RESUMEN
We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.).
Asunto(s)
Anticuerpos Neutralizantes , Autoanticuerpos , Enfermedades Inflamatorias del Intestino , Interleucina-10 , Humanos , Interleucina-10/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Femenino , Linfocitos B/inmunología , Lactante , NiñoRESUMEN
A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n = 113, 22.9%) or non-SCID IEI (n = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19-8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n = 18, 60.0%; without, n = 6, 20.0%). Patients received grafts from peripheral blood stem cell (n = 25, 83.3%) or bone marrow (n = 5, 16.7%) with median stem cell dose 9.5 × 106 CD34 + cells/kilogram (range: 1.4-32.3). Median follow-up was 1.92 years (0.22-16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I-II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 (n = 6), CMV (n = 4), and adenovirus (n = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Estudios Retrospectivos , Adenoviridae , Quimerismo , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment for CGD but has rarely been reported in individual symptomatic carriers to date. We undertook a retrospective international survey of outcome of HSCT for symptomatic XL-CGD carriers. Seven symptomatic female XL-CGD carriers aged 1-56 years underwent HSCT in four centers, indicated for severe and recurrent infection, colitis, and autoimmunity. Two patients died from transplant-related complications, following donor engraftment and restoration of oxidative burst. All surviving patients demonstrated resolution of their neutrophil oxidative burst defect with concordant reduction in infection and inflammatory symptoms and freedom from further immunosuppressive therapy. In conclusion, allogeneic HSCT may cure the phagocyte defect in symptomatic XL-CGD carriers and improve their recurrent and disabling infective and inflammatory symptoms but risks transplant-related complications.
Asunto(s)
Enfermedad Granulomatosa Crónica , Trasplante de Células Madre Hematopoyéticas , Humanos , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/terapia , Estudios Retrospectivos , Estallido Respiratorio , NeutrófilosRESUMEN
Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαß/CD19-depleted haploidentical family donor transplant (TCRαß-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαß-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαß-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαß-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαß-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαß-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Alemtuzumab , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/cirugía , Acondicionamiento Pretrasplante , Donante no EmparentadoRESUMEN
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.
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Adenosina Desaminasa , Agammaglobulinemia , Terapia de Reemplazo Enzimático , Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Adenosina Desaminasa/genética , Agammaglobulinemia/cirugía , Alemtuzumab/uso terapéutico , Terapia de Reemplazo Enzimático/métodos , Terapia Genética/métodos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/cirugía , Acondicionamiento PretrasplanteRESUMEN
MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/mortalidad , Antígenos de Histocompatibilidad Clase II/genética , Edad de Inicio , Alelos , Biomarcadores , Niño , Preescolar , Femenino , Genotipo , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Recién Nacido , Masculino , Cuidados Paliativos , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Acondicionamiento Pretrasplante , Donante no EmparentadoRESUMEN
An MHC class II deficient 2-year-old boy presented with fever and an enlarging left neck mass 100 days post allogeneic haematopoietic stem cell transplant (HSCT). Fever persisted despite treatment with broad-spectrum ß-lactam antibiotics. His BCG vaccination site at presentation was quiescent. Ultrasound showed enlarged cervical lymph nodes. An incisional biopsy of the large nodal mass yielded acid-fast bacilli, identified as Mycobacterium bovis by genome sequencing. Treatment with rifampicin, isoniazid and pyridoxine was started. The mass suppurated (figure 1), before healing concurrently with T-lymphocyte reconstitution at approximately day 130 post-HSCT.
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Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Linfadenitis , Vacuna BCG/efectos adversos , Niño , Preescolar , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recién Nacido , Isoniazida/uso terapéutico , Linfadenitis/inducido químicamente , Linfadenitis/terapia , Masculino , RifampinRESUMEN
Type 1 diabetes is a self-managed condition. Regular monitoring of blood glucose (BG) levels has been the cornerstone of diabetes management. Finger prick BG testing traditionally has been the standard method employed. More recently, rapid advancements in the development of continuous glucose monitoring devices have led to increased use of technology to help children and young people with diabetes manage their condition. These devices have the potential to improve diabetes control and reduce hypoglycaemia especially if used in conjunction with a pump to automate insulin delivery. This paper aims to provide an update on main CGM devices available and practical considerations for doctors if they come across a child with diabetes who is using one of these devices.
Asunto(s)
Diabetes Mellitus Tipo 1 , Hipoglucemia , Adolescente , Glucemia , Automonitorización de la Glucosa Sanguínea , Niño , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Hipoglucemia/diagnóstico , Hipoglucemia/prevención & control , Hipoglucemiantes , Insulina/uso terapéutico , Derivación y ConsultaRESUMEN
Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαß/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36-330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.
Asunto(s)
Enfermedades Genéticas Congénitas/terapia , Trasplante de Células Madre Hematopoyéticas , Infecciones por Mycobacterium/terapia , Adolescente , Antibacterianos/uso terapéutico , Niño , Preescolar , Femenino , Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Enfermedad Injerto contra Huésped , Humanos , Lactante , Masculino , Infecciones por Mycobacterium/genéticaRESUMEN
BACKGROUND: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. OBJECTIVES: This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. METHODS: We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. RESULTS: Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. CONCLUSIONS: The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos B/inmunología , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas , Factores Inmunológicos/uso terapéutico , Complicaciones Posoperatorias/epidemiología , Enfermedades de Inmunodeficiencia Primaria/terapia , Rituximab/uso terapéutico , Sirolimus/uso terapéutico , Niño , Terapia Combinada , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Incidencia , Masculino , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Reino Unido/epidemiologíaAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedades Autoinflamatorias Hereditarias/terapia , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adolescente , Productos Biológicos/uso terapéutico , Niño , Haploinsuficiencia , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Inmunosupresores/uso terapéutico , MasculinoRESUMEN
UNLABELLED: Congenital cytomegalovirus (cCMV) accounts for 20% of all childhood sensorineural hearing loss (SNHL) but is not routinely tested for at birth. Valganciclovir has been shown to prevent hearing deterioration and improve neurocognitive outcomes if started in the first month of life. This study aimed to assess the feasibility of integrating testing for cCMV using salivary swabs into the Newborn Hearing Screening Programme (NHSP). Parents of newborns <22 days old in South West London, who were referred after their initial newborn hearing screen for further audiological testing, were approached by hearing screeners to obtain a saliva sample for CMV DNA polymerase chain reaction (PCR). Eighty percent (203/255) of newborns who were eligible had a saliva swab taken by the hearing screener. Over 99% of results were delivered within the first month of life. Two newborns were identified with cCMV and both seen on day 10 of life by the paediatric specialist. All saliva samples tested delivered a result using real-time PCR. CONCLUSION: It is feasible for hearing screeners to obtain saliva swabs to test for CMV DNA using real-time PCR in newborns referred after their initial hearing screen. Rapid diagnostic testing for cCMV needs a more detailed clinical and cost-effectiveness analysis.
Asunto(s)
Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/genética , Pruebas Auditivas/métodos , Tamizaje Neonatal/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa , Saliva/química , Análisis Costo-Beneficio , Femenino , Humanos , Recién Nacido , Londres , MasculinoRESUMEN
OBJECTIVE: To determine the role of viral infections in causing fetal and infant death. STUDY DESIGN: We assessed a well-validated population database of fetal (≥20 weeks gestation) and infant death for infective deaths and deaths from viruses over a 21-year period (1988-2008). We analyzed by specific viral cause, timing (late fetal loss [20-23 weeks], stillbirth [≥24 weeks], neonatal death [0-27 days], and post-neonatal infant death [28-364 days]) and across time. RESULTS: Of the 989 total infective deaths, 108 were attributable to viral causes (6.5% of late fetal losses, 14.5% of stillbirths, 6.5% of neonatal deaths, and 19.4% of postneonatal infant deaths). Global loss (combined fetal and infant losses per 100,000 registerable births) was 139.6 (95% CI, 130.9-148.3) for any infective cause and 15.2 (95% CI, 12.3-18.1) for viral infections. More than one-third (37%) of viral-attributed deaths were before live birth, from parvovirus (63%) or cytomegalovirus (33%). Parvovirus accounted for 26% (28 of 108) of all viral deaths. Cytomegalovirus was associated with a global loss rate of 3.1 (95% CI, 1.8-4.4) and an infant mortality rate of 1.3 (95% CI, 0.4-2.1) per 100,000 live births; 91% of cases were congenital infections. Herpes simplex virus caused death only after live births (infant mortality rate, 1.4; 95% CI, 0.5-2.3). No changes in rates were seen over time. CONCLUSION: We have identified a substantial contribution of viral infections to global fetal and infant losses. More than one-third of these losses occurred before live births. Considering our methodology, our estimates represent the minimum contribution of viral illness. Strategies to reduce this burden are needed.
Asunto(s)
Muerte Fetal/epidemiología , Muerte Fetal/virología , Mortinato/epidemiología , Virosis/mortalidad , Edad Gestacional , Humanos , Lactante , Recién Nacido , Estudios RetrospectivosRESUMEN
AIM: Infection is an important cause of neonatal and infant mortality. We evaluated changes in infant deaths from infections from 1988 to 2008 in the North of England. METHODS: We interrogated a population-based survey and reviewed infant deaths from infection. Proportional contribution to deaths, pathogens identified and risk factors were analysed. RESULTS: Thirteen percentage of 4366 infant deaths from a population of 704 536 livebirths were infectious. The absolute numbers of infant deaths from infection fell over time but the proportion of deaths from infection increased (12.1%, 13.6% and 14.9%). Significantly preterm infants were increasingly represented in successive epochs (14%, 24% and 38%). Infant mortality rate (IMR) from meningococcus and Group B Streptococcus (GBS) fell in the latest epoch, but there was a corresponding increase from Escherichia coli and candida. DISCUSSION: This large study shows that infections have become proportionately more important causes of death especially in very preterm infants. Recent significant reductions in death from meningococcus and GBS are likely to represent successful achievements of vaccination and antibiotic prophylactic policies. Increases in IMR from E. coli may relate to GBS prophylaxis and increases in candida to the increase from preterm populations. Further efforts to understand these changing patterns and develop additional prevention and treatment strategies and vaccines remain an urgent priority.
Asunto(s)
Infecciones Bacterianas/mortalidad , Mortalidad Infantil/tendencias , Micosis/mortalidad , Virosis/mortalidad , Infecciones Bacterianas/etiología , Inglaterra/epidemiología , Encuestas Epidemiológicas , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/etiología , Enfermedades del Prematuro/mortalidad , Estudios Longitudinales , Micosis/etiología , Factores de Riesgo , Virosis/etiologíaRESUMEN
We report five discrete episodes of group B streptococcus (GBS) bacteraemia in an extremely premature infant, extending into early childhood. The first four episodes occurred during infancy despite appropriate treatment. Breastmilk was positive for group B streptococcal 16S DNA by polymerase chain reaction. The fifth episode occurred at 17 months of age, shortly after stopping antimicrobial prophylaxis.Radiological investigations did not identify a focus for recurrence of GBS bacteraemia, and immunological investigations and targeted whole genome sequencing yielded only transient hypogammaglobulinaemia of infancy, which resolved.This case highlights invasive GBS infection as a cause of infant morbidity. Premature infants are at particular risk of invasive as well as recurrent disease. GBS is typically a sensitive organism and each episode of GBS in our patient was effectively treated with penicillin. The role of breastmilk in recurrent GBS is controversial; in this case infant and mother isolated identical GBS serotypes and were concurrently treated with rifampicin.
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Bacteriemia , Complicaciones Infecciosas del Embarazo , Infecciones Estreptocócicas , Recién Nacido , Lactante , Humanos , Preescolar , Embarazo , Femenino , Recien Nacido Extremadamente Prematuro , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Penicilinas/uso terapéutico , Leche Humana , Streptococcus agalactiae , Complicaciones Infecciosas del Embarazo/tratamiento farmacológicoRESUMEN
This case describes a neonate who presented with spontaneous Clostridium perfringens meningitis and brain abscess. The abscess was drained, and the infant completed a 6-week course of antibiotics. Throughout this time the infant remained well with no need for intensive care. C. perfringens central nervous system infections are associated with trauma and poor outcomes. This case highlights that the spectrum of disease can include spontaneous infection with a relatively mildly clinical course demonstrating the importance of 16s polymerase chain reaction in culture-negative cases and its role in detecting rare causes of central nervous system infections such as C. perfringens .
Asunto(s)
Absceso Encefálico , Infecciones del Sistema Nervioso Central , Infecciones por Clostridium , Meningitis , Lactante , Recién Nacido , Humanos , Clostridium perfringens , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/etiología , Absceso Encefálico/diagnóstico , Absceso Encefálico/complicaciones , Meningitis/etiología , Infecciones del Sistema Nervioso Central/complicacionesRESUMEN
A minority of children experience significant graft dysfunction after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT in this scenario is unclear with respect to conditioning regimen and stem cell source. This single-center retrospective case series reports the outcomes of salvage CD3+TCRαß/CD19-depleted mismatched family or unrelated donor stem cell transplantation (TCRαß-SCT) between 2013 and 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event-free survival (EFS), graft-versus-host disease (GVHD)-free and event-free survival (GEFS), toxicities, GVHD, viremia and long-term graft function. In this retrospective audit of patients who underwent second CD3+TCRαß/CD19-depleted mismatched donor HSCT using treosulfan-based reduced-toxicity myeloablative conditioning, the median age at first HSCT was 8.76 months (range, 2.5 months to 6 years), and that at second TCRαß-SCT was 3.6 years (range, 1.2 to 11 years). The median interval between first and second HSCTs was 1.7 years (range, 3 months to 9 years). The primary diagnoses were severe combined immunodeficiency (SCID) (n = 5) and non-SCID IEI (n = 7). Indications for second HSCT were primary aplasia (n = 1), secondary autologous reconstitution (n = 6), refractory acute GVHD (aGVHD) (n = 3), and secondary leukemia (n = 1). Donors were either haploidentical parental donors (n = 10) or mismatched unrelated donors (n = 2). All patients received TCRαß/CD19-depleted peripheral blood stem cell (PBSC) grafts with a median CD34+ cell dose of 9.3 × 106/kg (range, 2.8 to 32.3 × 106/kg) and a median TCRαß+ cell dose of 4 × 104/kg (range, 1.3 to 19.2 × 104/kg). All patients engrafted, with a median time neutrophil and platelet recovery of 15 days (range, 12 to 24 days) and 12 days (range, 9 to 19 days). One patient developed secondary aplasia, and 1 had secondary autologous reconstitution; both underwent a successful third HSCT. Four (33%) had grade II aGVHD, and none had grade III-IV aGVHD. No patients had chronic GVHD (cGVHD), but 1 patient developed extensive cutaneous cGVHD after their third HSCT using PBSCs and antithymocyte globulin. Nine (75%) had at least 1episode of blood viremia with human herpesvirus 6 (n = 6; 50%), adenovirus (n = 6; 50%), Epstein-Barr virus (n = 3; 25%), or cytomegalovirus (n = 3; 25%). The median duration of follow-up was 2.3 years (range, .5 to 10 years), and the 2-year OS, EFS, and GEFS were 100% (95% confidence interval [CI], 0 to 100%), 73% (95% CI, 37% to 90%), and 73% (95% CI, 37% to 90%), respectively. TCRαß-SCT from mismatched family or unrelated donors, using a chemotherapy-only conditioning regimen, is a safe alternative donor salvage transplantation strategy for second HSCT in patients without a suitably matched donor.
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Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Niño , Humanos , Lactante , Receptores de Antígenos de Linfocitos T alfa-beta , Donante no Emparentado , Estudios Retrospectivos , Viremia , Herpesvirus Humano 4 , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodosRESUMEN
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterized by acute respiratory distress needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against COVID-19 and have persistent disease. Objective: Our aim was to describe a child with combined immunodeficiency and a favorable post-hematopoietic stem cell transplant (HSCT) course following a haploidentical HSCT in the presence of persistent SARS-CoV-2 infection. Methods: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to an incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution after HSCT, the patient's physicians performed a maternal (with a recent history of COVID-19 infection) haploidentical HSCT. The patient received regdanvimab (after stem cell infusion) and remdesivir (before and after stem cell infusion). Results: The patient exhibited a gradual increase in her cycle threshold values, implying a reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical and radiologic improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory addback T lymphocytes after haploidentical HSCT and use of regdanvimab (a SARS-CoV-2-neutralizing mAb) and remdesivir may have led to the successful outcome in our patient with severe immunodeficiency after she had undergone HSCT. This case highlights the role of novel antiviral strategies (mAbs and CD45RO+ memory T lymphocytes) in contributing to viral clearance in a challenging clinical scenario.
RESUMEN
Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell-replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell-depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αß (TCRαß)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαß/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged <5 years at HCT). For older patients (aged >5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαß/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.