Severe cardiac and abdominal manifestations without lung involvement in a child With COVID-19

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic, affecting humans of all ages. Clinical features of the pediatric population have been published, but there is not yet enough information to make a definitive description. Fever is typical, as it is respiratory symptom. Rarely are the infection and complications severe, and, when they are, it is almost always in a patient with another underlying disease. However, some otherwise healthy children with COVID-19 do suffer critical organ injury, such as acute myocarditis, heart failure and gastrointestinal inflammation. The mechanism of these organ damages remains unclear. An otherwise normally healthy 13-year-old male was admitted to the pediatric intensive care unit with acute abdomen pain, possible myocarditis and a suspected diagnosis of COVID-19. Noteworthy basal findings were ventricular extrasystoles in the electrocardiogram (EKG) and moderate left ventricular systolic dysfunction. Chest X-ray was normal. Blood tests revealed altered levels of inflammation factors (C-reactive protein (CRP), D-dimer, fibrinogen, interleukin 6 (IL-6)), lymphopenia and elevated cardiac enzymes. The first test for polymerase chain reaction (PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative. The patient’s condition worsened, and he entered cardiogenic shock (hypotension, tachycardia and oliguria). He was vomiting continuously, which made pain control difficult; imaging of his abdomen was undertaken. There was no response to fluid resuscitation, and so milrinone and epinephrine were administered. Empiric treatment began with azithromycin, foscarnet, carnitine and immunoglobulins. Hydroxychloroquine was given before the results of repeated SARSCoV-2 and serology tests were available. Tocilizumab was administered once COVID-19 had been confirmed and massive inflammation had been observed. Progressively the clinical situation and the levels of the parameters studied improved. The patient was discharged 8 days after admission. Most children with SARS-CoV-2 infection are asymptomatic or present only mild symptoms. However, physicians should be aware of atypical and severe manifestations that may occur in the hyperinflammatory phase of the illness

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript

Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection

Factor de impacto: 5,858 Q1Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCRγδ and more than 18-fold increased production of IFNγ upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics.This work was supported by NIH grant R01AI143567; the Spanish Ministry of Economy and Competitiveness (SAF2016-78480-R); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of María Rosa López-Huertas and Sara Rodríguez-Mora is financed by NIH grant R01AI143567. The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Elena Mateos is supported by the Spanish Ministry of Economy and Competitiveness SAF2016-78480-R.S

Best Treatment Option for Patients With Refractory Aggressive B-Cell Lymphoma in the CAR-T Cell Era: Real-World Evidence From GELTAMO/GETH Spanish Groups

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4-6 months, p <= 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44-0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31-0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria

Impact of SCHOLAR-1 Criteria on Chimeric Antigen Receptor T Cell Therapy Efficacy in Aggressive B Lymphoma: A Real-World GELTAMO/GETH Study

In the pre-chimeric antigen receptor T cell (CAR-T) therapy era, the SCHOLAR-1 study identified a group of patients with refractory aggressive B cell lymphoma (ABCL) with particularly poor prognoses. We recently published our real -world data from Spain, focused on this SCHOLAR-1 refractory group, and compared patients who underwent CAR-T therapy with the previous standard of care. In this study, we found that the efficacy of CAR-T therapy in refractory patients, in terms of progression-free survival (PFS) and overall survival (OS), was superior to that of the treatments available in the pre-CAR-T era. The main objective of these new analyses was to analyze treatment efficacy in terms of response rates and survival for patients with ABCL with or without the SCHOLAR-1 criteria. In addition, we ana-lyzed the prognostic impact of each SCHOLAR-1 criterion independently. Our study aimed to assess the prognostic impact of SCHOLAR-1 criteria on ABCL patients treated with CAR-T therapy in Spain. This multicenter, retrospective, observational study. We included all adult patients treated with commercially available CAR-T cell products and diag-nosed with ABCL different from primary mediastinal large B cell lymphoma between February 2019 and July 2022. Patients meeting any SCHOLAR-1 criteria (progressive disease as the best response to any line of therapy, stable dis-ease as the best response to >4 cycles of first-line therapy or >2 cycles of later-line therapy, or relapse at <12 months after autologous stem cell transplantation [auto-SCT]) in the line of treatment before CAR-T therapy (SCHOLAR-1 group) were compared with those not meeting any of these criteria (non-SCHOLAR-1 group). To analyze the prognos-tic impact of individual SCHOLAR-1 criteria, all the patients who met any of the SCHOLAR-1 criteria at any time were included to assess whether these criteria have the same prognostic impact in the CAR-T era. In addition, patients were grouped according to whether they were refractory to the first line of treatment, refractory to the last line of treatment, or relapsed early after auto-SCT. The PFS and OS were calculated from the time of appearance of the SCHOLAR-1 refractoriness criteria. Of 329 patients treated with CAR-T (169 with axi-cel and 160 with tisa-cel), 52 were in the non-SCHOLAR-1 group and 277 were in the SCHOLAR-1 group. We found significantly better outcomes in the non-SCHOLAR-1 patients compared with the SCHOLAR-1 patients (median PFS of 12.2 and 3.3 months, respectively; P = .009). In addition, axi-cel showed better results in terms of efficacy than tisa-cel for both the non SCHOLAR-1 group (hazard ratio [HR] for PFS, 2.7 [95% confidence interval (CI), 1.1 to 6.7; P = .028]; HR for OS, 7.1 [95% CI, 1.5 to 34.6; P = .015]) and SCHOLAR-1 group (HR for PFS, 1.8 [95% CI, 1.3 to 2.5; P < .001]; HR for OS, 1.8 [95% CI, 1.2 to 2.6; P = .002]), but also significantly more toxicity. Finally, separately analyzing the prognostic impact of each SCHOLAR-1 criterion revealed that refractoriness to the last line of treatment was the variable with the most significant impact on survival. In conclusion, SCHOLAR-1 refractoriness criteria notably influence the efficacy of CAR-T therapy. In our experience, axi-cel showed better efficacy than tisa-cel for both SCHOLAR-1 and non-SCHOLAR-1 patients. Refractoriness to the last line of treatment was the variable with the most significant impact on survival in the CAR-T therapy era.(c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc

Experimental ovine toxoplasmosis: influence of the gestational stage on the clinical course, lesion development and parasite distribution

P. 1-14The relation between gestational age and foetal death risk in ovine toxoplasmosis is already known, but the mechanisms involved are not yet clear. In order to study how the stage of gestation influences these mechanisms, pregnant sheep of the same age and genetic background were orally dosed with 50 oocysts of Toxoplasma gondii (M4 isolate) at days 40 (G1), 90 (G2) and 120 (G3) of gestation. In each group, four animals were culled on the second, third and fourth week post infection (pi) in order to evaluate parasite load and distribution, and lesions in target organs. Ewes from G1 showed a longer period of hyperthermia than the other groups. Abortions occurred in all groups. While in G2 they were more frequent during the acute phase of the disease, in G3 they mainly occurred after day 20 pi. After challenge, parasite and lesions in the placentas and foetuses were detected from day 19 pi in G3 while in G2 or G1 they were only detected at day 26 pi. However, after initial detection at day 19 pi, parasite burden, measured through RT-PCR, in placenta or foetus of G3 did not increase significantly and, at in the third week pi it was lower than that measured in foetal liver or placenta from G1 to G3 respectively. These results show that the period of gestation clearly influences the parasite multiplication and development of lesions in the placenta and foetus and, as a consequence, the clinical course in ovine toxoplasmosis.S

Efficacy of clozapine versus standard treatment in adult individuals with intellectual disability and treatment-resistant psychosis (CLOZAID): study protocol of a multicenter randomized clinical trial

BackgroundIntellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field.MethodsA Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them.DiscussionThe treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials.Trial registrationClinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37

Severe cardiac and abdominal manifestations without lung involvement in a child With COVID-19

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic, affecting humans of all ages. Clinical features of the pediatric population have been published, but there is not yet enough information to make a definitive description. Fever is typical, as it is respiratory symptom. Rarely are the infection and complications severe, and, when they are, it is almost always in a patient with another underlying disease. However, some otherwise healthy children with COVID-19 do suffer critical organ injury, such as acute myocarditis, heart failure and gastrointestinal inflammation. The mechanism of these organ damages remains unclear. An otherwise normally healthy 13-year-old male was admitted to the pediatric intensive care unit with acute abdomen pain, possible myocarditis and a suspected diagnosis of COVID-19. Noteworthy basal findings were ventricular extrasystoles in the electrocardiogram (EKG) and moderate left ventricular systolic dysfunction. Chest X-ray was normal. Blood tests revealed altered levels of inflammation factors (C-reactive protein (CRP), D-dimer, fibrinogen, interleukin 6 (IL-6)), lymphopenia and elevated cardiac enzymes. The first test for polymerase chain reaction (PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative. The patient’s condition worsened, and he entered cardiogenic shock (hypotension, tachycardia and oliguria). He was vomiting continuously, which made pain control difficult; imaging of his abdomen was undertaken. There was no response to fluid resuscitation, and so milrinone and epinephrine were administered. Empiric treatment began with azithromycin, foscarnet, carnitine and immunoglobulins. Hydroxychloroquine was given before the results of repeated SARSCoV-2 and serology tests were available. Tocilizumab was administered once COVID-19 had been confirmed and massive inflammation had been observed. Progressively the clinical situation and the levels of the parameters studied improved. The patient was discharged 8 days after admission. Most children with SARS-CoV-2 infection are asymptomatic or present only mild symptoms. However, physicians should be aware of atypical and severe manifestations that may occur in the hyperinflammatory phase of the illness

Trends and sex differences in atrial fibrillation among patients hospitalized due to asthma: Insights from a nationwide population-based discharge database in Spain, 2016–2021

Aims: To analyze changes in the prevalence of atrial fibrillation (AF) in patients hospitalized due to asthma; to compare hospital outcomes in asthma patients with and without AF, assessing sex differences; to identify variables associated with the presence of AF; and to analyze the factors associated with in-hospital mortality (IHM) among asthma patients with AF. Methods: We used data from the Registry of Specialized Care Activity-Basic Minimum Data Set to select all patients aged ≥40 years with an asthma diagnosis in Spain, from 2016 to 2021. We stratified the study population according to the presence of AF and sex. Results: We identified 65,233 hospitalizations that met the inclusion criteria (14.85 % with AF). The prevalence of AF significantly increased over time, with the male sex being a protective factor for its presentation. IHM were significantly higher in patients with AF. Older age, being a woman, congestive heart failure, renal disease, obstructive sleep apnea, hypertension, and hyperthyroidism were associated with the presence of AF. Advanced age and the presence of cancer and COVID-19 were factors associated with a higher IHM, as well as admission to an intensive care unit and the use of invasive mechanical ventilation. There were no association of sex with the IHM.Conclusions: AF is highly prevalent among subjects hospitalized due to asthma, with this prevalence having increased significantly in Spain over time. The presence of AF in patients with asthma was associated significantly with a higher LOHS and IHM. Sex was not associated with IHM in these patients.Convenio Plurianual con la Universidad Complutense de Madrid en línea con la Excelencia Programa para el profesorado universitario en el marco del V PRICITDepto. de Salud Pública y Materno - InfantilFac. de MedicinaTRUEpu