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1.
Blood ; 143(10): 872-881, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-37992218

RESUMEN

ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfohistiocitosis Hemofagocítica , Trastornos Linfoproliferativos , Recién Nacido , Humanos , Etopósido/uso terapéutico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/diagnóstico , Resultado del Tratamiento , Trasplante de Células Madre Hematopoyéticas/métodos , Trastornos Linfoproliferativos/etiología
2.
Artículo en Inglés | MEDLINE | ID: mdl-39147326

RESUMEN

BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1. OBJECTIVE: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

3.
J Clin Immunol ; 44(1): 39, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-38165471

RESUMEN

Newborn screening (NBS) for severe combined immunodeficiency (SCID) has been introduced in various countries with the aim of reducing morbidity and mortality. However, studies analyzing outcomes before and after the implementation of NBS programs remain limited. This study sought to compare the outcomes of SCID patients identified through Switzerland's national SCID NBS program, introduced in January 2019, with those of a historical cohort diagnosed between 2007 and 2019. The study included seven patients (32%) identified through NBS, and 15 (68%) born before NBS implementation and diagnosed based on clinical signs. Children in the NBS group were younger at diagnosis (median age 9 days vs 9 months, P = .002) and at hematopoietic stem cell transplantation (HSCT, median age 5 months vs 11 months, P = .003) compared to the clinical group. The NBS group had a lower incidence of infections before HSCT (29% vs 93%, P = .004). Although not statistically significant, the overall survival rate on last follow-up was higher in the NBS group (86% vs 67%, P = .62). Importantly, patients with active infections undergoing HSCT had a significantly lower overall survival probability compared to those without (P = .01). In conclusion, the introduction of NBS in Switzerland has led to earlier and often asymptomatic diagnosis of affected children, enabling timely intervention, infection prevention, and prompt treatment. These factors have contributed to higher survival rates in the NBS group. These findings underscore the critical importance of NBS for SCID, offering potential life-saving benefits through early detection and intervention.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Niño , Recién Nacido , Humanos , Lactante , Suiza/epidemiología , Tamizaje Neonatal , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/terapia , Morbilidad
4.
J Allergy Clin Immunol ; 151(4): 1081-1095, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36228738

RESUMEN

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.


Asunto(s)
Enfermedades del Sistema Inmune , Síndromes de Inmunodeficiencia , Niño , Humanos , Autoinmunidad/genética , Estudios de Cohortes , Mutación con Ganancia de Función , Síndromes de Inmunodeficiencia/genética , Mutación , Factor de Transcripción STAT3/genética , Proliferación Celular , Linfocitos
5.
J Allergy Clin Immunol ; 149(2): 736-746, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34111452

RESUMEN

BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.


Asunto(s)
Antígeno CTLA-4/genética , Mutación de Línea Germinal , Síndromes de Inmunodeficiencia/terapia , Adolescente , Adulto , Agammaglobulinemia/etiología , Anciano , Enfermedades Autoinmunes/etiología , Antígeno CTLA-4/deficiencia , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Lactante , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Adulto Joven
6.
Eur J Immunol ; 50(10): 1432-1446, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32845010

RESUMEN

This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4-, and LRBA-deficiency).


Asunto(s)
Inmunoglobulinas/uso terapéutico , Enfermedades de Inmunodeficiencia Primaria/terapia , Austria , Autoinmunidad , Consenso , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Medicina Basada en la Evidencia , Alemania , Humanos , Comunicación Interdisciplinaria , Guías de Práctica Clínica como Asunto , Enfermedades de Inmunodeficiencia Primaria/inmunología , Suiza
7.
Rev Med Suisse ; 17(726): 334-337, 2021 Feb 17.
Artículo en Francés | MEDLINE | ID: mdl-33599408

RESUMEN

Children appeared to be initially spared by the SARS-CoV-2 pandemic, however, in spring 2020, a new clinical entity was described related to the SARS-CoV-2 infection and named multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS). The gravity of this inflammatory syndrome, the time interval between infection and MIS-C, the response to the various immunomodulatory treatments are all suggestive of an immunologic reaction rather than a virus-mediatred phenomenon. The pathophysiological mechanisms and possible risk factors for MIS-C have not been elucidated. In this article, we summarize what is known to date about the immune response to SARS-CoV-2 in children and about the immune response to SARS-CoV-2 in children and about the MIS-C.


Alors que les enfants semblaient épargnés par la pandémie due au SARS-CoV-2, une nouvelle entité clinique a été décrite au printemps 2020 en lien avec cette infection et appelée syndrome inflammatoire multisystémique de l'enfant (MIS-C ou PIMS en anglais). La gravité du syndrome inflammatoire, le délai entre l'infection et le MIS-C, et la réponse aux différents traitements immunomodulateurs sont tous suggestifs d'une réaction immunologique plutôt que d'un phénomène uniquement médié par le virus. Les mécanismes physiopathologiques et les facteurs de risque possibles du MIS-C n'ont pas encore été élucidés. Dans cet article, nous résumons ce qui est connu à ce jour sur la réponse immune au SARS-CoV-2 chez l'enfant et sur le MIS-C.


Asunto(s)
COVID-19 , Niño , Predisposición Genética a la Enfermedad , Humanos , Inmunidad , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica
8.
Clin Immunol ; 210: 108316, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31770611

RESUMEN

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.


Asunto(s)
Mutación con Ganancia de Función/genética , Linfocitos/inmunología , Factor de Transcripción STAT3/genética , Autoinmunidad/genética , Proliferación Celular , Femenino , Humanos , Masculino , Familia de Multigenes , Penetrancia , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética
9.
J Allergy Clin Immunol ; 143(1): 292-304.e8, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29775636

RESUMEN

BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS: Ttc7-mutated (Ttc7fsn/fsn) mice were crossed to generate double-mutant (Rag2-/-Ttc7fsn/fsn) and triple-mutant (Rag2-/-IL2rg-/-Ttc7fsn/fsn) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7fsn/fsn mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7fsn/fsn fibroblasts. RESULTS: We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3γ (Reg3γ). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION: Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.


Asunto(s)
Proliferación Celular , Dermatitis/inmunología , Células Epiteliales/inmunología , Fibroblastos/inmunología , Enfermedades Genéticas Congénitas/inmunología , Linfocitos/inmunología , Mutación , Proteínas/inmunología , Animales , Células 3T3 BALB , Dermatitis/genética , Dermatitis/patología , Células Epiteliales/patología , Fibroblastos/patología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Humanos , Linfocitos/patología , Ratones , Ratones Noqueados , Proteínas/genética
10.
Blood ; 130(12): 1456-1467, 2017 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-28679735

RESUMEN

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Quinasa I-kappa B/genética , Mutación/genética , Preescolar , Estudios de Cohortes , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Heterocigoto , Humanos , Lactante , Recién Nacido , Inflamación/patología , Enfermedades Inflamatorias del Intestino/etiología , FN-kappa B/metabolismo , Fenotipo , Transducción de Señal/genética , Análisis de Supervivencia , Donantes de Tejidos , Acondicionamiento Pretrasplante , Resultado del Tratamiento
12.
J Allergy Clin Immunol ; 142(6): 1932-1946, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29729943

RESUMEN

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.


Asunto(s)
Antígeno CTLA-4/genética , Síndromes de Inmunodeficiencia/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Síndromes de Inmunodeficiencia/diagnóstico por imagen , Síndromes de Inmunodeficiencia/terapia , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Adulto Joven
14.
Ann Hematol ; 97(10): 1961-1973, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29947977

RESUMEN

Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.


Asunto(s)
Factor de Transcripción GATA2/deficiencia , Trasplante de Células Madre Hematopoyéticas , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Síndromes de Inmunodeficiencia/terapia , Infecciones por Mycobacterium no Tuberculosas/etiología , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/patología , Mycobacterium abscessus/aislamiento & purificación , Síndromes Mielodisplásicos/etiología , Trasplante de Células Madre de Sangre Periférica , Embolia Pulmonar/etiología , Úlcera Cutánea/etiología , Verrugas/etiología , Adulto Joven
15.
BMC Infect Dis ; 18(1): 33, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29325543

RESUMEN

BACKGROUND: We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case. CASE PRESENTATION: The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted. CONCLUSION: This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation.


Asunto(s)
Infecciones por Adenoviridae/virología , Infecciones por Coxsackievirus/virología , Síndromes de Inmunodeficiencia/complicaciones , Metagenómica/métodos , Infecciones por Reoviridae/virología , Infecciones por Adenoviridae/etiología , Niño , Coinfección , Infecciones por Coxsackievirus/etiología , Diarrea/virología , Enterovirus/genética , Enterovirus/patogenicidad , Infecciones por Enterovirus/virología , Femenino , Humanos , Síndromes de Inmunodeficiencia/virología , Orthoreovirus de los Mamíferos/genética , Orthoreovirus de los Mamíferos/patogenicidad , Infecciones por Reoviridae/etiología
17.
Ann Rheum Dis ; 75(3): 481-9, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26865703

RESUMEN

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.


Asunto(s)
Artritis Juvenil/complicaciones , Síndrome de Activación Macrofágica/clasificación , Niño , Técnica Delphi , Europa (Continente) , Humanos , Modelos Logísticos , Síndrome de Activación Macrofágica/complicaciones , Síndrome de Activación Macrofágica/diagnóstico , Reproducibilidad de los Resultados , Reumatología , Sociedades Médicas , Estados Unidos
19.
Blood ; 121(4): 595-603, 2013 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-23160464

RESUMEN

Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11-deficient (Stx11(-/-)) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11(-/-) murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal-truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11-deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.


Asunto(s)
Citotoxicidad Inmunológica/genética , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Qa-SNARE/genética , Proteínas de Unión al GTP rab/genética , Animales , Degranulación de la Célula , Modelos Animales de Enfermedad , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Virus de la Coriomeningitis Linfocítica , Linfohistiocitosis Hemofagocítica/virología , Masculino , Ratones , Ratones Noqueados , Mutación , Proteínas Citotóxicas Formadoras de Poros/inmunología , Proteínas Qa-SNARE/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Proteínas de Unión al GTP rab/inmunología
20.
Haematologica ; 100(7): 978-88, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26022711

RESUMEN

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/µL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.


Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Linfohistiocitosis Hemofagocítica/diagnóstico , Trastornos Linfoproliferativos/diagnóstico , Sistema de Registros , Adolescente , Adulto , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/inmunología , Niño , Preescolar , Diagnóstico Diferencial , Europa (Continente) , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Síndromes de Inmunodeficiencia/inmunología , Factores Inmunológicos/uso terapéutico , Lactante , Recién Nacido , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Leishmaniasis/complicaciones , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/inmunología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/patología , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/inmunología , Masculino , Micosis/complicaciones , Micosis/tratamiento farmacológico , Micosis/inmunología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/tratamiento farmacológico , Infecciones Oportunistas/inmunología , Esteroides/uso terapéutico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Terminología como Asunto , Virosis/complicaciones , Virosis/tratamiento farmacológico , Virosis/inmunología
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