ABSTRACT
The emergence of SARS-CoV-2, as of July 2021 has affected 469,042 individuals and accounted for 12,851 deaths nationally in Greece, according to WHO database. Mortality rate is higher in elderly patients (pts) and in pts with comorbidities, including malignancies. However, there is a growing interest on COVID-19 outcomes in pts with hematologic diseases. The aim of this study was to perform a systematic registration and analysis of the outcomes of pts with hematologic disease and COVID-19 in our center. The study is a single-center, retrospective study, conducted at a Hematology Department and HCT unit of a tertiary Hospital after approval from local Ethics Committee. We included pts with a hematologic disease and RT-PCR confirmed COVID-19 infection between October 2020 and July 2021. We reviewed hematological medical records to extract demographic and clinical data of COVID-19 infections. Most of the data have already been intergraded in ASH Research Collaborative Data Hub. Hematologic diseases were categorized to: Acute Myeloblastic Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Non-Hodgkin Lymphomas (NHL), Chronic Lymphocytic Leukemia (CLL), Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Chronic Myeloid Leukemia (CML), Myeloproliferative Neoplasms (MPN, including all Philadelphia-negative MPN) and other hematologic conditions. We evaluated a total of 89 pts, 54% were male and 46% female, with a median age of 64.5 (20-86) and 59.5 (21-85) years respectively. 83% of pts were ≥40 years and 27% ≥70 years old. Most of them (92%) acquired infection outside a hospital setting. 13% of pts were asymptomatic and diagnosis was confirmed only with positive RT-PCR test. The most common represented malignancies were NHL 26%, CLL 20% and acute leukemias 13.5%, while 15% of pts underwent transplantation (HCT). Pts presented with moderate/severe COVID-19 were 55%, while 43% of hospitalized pts required Intensive Care Unit (ICU) admission. Overall, the death rate was 24%, while remarkably almost all pts required ICU support did not survive (mortality 94%). Higher mortality observed in patients with MDS (50%), MM (43%), CLL (39%), ALL (33%) and NHL (30%). Further analysis showed a positive correlation between mortality and male gender with 16 deaths out of 21 (p =.0245), as well as mortality and ICU admission (p <.001). A chi-square test of independence was performed to examine the relation between age and COVID-19 severity, without any statistically significant result [x 2 (2, N = 87) = 3.475, p =.176]. Whereas the only significant correlation between age and mortality was among age groups 18-39 and >70 years (p =.0146). Regarding treatment, pts were divided into two subgroups, 78% of them received anticancer therapy at least once in their lives, while 22% of them have never been on treatment, mainly pts with CLL and indolent NHL. 62% of the first subgroup manifested moderate/severe COVID-19 infection requiring hospitalization with 28% death rate, while the same rates in the 2 nd subgroup were 30% and 10% respectively. Although there was a significant correlation between the treatment status and the severity of COVID-19 infection (p =.020), the above was not translated in statistically higher death rate in the first subgroup (p =.14). There was also a correlation between HCT and COVID-19 severity in general (p =.005), with autologous HCT having statistically higher mortality than the allogeneic subgroup (p =.032). Α similar analysis in CLL and NHL groups showed no relation among treatment status, COVID-19 severity, and mortality (p values.638 and.115/.34 and.62 respectively). As anticipated in hematological pts, the immunocompromised nature of the underlying disease makes them extremely vulnerable to COVID-19 infection regardless of their treatment status, a fact that is also reflected in mortality despite ICU admission and support. In general, the severity of infection is correlated to anticancer therapy, while mortality to male sex, ICU admission and autologous HCT. Larger number of pts are necessary for further studies to better understand the parameters that impact the outcome of COVID-19 in hematological pts. Hematology departments should remain COVID-19 free zones, dedicated only to hematologic treatment and pts should strictly comply with social distancing. It remains to see if vaccines can play a key role to protect this special group of pts. [Formula presented] Disclosures: Anagnostopoulos: Abbvie: Other: clinical trials;Sanofi: Other: clinical trials;Ocopeptides: Other: clinical trials;GSK: Other: clinical trials;Incyte: Other: clinical trials;Takeda: Other: clinical trials;Amgen: Other: clinical trials;Janssen: Other: clinical trials;novartis: Other: clinical trials;Celgene: Other: clinical trials;Roche: Other: clinical trials;Astellas: Other: clinical trials.
ABSTRACT
Background. Hematopoietic cell transplant (HCT) recipients who develop coronavirus disease 2019 (COVID-19), have dismal prognosis with approximately 20% mortality. Given the lack of a specific and effective therapy, the availability of various vaccination platforms against SARS-CοV-2 has generated optimism towards the development of a robust herd immunity. Notwithstanding the prioritization of HCT recipients to COVID-19 vaccination, limited information is available on whether and to what extent, they mount an immune response to SARS-CοV-2 vaccination as they were generally excluded from vaccination trials. Aim. To gain insights in the immune responses developed to SARS-CoV-2 vaccines under immunosuppression, we studied the humoral and cellular immune responses to SARS-CoV-2 vaccination in HCT recipients. Methods. We prospectively studied (April-July 2021), adult patients who had undergone HCT in our Unit and received two doses of a SARS-CoV-2 vaccine (as per international guidelines) after providing written informed consent. Responses were studied before each vaccination dose and 12-51 days later after the second dose. Neutralizing antibodies against SARS-CoV-2 (CoV-2-NAbs) were measured using an FDA approved methodology for diagnostic use (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit;GenScript, Piscataway, NJ, USA;cut-off value for a positive result set at ≥30%) and SARS-CoV-2 spike-specific T cells (spike-STs) by interferon-γ Elispot after pulsing peripheral blood mononuclear cells with spike pepmixes. Results. Humoral responses were studied on 65 patients, (50 allo-HCT/15 auto-HCT, Figure A). T cell responses were measured on 38/65 vaccinated patients (32 allo-HCT/6 auto-HCT) with a median of 3 (0.17-31) and 2 years (1.25-8) post allo- and auto-HCT respectively, and 19 healthy, unexposed vaccinees. One patient with prior COVID-19, was excluded from analysis. All patients were vaccinated with the Pfizer-BioNTech, except for 2 vaccinated with the AstraZeneca vaccine. Both CoV-2-NAbs and spike-STs were barely detectable before vaccination but could be detected in both allo- and auto-HCT patients after the first vaccination dose, reaching statistically significant increase after the second vaccination dose (p<0.001 and p=0.036, respectively). Circulating spike-STs in allo-HCT recipients, although present, were lower over their counterparts in healthy volunteers (p<0.001) and auto-HCT patients (p=0.080). In the latter patient cohort, the rather long period post auto-HCT (≥1.25 years for all patients) might have generated unintended bias towards elevated immune responses. The longer time post HCT in all patients was associated with increased CoV-2-NAbs and spike-STs (p=0.004 and p=0.030). Allo-HCT recipients under immunosuppression had lower levels of CoV-2-NAbs and spike-STs after the booster dose compared to patients off-treatment (Figure B and C, p<0.001 and p=0.021 respectively). In particular, only 50% and 40% of patients on systemic immunosuppression reached adequate CoV-2-Nab and spike-ST levels after the second dose, as compared to 98% and 94% of immunosuppression-free patients. One allo-HCT recipient with failure to mount any immune response post booster vaccination, developed 40 days later COVID-19 infection and succumbed. The one allo-HCT recipient off treatment who did not elicit protective immune response after vaccination, was suffering from metabolic syndrome, a potentially immunosuppressive entity. Overall, there was a good correlation between humoral and T-cellular responses (p=0.013), although few cases were observed with sufficient T-cell response but no humoral reactivity and vice versa. Conclusion. Herein, we report for first time humoral and T cell responses post SARS-CoV-2 vaccination in HCT recipients. Transplant recipients not under active and intense immunosuppression at the time of vaccination may benefit significantly from COVID-19 vaccination even though these responses are blunted compared to healthy individuals. However, for the severely immunocompromised patients it seems high y unlikely that they could be protected by vaccination and for this vulnerable population, different vaccination schemes or therapeutic platforms should be developed along with collateral measures including minimal exposure and immunization of caregivers and health care providers. [Formula presented] Disclosures: Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy;Pfizer Corporation: Research Funding;Gilead Corporation: Honoraria. Yannaki: SANDOZ: Speakers Bureau;Gilead: Speakers Bureau;Novartis: Speakers Bureau;bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials;Sanofi: Other: clinical trials;Ocopeptides: Other: clinical trials;GSK: Other: clinical trials;Incyte: Other: clinical trials;Takeda: Other: clinical trials;Amgen: Other: clinical trials;Janssen: Other: clinical trials;novartis: Other: clinical trials;Celgene: Other: clinical trials;Roche: Other: clinical trials;Astellas: Other: clinical trials.
ABSTRACT
Background: Complement dysregulation has been documented in the molecular pathophysiology of COVID-19 and recently implicated in the relevant pediatric patient inflammatory responses. Aims: Based on our previous data in adults, we hypothesized that signatures of complement genetic variants would also be detectable in pediatric patients exhibiting COVID-19 signs and symptoms. Methods: We prospectively studied consecutive pediatric patients from our COVID-19 Units (November 2020-March 2021). COVID-19 was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). Patient data were recorded by treating physicians that followed patients up to discharge. DNA was obtained from peripheral blood samples. Probes were designed using the Design studio (Illumina). Amplicons cover exons of complement-associated genes (C3, C5, CFB, CFD, CFH, CFHR1, CFI, CD46, CD55, MBL2, MASP1, MASP2, COLEC11, FCN1, FCN3 as well as ADAMTS13 and ΤHBD) spanning 15 bases into introns. We used 10ng of initial DNA material. Libraries were quantified using Qubit and sequenced on a MiniSeq System in a 2x150 bp run. Analysis was performed using the TruSeq Amplicon application (BaseSpace). Alignment was based on the banded Smith-Waterman algorithm in the targeted regions (specified in a manifest file). We performed variant calling with the Illumina-developed Somatic Variant Caller in germline mode and variant allele frequency higher than 20%. Both Ensembl and Refseq were used for annotation of the output files. A preliminary analysis (A) for the identification of variants of clinical significance was based on annotated ClinVar data, while a further and more selective analysis (B) was performed to identify missense complement coding variants that may biochemically contribute to the deregulation of innate responses during infection. This analysis was mainly based on the dbSNP and UniProt databases and available literature. Results: We studied 80 children and adolescents, 8 of whom developed inflammatory syndromes (MIS-C group). Among them, 41 were hospitalized and eventually all survived. 1. In our preliminary analysis, patients exhibited heterogeneous variant profiles including pathogenic, benign, likely benign, and variants of unknown significance (median number of variants: 97, range: 61-103). We found a variant of ADAMTS13 (rs2301612, missense) in 39 patients. We also detected two missense risk factor variants, previously detected in complement-related diseases: rs2230199 in C3 (33 patients);and rs800292 in CFH (36 patients). Among them, 40 patients had a combination of these characterized variants. This combination was significantly associated with the presence of dyspnea (p=0.031) and cough (p=0.042). Furthermore, 27 patients had a pathogenic variant in MBL2 (rs1800450), and 7 a pathogenic deletion in FCN3 that have been previously associated with inflammatory syndromes. 2. The results of our further analysis are summarized in Figure. We identified common variants, some well represented by relatively high frequencies (>70%) (rs11098044 in CFI, rs1061170 in CFH and rs12711521 in MASP2) and others less abundant, but varying considerably between the hospitalized group, the non-admitted group and the MIS-C individuals (rs2230199 in C3, rs1065489 in CFH, rs12614 and rs641153 in CFB, rs1800450 in MBL2, rs2273346 and rs72550870 in MASP2, rs72549154 in MASP3 and rs7567833 in COLEC11, all highlighted in Figure in red).). Structurally, the majority of these common variants of interest encode charge reversal mutations. These may influence protein-protein interactions in complex formations that are important for complement activation and/or regulation. Conclusion: In pediatric COVID-19 we have detected a novel set of complement missense coding variants some of which have been implicated earlier in inflammatory syndromes and endothelial stress responses. Certain combinations of mutations of alternative and/or lectin pathway components may increase the threshold dynamics of complement consumption and therefore alter COVID-19 phenotypes. [Formula prese ted] Disclosures: Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy;Gilead Corporation: Honoraria;Pfizer Corporation: Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials;Sanofi: Other: clinical trials;Ocopeptides: Other: clinical trials;GSK: Other: clinical trials;Incyte: Other: clinical trials;Takeda: Other: clinical trials;Amgen: Other: clinical trials;Janssen: Other: clinical trials;novartis: Other: clinical trials;Celgene: Other: clinical trials;Roche: Other: clinical trials;Astellas: Other: clinical trials.
ABSTRACT
Background: Healthcare systems around the globe are still facing the evolving threat of the corovavirus-19 (COVID-19) pandemic. Hemoglobinopathies include a group of genetic disorders, with the two main pillars being thalassemias and sickle cell disease (SCD). Due to their immunocompromised status, such patients (pts) have been protected as extremely vulnerable to COVID-19 infection. Despite limited data in literature, recent reports present conflicting results Aims: We prospectively investigated the incidence and outcomes of COVID-19 in pts with hemoglobinopathies and correlated them to their coexistent comorbidities. Methods: We studied pts with different hemoglobinopathies, consecutively monitored at our Center, who were infected with SARS-COV 2 during the first and second "waves" of the pandemic in Greece (March - December 2020). The following factors were studied: age, employment, blood type, liver and heart hemosiderosis, splenectomy, concomitant endocrine disorders and transfusion dependency. Results: Among 250 pts regularly followed-up at our Center (7 with HbH hemoglobinopathy 150 with Thalassemia major, 53 with SCD and 41 with non transfusion dependent thalassemia), 9 (3.4%) were infected with COVID-19 (5 male: 4 female). COVID-19 pts' age range was 20-46 (median 35.1). During the same time period the prevalence of COVID-19 infection in Greece's general population, regarding the same age groups, was 1.89%. Two pts had HbH hemoglobinopathy, 1 Sickle Cell Disease (SCD), and 6 transfusion dependent β-thalassemia (TDT). In total, 7/9 pts were transfusion dependent (TD). Blood type was A+ in 55.5%, B+ in 11.1%, AB+ in 11.1% and O+ in 22.2% of pts. The range of ferritin levels at the time of infection was 180-992 ng/ ml (median 434). Seven out of 9 pts had median MRI T2∗ liver iron concentration (LIC) of 1.696 g/dw and median MRIT2∗ of the heart 33.7 tms. However, their ejection fracture (EF) was >50% at all cases. Two pts were splenectomized and 1 had functional asplenia. Only 2 pts had concomitant endocrine disorders (hypothyroidism and hypogonadism). These pts were on hormone replacement therapy. All TD pts were on iron chelation therapy (5 on deferasirox and 1 on both deroxamine and deferiprone). Three pts were healthcare employees.Six out of 9 pts required hospitalization for a median time of 5.8 days (1 with HbH, 1 with SCD during crisis and 4 with TDT), but no one required Intensive Care Unit (ICU) monitoring, intubation or intensive ventilation support. All pts presented with fever (3 with febrile neutropenia), while 2 TDT pts had ground-glass opacities. All hospitalized pts received wide-range antibiotics plus azithromycin (as did 1 TDT pt who stayed at home). Heparin was administered in the SCD pt and in 1 of the TDT pts. One pt with HbH also received hydroxychloroquine and 1 with TDT dexamethasone. At the end of follow-up (median of 3.5 months, range 1.2-4.2), all pts are alive. On the contrary, mortality of the general Greek population in the same age group and time period was 1%. Summary/Conclusion: Our real-world data suggest that the prevalence of COVID-19 in pts with hemoglobinopathies is slightly increased compared to the general population. Considering that these pts are more strictly monitored, we could hypothesize that self-applied precautions are effective. No death or severe pulmonary disease requiring intubation was observed. In compliance with recent data, our findings do not indicate increased mortality and morbidity of COVID-19 in pts with hemoglobinopathies, followed in a Specialized Center. However, more data are needed for a safe conclusion to be extracted.
ABSTRACT
Background: SARS-CoV-2 is a novel coronavirus causing an infection, named Coronavirus Disease 2019 (COVID-19). As of February 22, 2021, the virus had affected more than112 millions individuals and resulted in over 2,4 millions deaths worldwide. Mortality can be as high as15% in elderly patients, and/or in patients with comorbidities. Data from studies suggest that patients with cancer have a higher incidence of severe events after contacting the virus. Very few data are available on COVID-19 outcomes in patients with hematologic diseases who are highly immunocompromised due to their underlying disease and the treatments they receive, with high risk of morbidity and mortality from COVID-19. Aims: The purpose of this study was to perform a review to quantify the outcomes (hospitalizations and deaths) of patients with hematologic malignancy and COVID-19. Methods: Our department consists of Hematology Clinic and BMT Unit. We included patients with a hematologic disease, with laboratory- confirmed COVID-19 infection between October 2020 and February 2021. A confirmed case of COVID-19 was defined by a positive result on RT-PCR assay. We reviewed hematological medical records to collect demographic, clinical, and treatment data and outcomes of COVID-19. We evaluated 73 patients (43 male, 30 female, median age 61). Information extracted included total number of patients, coronavirus symptoms, hospital admission rate, death rate. Hematologic malignancy subtypes were: acquired bone marrow failure syndromes;acute leukemias;lymphomas;chronic lymphocytic leukemia;plasma cell dyscrasias;MPNs;other hematologic conditions;stem cell transplantation. Results: According to our analysis, regarding COVID-19 symptoms at diagnosis, 47 of 73 pts (64%) presented fever, as single symptom or combined with at least one more symptom, 20 of 73 pts (27%) presented two or more symptoms, including anosmia, cough, shortness of breath, myalgias, fatigue, while 9 of 73 pts (12%) were asymptomatic and diagnosis confirmed only with positive PCR test. Patients presented with moderate or severe COVID-19 were 28 of 73 (38%), while 9 of 28 hospitalized pts (32%) required Intensive Care Unit (ICU) admission. Data collected regarding hematologic malignancy subtype showed: lymphomas, non including CLL, 24 of 73 pts (33%), CLL,17 of 73 pts (23%), acute leukemias, 7 of 73 pts (10%), MPNs, 8 of 73 pts (11%), acquired bone marrow failure syndromes, 5 of 73 pts (7%), multiple myeloma, 3 of 73 pts (4%), other hematologic conditions 5 of 73 (7%), while patients who underwent transplantation were 4 of 73 (5%). Regarding treatment, patients divided in two subgroups, 52 of 73 (71%) received anticancer therapy at some time in their lives, while 21 of 73 pts (29%) have never been on treatment. Total death rate was 23% (17 of 73 pts), while among hospitalized pts was nearly 54% (15 of 28), with all patients requiring ICU not surviving (9 of 9, rate100%). 2 of17 pts (11%) died without hospitalization. Death rate in CLL pts was 41% (7 of17 pts) with 2 of17 (11%) not on treatment, in lymphomas16% (4 of 24 pts), while in other hematologic subgroups were reported from1 to 2 deaths per group. Summary/Conclusion: Hematological patients appear to be a population very vulnerable to COVID-19 infection, with significant morbidity and mortality. More data are necessary in further surveys from more centers and larger number of patients. Hematology departments should remain COVID-19 free zones dedicated only to hematologic treatment and patients should strictly comply with social distancing.