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Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.
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Imiquimode , Células Matadoras Naturais , Ativação Linfocitária , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Poli I-C/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Imiquimode/farmacologia , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Criança , Oligodesoxirribonucleotídeos/farmacologia , Citocinas/metabolismo , Feminino , Interferon gama/metabolismo , Masculino , Imidazóis/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Pré-Escolar , Agonistas do Receptor Semelhante a TollRESUMO
Background: More than two years after the pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) there is a great lack of information. The presence of immunoglobulin G (IgG) have been related with disease severity. Patients with comorbidities could develop more severe infection; however, the evaluation of the humoral response in pediatric population are needed especially in patients with comorbidities. Our aim was to describe the behavior of IgG in pediatric patients and to know if there is a difference between patients with comorbidities. Methods: A prospective comparative cohort study was carried out in a single center from June 2020 to January 2021, with a follow-up of 6 months. The study included all the subjects with confirmatory test for SARS-CoV-2 from 1 month to 17 years 11 months, the follow-up of the disease's evolution and measurement of IgG antibodies was collected. We obtained the clinical data, and comorbidities like arterial hypertension, diabetes, obesity, and cancer, the initial symptoms were recorded as well as the evolution regarding the severity of COVID-19 and the need for hospitalization, intensive care unit or mechanical ventilation. The follow up was carried out through medical consultation with an appointment every month that included direct interrogation, examination, and peripheral blood collection for the IgG quantification. The antibodies detection was done through peripheral blood and chemiluminescence microparticle immunoassay. Results: A total of 237 patients with positive polymerase chain reaction (PCR) for SARS-COV-2 were included, of which 147 presented IgG antibodies (62%), 112 (76%) without comorbidity and 35 (24%) with comorbidities, by the sixth month only 2.7% continue with positive antibody measurements. Patients with comorbidities reach higher IgG levels than patients without comorbidities the basal titters were: 5.17 for patients without comorbidities vs. 6.96 for the group with comorbidities (P<0.001). Conclusions: We found an association between the presence of comorbidities and high levels of IgG units in pediatric patients with COVID-19. Additionally, patients with more severe course of the disease have higher levels of IgG and by the third month less than 35% have immunity.
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Introduction: Multisystem inflammatory syndrome in children associated with coronavirus disease 2019 (MIS-C), a novel hyperinflammatory condition secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with severe outcomes such as coronary artery aneurysm and death. Methods: This multicenter, retrospective, observational cohort study including eight centers in Mexico, aimed to describe the clinical characteristics and outcomes of patients with MIS-C. Patient data were evaluated using latent class analysis (LCA) to categorize patients into three phenotypes: toxic shock syndrome-like (TSSL)-MIS-C, Kawasaki disease-like (KDL)-MIS-C, and nonspecific MIS-C (NS-MIS-C). Risk factors for adverse outcomes were estimated using multilevel mixed-effects logistic regression. Results: The study included 239 patients with MIS-C, including 61 (26%), 70 (29%), and 108 (45%) patients in the TSSL-MIS-C, KDL-MIS-C, and NS-MIS-C groups, respectively. Fifty-four percent of the patients were admitted to the intensive care unit, and 42%, 78%, and 41% received intravenous immunoglobulin, systemic glucocorticoids, and anticoagulants, respectively. Coronary artery dilatation and aneurysms were found in 5.7% and 13.2% of the patients in whom coronary artery diameter was measured, respectively. Any cause in-hospital mortality was 5.4%. Hospitalization after ten days of symptoms was associated with coronary artery abnormalities (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2-2.0). Age ≥10 years (OR: 5.6, 95% CI: 1.4-2.04), severe underlying condition (OR: 9.3, 95% CI: 2.8-31.0), platelet count <150,000â /mm3 (OR: 4.2, 95% CI: 1.2-14.7), international normalized ratio >1.2 (OR: 3.8, 95% CI: 1.05-13.9), and serum ferritin concentration >1,500 mg/dl at admission (OR: 52, 95% CI: 5.9-463) were risk factors for death. Discussion: Mortality in patients with MIS-C was higher than reported in other series, probably because of a high rate of cases with serious underlying diseases.
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Introduction: In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. Methods: This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. Results: The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. Conclusions: This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children.
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Hyperinflammation present in individuals with severe COVID-19 has been associated with an exacerbated cytokine production and hyperactivated immune cells. Endoplasmic reticulum stress leading to the unfolded protein response has been recently reported as an active player in inducing inflammatory responses. Once unfolded protein response is activated, GRP78, an endoplasmic reticulum-resident chaperone, is translocated to the cell surface (sGRP78), where it is considered a cell stress marker; however, its presence has not been evaluated in immune cells during disease. Here we assessed the presence of sGRP78 on different cell subsets in blood samples from severe or convalescent COVID-19 patients. The frequency of CD45+sGRP78+ cells was higher in patients with the disease compared to convalescent patients. The latter showed similar frequencies to healthy controls. In patients with COVID-19, the lymphoid compartment showed the highest presence of sGRP78+ cells versus the myeloid compartment. CCL2, TNF-α, C-reactive protein, and international normalized ratio measurements showed a positive correlation with the frequency of CD45+sGRP78+ cells. Finally, gene expression microarray data showed that activated T and B cells increased the expression of GRP78, and peripheral blood mononuclear cells from healthy donors acquired sGRP78 upon activation with ionomycin and PMA. Thus, our data highlight the association of sGRP78 on immune cells in patients with severe COVID-19.
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COVID-19 , Chaperona BiP do Retículo Endoplasmático , Humanos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Leucócitos Mononucleares/metabolismo , COVID-19/metabolismo , Chaperonas Moleculares/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo EndoplasmáticoRESUMO
Background: Pediatric inflammatory multisystem syndrome (PIMS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that resembles Kawasaki syndrome and places them at high risk of cardiorespiratory instability and/or cardiac damage. This study aims to describe the clinical presentation and outcomes of patients with PIMS in Mexico City. Methods: This was an observational study of children hospitalized for PIMS based on the Centers for Disease Control and Prevention case definition criteria, in a single tertiary care pediatric center in Mexico City between May 1, 2020, and September 30, 2021. Demographic characteristics, epidemiological data, medical history, laboratory tests, cardiologic evaluations, treatment, and clinical outcomes were analyzed. Results: Seventy-five cases fulfilled the case definition criteria for PIMS [median age: 10.9 years, Interquartile range (IQR): 5.6-15.6]. Fifteen (20%) patients had a severe underlying disease, 48 (64%) were admitted to the intensive care unit, 33 (44%) required invasive mechanical ventilation and 39 (52%) received vasopressor support. The patients were clustered through latent class analysis based on identified symptoms: Cluster 1 had rash or gastrointestinal symptoms (n = 60) and cluster 2 were those with predominantly respiratory manifestations (n = 15). Two patients (2.7%) died, and both had severe underlying conditions. Five patients (6.7%), all from cluster 1, developed coronary aneurysms. Conclusion: There were a high proportion of patients with severe respiratory involvement and positive RT-PCR SARS-CoV-2 and very few cases of coronary aneurysms in our study which suggests that a high proportion of the children had severe acute COVID-19. The clinical manifestations and outcomes are comparable to previously reported international studies.
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The pandemic caused by SARS CoV-2 (COVID-19) has affected millions of people since 2020. There are clinical differences and in mortality between the adult and paediatric population. Recently, the immune response through the development of antibodies has gained relevance due to the risk of reinfection and vaccines' development. Objective: Was to compare the association of clinical history and the clinical presentation of the disease with the development of IgG antibodies against SARS-CoV-2 in paediatric and adult patients with a history of positive reverse transcriptase-polymerase chain reaction (RT-PCR) results. Methods: Cross-sectional observational study carried out in a Paediatric Hospital in Mexico City included patients under 18 years of age and health personnel with positive RT-PCR for COVID-19 comparing antibody expression. The development of specific IgG antibodies was measured, the presence of comorbidities, duration, and severity of symptoms was determined. Results: Sixty-one subjects (20 < 18 years and 41 > 18 years) were analysed. The median sample collection was 3 weeks. There were no differences in the expression of specific antibodies; no differences were shown according to the symptoms' severity. A positive correlation (r = 0.77) was demonstrated between the duration of symptoms and antibody levels. Conclusions: In conclusion, there is a clear association between the duration of the symptoms associated with SARS-CoV-2 infection and the IgG units generated in paediatric and adult patients convalescing from COVID-19.
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Introduction: Respiratory viruses are among the leading causes of disease and death among children. Co-circulation of influenza and SARS-CoV2 can lead to diagnostic and management difficulties given the similarities in the clinical picture. Methods: This is a cohort of all children hospitalized with SARS-CoV2 infection from March to September 3rd 2020, and all children admitted with influenza throughout five flu-seasons (2013-2018) at a pediatric referral hospital. Patients with influenza were identified from the clinical laboratory database. All hospitalized patients with confirmed SARS-CoV2 infection were followed-up prospectively. Results: A total of 295 patients with influenza and 133 with SARS-CoV2 infection were included. The median age was 3.7 years for influenza and 5.3 years for SARS-CoV2. Comorbidities were frequent in both groups, but they were more common in patients with influenza (96.6 vs. 82.7%, p < 0.001). Fever and cough were the most common clinical manifestations in both groups. Rhinorrhea was present in more than half of children with influenza but was infrequent in those with COVID-19 (53.6 vs. 5.8%, p < 0.001). Overall, 6.4% percent of patients with influenza and 7.5% percent of patients with SARS-CoV2 infection died. In-hospital mortality and the need for mechanical ventilation among symptomatic patients were similar between groups in the multivariate analysis. Conclusions: Influenza and COVID-19 have a similar picture in pediatric patients, which makes diagnostic testing necessary for adequate diagnosis and management. Even though most cases of COVID-19 in children are asymptomatic or mild, the risk of death among hospitalized patients with comorbidities may be substantial, especially among infants.
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Overview of the pandemic In December 2019, a new virus named SARS-CoV-2 was reported in Wuhan province, China. The first case of COVID-19 in Mexico was confirmed on February 28, 2020, and the World Health Organization declared the pandemic on March 11.