RESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient's hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.
Asunto(s)
Agammaglobulinemia , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Femenino , Agammaglobulinemia/inmunología , Agammaglobulinemia/terapia , Adolescente , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/inmunología , Linfocitos B/inmunología , Quimera por Trasplante , Antígenos HLA/inmunología , Antígenos HLA/genéticaRESUMEN
Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign. Methods: This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections. Results: After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer. Conclusion: Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.
Asunto(s)
Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Masculino , Femenino , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Adulto , Persona de Mediana Edad , Vacuna nCoV-2019 mRNA-1273/inmunología , Estudios de Seguimiento , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Estudios Prospectivos , Linfocitos T/inmunología , Adulto Joven , Vacunación , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Síndromes de Inmunodeficiencia/inmunología , AdolescenteRESUMEN
PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID). METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed. RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines. CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.
Asunto(s)
COVID-19 , Inmunodeficiencia Variable Común , Enfermedades de Inmunodeficiencia Primaria , Humanos , Vacuna nCoV-2019 mRNA-1273 , Vacunas contra la COVID-19 , COVID-19/prevención & control , Estudios Prospectivos , SARS-CoV-2 , Vacunación , Anticuerpos Antivirales , Inmunoglobulina G , ARN Mensajero/genética , InmunidadRESUMEN
BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.
Asunto(s)
Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , COVID-19 , Enfermedades Genéticas Congénitas , Síndromes de Inmunodeficiencia , Vacuna nCoV-2019 mRNA-1273/sangre , Vacuna nCoV-2019 mRNA-1273/inmunología , Vacuna nCoV-2019 mRNA-1273/uso terapéutico , Adulto , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Estudios Prospectivos , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance. LAY SUMMARY: Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Animales , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/veterinaria , Reglas de Decisión Clínica , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/veterinaria , Triazoles/uso terapéutico , Voriconazol/uso terapéuticoRESUMEN
Vaccination is the most effective measure to prevent infections in the general population. Its efficiency strongly depends on the function and composition of the immune system. If the immune system lacks critical components, patients will not be fully protected despite a completed vaccination schedule. Antigen-specific serum immunoglobulin levels are broadly used correlates of protection. These are the products of terminally differentiated B cells - plasma cells. Here we reviewed the literature on how aberrancies in B-cell composition and function influence immune responses to vaccinations. In a search through five major literature databases, 6,537 unique articles published from 2000 and onwards were identified. 75 articles were included along three major research lines: extremities of life, immunodeficiency and immunosuppression. Details of the protocol can be found in the International Prospective Register of Systematic Reviews [PROSPERO (registration number CRD42021226683)]. The majority of articles investigated immune responses in adults, in which vaccinations against pneumococci and influenza were strongly represented. Lack of baseline information was the most common reason of exclusion. Irrespective of study group, three parameters measured at baseline seemed to have a predictive value in assessing vaccine efficacy: (1) distribution of B-cell subsets (mostly a reduction in memory B cells), (2) presence of exhausted/activated B cells, or B cells with an aberrant phenotype, and (3) pre-existing immunological memory. In this review we showed how pre-immunization (baseline) knowledge of circulating B cells can be used to predict vaccination efficacy. We hope that this overview will contribute to optimizing vaccination strategies, especially in immunocompromised patients.
Asunto(s)
Linfocitos B/inmunología , Huésped Inmunocomprometido , Inmunogenicidad Vacunal , Inmunofenotipificación , Vacunación , Vacunas/administración & dosificación , Linfocitos B/metabolismo , Biomarcadores/metabolismo , Humanos , Seguridad del Paciente , Fenotipo , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Vacunación/efectos adversos , Vacunas/efectos adversosRESUMEN
In healthy individuals and in patients with invasive aspergillosis, Aspergillus-specific T-cells in peripheral blood display mainly a Thelper1 phenotype. Although in other fungal infections Thelper17 immunity is important, it was suggested that in aspergillus infection Thelper17 cells do not play a role or may even be detrimental. OBJECTIVES: To compare the cytokine profiles of Aspergillus-specific CD4+ T-cells in peripheral blood and in the lung. To investigate the Thelper phenotype at the primary location of A. fumigatus exposure. METHODS: Lung-derived T-cells and peripheral blood T-cells from COPD-patients were stimulated with overlapping peptides of 6 A. fumigatus proteins. Aspergillus-specific T-cells were identified on the basis of the activation marker CD154 and production of TNFα. In addition, production of the cytokines IFNγ, IL-17, IL-4 and IL-5 by the Aspergillus-specific T-cells was measured. RESULTS: The majority of lung-derived Aspergillus-specific T-cells displayed a Thelper17 phenotype, and only low percentages of cells produced IFNγ. In contrast, in the peripheral blood of COPD patients Aspergillus-specific T-cells displayed a Thelper1 phenotype, similar as peripheral blood-derived Aspergillus-specific T-cells from healthy individuals. CONCLUSIONS: These data demonstrate that in A. fumigatus infection, similar as in other fungal infections, Thelper17 cells may play a more important role in the immune response than was appreciated until now.
Asunto(s)
Aspergillus fumigatus/inmunología , Citocinas/inmunología , Interleucina-17/biosíntesis , Aspergilosis Pulmonar Invasiva/inmunología , Pulmón/inmunología , Células Th17/inmunología , Anciano , Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Femenino , Humanos , Interleucina-17/inmunología , Aspergilosis Pulmonar Invasiva/microbiología , Pulmón/microbiología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Fenotipo , Células TH1/inmunologíaRESUMEN
After allogeneic stem cell transplantation patients are at risk of invasive aspergillosis, especially during the period of neutropenia. Recent data suggest that impaired T-cell immune reconstitution after transplantation plays an important role in this increased risk. In this study we investigated whether Aspergillus-specific T cells are involved in the recovery from invasive aspergillosis by analyzing the Aspergillus-specific T-cell response in patients with invasive aspergillosis. In nine patients whose Aspergillus infection improved, we identified Crf1- or Catalase1-specific T cells on the basis of CD154 expression and interferon-γ production following stimulation with overlapping peptides of the A. fumigatus proteins Crf1 and Catalase1. These Aspergillus-specific T cells were induced at the moment of regression of the aspergillus lesions. Crf1- and Catalase1-specific T cells, sorted on the basis of CD154 expression at the peak of the immune response, had a T helper-1 phenotype and recognized a variety of T-cell epitopes. In contrast, in two patients with progressive invasive aspergillosis, no Crf1- or Catalase1-specific T cells were identified. These data indicate that the presence of Aspergillus-specific T cells with a T helper-1 phenotype correlates with the clearance of aspergillus infection.
Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Linfocitos T CD4-Positivos/inmunología , Adulto , Anciano , Antígenos Fúngicos/inmunología , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergilosis/etiología , Linfocitos T CD4-Positivos/metabolismo , Epítopos de Linfocito T/inmunología , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunofenotipificación , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/etiología , Aspergilosis Pulmonar Invasiva/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Tomógrafos Computarizados por Rayos X , Trasplante HomólogoRESUMEN
Invasive aspergillosis is a serious infectious complication after allogeneic stem cell transplantation. One of the strategies to improve the management of aspergillosis is the adoptive transfer of antigen-specific T cells, the success of which depends on the development of a broad repertoire of antigen-specific T cells. In this study, we identified CD4+ T cells specific for the Aspergillus proteins Crf1 and catalase 1 in 18 of 24 healthy donors by intracellular staining for interferon γ and CD154. Crf1- and catalase 1-specific T cells were selected on the basis of CD137 expression and underwent single-cell expansion. Aspergillus-specific T-cell clones mainly exhibited a T-helper cell 1 phenotype and recognized a broad variety of T-cell epitopes. Five novel Crf1 epitopes, 2 previously described Crf1 epitopes, and 30 novel catalase 1 epitopes were identified. Ultimately, by using overlapping peptides of Aspergillus fumigatus proteins, Aspergillus-specific T-cell lines that have a broad specificity and favorable cytokine profile and are suitable for adoptive T-cell therapy can be generated in vitro.
Asunto(s)
Antígenos Fúngicos/inmunología , Aspergillus fumigatus/inmunología , Linfocitos T CD4-Positivos/inmunología , Catalasa/inmunología , Proteínas Fúngicas/inmunología , Ligando de CD40/biosíntesis , Mapeo Epitopo , Epítopos de Linfocito T/inmunología , Humanos , Interferón gamma/biosíntesis , Coloración y EtiquetadoRESUMEN
The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95%CI 1.08-13.2, pâ=â0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (pâ=â0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp.
Asunto(s)
Aspergilosis/etiología , Aspergilosis/genética , Predisposición Genética a la Enfermedad/genética , Inmunidad Innata/genética , Polimorfismo de Nucleótido Simple , Trasplante de Células Madre/efectos adversos , Adulto , Femenino , Frecuencia de los Genes , Humanos , Interferón gamma/genética , Interleucina-12/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Receptores Toll-Like/genéticaRESUMEN
A patient known to have renal insufficiency was admitted to the hospital with fever and pancytopenia after returning from a trip to Mali. Pancytopenia was not caused by a tropical infection but was a side effect of atovaquone/proguanil used as malaria chemoprophylaxis. High and prolonged detectable proguanil serum levels can result in bone marrow suppression in patients with renal insufficiency. This should be taken into account in a returning traveller with fever and pancytopenia.