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BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.
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Mutación de Línea Germinal , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Niño , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Femenino , Masculino , Reparación de la Incompatibilidad de ADN/genética , Preescolar , Adolescente , AlelosRESUMEN
The EPICO (Spanish general registry of COVID-19 in children)-SEHOP (Spanish Society of Pediatric Hematology and Oncology) platform gathers data from children with SARS-CoV-2 in Spain, allowing comparison between children with cancer or allogeneic hematopoietic stem cell transplantation (alloHSCT) and those without. The infection is milder in the cancer/alloHSCT group than in children without comorbidities (7.1% vs. 14.7%), except in children with recent alloHSCT (less than 300 days), of which 35.7% experienced severe COVID-19. These data have been shared with the SEHOP members to support treatment and isolation policies akin to those for children without cancer, except for those with recent alloHSCT or additional comorbidities. This highlights the collaborative registries potential in managing pandemic emergencies.
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COVID-19 , Comorbilidad , Trasplante de Células Madre Hematopoyéticas , Neoplasias , SARS-CoV-2 , Humanos , COVID-19/epidemiología , COVID-19/complicaciones , Niño , Masculino , Adolescente , Femenino , Preescolar , Factores de Riesgo , Neoplasias/epidemiología , Neoplasias/terapia , Lactante , España/epidemiología , Sistema de Registros , Trasplante HomólogoRESUMEN
INTRODUCTION: High-dose methotrexate (HDMTX) is administered for the treatment of some cancers. HDMTX is usually safe but may crystallize in renal tubules causing acute kidney injury (AKI). Consequently, MTX elimination is delayed, resulting in a severe and life-threatening condition. No studies have been published about the impact of MTX toxicity in Spain. This study aims to estimate the incidence and management of MTX delayed elimination and toxicity. METHODS: A two-round Delphi study was performed to reach consensus between 10 medical experts on haemato-oncology and paediatric oncology with experience in the management of HDMTX treated patients from leading Spanish hospitals. An online questionnaire was developed based on national and international guidelines and previous evidence regarding HDMTX-related toxicity. Consensus was established at 80% agreement. Median and interquartile ranges were calculated, and incidence data were extrapolated to the Spanish general population. RESULTS: Out of 1.475 patients estimated to receive HDMTX treatment annually in Spain, 27.5% present MTX delayed elimination and 11.6% develop HDMTX-induced AKI (35.4% with severe systemic toxicities (>grade 3) and 18.8% develop chronic renal disease). Mortality is estimated in 4.2%. Immuno-enzymatic assay is used in most of the hospitals (90%) for MTX serum level monitoring. All experts use increased supportive care and high leucovorin as first-line treatment. Available treatments in experts' hospitals in case toxicity persists are haemodialysis (90% of hospitals), glucarpidase (60%) and hemofiltration (50%). Most prevalent non-renal systemic toxicities are haematologic and mucositis (21-40% of patients). Patients with HDMTX-induced AKI require from intensive care (5% of patients), more than 3 sessions and 4 days of dialysis, and about 8.5 days of hospitalization (non-ICU patients) and 12 days in case of patients requiring ICU. CONCLUSIONS: These results are the first evidence regarding HDMTX-induced AKI in Spain. Incidence and mortality results are in line with previous studies. Clinical management is based on preventive measures and the treatment depend on the availability in the hospital. The need for effective, safe and rapid treatment for the reduction of MTX toxic levels and the improvement of monitoring methods were noted by experts as urgent needs. Further observational studies to validate these results would be needed.
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Lesión Renal Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias , Niño , Humanos , Metotrexato/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , Técnica Delphi , Incidencia , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Neoplasias/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológicoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azitromicina/uso terapéutico , Criptosporidiosis/tratamiento farmacológico , Cryptosporidium/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Paromomicina/uso terapéutico , Antibacterianos/uso terapéutico , Antiprotozoarios/uso terapéutico , Niño , Criptosporidiosis/etiología , Criptosporidiosis/parasitología , Cryptosporidium/aislamiento & purificación , Manejo de la Enfermedad , Humanos , Leucemia Mieloide Aguda/patología , Masculino , PronósticoAsunto(s)
Betacoronavirus , Infecciones por Coronavirus , Neoplasias , Pandemias , Neumonía Viral , Adolescente , COVID-19 , Niño , Humanos , Neumonía Viral/epidemiología , SARS-CoV-2Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Linfoma Folicular/diagnóstico , Niño , Diagnóstico Diferencial , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Linfoma Folicular/sangre , Linfoma Folicular/patología , Linfoma Folicular/terapia , MasculinoRESUMEN
PURPOSE: This retrospective study evaluated the effectiveness and tolerability in clinical practice of an L-proline-stabilized 10 % intravenous immunoglobulin (IVIG; Privigen®) in patients with primary (PID) or secondary immunodeficiency (SID). METHODS: Patients from 6 centers in Europe and the US were treated with individually determined regimens of Privigen® for ≥3 months. Serum immunoglobulin G (IgG) trough levels, annualized rates of infection, hospitalization and antibiotics use, and the incidence of adverse events (AEs) were analyzed. RESULTS: Of 72 patients, three infants with severe combined immunodeficiency (SCID) were analyzed separately. The remaining 69 patients (52.2 % male; median age 38 years [range: 0.1-90.0]) with PID (82.6 %) or SID (17.4 %) received a mean (±standard deviation) Privigen® dose of 532 ± 250 mg/kg/month resulting in trough serum IgG levels of 407-1,581 mg/dL (median: 954 mg/dL). Ten patients (14.5 %) experienced 11 serious bacterial infections over 22.0 ± 15.0 months of treatment (0.087 events/patient/year, upper one-sided 99 % confidence interval: 0.170), the most common being pneumonia (11.6 %). The rates for any infection and hospitalization were 1.082 events/patient/year and 3.63 days/patient/year, respectively. Two patients with severe disease accounted for 303 of 460 hospital days. Across all 72 patients, 13 (18.1 %) patients experienced AEs, including 10 (13.9 %) patients with AEs at least possibly related to Privigen®, including headache (8.3 %), fever, and chills (2.8 % each). No related serious AEs were reported. One infant with SCID died due to severe viral infection. CONCLUSIONS: Despite the heterogeneous population, effectiveness and tolerability of Privigen® in clinical practice closely matched those reported in clinical studies.
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Antibacterianos/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Síndromes de Inmunodeficiencia/terapia , Infecciones/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Europa (Continente) , Femenino , Cefalea/etiología , Hospitalización , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Inmunoglobulinas Intravenosas/química , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Lactante , Infecciones/etiología , Infecciones/inmunología , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Prolina/química , Estabilidad Proteica , Estudios Retrospectivos , Estados Unidos , Adulto JovenRESUMEN
Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for â¼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.
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Autoanticuerpos , Gripe Humana , Interferón Tipo I , Neumonía , COVID-19/complicaciones , COVID-19/inmunología , Humanos , Gripe Humana/complicaciones , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Neumonía/complicaciones , Neumonía/inmunología , Vacuna contra la Fiebre Amarilla/efectos adversosAsunto(s)
Ligando de CD40/genética , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Leishmaniasis Visceral/etiología , Mutación , Linfocitos T/inmunología , Preescolar , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM/inmunología , Inmunoglobulina M , Leishmaniasis Visceral/diagnóstico , MasculinoRESUMEN
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
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Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/inmunología , Síndrome Linfoproliferativo Autoinmune/terapia , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/terapia , Diagnóstico Precoz , HumanosAsunto(s)
Bacteriemia/complicaciones , Leucemia Promielocítica Aguda/etiología , Piomiositis/complicaciones , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/aislamiento & purificación , Adolescente , Bacteriemia/diagnóstico , Bacteriemia/microbiología , Terapia Combinada , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/terapia , Imagen por Resonancia Magnética , Piomiositis/diagnóstico , Piomiositis/microbiología , Cintigrafía , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/microbiologíaRESUMEN
INTRODUCTION: Infections are significant cause of morbidity and mortality in cancer patients (mortality is estimated at around 3%). Febrile neutropenia often leads to the hospitalisation of cancer patients, increasing the risk of nosocomial infection, as well as health costs due to the hospital admission. METHODS: An ambispective (01 July 2015 - 12 July 2018) observational study was conducted on all episodes of chemotherapy-induced febrile neutropenia in a paediatric population. A record was made of age, gender, weight percentile (WHO), length of hospital stay (days), temperature (oC), microbial isolation, infectious source, antibiotic or antifungal prophylaxis, haemoglobin (g/dl), platelets (/mm3), neutrophils (/mm3), lymphocytes (/mm3), monocytes (/mm3), CRP (mg/L) and procalcitonin (PCT) (ng/ml) on admission, and days with neutropenia<500/mm3. Statistical analysis was performed using the SPSSv.23 program. RESULTS: The study included 69 patients, and 101 episodes were recorded. The mean stay was 7.43 days (median 6 days). Microbial isolation was found in 44.6% of the episodes, with no infectious source identified in 36% of them. An inverse correlation was found between haemoglobin, platelets, and lymphocytes on admission and the hospital stay (-0.356: P=.001, -0.216: P=.042, and -0.216: P=.042, respectively). The mean stay was greater if there was a CRP>90mg/L (10.94 vs. 6.66 days, P=.017), if PCT>1ng/ml (16.50 vs. 6.77 days, P=.0002), if ≤ 100 neutrophils (8.27 vs. 5.04 days P=.039) on admission, and if there was microbe isolation (9.54 vs. 5.78 days P=.006). CONCLUSION: The relationship between haemoglobin, platelets, and lymphocytes on admission and the mean stay is inversely proportional. In addition, those patients with ≤100 neutrophils, CRP>90mg/L, and PCT>1ng/ml on admission had a longer hospital stay.
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Antineoplásicos/efectos adversos , Neutropenia Febril/inducido químicamente , Tiempo de Internación , Antineoplásicos/uso terapéutico , Niño , Neutropenia Febril/epidemiología , Neutropenia Febril/terapia , Femenino , Humanos , Infecciones/epidemiología , Infecciones/microbiología , Masculino , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Since December 2019, severe acute respiratory syndrome coronavirus 2 infection has spread worldwide. We all are concerned about immunocompromised children, especially hematologic and oncologic pediatric patients. We want to share our experience with 2 pediatric cancer patients with severe acute respiratory syndrome coronavirus 2 infection. Both presented mild disease and good outcome. No respiratory symptoms were identified, but both developed diarrhea, one probably secondary to lopinavir/ritonavir. Pediatric cancer patients may have milder disease than adults, but larger studies are needed to make conclusions.
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Infecciones por Coronavirus/diagnóstico , Neoplasias Renales/virología , Neumonía Viral/diagnóstico , Sarcoma de Ewing/virología , Tumor de Wilms/virología , Adolescente , Betacoronavirus/aislamiento & purificación , COVID-19 , Niño , Preescolar , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Diarrea/etiología , Diarrea/virología , Femenino , Humanos , Neoplasias Renales/epidemiología , Lopinavir/uso terapéutico , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Ritonavir/uso terapéutico , SARS-CoV-2 , Sarcoma de Ewing/epidemiología , España/epidemiología , Tumor de Wilms/epidemiologíaRESUMEN
INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
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Antineoplásicos/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Neoplasias/tratamiento farmacológico , Neumonía Viral/complicaciones , Adolescente , COVID-19 , Niño , Infecciones por Coronavirus/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/complicaciones , Pandemias , Neumonía Viral/tratamiento farmacológico , SARS-CoV-2 , Encuestas y Cuestionarios , Tratamiento Farmacológico de COVID-19RESUMEN
Background: NF-κB1 is a master regulator of both acquired and innate responses. NFKB1 loss-of-function mutations elicit a wide clinical phenotype with asymptomatic individuals at one end of the spectrum and patients with common variable immunodeficiency, combined immunodeficiency or autoinflammation at the other. Impairment of acquired and innate immunity and disseminated Mycobacterium genavense infection expands the clinical and immunological phenotype of NF-κB1 deficiency. Objective: Functional and molecular characterization of a patient with a novel phenotype of NF-κB1 deficiency. Methods: Circulating T, B, dendritic cell subsets and innate or unconventional T-cells were quantified. The cytokine production in stimulated whole blood samples was assessed and molecular characterization by next generation sequencing and gene expression assays were also performed. Results: We report a patient presenting with features of combined immunodeficiency (CID) and disseminated Mycobacterium genavense infection. Sequencing of genomic DNA identified a novel synonymous mutation (c.705G > A) in NFKB1 gene which resulted in exon 8 skipping and haploinsufficiency of the NF-κB1 subunit p50. The susceptibility to atypical mycobacterial infection has not been previously reported and may be the result of a dendritic cell deficiency. A selective deficiency of circulating follicular helper T (cTFH) cells responsible for mediating the differentiation of naive B cells into memory and plasma cells was also present in the patient. It could affect the maturation of innate or unconventional T cells where NF-κB1 could also be involved. Conclusion: These findings showed that the role of NF-κB1 in humans could be critical for the development of acquired and innate immunity and further highlights the role of human T cells in anti-mycobacterial immunity.
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Inmunidad Adaptativa , Inmunidad Innata , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/etiología , Mycobacterium/inmunología , Subunidad p50 de NF-kappa B/deficiencia , Biopsia , Médula Ósea/metabolismo , Niño , Citocinas/metabolismo , Humanos , Inmunofenotipificación , Masculino , Mutación , Linaje , Fenotipo , Piel/patologíaRESUMEN
Cernunnos/XLF deficiency is a rare primary immunodeficiency classified within the DNA repair defects. Patients present with severe growth retardation, microcephaly, lymphopenia and increased cellular sensitivity to ionizing radiation. Here, we describe two unrelated cases with the same non-sense mutation in the NHEJ1 gene showing significant differences in clinical presentation and immunological profile but a similar DNA repair defect.
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Enzimas Reparadoras del ADN/deficiencia , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Fenotipo , Enfermedades Raras/genética , Inmunodeficiencia Combinada Grave/genética , Anticuerpos/sangre , Linfocitos B , Niño , Codón sin Sentido , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/genética , Fibroblastos/efectos de la radiación , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Linfopenia/diagnóstico , Microcefalia/diagnóstico , Linaje , Tolerancia a Radiación , Enfermedades Raras/diagnóstico , Enfermedades Raras/patología , Enfermedades Raras/terapia , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/patología , Inmunodeficiencia Combinada Grave/terapia , Linfocitos T , Resultado del TratamientoRESUMEN
Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSα, MutLα, and MutSß (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks. A varying degree of antibody formation defect, from IgA or selective IgG subclass deficiency to common variable immunodeficiency and hyper-IgM syndrome, has been detected in a small number of patients with constitutional mismatch repair deficiency (CMMRD) due to biallelic loss-of-function mutations in one of the MMR genes (PMS2, MSH6, MLH1, or MSH2). To elucidate the clinical relevance of a presumed primary immunodeficiency (PID) in CMMRD, we systematically collected clinical history and laboratory data of a cohort of 15 consecutive, unrelated patients (10 not previously reported) with homozygous/compound heterozygous mutations in PMS2 (n = 8), MSH6 (n = 5), and MLH1 (n = 2), most of whom manifested with typical malignancies during childhood. Detailed descriptions of their genotypes, phenotypes, and family histories are provided. Importantly, none of the patients showed any clinical warning signs of PID (infections, immune dysregulation, inflammation, failure to thrive, etc.). Furthermore, we could not detect uniform or specific patterns of laboratory abnormalities. The concentration of IgM was increased in 3 out of 12, reduced in 3 out of 12, and normal in 6 out of 12 patients, while concentrations of IgG and IgG subclasses, except IgG4, and of IgA, and specific antibody formation were normal in most. Class-switched B memory cells were reduced in 5 out of 12 patients, and in 9 out of 12 also the CD38hiIgM- plasmablasts were reduced. Furthermore, results of next generation sequencing-based analyses of antigen-selected B-cell receptor rearrangements showed a significantly reduced frequency of SHM and an increased number of rearranged immunoglobulin heavy chain (IGH) transcripts that use IGHG3, IGHG1, and IGHA1 subclasses. T cell subsets and receptor repertoires were unaffected. Together, neither clinical nor routine immunological laboratory parameters were consistently suggestive of PID in these CMMRD patients, but previously shown abnormalities in SHM and rearranged heavy chain transcripts were confirmed.
RESUMEN
INTRODUCCIÓN: Las infecciones son una causa importante de morbimortalidad en los pacientes con cáncer (mortalidad estimada en 3%). La neutropenia febril conlleva con frecuencia el ingreso hospitalario de los pacientes oncológicos, incrementando el riesgo de infección nosocomial así como los costes sanitarios por ingresos. MÉTODOS: Estudio observacional ambispectivo (01/07/2015 - 31/12/2018) de los episodios de neutropenia febril posquimioterapia en población pediátrica. Se recogieron edad, sexo, percentil de peso (OMS), estancia hospitalaria (días), temperature (oC), aislamiento de germen, foco infeccioso, profilaxis o no antibiótica y antifúngica, cifras de hemoglobina (g/dl), plaquetas (/mm3), neutrófilos (/mm3), linfocitos (/mm3), monocitos (/mm3), proteína C reactiva (PCR) (mg/L) y procalcitonina (PCT) (ng/ml) al ingreso y días con neutropenia < 500/mm3. El análisis estadístico se realizó con el programa SPSSv.23. RESULTADOS: De 69 pacientes, se registraron 101 episodios. La estancia media fue de 7,43 días (mediana 6 días). Se aisló germen en un 44,6% de los episodios, no identificándose foco infeccioso en un 36% de los mismos. Se halló correlación inversa entre hemoglobina, plaquetas y linfocitos al ingreso con la estancia hospitalaria (-0,356 (p 0,001); -0,216 (p 0,042) y -0,216 (p 0,042) respectivamente). La estancia media fue mayor si al ingreso presentaron PCR > 90 mg/L (10,94 vs. 6,66 días p 0,017), si PCT > 1 ng/ml (16,50 vs. 6,77 días p 0,0002), si ≤ 100 neutrófilos (8,27 vs. 5,04 días p 0,039) y si hubo aislamiento microbiológico (9,54 vs. 5,78 días p 0,006). CONCLUSIÓN: La relación entre hemoglobina, plaquetas y linfocitos al ingreso con la estancia media es inversamente proporcional. Además, aquellos pacientes con ≤ 100 neutrófilos al ingreso, PCR > 90 mg/L y PCT > 1 ng/ml presentaron mayor estancia media. Estos factores podrían ser importantes en el manejo de la neutropenia febril en el paciente con cáncer infantil
INTRODUCTION: Infections are significant cause of morbidity and mortality in cancer patients (mortality is estimated at around 3%). Febrile neutropenia often leads to the hospitalisation of cancer patients, increasing the risk of nosocomial infection, as well as health costs due to the hospital admission. METHODS: An ambispective (01 July 2015 - 12 July 2018) observational study was conducted on all episodes of chemotherapy-induced febrile neutropenia in a paediatric population. A record was made of age, gender, weight percentile (WHO), length of hospital stay (days), temperature (oC), microbial isolation, infectious source, antibiotic or antifungal prophylaxis, haemoglobin (g/dl), platelets (/mm3), neutrophils (/mm3), lymphocytes (/mm3), monocytes (/mm3), CRP (mg/L) and procalcitonin (PCT) (ng/ml) on admission, and days with neutropenia < 500/mm3. Statistical analysis was performed using the SPSSv.23 program. RESULTS: The study included 69 patients, and 101 episodes were recorded. The mean stay was 7.43 days (median 6 days). Microbial isolation was found in 44.6% of the episodes, with no infectious source identified in 36% of them. An inverse correlation was found between haemoglobin, platelets, and lymphocytes on admission and the hospital stay (-0.356: P = .001, -0.216: P = .042, and -0.216: P = .042, respectively). The mean stay was greater if there was a CRP > 90 mg/L (10.94 vs. 6.66 days, P=.017), if PCT > 1 ng/ml (16.50 vs. 6.77 days, P = .0002), if ≤ 100 neutrophils (8.27 vs. 5.04 days P=.039) on admission, and if there was microbe isolation (9.54 vs. 5.78 days P = .006). CONCLUSION: The relationship between haemoglobin, platelets, and lymphocytes on admission and the mean stay is inversely proportional. In addition, those patients with ≤ 100 neutrophils, CRP > 90 mg/L, and PCT>1ng/ml on admission had a longer hospital stay
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Humanos , Masculino , Femenino , Niño , Antineoplásicos/efectos adversos , Neutropenia Febril/inducido químicamente , Tiempo de Internación , Antineoplásicos/uso terapéutico , Neutropenia Febril/epidemiología , Neutropenia Febril/terapia , Infecciones/epidemiología , Infecciones/microbiología , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Severe combined immunodeficiency can cause severe, life-threatening viral, bacterial and fungal infections at an early age. We report a case of a 4-month-old boy with co-infection by respiratory syncytial virus and Pneumocystis jiroveci infection that led to recognition of severe combined immunodeficiency.
Asunto(s)
Coinfección/diagnóstico , Neumonía por Pneumocystis/complicaciones , Neumonía por Pneumocystis/diagnóstico , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/diagnóstico , Coinfección/patología , Humanos , Lactante , Pulmón/patología , Masculino , Radiografía TorácicaRESUMEN
Acquired hemophagocytic lymphohistiocitosis (HLH) syndrome can be a complication of visceral leishmaniasis (VL). A multicenter prospective study was conducted to determine the frequency of HLH syndrome in children with VL. Twenty-four children with VL were identified, and 10 (41%) developed HLH syndrome. VL should be ruled out in all children with HLH criteria living in or coming from endemic areas.