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1.
Sci Rep ; 14(1): 13499, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866888

RESUMO

Acute, transient lymphocytopenia, not clinically significant was observed in the CAPRISA 012B phase 1 clinical trial following administration of broadly neutralizing antibodies (bnAb)-CAP256V2LS alone or with VRC07-523LS. Lymphocytopenia was assigned upon a > 50% decline in absolute lymphocyte counts following bnAb administration. We posited that systemic immunoglobulins (Igs), and cytokine profiles of eight women who developed lymphocytopenia were different to the 12 women without lymphocytopenia. Plasma Ig subclasses (IgG)/isotypes (IgM/IgA), and 27 cytokines were measured at enrolment (prior to bnAbs) and at days 1, 7, 28, 56 post-bnAb administration. IgG subclasses, IgM and total lymphocyte counts were significantly lower prior to bnAbs in women with gradable lymphocytopenia than those without. Gradable lymphocytopenia compared to non-lymphocytopenia women had significantly higher MIP-1ß from enrolment up to day 56. TNF-α was significantly lower in gradable lymphocytopenia compared to non-lymphocytopenia women for enrolment, days 7, 28 and 56 except for day 1. Within the gradable and within the non-lymphocytopenia women, from enrolment to day 1, significantly elevated IL-6, IL-8, IP-10, MCP-1, G-CSF and IL-1RA were found. Additionally, within the gradable lymphocytopenia women, 9 additional cytokines (TNF-α, MIP-1α, MIP-1ß, RANTES, Basic FGF, eotaxin, IFN-γ, IL-17A and IL-4) were significantly elevated at day 1 post-bnAbs compared to enrolment. This sub study presents preliminary findings to support the monitoring of baseline immunological markers including lymphocyte counts for assessing the development of transient lymphocytopenia. In high-risk settings conducting clinical trials testing bnAbs for HIV prevention, understanding factors that could amplify rates of lymphocytopenia, even if transient, remain undefined.


Assuntos
Linfopenia , Humanos , Feminino , Linfopenia/imunologia , Linfopenia/sangue , Adulto , Citocinas/sangue , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/sangue , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunoglobulinas/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Pessoa de Meia-Idade
2.
Sci Rep ; 14(1): 11102, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750134

RESUMO

Lymphopenia is a common feature of acute COVID-19 and is associated with increased disease severity and 30-day mortality. Here we aim to define the demographic and clinical characteristics that correlate with lymphopenia in COVID-19 and determine if lymphopenia is an independent predictor of poor clinical outcome. We analysed the ENTER-COVID (Epidemiology of hospitalized in-patient admissions following planned introduction of Epidemic SARS-CoV-2 to highly vaccinated COVID-19 naïve population) dataset of adults (N = 811) admitted for COVID-19 treatment in South Australia in a retrospective registry study, categorizing them as (a) lymphopenic (lymphocyte count < 1 × 109/L) or (b) non-lymphopenic at hospital admission. Comorbidities and laboratory parameters were compared between groups. Multiple regression analysis was performed using a linear or logistic model. Intensive care unit (ICU) patients and non-survivors exhibited lower median lymphocyte counts than non-ICU patients and survivors respectively. Univariate analysis revealed that low lymphocyte counts associated with hypertension and correlated with haemoglobin, platelet count and negatively correlated with urea, creatinine, bilirubin, and aspartate aminotransferase (AST). Multivariate analysis identified age, male, haemoglobin, platelet count, diabetes, creatinine, bilirubin, alanine transaminase, c-reactive protein (CRP) and lactate dehydrogenase (LDH) as independent predictors of poor clinical outcome in COVID-19, while lymphopenia did not emerge as a significant predictor.


Assuntos
COVID-19 , Hospitalização , Linfopenia , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/mortalidade , COVID-19/sangue , COVID-19/complicações , Linfopenia/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , SARS-CoV-2/isolamento & purificação , Contagem de Linfócitos , Austrália/epidemiologia , Unidades de Terapia Intensiva , Comorbidade , Idoso de 80 Anos ou mais , Prognóstico
3.
BMC Infect Dis ; 24(1): 519, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783176

RESUMO

BACKGROUND: Targeting mucosal immunity of the gut, which is known to provide antigen processing, while avoiding excessive or unnecessary inflammation, was tested as a way to modulate COVID-19 severity. METHODS: Randomized open-label trial in 204 adults hospitalized with non-critical COVID-19 who received for 14 days in addition to standard of care (SOC) degalactosylated bovine glycoproteins formulations of either MAF capsules (MAF group) or M capsules (M group) or SOC only (control group). RESULTS: Median recovery time when patients did not require supplemental oxygen was 6 days in both study groups compared to 9 days in the control (MAF vs. control; P = 0.020 and M vs. control; P = 0.004). A greater reduction in mortality was seen in the MAF group compared to the control by day 14 (8.3% vs. 1.6%; P = 0.121) and by day 29 (15.3% vs. 3.2%; P = 0.020), and similarly in the M group by day 14 (8.3% vs. 2.9%; P = 0.276) and by day 29 (15.3% vs. 2.9%; P = 0.017). The proportion of those who had baseline absolute lymphocyte count (ALC) lower than 0.8 × 109/L was 13/63 (20.6%), 17/69 (24.6%), and 18/72 (25.0%) of patients in MAF, M, and control group respectively. Day 29 mortality among these lymphopenic patients was three times higher than for the intent-to-treat population (21% vs. 7%) and consisted in above subgroups: 2/13 (15%), 2/17 (12%), and 6/18 (33%) of patients. The decreased mortality in both study subgroups correlated with greater ALC restoration above 0.8 × 109/L level seen on day 14 in 91% (11/12) and 87.5% (14/16) of survivors in MAF and M subgroups respectively compared to 53.3% (8/15) of survivors in control subgroup. Incidences of any ALC decrease below the baseline level on day 14 occurred in 25.4% of patients in the MAF group and 29.0% of patients in the M group compared to 45.8% in control and ALC depletion by ≥ 50% from the baseline level consisted of 7.9%, 5.8%, and 15.3% of cases in these groups respectively. CONCLUSION: This study showed that both study agents prevented ALC depletion and accelerated its restoration, which is believed to be one of the mechanisms of improved crucial clinical outcomes in hospitalized COVID-19 patients. TRIAL REGISTRATION: The trial was registered after the trial start in ClinicalTrials.gov NCT04762628, registered 21/02/2021, https://www. CLINICALTRIALS: gov/ct2/show/NCT04762628 .


Assuntos
COVID-19 , Glicoproteínas , Linfopenia , SARS-CoV-2 , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , COVID-19/mortalidade , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/imunologia , Idoso , Glicoproteínas/imunologia , Glicoproteínas/uso terapêutico , Resultado do Tratamento , Tratamento Farmacológico da COVID-19 , Bovinos , Animais , Adulto , Hospitalização/estatística & dados numéricos , Cápsulas
4.
J Radiat Res ; 65(3): 337-349, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38718391

RESUMO

Lymphocytes, which are highly sensitive to radiation, play a crucial role in the body's defense against tumors. Radiation-induced lymphopenia has been associated with poorer outcomes in different cancer types. Despite being the largest secondary lymphoid organ, the spleen has not been officially designated as an organ at risk. This study hypothesizes a connection between spleen irradiation and lymphopenia and seeks to establish evidence-based dosage limits for the spleen. We retrospectively analyzed data from 96 patients with locally advanced gastric cancer who received postoperative chemoradiotherapy (CRT) between May 2010 and May 2017. Complete blood counts were collected before, during and after CRT. We established a model for predicting the minimum absolute lymphocyte count (Min ALC) and to investigate potential associations between spleen dosimetric variables and Min ALC. The median follow-up was 60 months. The 5-year overall survival (OS) and disease-free survival (DFS) were 65.2% and 56.8%, respectively. The median values of pre-treatment ALC, Min ALC and post-treatment ALC were 1.40 × 109, 0.23 × 109 and 0.28 × 109/L, respectively. Regression analysis confirmed that the primary tumor location, number of fractions and spleen V5 were significant predictors of Min ALC during radiation therapy. Changes in ALC (ΔALC) were identified as an independent predictor of both OS and DFS. Spleen V5 is an independent predictor for Min ALC, and the maximum dose of the spleen is associated with an increased risk of severe lymphopenia. Therefore, these doses should be restricted in clinical practice. Additionally, ΔALC can serve as a prognostic indicator for adjuvant radiotherapy in gastric cancer.


Assuntos
Linfopenia , Baço , Neoplasias Gástricas , Humanos , Linfopenia/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Baço/efeitos da radiação , Baço/patologia , Idoso , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/patologia , Adulto , Relação Dose-Resposta à Radiação , Contagem de Linfócitos , Intervalo Livre de Doença , Estudos Retrospectivos , Quimiorradioterapia , Dosagem Radioterapêutica , Idoso de 80 Anos ou mais
5.
J Pak Med Assoc ; 74(5): 911-916, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38783439

RESUMO

OBJECTIVE: To compare the extent of cytopenias and systemic immune inflammation index of hospitalised coronavirus disease-2019 patients during the first and second/third waves of the pandemic. Methods: The retrospective, cross-sectional study was conducted in October 2021 at Fatima Memorial Hospital, Lahore, Pakistan, and comprised data of hospitalised coronavirus disease-2019 patients regardless of age and gender from May 2020 to June 2021. Data was segregated into first wave that lasted from May to July 2020, second wave that lasted from early November to mid-December 2020, and third wave that ranged from mid-March to June 2021. For comparison purposes, the data of first wave was in group A, while data of second and third waves was pooled into group B. Age, gender, comorbidities, requirement of ventilator support and outcome of the patients was noted. Inflammatory markers were compared on the basis of complete blood count and systemic immune-inflammation index data. Data was analysed using SPSS 25. RESULTS: Of the 202 patients, 90(44.5%) were in group A and 112(55.4%) were in group B. There were 108(53.5%) males and 94(46.5%) females. The median age in males was 58 years (interquartile range: 21 years) and it was 56 years (interquartile range: 21 years) in females. Neutrophilia (p<0.001), leukocytosis (p<0.001) and lymphocytopenia (p<0.001) had direct association with increased systemic immune-inflammation. Raised systemic immune-inflammation also had an association with increased requirement of ventilator support (p=0.2) and increased mortality (p=0.001). There were more females, more critical patients, more patients with anaemia, leukopenia, lymphocytopenia and thrombocytopenia in group B compared to group A (p<0.05). Need for ventilator support and mortality were also higher in group B compared to group A (p<0.05). Conclusion: All the indicators analysed were worse during the second and third waves of coronavirus disease-2019 compared to the first wave of the pandemic.


Assuntos
COVID-19 , SARS-CoV-2 , Trombocitopenia , Humanos , COVID-19/imunologia , COVID-19/terapia , COVID-19/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos Transversais , Paquistão/epidemiologia , SARS-CoV-2/imunologia , Adulto , Idoso , Trombocitopenia/epidemiologia , Trombocitopenia/imunologia , Hospitalização/estatística & dados numéricos , Leucopenia/epidemiologia , Linfopenia/imunologia , Respiração Artificial/estatística & dados numéricos , Inflamação/imunologia , Citopenia
6.
Front Immunol ; 15: 1352330, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694513

RESUMO

Introduction: COVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have. Methods: We evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients' lymphocytes and examined its correlation with lymphocyte numbers during acute disease. Results: Compared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients' CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients. Discussion: IgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.


Assuntos
Autoanticorpos , COVID-19 , Ativação do Complemento , Imunoglobulina M , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/sangue , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Autoanticorpos/sangue , Autoanticorpos/imunologia , Ativação do Complemento/imunologia , SARS-CoV-2/imunologia , Idoso , Adulto , Linfócitos/imunologia , Prevalência , Linfócitos T CD4-Positivos/imunologia , Linfopenia/imunologia , Linfopenia/sangue , Complemento C3b/imunologia
7.
Cell Death Differ ; 31(6): 820-832, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734851

RESUMO

The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1ΔCD4) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4+, naive CD8+, and FoxP3+ regulatory T cells. Interestingly, peripheral naive CD8+ T cells in Ripk1ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4+ T cells. Ripk1K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1ΔCD4 naive T cells expressed the proliferation marker Ki-67+ despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1ΔCD4Casp8 ΔCD4 and Ripk1ΔCD4Tnfr1-/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4+ and CD8+ cells and FoxP3+ regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.


Assuntos
Apoptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Receptores Tipo I de Fatores de Necrose Tumoral , Linfócitos T Reguladores , Animais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Camundongos Knockout , Caspase 8/metabolismo , Linfopenia/patologia , Linfopenia/imunologia
8.
Pediatr Blood Cancer ; 71(7): e31022, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38644606

RESUMO

BACKGROUND: Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve. PROCEDURE: We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21 years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. RESULTS: Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0 months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p = .016; Cox p = .03) and Week 5 (log-rank p = .024; Cox p = .032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p = .04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT. CONCLUSIONS: Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.


Assuntos
Neoplasias Cerebelares , Linfopenia , Meduloblastoma , Recidiva Local de Neoplasia , Humanos , Meduloblastoma/radioterapia , Linfopenia/etiologia , Criança , Feminino , Masculino , Adolescente , Pré-Escolar , Recidiva Local de Neoplasia/patologia , Neoplasias Cerebelares/radioterapia , Adulto Jovem , Estudos Retrospectivos , Radiação Cranioespinal/efeitos adversos , Seguimentos , Adulto , Prognóstico , Taxa de Sobrevida , Fatores de Risco
9.
Front Public Health ; 12: 1278046, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572008

RESUMO

Background: COVID-19 is associated with significant morbidity and mortality. This study aimed to explore the early predictors of intensive care unit (ICU) admission among patients with COVID-19. Methods: This was a case-control study of adult patients with confirmed COVID-19. Cases were defined as patients admitted to ICU during the period February 29-May 29, 2020. For each case enrolled, one control was matched by age and gender. Results: A total of 1,560 patients with confirmed COVID-19 were included. Each group included 780 patients with a predominant male gender (89.7%) and a median age of 49 years (interquartile range = 18). Predictors independently associated with ICU admission were cardiovascular disease (adjusted odds ratio (aOR) = 1.64, 95% confidence interval (CI): 1.16-2.32, p = 0.005), diabetes (aOR = 1.52, 95% CI: 1.08-2.13, p = 0.016), obesity (aOR = 1.46, 95% CI: 1.03-2.08, p = 0.034), lymphopenia (aOR = 2.69, 95% CI: 1.80-4.02, p < 0.001), high AST (aOR = 2.59, 95% CI: 1.53-4.36, p < 0.001), high ferritin (aOR = 1.96, 95% CI: 1.40-2.74, p < 0.001), high CRP (aOR = 4.09, 95% CI: 2.81-5.96, p < 0.001), and dyspnea (aOR = 2.50, 95% CI: 1.77-3.54, p < 0.001). Conclusion: Having cardiovascular disease, diabetes, obesity, lymphopenia, dyspnea, and increased AST, ferritin, and CRP were independent predictors for ICU admission in patients with COVID-19.


Assuntos
COVID-19 , Doenças Cardiovasculares , Diabetes Mellitus , Linfopenia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , COVID-19/epidemiologia , Estudos de Casos e Controles , Catar/epidemiologia , Fatores de Risco , Unidades de Terapia Intensiva , Obesidade , Dispneia , Ferritinas
10.
Pediatr Transplant ; 28(3): e14753, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38623881

RESUMO

BACKGROUND: Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse. METHODS: We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m2/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia. RESULTS: Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia. CONCLUSIONS: A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.


Assuntos
Transplante de Rim , Linfopenia , Criança , Humanos , Alemtuzumab/uso terapêutico , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Imunossupressores/uso terapêutico , Estudos Retrospectivos , Esteroides , Viremia/epidemiologia
11.
Clin Exp Med ; 24(1): 77, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630321

RESUMO

Transient or persistent immunosuppression is a known risk factor for morbidity and mortality in critically ill patients. Aim of the present study is to evaluate the lymphopenia in patients admitted to the Emergency Unit of AOU Policlinico Umberto I, to investigate its prevalence at admission and the persistence during hospitalization until discharge. Possible correlations were evaluated between lymphopenia, diagnosis of admission, comorbidities and chronic treatments. In this study, 240 patients (142 men; 98 female; mean age 75.1 ± 15.1) were enrolled. Patients were divided into two groups according to the lymphocytes count at hospital admission, namely "Group A" with lymphopenia and "Group B" with values in the normal range. Moreover, the patients in group A were distinguished in relation to the regression or persistence of the lymphopenia assessed at the time of hospital discharge (Group A1: persistence; Group A2: normalization). Prevalence of lymphopenia at admission was 57%; Group A showed higher mean age and percentage of patients over 65 years of age; and none differences were observed regarding gender. Prevalence of lymphopenia at admission was 57%; Group A showed higher mean age and percentage of patients over 65 years of age; no differences were observed regarding gender. All subsets of the lymphocytes (CD4+, CD8+, NK) were equally reduced. Persistent lymphopenia was found in 19% of patients. Lymphopenia should be valued at the time of hospital admission as a factor influencing the prognosis, the management and the treatment of these patients.


Assuntos
Linfopenia , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Linfopenia/epidemiologia , Alta do Paciente , Serviço Hospitalar de Emergência , Fatores de Risco
12.
BMC Infect Dis ; 24(1): 392, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605300

RESUMO

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is burdened by high mortality. Data are lacking about non-ICU patients. Aims of this study were to: (i) assess the incidence and prevalence of CAPA in a respiratory sub-intensive care unit, (ii) evaluate its risk factors and (iii) impact on in-hospital mortality. Secondary aims were to: (i) assess factors associated to mortality, and (ii) evaluate significant features in hematological patients. MATERIALS AND METHODS: This was a single-center, retrospective study of COVID-19 patients with acute respiratory failure. A cohort of CAPA patients was compared to a non-CAPA cohort. Among patients with CAPA, a cohort of hematological patients was further compared to another of non-hematological patients. RESULTS: Three hundred fifty patients were included in the study. Median P/F ratio at the admission to sub-intensive unit was 225 mmHg (IQR 155-314). 55 (15.7%) developed CAPA (incidence of 5.5%). Eighteen had probable CAPA (37.3%), 37 (67.3%) possible CAPA and none proven CAPA. Diagnosis of CAPA occurred at a median of 17 days (IQR 12-31) from SARS-CoV-2 infection. Independent risk factors for CAPA were hematological malignancy [OR 1.74 (95%CI 0.75-4.37), p = 0.0003], lymphocytopenia [OR 2.29 (95%CI 1.12-4.86), p = 0.02], and COPD [OR 2.74 (95%CI 1.19-5.08), p = 0.014]. Mortality rate was higher in CAPA cohort (61.8% vs 22.7%, p < 0.0001). CAPA resulted an independent risk factor for in-hospital mortality [OR 2.92 (95%CI 1.47-5.89), p = 0.0024]. Among CAPA patients, age > 65 years resulted a predictor of mortality [OR 5.09 (95% CI 1.20-26.92), p = 0.035]. No differences were observed in hematological cohort. CONCLUSION: CAPA is a life-threatening condition with high mortality rates. It should be promptly suspected, especially in case of hematological malignancy, COPD and lymphocytopenia.


Assuntos
COVID-19 , Neoplasias Hematológicas , Linfopenia , Aspergilose Pulmonar , Doença Pulmonar Obstrutiva Crônica , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , Humanos , Idoso , COVID-19/complicações , COVID-19/epidemiologia , Estudos Retrospectivos , SARS-CoV-2 , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/epidemiologia , Neoplasias Hematológicas/complicações , Unidades de Terapia Intensiva , Fatores de Risco , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/etiologia
13.
Rev Alerg Mex ; 71(1): 59, 2024 Feb 01.
Artigo em Espanhol | MEDLINE | ID: mdl-38683077

RESUMO

BACKGROUND: Variants in intracellular calcium transport genes have been associated with syndromic immunodeficiencies with a SCID phenotype. CASE REPORT: Seven-year-old girl of non-consanguineous parents, in Cartagena-Colombia. At two months of age, he presented hematochezia and was diagnosed with alimentary proctolitis without improvement with restriction to milk, wheat and eggs, and malnutrition developed. At eight months, a colon biopsy shows chronic lymphoid hyperplasia, presenting with anemia, eosinophilia, but total and specific IgE to normal foods. After four years, the Immunology Service found her asymptomatic, nutritionally recovered and without allergic sensitization, but eosinophilia and elevated calprotectin persisted, suggesting an early-onset inflammatory bowel disease. Immunoglobulins were normal, lymphocyte populations with CD3, CD4 and CD8 lymphopenia. At six years old, she presented atopic dermatitis, still had elevated calprotectin and was lymphopenic. Immunophenotyping by spectral cytometry using Cytek®cFluor®Immunoprofiling-Kit14 showed lymphopenia and CD4/CD8 inversion. Naïve CD4+ and CD8+ T lymphocytes were decreased, while T-CD8+CD45RA-CCR7- and T-CD8+CD45RA+CCR7- effector memory populations were expanded. Effector and central memory CD4+ T-lymphocytes were also increased1 (Image 1). The exome revealed a heterozygous variant in the ITPR3 gene (carrier father), c.7571G>A, p.(Arg2524His); predictors classify it as having a potential eliminating effect. CONCLUSIONS: The clinical features and immunophenotype of this candidate variant differ from others related to intracellular calcium transport. They are functional studies necessary to validate their causality. A patient with a potentially deleted variant presents an immunophenotype with CD3 lymphopenia and persistent lymphocyte activation.


ANTECEDENTES: Las variantes en genes del transporte de calcio intracelular han sido asociadas a inmunodeficiencias sindrómicas con un fenotipo IDCG. REPORTE DE CASO: Niña de siete años, de padres no consanguíneos, en Cartagena-Colombia. A los dos meses de vida, presenta hematoquecia y se diagnostica con proctolitis alimentaria sin mejoría con restricción a leche, trigo y huevo, desarrollando desnutrición. A los ocho meses, una biopsia de colon muestra hiperplasia linfoide crónica, cursa con anemia, eosinofilia, pero IgE total y específica a alimentos normales. A los cuatro años, el Servicio de Inmunología la encuentra asintomática, recuperada nutricionalmente y sin sensibilización alérgica, pero persiste eosinofilia y calprotectina elevada, sugiriendo una enfermedad inflamatoria intestinal de inicio temprano. Las inmunoglobulinas fueron normales, poblaciones linfocitarias con linfopenia CD3, CD4 y CD8. A los seis años, presenta dermatitis atópica, sigue con calprotectina elevada y linfopénica. El inmunofenotipo por citometría espectral mediante Cytek®cFluor®Immunoprofiling-Kit14, mostró linfopenia e inversión CD4/CD8. Los linfocitos T-vírgenes CD4+ y CD8+ estaban disminuidos, en cambio las poblaciones de memoria efectora T-CD8+CD45RA-CCR7- y T-CD8+CD45RA+CCR7­ estaban expandidas. Los linfocitos T-CD4+ de memoria efectora y central, también estaban aumentados1 (Imagen 1). El exoma reveló una variante heterocigótica en el gen ITPR3 (padre portador), c.7571G>A, p.(Arg2524His); los predictores la clasifican como de potencial efecto deletéreo. CONCLUSIONES: La clínica y el inmunofenotipo de esta variante candidata difiere de otras relacionadas con el transporte del calcio intracelular. Son necesarios estudios funcionales para validar su causalidad. Una paciente con una variante potencialmente deletérea, presenta un inmunofenotipo con linfopenia CD3 y activación persistente de los linfocitos.


Assuntos
Imunofenotipagem , Receptores de Inositol 1,4,5-Trifosfato , Linfopenia , Humanos , Feminino , Criança , Linfopenia/genética , Linfopenia/etiologia , Receptores de Inositol 1,4,5-Trifosfato/genética , Mutação , Citometria de Fluxo , Células T de Memória/imunologia
14.
J Clin Immunol ; 44(4): 85, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578354

RESUMO

INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.


Assuntos
Candidíase Mucocutânea Crônica , Inibidores de Janus Quinases , Linfopenia , Nitrilas , Pirazóis , Pirimidinas , Trombocitopenia , Adulto , Humanos , Mutação com Ganho de Função , Inibidores de Janus Quinases/uso terapêutico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Mucocutânea Crônica/genética , Interferons , Fator de Transcrição STAT1/metabolismo
15.
J Clin Immunol ; 44(4): 93, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578360

RESUMO

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41% of whom were born preterm. After lymphocyte subsets were assessed via flow cytometry, samples of 18 infants (0.09‰) were sent for whole exome sequencing. Confirmed genetic defects were consistent with autosomal recessive agammaglobulinemia in 1/18, severe combined immunodeficiency - in 7/18, 22q11.2DS syndrome - in 4/18, combined immunodeficiency - in 1/18 and trisomy 21 syndrome - in 1/18. Two patients in whom no genetic defect was found met criteria of (severe) combined immunodeficiency with syndromic features. Three patients appeared to have transient lymphopenia. Our findings demonstrate the value of implementing combined TREC/KREC NBS screening and inform the development of policies and guidelines for its integration into routine newborn screening programs.


Assuntos
Linfopenia , Imunodeficiência Combinada Severa , Lactente , Recém-Nascido , Humanos , Triagem Neonatal/métodos , Projetos Piloto , Linfopenia/diagnóstico , Linfócitos T , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , DNA , Receptores de Antígenos de Linfócitos T/genética
16.
Sultan Qaboos Univ Med J ; 24(1): 44-51, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38434464

RESUMO

Objectives: Dimethyl fumarate (DMF) is known to cause lymphopenia when used to treat patients with multiple sclerosis (MS). However, research on DMF therapy in the Arab world, especially in Oman, is scarce. This study aimed to analyse the prevalence of lymphopenia among Omani patients with MS and their reasons for discontinuing DMF therapy. Methods: In this retrospective study, the medical records of Omani patients with MS who were treated using DMF at two tertiary hospitals in Muscat, Oman, from February 2017 to February 2023 were reviewed. Their demographic, clinical and laboratory data were retrieved and analysed. Absolute lymphocyte count values at baseline and at the last follow-up, as well as the reasons for discontinuing DMF therapy, were collected. Descriptive and inferential statistical techniques were used for data analysis. Binary-logistic regression analysis was used to identify the risk factors for DMF-induced lymphopenia. Results: A total of 64 Omani patients with MS were included in this study. The majority of the study participants (n = 40; 63%) were female. All included patients started DMF therapy at the mean age of 33 ± 7.7 years. After administration of DMF, 14 (21.9%) patients developed grades 1-3 of lymphopenia. The DMF therapy was discontinued for 23 (36.0%) patients, mainly in response to adverse events or confirmed pregnancy. Female gender was the only significant predictor of DMF-induced lymphopenia (P = 0.037). Conclusions: Most Omani patients with MS had mild lymphopenia (grades 1-2). Early adverse events and pregnancy were the main reasons provided for discontinuing DMF therapy.


Assuntos
Linfopenia , Esclerose Múltipla , Gravidez , Humanos , Feminino , Masculino , Adulto , Fumarato de Dimetilo/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Estudos Retrospectivos , Linfopenia/induzido quimicamente , Linfopenia/epidemiologia , Mundo Árabe
17.
Scand J Immunol ; 99(1): e13335, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38441205

RESUMO

Major histocompatibility complex class II (MHC-II) deficiency or bare lymphocyte syndrome (BLS) is a rare, early-onset, autosomal recessive, and life-threatening inborn error of immunity. We aimed to assess the demographic, clinical, laboratory, follow-up, and treatment characteristics of patients with MHC-II deficiency, together with their survival. We retrospectively investigated 21 patients with MHC-II deficiency. Female/male ratio was 1.63. The median age at diagnosis was 16.3 months (5 months-9.7 years). Nineteen patients (90.5%) had parental consanguinity. Pulmonary diseases (pneumonia, chronic lung disease) (81%), diarrhoea (47.6%), and candidiasis (28.6%) were common. Four (19%) had autoimmunity, two developed septic arthritis, and three (14%) developed bronchiectasis in the follow-up. Three patients (14%) had CMV viraemia, one with bilateral CMV retinitis. Eight (38.1%) had lymphocytopenia, and four (19%) had neutropenia. Serum IgM, IgA, and IgG levels were low in 18 (85.7%), 15 (71.4%), and 11 (52.4%) patients, respectively. CD4+ lymphocytopenia, a reversed CD4+/CD8+ ratio, and absent/low HLA-DR expressions were detected in 93.3%, 86.7%, and 100% of the patients, respectively. Haematopoietic stem cell transplantation (HSCT) was performed on nine patients, and four died of septicaemia and ARDS after HSCT. The present median age of patients survived is 14 years (1-31 years). Genetic analysis was performed in 10 patients. RFX5 homozygous gene defect was found in three patients (P1, P4 and P8), and RFXANK (P2 and P14) and RFXAP (P18 and P19) heterozygous gene defects were found in each two patients, respectively. This large cohort showed that BLS patients have severe combined immunodeficiency (SCID)-like clinical findings. Flow cytometric MHC-II expression study is crucial for the diagnosis, differential diagnosis with SCID, early haematopoietic stem cell transplantation (HSCT), and post-HSCT follow-up. Genetic studies are required first for matched family donor evaluation before HSCT and then for genetic counselling.


Assuntos
Infecções por Citomegalovirus , Linfopenia , Imunodeficiência Combinada Severa , Humanos , Feminino , Masculino , Adolescente , Turquia , Estudos Retrospectivos
18.
J Immunother Cancer ; 12(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38458635

RESUMO

BACKGROUND: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC. METHODS: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m2 and cisplatin 25 mg/m2) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes. RESULTS: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients. CONCLUSIONS: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined. TRIAL REGISTRATION NUMBER: NCT04437212.


Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Linfopenia , Trombocitopenia , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Terapia Neoadjuvante , Carcinoma de Células Escamosas/tratamento farmacológico , Resultado do Tratamento , Recidiva Local de Neoplasia , Paclitaxel , Antígenos HLA-DR , Células Epiteliais/patologia
19.
Radiother Oncol ; 195: 110230, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38503355

RESUMO

BACKGROUND AND PURPOSE: Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. MATERIALS AND METHODS: Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/µL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. RESULTS: Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996-0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25-6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002-1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954-10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. CONCLUSIONS: Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk.


Assuntos
Medula Óssea , Linfopenia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Linfopenia/etiologia , Estudos Prospectivos , Idoso , Medula Óssea/efeitos da radiação , Pessoa de Meia-Idade , Pelve/efeitos da radiação , Dosagem Radioterapêutica , Irradiação Linfática/efeitos adversos , Irradiação Linfática/métodos , Idoso de 80 Anos ou mais
20.
Int J Radiat Biol ; 100(5): 669-677, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38442137

RESUMO

PURPOSE: Lymphopenia is now generally recognized as a negative prognostic factor in radiotherapy. Already at the beginning of the century we demonstrated that high-energy carbon ions induce less damage to the lymphocytes of radiotherapy patients than X-rays, even if heavy ions are more effective per unit dose in the induction of chromosomal aberrations in blood cells irradiated ex-vivo. The explanation was based on the volume effect, i.e. the sparing of larger volumes of normal tissue in Bragg peak therapy. Here we will review the current knowledge about the difference in lymphopenia between particle and photon therapy and the consequences. CONCLUSIONS: There is nowadays an overwhelming evidence that particle therapy reduces significantly the radiotherapy-induced lymphopenia in several tumor sites. Because lymphopenia turns down the immune response to checkpoint inhibitors, it can be predicted that particle therapy may be the ideal partner for combined radiation and immunotherapy treatment and should be selected for patients where severe lymphopenia is expected after X-rays.


Assuntos
Linfopenia , Humanos , Linfopenia/etiologia , Neoplasias/radioterapia , Radioterapia com Íons Pesados/efeitos adversos , Linfócitos/efeitos da radiação
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