. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet.2018;391:155–67.4. Karimi M, De Sanctis V. Implications of SARSr-CoV 2 infection in tha-lassemias: do patients fall into the "high clinical risk" category? ActaBiomed. 2020;91:50–6.5. Corman, VM, Landt, O, Kaiser, M, Molenkamp, R, Meijer, A & Chu, DK,et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance. 2020 Jan;25(3):20000456. National Health Commission of China. The guidelines for diagnosis andtreatment of novel coronavirus (2019-nCoV) infected pneumonia (6th ed,in Chinese) issued by the National Health Commission of China. Availablefrom: http://www.gov.cn/zhengce/zhengceku/2020-02/19/ content5480948.htm2020 (Accessed February, 2020).7. Motta I, Migone De Amicis M, Pinto VM, Balocco M, Longo F, Bonetti F,et al. SARS-CoV-2 infection in beta thalassemia: preliminary data from theItalian experience. Am J Hematol. 2020. [Epub ahead of print]. https://doi.org/10.1002/ajh.258408. Zimmermann P, Curtis N. Coronavirus infections in children includingCOVID-19: an overview of the epidemiology, clinical features, diagnosis,treatment and prevention options in children. Pediatr Infect Dis J.2020;39:355.9. Zhao J, Yang Y, Huang H-P, Li D, Gu D-F, Lu X-F, et al. Relationshipbetween the ABO Blood Group and the COVID-19 Susceptibility. MedRxiv.2020. https://doi.org/10.1101/2020.03.11.20031096.tCorrespondencee140 ª 2020 British Society for Haematology and John Wiley & Sons LtdBritish Journal of Haematology, 2020, 190, e126–e156

Prevalence and mortality in Î²-thalassaemias due to outbreak of novel coronavirus disease (COVID-19): the nationwide Iranian experience

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Prevalence and mortality in Î²-thalassaemias due to outbreak of novel coronavirus disease (COVID-19): the nationwide Iranian experience

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