key: cord-0786531-7pdhxdzc authors: Farmakis, Dimitrios; Giakoumis, Anastasios; Cannon, Lily; Angastiniotis, Michael; Eleftheriou, Androulla title: COVID‐19 and thalassaemia: A position statement of the Thalassaemia International Federation date: 2020-07-13 journal: Eur J Haematol DOI: 10.1111/ejh.13476 sha: 4705180ea77e1535ed07373763accc94584cad73 doc_id: 786531 cord_uid: 7pdhxdzc OBJECTIVES: Many patients with haemoglobinopathies, including thalassaemia and sickle cell disease, are at increased risk of developing severe complications from the coronavirus disease 2019 (COVID‐19). Although epidemiologic evidence concerning the novel coronavirus (SARS‐CoV‐2) infection in these patients is currently lacking, the COVID‐19 pandemic represents a significant challenge for haemoglobinopathy patients, their families and their attending physicians. METHODS: The present statement summarizes the key challenges concerning the management of haemoglobinopathies, with particular focus on patients with either transfusion‐dependent or non‐transfusion‐dependent thalassaemia, identifies the gaps in knowledge and suggests measures and strategies to deal with the pandemic, based on available evidence and expert opinions. Key areas covered include patients’ risk level, adaptation of haemoglobinopathy care, safety of blood transfusions, blood supply challenges, and lifestyle and nutritional considerations. CONCLUSIONS: The proposed measures and strategies may be useful as a blueprint for other disorders which require regular hospital visits, as well as for the timely adaptation of patient care during similar future pandemics. The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions across the world, having caused hundreds of thousands deaths. 1 Inherited haemoglobin disorders or haemoglobinopathies, including thalassaemias and sickle cell disease (SCD), are the most common monogenic disorders in human, being associated with significant burden, with multisystemic involvement and need for intensive life-long therapy and follow-up. 2, 3 Multiple sequelae often complicate the course of the disease, requiring special care. This is particularly true for patients living in developing or low-income countries, where disease-specific management programmes are lacking and access to modern therapy is limited. On the other hand, therapeutic advances of the past decades have resulted in a significant improvement in the once ominous prognosis of thalassaemia patients, and thus, patients with access to modern treatment modalities and well-organized follow-up programmes grow old and face a new spectrum of comorbidities related to ageing. 4 As a result, many haemoglobinopathy pa- The information provided herein is relevant to patients with (a) homozygous β-thalassaemia, including thalassaemia major and intermedia; (b) combined forms of thalassaemia, such as β-thalassaemia/ HbE; (c) α-thalassaemia, particularly HbH, the most clinically significant form. At this stage, sickle cell syndromes will not be further discussed, even though patients affected are expected to be at greater risk of COVID-19 complications due to the danger of the virus triggering an acute chest syndrome as well as vascular complications. [6] [7] [8] Thalassaemia patients stand out in the situation of the pandemic because of their need to frequently visit healthcare facilities for blood transfusion. This makes the need for protection measures imperative as hospital environments may be regarded as "hotspots" for viral transmission. In addition, from TIF contact with patient organization across the world, the pandemic has secondary consequences, such as blood shortages, medication shortages reduced access in some situations to expert care, that may have long-term effects on the health status. It should be stressed that as our yet limited knowledge on COVID-19 progresses, 5 new evidence becomes continuously available that may challenge some of the information and guidance provided herein. The proposed measures and strategies may be useful as a blueprint for other disorders which require regular hospital visits, as well as for the timely adaptation of patient care during similar future pandemics. The SARS-CoV-2 infection presents particular challenges and dangers to patients with haemoglobin disorders. The virus affects primarily the respiratory system, with a disease spectrum ranging from nasopharyngeal symptoms to full blown pneumonia. 9 Generally, these infections can cause more severe symptoms in people with weakened immune systems, older and/or frail people, and those with long-term conditions like diabetes, cancer and chronic lung disease. 10 Most people (about 80%) who become infected experience mild illness and recover, but it can be more severe for others. 9 Most deaths are related to respiratory complications requiring intensive care and respiratory support, even though an overexuberant inflammatory response with multi-organ failure may be prevalent in some cases. So far, very little clinical experience of infected patients with haemoglobin disorders has been recorded. 5 Any statement on these subjects may be regarded as speculations; cautionary thoughts are however necessary, in view of the rapid spread of the virus and the possible factors which may render these patients vulnerable in front of this infection. TIF believes that health services should be alerted to these risks and affected patients warned so that extra precautionary measures can be taken. Haemoglobin disorders are not directly associated with respiratory conditions. However, disease-related complications may affect multiple organs including the heart, liver, endocrine glands, lungs and the immune system, thus rendering this patient population at an increased risk to develop serious complications during COVID-19. 2, 3, 11 This is especially so in patients who receive suboptimal management and lack access to modern therapy and Thalassaemia patients do not have the same risk of pulmonary infections with sickle cell disease patients but, they may have multiple organ complications, often due to iron overload, including cardiac and hepatic, diabetes mellitus and endocrine disease. [2] [3] [4] One particular endocrine complication, adrenal hypofunction, is often not recognized and may render the patient particularly susceptible to severe infections. This condition requires glucocorticoid supplementation; however, corticosteroids have been shown to slow down the clearance of viral RNA from respiratory tract in patients with SARS-CoV or MERS-CoV infections increasing the complications rate. 12 Thalassaemia patients, particularly of the older age groups, have often been splenectomized while SCD patients often suffer from functional hyposplenism or asplenia. This renders these patients vulnerable to bacterial infections that may lead to serious illness or life-threatening sepsis. When infected by SARS-CoV-2, these patients may also develop secondary bacterial infections. Patients with thalassaemia can be grossly divided into three risk groups: (a) Group A, patients at "moderate risk," (b) Group B, patients at "high risk" and (c) Group C, patients at "highest risk"; the classification criteria are presented in detail in Table 1 . It should be stressed that the proposed risk classification is mainly based on the level of adherence to disease-specific care, since quality of care is the crucial determinant of morbidity in these patients. varying from country to country, and therefore, local and national guidance should be followed. [13] [14] [15] Adherence to the instructions and recommendations of the national health committees is of pivotal importance and should be incorporated in the care of patients with haemoglobinopathies. The following are measures that need to be taken in the care of thalassaemia patients. • All patients should comply with the social distancing measures and family practices recommended by local authorities to prevent their exposure to confirmed or possible COVID-19 cases among their social contacts, including family members or friends. • In patients with symptoms of cough, fever, fatigue or other symptoms suggestive of an acute respiratory illness, it is required to test for COVID-19 along with other respiratory viral pathogens. • If suspicion for COVID-19 is high or the test is positive, the treating physician who is fully aware of the individual's care plan should be contacted immediately. • Particularly in those patients with comorbidities, a close collaboration of the attending physician team with the patients' treating physician is of utmost importance. tests that may need to be rearranged based on prioritization and individual patient needs. All this must be considered but the need for short-and long-term adhesion to patient treatment programmes and protocols to avoid adverse effects must not be neglected. It is important to stress that all thalassaemia patients should receive proper care regardless of whether they are exposed to or infected by COVID-19. This can be accomplished by the adoption of appropriate patient care pathways, as described in detail below. In addition, enrolment of thalassaemia patients into COVID-19 trials should be encouraged as it would generate important evidence for both conditions. To will ask the patient a series of questions, as per national guidelines for COVID-19) and will check the patient's vitals, including temperature, heart rate, respiratory rate, blood pressure and pulse oximetry along with the haemoglobin level. If any COVID-19-like symptoms are present such as high temperature or dry cough, the triage nurse will consult with the treating physicians to decide upon granting admission to the clinic or not. A proposed algorithm for the screening for COVID-19 in patients with haemoglobinopathies is presented in Figure 3 . In the case that admission is permitted to the patient with COVID-19-like symptoms, he/she should receive the required medical care in a designated "isolation room" by doctors and nurses wearing appropriate personal protective equipment. 16 The haemoglobinopathy units and clinics are thus advised to designate a dedicated room within the medical facility that will be used to provide medical care to thalassaemia patients who are suspected or confirmed COVID-19 patients. This room should ideally have a separate entrance and exit to the rest of the clinic so as to limit contact with other patients, thus preventing transmission of COVID-19. The room should be disinfected regularly. The routine tests that are crucial for the monitoring of thalassae- Despite the fact that coronavirus RNA can be amplified from patients' blood, there is no hitherto evidence of coronavirus transmission through transfusion of blood and blood products. 19 All The routine practices for donor management and infectious disease testing should not be changed. However, in extreme blood shortage, reduction of whole blood donation intervals may be con- The optimization of blood use will help safeguard blood supplies during the pandemic. 21 In this context, adoption of a patient blood management (PBM) system, based on three pillars, optimization of pa- Conversely, immunosuppressed transplant recipients who regularly visit hospital settings may be exposed to the SARS-CoV-2 in hospital settings with a higher possibility to develop severe illnesses. The influenza A virus subtype H1N1 (H1N1) pandemic had a significant impact on the blood supply due to donors' fear of exposure to the virus at a hospital or a free-standing donor facility. 32 Similarly, the COVID-19 pandemic has already led to reduced blood supplies due to the cancellation of numerous community-based and mobile blood donation drives, as well as a marked reduction in donors arriving for scheduled appointments. 31 In the US, nearly 4000 American Red Cross blood drives, that account for more than 80% of its blood collects, have been cancelled across the country, 33 while cancellation of hospital-based collections resulted in 130 000 fewer donations in only a few weeks. 27 Besides the cancellation of organized blood donation drives and campaigns and the significant reduction in the number of donors arriving at blood donation facilities due to self-quarantine, social isolation measures and the fear of exposure to COVID-19, there is further the inevitable deferral of donors due to the more meticulous donor selection process with additional criteria discussed above. The situation further worsens by the fact that an increasing number of staff members in the blood services become ill or are required to self-isolate, while part of the blood donation and processing procedures may potentially be diverted to the preparation of convalescent plasma from patients who have recovered from COVID-19. Finally, the blood supply chain can be affected by travel restrictions as well as factory closing that may affect the blood product testing and production. At a later stage of the pandemic, a considerable percentage of the population is expected to be unknowingly infected by SARS-CoV-2, including the young blood donor population in which asymptomatic cases are more common; this will render the deferral of potential asymptomatic affected donors much more challenging. On the other hand, the demand for blood and components may decrease during the pandemic as elective and non-urgent surgical interventions are deferred and road and other society-related accidents may decrease due to isolation measures. This may compensate to a certain extend the anticipated reduction of blood supplies for chronically transfusion-dependent patients. In addition to the well-known personal hygiene and preventive measures against the new coronavirus, thalassaemia patients can also follow some simple recommendations regarding their lifestyle and nutrition that strengthen their immune system and could better prepare them for the ongoing pandemic. 34, 35 These recommendations are based on the implementation of common sense and moderation, and consist of: 1. Sufficient hydration with 2-3 litres of water consumed throughout the day, if health conditions allow it. 2. Adequate rest with 7-8 hours of sleep daily. 3. Regular but not exhaustive exercise with a half-hour walk, 3 days a week. 4. Normal body weight maintenance through a well-balanced diet. Especially during the pandemic patients should consume frequent small and light meals, mainly consisting of fruits and vegetables. 5. Effective stress management through calm mindfulness. 6. Continuous management of chronic comorbidities, especially cardiac and pulmonary conditions, and diabetes mellitus. 7. Self-disciplined smoking cessation as even otherwise healthy smokers are considered of high risk for suffering severe complications from COVID-19. boosting, sleep regulation, as well as for essential vitamin D production. Regarding nutrition in particular, thalassaemia patients are encouraged to consume natural sources containing vitamin C (citrus fruits), vitamin D (sardine, mackerel, dairy products), zinc (legumes, seeds and nuts) and omega-3 fatty acids (sardine, mackerel) as these foods have been found in applied basic research to provide necessary vitamins, minerals and anti-oxidants that boost the immune response. Caution is advised if patients turn to dietary supplements as the danger of over-supplementation (especially for vitamin C) is quite consid- The clinical impact of COVID-19 in haemoglobinopathy patients is not yet defined and thus infected cases should be under meticulous observation with comprehensive reporting of their clinical outcomes. This will contribute to the prompt management of the potential complications that may arise in infected patients, but also to the collection and sharing with other treating physicians of important information and data that will support the better understand- World Health Organization (WHO) Guidelines for the Management of Transfusion Dependent Thalassaemia Guidelines for the Management of Non-Transfusion Dependent Thalassaemias The changing epidemiology of the ageing thalassaemia populations: a position statement of the Thalassaemia International Federation SARS-CoV-2 infection in beta thalassemia: preliminary data from the Italian experience Burden of influenza-related hospitalizations among children with sickle cell disease COVID-19 pneumonia as a cause of acute chest syndrome in an adult sickle cell patient Vasoocclusive crisis and acute chest syndrome in sickle cell disease due to 2019 novel coronavirus disease (COVID-19) Clinical characteristics of coronavirus disease 2019 in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan Pathogenetic aspects of immune deficiency associated with beta-thalassemia Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury World Health Organization. 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