Prevalence of SARS-CoV-2 in hemoglobinopathies is modified by age and race.

Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating COVID-19 testing devices (n = 10,567) was used to examine the association between underlying health conditions and SARS-CoV-2 infection in an urban metropolis in the southern United States. Firth's logistic regression was used to fit the model predicting SARS-CoV-2 positivity using vaccine status and different medical conditions commonly associated with COVID-19. Another model using the same method was built using SARS-CoV-2 positivity as the outcome and hemoglobinopathy presence, age (<16 Years vs. ≥16 Years), race/ethnicity and comorbidities, including hemoglobinopathy, as the factors. Our first model showed a significant association between hemoglobinopathy and SARS-CoV-2 infection (OR: 2.28, 95 % CI: (1.17,4.35), P = 0.016). However, in the second model, this association was not maintained (OR: 1.35, 95 % CI: (0.72,2.50), P = 0.344). We conclude that the association between SARS-CoV-2 positivity and presence of hemoglobinopathies like sickle cell disease is confounded by race, age, and comorbidity status. Our results illuminate previous findings by identifying underlying clinical/demographic factors that confound the reported association between hemoglobinopathies and SARS-CoV-2. These findings demonstrate how social determinants of health may influence disease manifestations more than genetics alone.

Hemoglobinopathies and COVID-19: The Experience of a Center in Northern Greece.

Healthcare systems around the globe are still facing the evolving threat of the coronavavirus-19 (COVID-19) pandemic. Hemoglobinopathies include a group of genetic disorders, with the two main entities being thalassemias and sickle cell disease. Due to their immunocompromised status, such patients have been protected as extremely vulnerable to COVID-19 infection. We studied patients with different hemoglobinopathies, consecutively monitored at our center, who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) during the second and third waves of the pandemic in Greece (September 2020-April 2021), and associated the outcomes of the infection with the following factors: age, employment, blood type, liver and heart hemosiderosis, splenectomy, concomitant endocrine disorders and transfusion dependency. Among 250 patients monitored at our center, 14 were infected with COVID-19. Nine of them were hospitalized but no one required intensive care unit support and all of them responded to the generally applied treatment plan, despite their comorbidities. Notwithstanding the slightly increased prevalence of COVID-19 in patients with hemoglobinopathies compared to the general population, self-applied measures are still thought to be effective, as our patients got infected through their already sick family members.

From H1N1 to COVID-19: What we have seen in children with hemoglobinopathies.

This work aimed to better understand the impact of pandemics of respiratory viruses on children with hemoglobinopathies through a comprehensive review of the literature. MEDLINE, SCIELO, LILACS, and PUBMED were used as data sources to find articles without time period restrictions. Previous observations suggest that patients with hemoglobinopathies are a group especially susceptible to the complications of viral respiratory infections, with greater morbidity and mortality related to them. Within this context, this review found that, during the 2009 H1N1 pandemic, the risk of hospitalization in children and adults increased, especially in patients with a history of complications such as acute chest syndrome. In addition, the Coronavirus Disease 2019 (COVID-19) pandemic appears to have less repercussion among children with hemoglobinopathies compared to adults, similar to what is seen in the general population. In the H1N1 pandemic, patients with hemoglobinopathies behaved as a group more susceptible to complications, with increased morbidity and mortality. However, for COVID-19, the existing data to date on these patients do not show the same clinical impact. Thus, although these children deserve attention in case of infection due to their potential risks, they seem to have a favorable evolution.

Risk factors for severe PCR-positive SARS-CoV-2 infection in hospitalized children: a multicenter cohort study (preprint)

Importance: Children are less likely than adults to have severe outcomes from SARS-CoV-2 infection and the corresponding risk factors are not well established. Objective: To identify risk factors for severe disease in symptomatic children hospitalized for PCR-positive SARS-CoV-2 infection. Design: Cohort study, enrollment from February 1, 2020 until May 31, 2021 Setting 15 children's hospitals in Canada, Iran, and Costa Rica Participants: Patients <18 years of age hospitalized with symptomatic SARS-CoV-2 infection, including PCR-positive multisystem inflammatory syndrome in children (MIS-C) Exposures: Variables assessed for their association with disease severity included patient demographics, presence of comorbidities, clinical manifestations, laboratory parameters and chest imaging findings. Main Outcomes and Measures: The primary outcome was severe disease defined as a WHO COVID-19 clinical progression scale of [≥]6, i.e., requirement of non-invasive ventilation, high flow nasal cannula, mechanical ventilation, vasopressors, or death. Multivariable logistic regression was used to evaluate factors associated with severe disease. Results: We identified 403 hospitalizations. Median age was 3.78 years (IQR 0.53-10.77). At least one comorbidity was present in 46.4% (187/403) and multiple comorbidities in 18.6% (75/403). Severe disease occurred in 33.8% (102/403). In multivariable analyses, presence of multiple comorbidities (adjusted odds ratio 2.24, 95% confidence interval 1.04-4.81), obesity (2.87, 1.19-6.93), neurological disorder (3.22, 1.37-7.56), anemia, and/or hemoglobinopathy (5.88, 1.30-26.46), shortness of breath (4.37, 2.08-9.16), bacterial and/or viral coinfections (2.26, 1.08-4.73), chest imaging compatible with COVID-19 (2.99, 1.51-5.92), neutrophilia (2.60, 1.35-5.02), and MIS-C diagnosis (3.86, 1.56-9.51) were independent risk factors for severity. Comorbidities, especially obesity (40.9% vs 3.9%, p<0.001), were more frequently present in adolescents [≥]12 years of age. Neurological disorder (3.16, 1.19-8.43) in children <12 years of age and obesity (3.21, 1.15-8.93) in adolescents were the specific comorbidities associated with disease severity in age-stratified adjusted analyses. Sensitivity analyses excluding the 81 cases with MIS-C did not substantially change the identified risk factors. Conclusions and Relevance: Pediatric risk factors for severe SARS-CoV-2 infection vary according to age and can potentially guide vaccination programs and treatment approaches in children.

Prevalence of COVID-19 in Egyptian Children With Hemoglobinopathies and Inherited Anemias.

Since the World Health Organization (WHO) announced coronavirus disease-2019 (COVID-19) to be a pandemic, children's COVID-19 cases were generally less severe than adults. The aim of the study was to determine the prevalence of COVID-19 cases among children with hemoglobinopathies and other inherited anemias living in El-Minya Governorate, Egypt, who are at high risk of exposure to infection. This cross-sectional study evaluated data from 258 children with hemoglobinopathies and inherited anemias. A questionnaire was used to collect data about COVID-19 symptoms coupled with appropriate investigations (complete blood count, d-dimer, anti-COVID antibodies, chest computed tomography scans, and polymerase chain reaction). We found 38 of 258 (14.7%) children had mild to moderate COVID-19, while there were no cases with severe form of COVID-19. COVID-19 cases were significantly older (8.63±3.37 vs. 6.71±3.56 y, P =0.01), noncompliant to iron chelators (63.2% vs. 11.8%, P =0.01), had higher serum ferritin (2639.47±835.06 vs. 1038.95±629.87 ng/mL, P <0.0001) and serum iron levels (803.68±261.36 vs. 374.18±156.15 µg/dL, P <0.0001) and more frequently had undergone splenectomy (78.9% vs. 25.5%; P <0.0001) than non-COVID-19 cases. In conclusion, only 14.7% of children with hemoglobinopathies and inherited anemias were recorded to have contracted mild to moderate COVID-19, with no reported severe cases.

Oxyhemoglobin concentrations do not support hemoglobinopathy in COVID-19.

Based on computerized modeling studies, it has been postulated that the severe hypoxemia in COVID-19 may result from impaired oxygen carrying capacity on hemoglobin. Standard pulse oximetry may not detect hypoxemia resulting from hemoglobinopathy, therefore hemoglobin co-oximetry is needed to evaluate this divergence. In a clinical data analysis of a multicenter cohort of hospitalized patients with COVID-19, we found a minimal effect, less than 1%, on the correlation between oxyhemoglobin concentration and predicted oxygen saturation in the presence of COVID-19 infection. This effect is unlikely to explain the clinically significant hypoxia in COVID-19 patients.

Incidence Rate of COVID-19 Infection in Hemoglobinopathies: A Systematic Review and Meta-analysis.

During the coronavirus-19 disease (COVID-19) pandemic, several studies were performed to determine the mortality and incidence rates of coronavirus infection among patients with hemoglobinopathies. However, there has been no systematic approach or meta-analysis to evaluate the results worldwide. This meta-analysis summarized the existing evidence of incidence and mortality rates of COVID-19 and related risk factors among patients with hemoglobinopathies with a focus on ß-thalassemia (ß-thal) and sickle cell disease. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Two authors independently screened the articles, extracted eligible ones, and assessed the quality of studies using the Joanna Briggs Institute (JBI) checklist. The collected data were analyzed by the Stata software. The amount of heterogeneity was demonstrated by the I2 test. The incidence of COVID-19 among patients with a hemoglobinopathy, ß-thal and sickle cell disease was 4.44, 1.34, and 17.22 per 100,000 person-day, respectively, to June 15 2020. The mortality rate of COVID-19 in patients with hemoglobin (Hb) disorders was calculated as 1.07 per 1000 person-day in the same period. Our findings showed a higher incidence rate of COVID-19 in sickle cell disease patients compared to the general population. A slightly higher mortality rate was also observed in patients with hemoglobinopathies compared to the general population, possibly due to the associated risk factors and comorbidities in this vulnerable group, which underscore special care, timely diagnosis and management along with current immunization, were crucial in decreasing the frequency, disease severity and mortality of these patients.

COULD COVID-19 BE A HEMOGLOBINOPATHY?

The world is struggling to deal with the corona pandemic. Effective therapies are still awaited due to the lack of understanding of the pathophysiological mechanism of the disease. Bearing recent research and clinical observations in mind, the authors propose a novel physiological mechanism of COVID-19 and explain development of COVID-19 related acute respiratory distress syndrome (ARDS) secondary to COVID-19 related hemoglobinopathy. It is a consistent observation that the radiological picture of COVID-19 related ARDS bears more resemblance to high altitude pulmonary edema (HAPE) than typical ARDS. There has been great controversy regarding this proposed similarity. The main argument from those objecting to this comparison is that the etiology is hypoxia in case of HAPE and inflammation in COVID-19 related ARDS. We propose that considering the recent bioinformatics prediction models, COVID-19 might first infect red blood cells via CD147 and cause hemoglobin damage. The resulting hypoxemia may cause pulmonary hypoxic vasoconstriction leading to HAPE-like lung lesions. The now introduced alveolar hypoxia further exaggerates hemoglobinopathy hypoxemia leading to a vicious cycle. In this review, the authors recommend laboratory experiments to prove these hypotheses. The proposed physiological mechanism has significant therapeutic implications. If proven, the authors suggest the use of exchange transfusion as adjunct therapy and development of anti-CD147 drugs.

A comprehensive review of hydroxyurea for ß-haemoglobinopathies: the role revisited during COVID-19 pandemic.

BACKGROUND: Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include ß-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in ß-thalassaemia major and haemoglobin E ß-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with ß-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in ß-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. MAIN BODY: Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with ß-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent ß-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent ß-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. CONCLUSION: Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with ß-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent ß-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent ß-thalassaemia which should be confirmed by randomised clinical trials.

The impact of COVID-19 pandemic on blood supplies and transfusion services in Eastern Mediterranean Region.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred a global health crisis. The safety and supply of blood during this pandemic has been a concern of blood banks and transfusion services as it is expected to adversely affect blood system activities. We aim to assess the situation in the Eastern Mediterranean Region (EMR) during the first months of the pandemic. MATERIALS AND METHODS: A survey was designed to address blood supply, transfusion demand, and donor management during the coronavirus disease-19 (COVID-19) pandemic. Medical directors of different blood banks were invited to participate. RESULTS: A total of 16 centers participated with representation from 15/19 countries in the region. In total, 75% were from national blood banks. Most centres had a decrease in the blood supply, ranging from 26-50%. Representatives from 14 countries (93.3%) believed that public fear has contributed to a decrease in donations. Most centres (n=12, 75%) had a reduction in transfusion demand, while those who did not, reported heavy involvement in treating patients with underlying haemoglobinopathies and haematological malignancies. Half of the centres activated their contingency plans. Four centres had to alter the blood donor eligibility criteria to meet demands. All centres implemented donor deferral criteria in relation to SARS-CoV-2, but were variable in measures to mitigate the risk of donor and staff exposure. CONCLUSION: Blood services in the region faced variable degrees of blood shortages. We summarize lessons learnt during this pandemic for the blood banks to consider to plan, assess, and respond proportionately to future similar pandemics.

Is sickle cell disease a risk factor for severe COVID-19 : a multicenter national retrospective cohort (preprint)

Introduction Coronavirus disease (COVID-19) caused by the novel coronavirus SARS-CoV-2 is an infectious disease which has evolved into a worldwide pandemic. Growing evidence suggests that individuals with pre-existing comorbidities are at higher risk of a more serious COVID-19 illness. Sickle cell disease (SCD) is an inherited hemoglobinopathy which increases the susceptibility to infections and as a consequent has higher risks of morbidity and mortality. The impact of COVID-19 on SCD patients could lead to further increase in disease severity and mortality. Studies that examine the effect of SCD on COVID-19 outcomes are lacking. This study aims to determine whether SCD is a risk factor for severe COVID-19 infection in regards to the requirement of non-invasive ventilation/high flow nasal cannula (NIV/HFNC), mechanical intubation (MV) or death. Methods Retrospective cohort study which included COVID-19 patients admitted to four Ministry of Health COVID-19 treatment facilities in Bahrain during the period of 24, February 2020, to 31, July 2020. All SCD patients with COVID-19 were included and compared to randomly selected non-SCD patients with COVID-19. Data for the selected patients were collected from the medical records. Multivariate logistic regression models were used to control for confounders and estimate the effect of SCD on the outcomes. Results A total of 1,792 patients with COVID-19 were included; 38 of whom were diagnosed with SCD as well. In the SCD group, one (2.6%) patient required NIV/HFNC, one (2.6%) required MV and one (2.6%) death occurred. In comparison, 56 (3.2%) of the non-SCD patients required NIV/HFNC, 47 (2.7%) required MV and death occurred in 58 (3.3%) patients. Upon adjusting for confounders, SCD had an odds ratio of 1.847 (95% CI: 0.39 – 8.83; p=0.442). Conclusion Our results indicate that SCD is not a risk factor for worse disease outcomes in COVID-19 patients.

Effects of the COVID-19 pandemic on supply and use of blood for transfusion.

The COVID-19 pandemic has major implications for blood transfusion. There are uncertain patterns of demand, and transfusion institutions need to plan for reductions in donations and loss of crucial staff because of sickness and public health restrictions. We systematically searched for relevant studies addressing the transfusion chain-from donor, through collection and processing, to patients-to provide a synthesis of the published literature and guidance during times of potential or actual shortage. A reduction in donor numbers has largely been matched by reductions in demand for transfusion. Contingency planning includes prioritisation policies for patients in the event of predicted shortage. A range of strategies maintain ongoing equitable access to blood for transfusion during the pandemic, in addition to providing new therapies such as convalescent plasma. Sharing experience and developing expert consensus on the basis of evolving publications will help transfusion services and hospitals in countries at different stages in the pandemic.

A hypothesis about the role of fetal hemoglobin in COVID-19.

COVID-19 infection is less common in children (with higher fetal hemoglobin levels). In our preliminary study, we also observed a low prevalence and fatality of COVID-19 in countries with high rate of hemoglobinopathy carries. Given these two facts, the hemoglobin structure can play a role in the physiopathology of COVID-19 disease. Several drugs are known to increase fetal hemoglobin in adults. Adding these drugs to COVID-19 clinical trials may improve the patients' outcomes.