Background Cancer patients are vulnerable to infections, are older and often have comorbidities in comparison to the general population, which increases the risk for severe outcomes related to COVID-19 diagnosis.
Background: Patients with red blood cell disorders (RBCD), are likely to be at increased risk of complications from SARS-Cov-2 (Covid-19), but evidence in this population is scarce due to its low frequency and heterogeneous distribution. Aims: ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting severe outcomes. Methods: The ERN-EuroBloodNet registry was established in March 2020 by VHIR based on Redcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirmed that the exceptional case of the pandemic justifies the waiver of informed consent. Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 symptoms and management. For analysis of COVID-19 severity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Severe: pneumonia requiring oxygen/respiratory support and/or admission to intensive care unit. Continuous variables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical variables were analyzed using the Chi-square test or Fisher’s Exact test. Relevant factors influencing disease or severity were examined by the logistic regression adjusted for age. Results: As of February 25, 2022, 42 medical centers from 10 EU countries had registered 428 patients: 212 Sickle cell disease (SCD), 186 Thalassemia major and intermedia (THAL). The mean age of SCD was lower (22y) than of THAL (39.4y). Splenectomy and comorbidities were higher in THAL (51.4% and 61,3%) than in SCD (16,3% and 46,8%) (p<0.001, p=0.004). Age and BMI correlated with COVID-19 severity, as described in the general population (p=0.003, p<0.001). Fig 1 shows age distribution and COVID-19 severity by disease severity groups. The mean age for severe COVID-19 was lower in patients with severe SCD (SS/SB0 vs SC/SB+: 23y vs 67.5y) and THAL (major vs intermedia: 43.5 vs 51.3y) (p<0.001). Potential risk factors such as elevated ferritin, current chelation or history of splenectomy did not confer additional risk for developing severe COVID-19 in any patient group. Only diabetes as a comorbidity correlated with severity grade in SCD (p=0.01) and hypertension in THAL (p=0.009). While severe COVID-19 infection in SCD was associated with both ACS (p<0.001) and kidney failure requiring treatment (p<0.001), this was not predicted by a history of previous ACS or kidney disease in steady state. Overall, 14,6% RBC patients needed oxygen/respiratory support, 4% were admitted to ICU with an overall mortality rate of 1%, much lower than reported in other similar cohorts. Image:Summary/Conclusion: Results obtained so far show that severe COVID-19 occurs at younger ages in more aggressive forms of SCD and THAL. Current preventive approaches focus on age over disease severity. Our data highlights the risk of severe COVID-19 infection in some young patients, particularly those with SS/SB0 SCD, suggesting that immunization should be considered in this pediatric group as well. Results between similar sized cohorts of RBCD patients vary between each other and those presented here, highlighting the importance of collecting all of these small cohorts together to ensure adequate statistical power so that definitive risk factors can be reliably identified and used to guide management of patients with these rare disorders in the light of the ongoing pandemic.
Abstract Background Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death. Case presentation This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically. Conclusions Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.
In 2020, a 2-month-old ethnically Danish girl was diagnosed with β-thalassemia after presenting with persistent jaundice. The peripheral blood smear showed significant aniso- and poikilocytosis, increased number of reticulocytes and erythroblastosis. Trio analysis of the index patient and both parents was performed by whole-genome sequencing. Here, both parents were found normal, however the analysis revealed an apparently de novo HBB:c.444A > C variant in the child. The child has recently been discharged three months after a successful bone marrow transplantation with a matched sibling-donor.
Department of Medicine, Thisted, Department of Clinical Physiology, Glostrup Hospital, and Department of Obstetrics and Gynaecology, Rigshospitalet, Copenhagen
Background: Pyruvate kinase (PK) deficiency is a rare, inherited, non-spherocytic hemolytic anemia associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea. PK deficiency has a profound wide-ranging impact on health-related quality of life (HRQoL). Mitapivat (AG-348), a first-in-class, oral, allosteric activator of PK, was shown to improve hemoglobin (Hb), hemolysis, and hematopoiesis in a global, phase 3, randomized, placebo (PBO)-controlled trial evaluating mitapivat efficacy and safety in adults with PK deficiency who were not regularly transfused (ACTIVATE; NCT03548220). Furthermore, significant improvements in patient-reported outcomes (PROs) (measured by disease-specific PRO instruments: the PK deficiency diary [PKDD] and the PK deficiency impact assessment [PKDIA]) were demonstrated in patients (pts) receiving mitapivat compared with PBO. The PKDD is a self-administered, 7-item daily diary to assess the signs and symptoms of PK deficiency (including jaundice, tiredness, and shortness of breath), while the PKDIA is a 12-item weekly measure assessing the impacts of PK deficiency (pts rated the frequency of occurrence or difficulty of various activities). Aims: To describe PKDD and PKDIA outcomes for the subset of pts in the ACTIVATE trial who achieved the primary endpoint of Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline (BL), sustained at ≥2 scheduled assessments at weeks (wks) 16, 20, and 24. Methods: Eighty pts were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 wks in the ACTIVATE trial. Change from BL to wk 24 in PKDD and PKDIA scores were prespecified secondary endpoints. For this post hoc analysis, changes from BL in PKDD weekly mean scores and PKDIA scores measured at scheduled visits (wks 4, 8, 12, 16, 20, and 24) were summarized for Hb responders, the overall mitapivat treatment arm, and PBO, using mean and 95% confidence intervals (CIs). For both the PKDD and the PKDIA, a lower score represents a lower disease burden. Results: In the ACTIVATE trial, 16/40 (40%) pts receiving mitapivat met the primary endpoint of Hb response compared with none for PBO (0/40; 0%). At wk 24, mean (95% CI) change from BL in PKDD weekly mean score was ‒7.12 (‒10.98, ‒3.27) for pts who achieved Hb response, ‒5.43 (‒7.47, ‒3.40) for the overall mitapivat treatment arm, and ‒1.86 (–4.04, 0.32) for the PBO arm (Figure 1a). At wk 24, mean (95% CI) change from BL in PKDIA score was ‒8.07 (‒11.05, ‒5.08) for pts who achieved Hb response, ‒4.82 (‒7.18, ‒2.46) for the overall mitapivat treatment arm, and ‒1.06 (‒3.70, 1.59) for the PBO arm (Figure 1b). Across both PRO instruments, improvements among mitapivat pts who achieved Hb response were sustained over time. Image:Summary/Conclusion: In the ACTIVATE trial, mitapivat-treated pts demonstrated significant improvements in signs, symptoms, and impacts based on PK deficiency-specific PRO instruments, compared with PBO. This analysis further reveals that improvements were greater in the subset of mitapivat-treated pts who achieved the primary endpoint. Together, these data indicate that mitapivat has the potential to improve HRQoL in pts with PK deficiency who are not regularly transfused.
The spleen plays an important role in the body's defence against bacterial infections. Measuring splenic function is of interest in multiple conditions, including sickle cell anaemia (SCA), where spleen injury occurs early in life. Unfortunately, there is no direct and simple way of measuring splenic function, and it is rarely assessed in clinical or research settings. Manual counts of pitted red blood cells (RBCs) observed with differential interference contrast (DIC) microscopy is a well-validated surrogate biomarker of splenic function. The method, however, is both user-dependent and laborious. In this study, we propose a new automated workflow for counting pitted RBCs using deep neural network analysis. Secondly, we assess the durability of fixed RBCs for pitted RBC counts over time. We included samples from 48 children with SCA and 10 healthy controls. Cells were fixed in paraformaldehyde and examined using an oil-immersion objective, and microscopy images were recorded with a DIC setup. Manual pitted RBC counts were performed by examining a minimum of 500 RBCs for pits, expressing the proportion of pitted RBCs as a percentage (%PIT). Automated pitted RBC counts were generated by first segmenting DIC images using a Zeiss Intellesis deep learning model, recognising and segmenting cells and pits from background. Subsequently, segmented images were analysed using a small ImageJ macro language script. Selected samples were stored for 24 months, and manual pitted RBC counts performed at various time points. When comparing manual and automated pitted RBC counts, we found the two methods to yield comparable results. Although variability between the measurements increased with higher %PIT, this did not change the diagnosis of asplenia. Furthermore, we found no significant changes in %PIT after storing samples for up to 24 months and under varying temperatures and light exposures. We have shown that automated pitted RBC counts, produced using deep neural network analysis, are comparable to manual counts, and that fixed samples can be stored for long periods of time without affecting the %PIT. Automating pitted RBC counts makes the method less time consuming and results comparable across laboratories.
Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals.
