COVID19 and thalassaemia: A position statement of the Thalassaemia International Federation

 [bib_ref] Burden of influenza-related hospitalizations among children with sickle cell disease, Bundy [/bib_ref] [bib_ref] COVID-19 pneumonia as a cause of acute chest syndrome in an adult..., Beerkens [/bib_ref] [bib_ref] Vasoocclusive crisis and acute chest syndrome in sickle cell disease due to..., Nur [/bib_ref] 

## | g ener al con s ider ati on s and le vel of ris k
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. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] 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. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] Most people (about 80%) who become infected experience mild illness and recover, but it can be more severe for others. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] 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. [bib_ref] SARS-CoV-2 infection in beta thalassemia: preliminary data from the Italian experience, Motta [/bib_ref] 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. [bib_ref] Pathogenetic aspects of immune deficiency associated with beta-thalassemia, Farmakis [/bib_ref] 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. [bib_ref] The changing epidemiology of the ageing thalassaemia populations: a position statement of..., Farmakis [/bib_ref] 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. [bib_ref] Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Russell [/bib_ref] 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 [fig_ref] 1: Sufficient hydration with 2-3 litres of water consumed throughout the day, if... [/fig_ref]. 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.

## | adap tation of haemog lob inopathy c are

## Instructions concerning avoiding sars-cov-2 infection, reducing spread of the virus, and what to do if infection is suspected are
varying from country to country, and therefore, local and national guidance should be followed.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.

## Ta b l e 1 risk levels in patients with haemoglobinopathies and corresponding guidance considerations regarding work, schooling or educational activities

## Risk level criteria guidance
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.

## | communication channels and tools

## | patient care pathways
To 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 . 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.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.

## | monitoring tests and medications
The routine tests that are crucial for the monitoring of thalassae-

## | safe t y of b lood tr an s fus i on s
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. [bib_ref] Acute respiratory syndrome Coronavirus 2 RNA detected in blood donations, Chang [/bib_ref] 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.In this context, adoption of a patient blood management (PBM) system, based on three pillars, optimization of patient's own blood volume, minimization of blood loss and harnessing the physiological anaemia reserve, reduces the need for transfusions, improves patient outcomes and reduces length of hospital stay and costs. [bib_ref] The essential role of patient blood management in a pandemic: a call..., Shander [/bib_ref] One particular aspect of optimizing blood usage could be to the use of erythropoiesis stimulants, with a view to reducing transfusion requirements. Currently, this is possible through various approaches with varying levels of success, including the use of hydroxyurea, 28 enhancers of HbF production, [bib_ref] Clinical experience with fetal hemoglobin induction therapy in patients with -thalassemia, Musallam [/bib_ref] 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.

## | b lood supply challeng e s
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. 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.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,while cancellation of hospital-based collections resulted in 130 000 fewer donations in only a few weeks. [bib_ref] The essential role of patient blood management in a pandemic: a call..., Shander [/bib_ref] 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.

## | life s t yle and n utriti onal cons ider ations
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. [bib_ref] Integrative considerations during the COVID-19 pandemic, Alschuler [/bib_ref] These recommendations are based on the implementation of common sense and moderation, and consist of:

## | con clus ions
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-
[fig] 21 F: sidered for donors with robust haemoglobin level who are able to tolerate more frequent donations.21 Screening of the blood and blood product supplies for SARS-CoV-2 is not currently recommended in the absence of documented transfusion transmission, demonstrated infectivity of SARS-CoV-2 in blood collected from asymptomatic persons or availability of a nucleic acid testing (NAT) for blood screening specific for this virus. programmes should be in place to capture any possible cases of viral transmission while facilitating the understanding the behaviour of the virus.21 Such programmes are however in place only in a small number of countries and mainly in the Western World. [/fig]
[table] 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-19.8. Controlled brief exposures to direct sunlight for moodboosting, 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 considerable. While there are no clinical data available there is a belief that probiotics (especially preparations with lactobacilli and bifidobacteria species) could help against most viral infections, COVID-19 included, and their use towards this direction should be further investigated given their rather safe profile. Other potentially beneficial phytochemicals against the coronavirus infection, with strong preclinical evidence but not actually tested on human subjects in randomized clinical trials, include procyanidins, 36 lectins, 36,37 luteolin, 36 hesperetin, 37 catechins and sulforaphanes. They are all found within a flavonoid-rich plantbased diet. Caution is again advised regarding possible food-drug interactions. [/table]