The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Usefulness of fibrosis-4 (FIB-4) score and metabolic alterations in the prediction of SARS-CoV-2 severity.

Despite vaccination programs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health problem. Identifying key prognostic determinants of severity of the disease may help better focus health resources. The negative prognostic role for metabolic and hepatic alterations is established; however, the interplay among different metabolic comorbidities and their interconnections with the liver have never been explored.The objective of this study is to evaluate the impact of liver alterations in addition to metabolic comorbidities as a predictor of SARS-CoV-2 severity. 382 SARS-CoV-2 patients were enrolled. Severe SARS-CoV-2 was diagnosed according to international consensus. Transaminases > 2 times the upper limit of normality (2ULN), hepatic steatosis (by ultrasound and/or computed tomography in 133 patients), and FIB-4 defined liver alterations. All data were collected on admission. The results are severe SARS-CoV-2 infection in 156 (41%) patients (mean age 65 ± 17; 60%males). Prevalence of obesity was 25%; diabetes, 17%; hypertension, 44%; dyslipidaemia, 29%; with 13% of the cohort with ≥ 3 metabolic alterations. Seventy patients (18%) had transaminases > 2ULN, 82 (62%) steatosis; 199 (54%) had FIB-4 < 1.45 and 45 (12%) > 3.25. At multivariable analysis, ≥ 3 metabolic comorbidities (OR 4.1, CI 95% 1.8-9.1) and transaminases > 2ULN (OR 2.6, CI 95% 1.3-6.7) were independently associated with severe SARS-CoV-2. FIB-4 < 1.45 was a protective factor (OR 0.42, CI 95% 0.23-0.76). Hepatic steatosis had no impact on disease course. The presence of metabolic alterations is associated with severe SARS-CoV-2 infection, and the higher the number of coexisting comorbidities, the higher the risk of severe disease. Normal FIB-4 values are inversely associated with advanced SARS-CoV-2 regardless of metabolic comorbidities, speculating on use of these values to stratify the risk of severe infection.

Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.

Differential Redox State and Iron Regulation in Chronic Obstructive Pulmonary Disease, Acute Respiratory Distress Syndrome and Coronavirus Disease 2019.

In patients affected by Acute Respiratory Distress Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD) and Coronavirus Disease 2019 (COVID-19), unclear mechanisms negatively interfere with the hematopoietic response to hypoxia. Although stimulated by physiological hypoxia, pulmonary hypoxic patients usually develop anemia, which may ultimately complicate the outcome. To characterize this non-adaptive response, we dissected the interplay among the redox state, iron regulation, and inflammation in patients challenged by either acute (ARDS and COVID-19) or chronic (COPD) hypoxia. To this purpose, we evaluated a panel of redox state biomarkers that may integrate the routine iron metabolism assays to monitor the patients' inflammatory and oxidative state. We measured redox and hematopoietic regulators in 20 ARDS patients, 20 ambulatory COPD patients, 9 COVID-19 ARDS-like patients, and 10 age-matched non-hypoxic healthy volunteers (controls). All the examined pathological conditions induced hypoxia, with ARDS and COVID-19 depressing the hematopoietic response without remarkable effects on erythropoietin. Free iron was higher than the controls in all patients, with higher levels of hepcidin and soluble transferrin receptor in ARDS and COVID-19. All markers of the redox state and antioxidant barrier were overexpressed in ARDS and COVID-19. However, glutathionyl hemoglobin, a candidate marker for the redox imbalance, was especially low in ARDS, despite depressed levels of glutathione being present in all patients. Although iron regulation was dysfunctional in all groups, the depressed antioxidant barrier in ARDS, and to a lesser extent in COVID-19, might induce greater inflammatory responses with consequent anemia.

COVID 19 and Hemoglobinopathies: Update of the Italian Experience

Background. Patients with pre-existent chronic morbidities are likely to be more severely affected by SARS-Cov2 infection. In Italy, the "Società Italiana Talassemie ed Emoglobinopatie" (SITE) has recently estimated the number of patients (Pts) with Hemoglobinopathies followed by Italian Specialized Centers (SITE Network). Five thousand Transfusion-dependent beta-thalassemia (TDT), 1900 Non-Transfusion-dependent beta-thalassemia (NTDT) and 2000 Sickle Cell Disease (SCD) were registered [1]. To verify the impact of SARS-CoV-2 infection on Pts with Hemoglobinopathies, we performed a specific survey by electronic Case Report Form (eCRF). Inclusion criteria included positive swab or serology in a patient with hemoglobinopathy and at least 15 days of follow-up from either the onset of symptoms or SARS-CoV2 positivity. The survey was approved by the Ethics Committee, and eCRF was shared with the Centers of Italian Hemoglobinopathies Network. Preliminary data updated to April 10, 2020, were published [2].Results. As of July 31, 2020, 27 cases have been reported: 18 TDT, 4 NTDT, 5 SCD. 89% of the cases were in Northern Italy, where the rate of infection was much higher than the rest of the country, reflecting the national epidemiology. The mean age of thalassemia patients (TDT and NTDT) was 43±11 years, and 55% were male;the mean age of SCD patients was 33±15 years, and 40% was male. The likely source of infection has been detected in 63% (17/27) of cases: 11 had occupational exposure, 6 had a positive relative. Five patients were asymptomatic: for them, the SARS-CoV-2 infection was identified by positive swab for 1 patient and by positive level of IgG for 4. Twenty patients had associated comorbidities, 14 were splenectomized, and 3 had functional asplenia. Eleven patients were hospitalized, only one in high-intensity care unit. Three patients required more intensive ventilation support with continuous positive airway pressure (CPAP), one of these has a history of diffuse large B-cell lymphoma treated with chemotherapy in the previous year. Three other patients required support by oxygen. No Pts required intubation. Two Pts increased blood requirement. Only five received supposedly specific treatment for COVID-19: two hydroxychloroquine (HCQ), one HCQ plus ritonavir/darunavir, and one HCQ plus anakinra, one HCQ plus Tocilizumab plus Lopinavir/Ritonavir. The clinical course of hospitalized patients was 18±7 days. All patients recovered.Conclusions. The prevalence of COVID-19 infection in Italian patients with Hemoglobinopathies result 0,3% while in general population the prevalence in Italy is 0,4% [3]. Considering that the thalassemia population is more strictly observed, we could postulate that the precautions suggested or self-applied by the Pts were effective. No death nor severe SARS with intubation, nor signs of cytokines storm, only one thromboembolic event was observed although most individuals had pre-existing complications. A single case with pulmonary hypertension has been described in detail [4]. In most individuals the infection has been pauci or asymptomatic and all recovered. This experience differs from what has been observed in Iran on a similar series with different severity and mortality and ask for a more in-depth comparison [5]. In conclusion, our data do not indicate increased severity of COVID-19 in Pts with Hemoglobinopathies followed in Specialized Centers.Acknowledgment. We would like to thank ALT (Associazione per la Lotta alla Talassemia R.Vullo - Ferrara)..References1. http://www.site-italia.org/2020/covid-19.php. SITE communication. Accessed April 1, 20202. Motta I, Migone De Amicis M, Pinto VM, et al. SARS-CoV-2 infection in beta thalassemia: Preliminary data from the Italian experience. Am J Hematol. 2020;95(8): E198-E199.3. https://www.epicentro.iss.it/coronavirus/sars-cov-2-dashboard, Accessed July 31, 20204. Pinto VM, Derchi GE, Bacigalupo L, Pontali E, Forni GL. COVID-19 in a Patient with β-Thalassemia Major and Severe Pulmonary Arterial Hypertension. Hemoglobin. 2020;44(3):218-220 5. Karimi M, Haghpanah S, Azarkeivan A, et al. Prevalence and mortality in β-thalassaemias due to outbreak of novel coronavirus disease (COVID-19): the nationwide Iranian experience. Br J Haematol. 2020;190(3):e137-e140.