Incidental osteonecrosis in the distal left femur in a case of beta-thalassemia with COVID-19: Role of [99mTc]Tc-MDP whole-body bone scan.

Secondary anemia in hemoglobinopathies like thalassemia can cause expansion of the bone marrow cavities because of compensatory marrow hyperplasia. This case demonstrates spontaneous osteonecrosis of the distal left femur in a patient with ß-thalassemia that may be secondary to ischemic infarction secondary to occlusion of the microvasculature within the expanded cancellous bone. This subject was referred to Hazrat Rasool Akram Hospital because of fever, cough, and bone pain. In the CT scan she had scattered peripheral CGO in both lungs due to COVID-19 with two paravertebral masses due to extramedullary hematopoiesis. The patient had also generalized bone pain so the physician asked for a whole-body bone scan and incidentally, we found a cold lesion with a rim of increased uptake in the distal left femur that with bone biopsy it was consistent with osteonecrosis. This case illustrates the importance of performing a whole-body bone scan in ß-thalassemia for the management of patients and diagnosis of occult osteonecrosis.

A Particular Focus on the Prevalence of α- and ß-Thalassemia in Western Sicilian Population from Trapani Province in the COVID-19 Era.

Thalassemia is a Mendelian inherited blood disease caused by α- and ß-globin gene mutations, known as one of the major health problems of Mediterranean populations. Here, we examined the distribution of α- and ß-globin gene defects in the Trapani province population. A total of 2,401 individuals from Trapani province were enrolled from January 2007 to December 2021, and routine methodologies were used for detecting the α- and ß-globin genic variants. Appropriate analysis was also performed. Eight mutations in the α globin gene showed the highest frequency in the sample studied; three of these genetic variants represented the 94% of the total α-thalassemia mutations observed, including the -α3.7 deletion (76%), and the tripling of the α gene (12%) and of the α2 point mutation IVS1-5nt (6%). For the ß-globin gene, 12 mutations were detected, six of which constituted 83.4% of the total number of ß-thalassemia defects observed, including codon ß039 (38%), IVS1.6 T > C (15.6%), IVS1.110 G > A (11.8%), IVS1.1 G > A (11%), IVS2.745 C > G (4%), and IVS2.1 G > A (3%). However, the comparison of these frequencies with those detected in the population of other Sicilian provinces did not demonstrate significant differences, but it contrarily revealed a similitude. The data presented in this retrospective study help provide a picture of the prevalence of defects on the α and ß-globin genes in the province of Trapani. The identification of mutations in globin genes in a population is required for carrier screening and for an accurate prenatal diagnosis. It is important and necessary to continue promoting public awareness campaigns and screening programs.

The effect of cryopreservation media on the quality of ß-thalassemia mouse spermatozoa.

Background: The mouse model of human diseases is commonly used for biomedical study, including ß-thalassemia (ß-thal), an inherited hemoglobin disorder. Maintaining the mice strain by natural mating systems is costly and seems impractical, especially during the COVID-19 pandemic. Sperm-freezing is a cost-effective solution for ß-thal mouse colony management. Aim: To determine appropriate cryopreservation media for ß-thal mouse spermatozoa to establish a ß-thal mouse sperm bank. Methods: The epididymal spermatozoa of C57BL/6 wild-type (WT) and ß-globin gene knockout thalassemia (BKO) mice were frozen in four freezing media: I) raffinose-skim milk-monothioglycerol (MTG), II) raffinose-skim milk-glutamine, III) raffinose-egg yolk-glycerol, and IV) egg yolk-TES-Tris. The sperm quality was assessed prior to and following freeze-thawing. Results: Compared with WT counterparts, the viable spermatozoa before freezing exhibiting elevated levels of oxidative stress were significantly greater in BKO (p = 0.01). After thawing, the membrane integrity of BKO spermatozoa preserved in I was significantly lower (p = 0.001). The sperm viability and membrane integrity of BKO males were also inferior when media III and IV were used (p = 0.008-0.027). The amount of oxidative stress in the spermatozoon of BKO mice was significantly greater when preserved in I, III, and IV (p = 0.002-0.044). Comparing freezing media, the motility and acrosome integrity of WT and BKO spermatozoa preserved in IV were significantly higher than those in other media (p < 0.001 to p = 0.01). Spermatozoa with the highest mitochondrial membrane potential were observed in I in both genotypes (p = 0.012 to p > 0.05). The viability, membrane integrity, and oxidative stress of post-thaw BKO spermatozoa did not significantly differ among freezing solutions. Conclusion: Irrespective of freezing media, spermatozoa of BKO males are rather more sensitive to cryopreservation than those of WT. Raffinose-skim milk-MTG/glutamine, raffinose-egg yolk-glycerol, and egg yolk-TES-Tris can all be used to preserve BKO mouse spermatozoa. However, with slightly better sperm characteristics, egg yolk-TES-Tris may be a diluent of choice for BKO mouse sperm cryopreservation. The addition of a reducing agent to thawing media is also strongly recommended to efficiently prevent oxidative stress and therefore improve frozen-thawed sperm survival.

Clinical Characteristics of Children With SARS-CoV-2 Infection During the Third Wave of the Pandemic: Single Center Experience.

OBJECTIVE: To evaluate pulmonary functions in children with transfusion-dependent thalassemia, and its reversal (lung dysfunction) using intensive intravenous chelation with desferrioxamine (DFO) (4 weeks). METHODS: This descriptive study enrolled 77 children with transfusion-dependent thalassemia. Pulmonary function test (PFT) and iron load (serum ferritin (SF) and T2* MRI of heart and liver) were done. PFT included spirometry, total lung capacity (TLC) by helium dilution test and diffusion capacity by carbon monoxide (DLCO). Follow-up PFT was available for 13 children with moderate to severe lung dysfunction given intravenous DFO. RESULTS: 50 (68.8%) patients had lung dysfunction, most commonly diffusional impairment (48; 96%), and reduced TLC (11; 22%); and none had obstructive pattern. 9 (81.8%) patients with restrictive defect had moderate to severely deranged DLCO. PFT and T2* MRI values were inversely correlated with serum ferritin. Among 13 patients receiving intensive chelation for 4 weeks, significant improvement was noticed in forced expiratory volume in one minute/ forced vital capacity ratio (DFEV1/FVC) (P=0.009), DDLCO (P=0.006) and DSF (P=0.01). CONCLUSIONS: Pulmonary dysfunction is common in children with multi-transfused thalassemia, and routine screening by PFT needs to be part of the management guidelines.

Survival and late effects of hematopoietic cell transplantation in patients with thalassemia major.

In this retrospective study, we evaluated long-term survival and late effects in 137 patients affected by thalassemia major (TM) who received an allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 10.1 years. After a median follow-up of 30 years, 114 (83.2%) patients are living and 108 (78.8%) are cured. The cumulative incidence of nonrelapse mortality and thalassemia recurrence was 9.5% at 1 year and 10.2% at 39 years respectively. The 39-years cumulative incidence of overall survival and disease-free survival were 81.4% and 74.5%. One hundred twenty-three patients who survived more than 2 years after HCT were evaluated for late effects concerning hematological disorders, iron burden, growth, obesity, diabetes mellitus, thyroid and gonadal function, eye, heart, liver, lung, kidney, gastrointestinal, neurologic and psychiatric system, osteoarticular system, secondary solid cancer (SSC), performance status, and Covid-19 infection. Fertility was preserved in 21 males whose partners delivered 34 neonates and 25 females who delivered 26 neonates. Fifteen cases of SSC were diagnosed for a 39-year cumulative incidence of 16.4%. HCT represents a definitive cure for the majority of TM patients at the price, however, of a non-negligible early and late mortality which in the long run affects survival and disease-free survival.

Beta-Thalassemia minor and SARS-CoV-2, prevalence, severity, morbidity and mortality: a systematic review study (preprint)

Background: Since the first year of the COVID-19 global pandemic, a hypothesis concerning the possible protection/immunity of beta-thalassemia carriers remains in abeyance. Methods: Three databases (Pubmed Central, Scopus and Google Scholar) were screened and checked in order to extract all studies about incidence of confirmed COVID-19 cases OR mortality rate OR severity assessment OR ICU admission among patients with beta-thalassemia minor, were included in this analysis. The language was limited to English. Studies such as case reports, review studies, and studies that did not have complete data for calculating incidences were excluded. Results and discussion: Three studies upon 2265 were selected. According to our systematic-review meta-analysis, beta-thalassemia carriers could be less COVID-19 affected than general population [IRR= 0.9250(0.5752;1.4877)], affected by COVID-19 with a worst severity [OR=1.5933(0.4884;5.1981)], less admissible into ICU [IRR=0.3620(0.0025;51.6821)] and more susceptible to die from COVID-19 or one of its consequences [IRR=1.8542(0.7819;4.3970)]. However, all of those results stay insignificant with a bad p-value (respectively 0.7479, 0.4400, 0.6881, 0.1610). Other large case-control or registry studies are needed to confirm these trends.

Humoral immune response to Comirnaty (BNT162b2) SARS-Cov2 mRNA vaccine in Thalassemia Major patients.

One of the most urgent needs worldwide is to vaccinate against SARS-CoV-2 as many people as possible. We evaluated humoral response to Comirnaty vaccine in Thalassemia Major patients (TM). We measured SARS-CoV-2-specific antibodies against Spike protein in 57 TM patients and 58 healthy blood donors (HBD). TM and HBD subjects revealed a homogeneous serological response to the Comirnaty (Mean ± SD; TM = 1917,21 ± 1384,49; HBD = 2039,81 ± 1064,44; p = 0,5884). No statistically significant differences were observed among two groups. Interestingly, we observed in 73.3% of asplenic patients Ab-S titres above 800 BAU, whereas only in 26% of non splenectomized patients showed Ab-S titres above 800 BAU). This differences were statistically significant p < 0.039. Further measurement on other Ab types was needed for better understanding humoral response to Comirnaty.

Impact of IFN- β1a in treatment of a COVID-19 Patient with Beta Thalassemia and Diabetes Mellitus: A Case Report (preprint)

The present study aimed to report a case with COVID-19 with a history of chronic diseases, beta thalassemia intermedia, and DM. A 25-year-old man visited with covid 19 and treatment with IFN-β1a. According to the present report, the use of IFN-β1a was effective as a treatment option for COVID-19.

Possible effects of sirolimus treatment on the long­term efficacy of COVID­19 vaccination in patients with ß­thalassemia: A theoretical perspective.

The pandemic caused by the severe acute respiratory syndrome coronavirus (SARS­CoV­2), responsible for coronavirus disease 2019 (COVID­19) has posed a major challenge for global health. In order to successfully combat SARS­CoV­2, the development of effective COVID­19 vaccines is crucial. In this context, recent studies have highlighted a high COVID­19 mortality rate in patients affected by ß­thalassemia, probably due to their co­existent immune deficiencies. In addition to a role in the severity of SARS­CoV­2 infection and in the mortality rate of COVID­19­infected patients with thalassemia, immunosuppression is expected to deeply affect the effectivity of anti­COVID­19 vaccines. In the context of the interplay between thalassemia­associated immunosuppression and the effectiveness of COVID­19 vaccines, the employment of immunomodulatory molecules is hypothesized. For instance, short­term treatment with mammalian target of rapamycin inhibitors (such as everolimus and sirolimus) has been found to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year following treatment. Recently, sirolimus has been considered for the therapy of hemoglobinopathies (including ß­thalassemia). Sirolimus induces the expression of fetal hemoglobin (and this may contribute to the amelioration of the clinical parameters of patients with ß­thalassemia) and induces autophagy (thereby reducing the excessive levels of α­globin). It may also finally contribute to the mobilization of erythroid cells from the bone marrow (thereby reducing anemia). In the present study, the authors present the hypothesis that sirolimus treatment, in addition to its beneficial effects on erythroid­related parameters, may play a crucial role in sustaining the effects of COVID­19 vaccination in patients with ß­thalassemia. This hypothesis is based on several publications demonstrating the effects of sirolimus treatment on the immune system.

Bilateral Sequential Acute Macular Neuroretinopathy in an Asian Indian Female with ß Thalassemia Trait following (Corona Virus Disease) COVID-19 Vaccination and Probable Recent COVID Infection - Multimodal Imaging Study.

INTRODUCTION: Corona virus disease (COVID-19) has been associated with a variety of ophthalmic manifestations including acute macular neuroretinopathy and paracentral middle maculopathy. Posterior segment manifestations after post COVID-19 vaccinations have been reported. CASE REPORT: A 25- year-old Asian Indian female developed sequential bilateral AMN following a single dose of COVISHIELD™ vaccine. On investigations she was found to have a ß thalassemia trait. Presentation started unilaterally and progressed to the other eye after a month. On clinical examination, the fundus was apparently normal in both eyes. Significant changes suggestive of AMN were seen on multimodal imaging of the posterior segment of the respective eye at the time of involvement which resolved spontaneously in due course. CONCLUSION: We report a temporal association of COVID-19 vaccination and AMN.

Prognostic factors associated with COVID-19 related severity in sickle cell disease.

BACKGROUND: Equipoise exists regarding sickle cell disease (SCD) as a risk factor for COVID-19 disease severity and variables that increase risk of COVID-19 severity in SCD. Given our health system's large SCD patient catchment, we analyzed our own experience in this regard. STUDY METHODS: Retrospective analysis of the clinical course and factors associated with need for hospitalization and ICU admission of SCD patients diagnosed with COVID-19 through the Northwell Health system from March 1 to Dec 31, 2020. RESULTS: Of 1098 patients with SCD, 3.3% were diagnosed with COVID-19. Overall rates of hospitalization, ICU admission, cohort mortality, and in-hospital mortality were 80%, 19%, 2.5%,and 3.1%, respectively. By multivariable analysis, hospitalization risk was decreased by 60% for every 1 g/dL increase in admission Hb. ICU admission risk was increased by 84% as a health care worker; increased by 45% for every 1000/uL increase in admission immature granulocyte count; and decreased by 17% with hydroxyurea use. DISCUSSION: High hospitalization rates are compatible with worsened severity upon COVID-19 infection in SCD compared to the general population. Patients should be placed on hydroxyurea to increase their Hb and perhaps lower their neutrophil counts. Health care workers with SCD may warrant special safety precautions.

Understanding the impact of COVID-19 pandemic on health-related quality of life amongst Iranian patients with beta thalassemia major: a grounded theory.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the resulting measures can impact daily life and healthcare management amongst patients with beta thalassemia major. METHODS: The Corbin and Strauss method of grounded theory was used to explore the impact of the COVID-19 pandemic on health-related quality of life (HRQoL) amongst Iranian patients with beta thalassemia major. Semi-structured interviews with 16 patients with thalassemia major in the eastern of Iran were performed. Data collection was conducted from 19 September through 18 November 2020. Collected data were recorded, transcribed, and coded to develop themes and subthemes. Paradigm components were sought to find out what happened to these patients and explore the process and events. RESULTS: Insights from these interviews led to five major themes: 'changing physical health', 'emotional and psychological reactions', 'changing the nature of relationships and the scope of social support', 'metamorphosis of ongoing healthcare, and 'functionality and adaptation to new realities.' The emerging core concept was labelled: 'maintaining well-being balance.' The COVID-19 pandemic disturbed the balance of life and health of the patients. Multiple strategies to maintain balance and reduce the negative effects of the COVID-19 pandemic on HRQoL were used by the patients, the healthcare team, and support systems. CONCLUSIONS: Due to the fear of COVID-19, the patients with beta thalassemia were less likely to contact healthcare professionals. They considered postponing blood transfusion and abandoned evaluating disease complications. Reduced access to the healthcare system and shifting resources from existing programmes to COVID-19 by the healthcare system were incompatible policies. These policies and strategies had strong and negative effects on the physical domain of HRQoL. The patients experienced a deterioration of emotional functioning. They reported a strong reduction in social functioning and felt lonely. Online interventions supporting mental health and social interactions and telemedicine can help during the times of social distancing and lockdowns.

Effect of Cognitive Behavioral Therapy Program on Mental Health Status Among Medical Student in Palestine During COVID Pandemic (preprint)

Background: Mental illnesses are widely acknowledged among medical students, at the same time, the COVID-19 pandemic had a significant effect on medical students. The main purpose of this study to (1) determine the prevalence of mental disorders among medical students and their associated factors, and (2) to examine the effectiveness of cognitive behaviour therapy on mental health problems among medical students. Methods: Between March and May 2021, we conducted a randomized controlled study on two phases among medical students at An-Najah National University. Data were collected using an online questionnaire and the Arabic version of the 12-item General Health Questionnaire (GHQ-12). We also used the MEDAS tool to assess their Mediterranean Diet (MD) adherence. In the second phase, sixty-six student were recruited and assigned randomly to control and intervention groups. Intervention impact was assessed using 12-item General Health Questionnaire at two time points; baseline, and 8 weeks post-intervention. The interventional model used was the cognitive behavioral therapy, and the control group received no treatment. Results: A total of 329 students were included in the analysis of the first phase of the study. Approximately 28% of students had mental health problems. We found a significant relationship between good mental health status with higher level of physical activity level, longer sleeping hours and shorter entertainment time (p< 0.05). In the second phase of the study, a total of 91 students were included. Overall, using CBT program showed a significant improvement in the outcome measures. At 8 weeks post-intervention, students had lower scores on total GHQ-12, depression and anxiety, and social dysfunction. Conclusion: These findings propose that adequate attention must be paid to the mental health of medical students, and that CBT program can be used for the management of mental health problems among medical students.

Uncertain crisis time affects psychosocial dimensions in beta-thalassemia patients during Covid-19 pandemic: A cross-sectional study.

Psychosocial variables are key factors influencing the delicate equilibrium of chronic patients during crisis time. In this study, we explored distress, anxiety, depression, loneliness, coping strategies, and changes in life habits in 43 beta-thalassemia patients and 86 controls during Covid-19 pandemic. Patients showed higher anxiety levels and a predominant transcendent coping profile compared to controls. Patients significantly differed from controls in outdoor habits. Social isolation and habits changes in uncertain life-threaten situations as Covid-19 pandemic are particularly detrimental in fragile beta-thalassemia patients. Structured support interventions are needed to promote well-being in the Covid-19 era.

SARS-CoV-2 infection in patients with ß-thalassemia: The French experience.

INTRODUCTION: Because of iron overload complications, thrombosis and infectious predisposition, patients with severe forms of thalassemia are likely to be at increased risk of COVID-19 complications. RESULTS: A national survey conducted during the year 2020 across the French reference centers for hemoglobinopathies identified 16 cases of COVID-19 confirmed by RT-PCR in beta-thalassemia patients. Their age ranged from 11 months to 60 years. 15 patients were transfusion-dependent and 6 were splenectomized. Concerning iron overload related complications, none had diabetes or cirrhosis and only one had experienced heart failure. All 4 pediatric patients were pauci-symptomatic during the viral episode. Three patients (41, 49 and 57 years old) developed COVID-19 pneumonia requiring oxygen therapy without the need for mechanical ventilation. Neutropenia (absolute neutrophils count <0.5 10 9/L) was observed in 2 patients receiving long-term treatment with hydroxycarbamide and deferiprone. No thrombosis event, organ failure or death occurred. All patients recovered. CONCLUSION: Severity of COVID-19 in this population of young and middle-aged patients appeared increased compared to the general population but remained mild to moderate as already described in the few series reported in the literature. Occurrence of adverse events related to chronic treatment administered in thalassemia disease may be favored by the infectious episode.