A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches

Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered

No disponible

El nuevo escenario de las inmunodeficiencias primarias y el rol del inmunólogo clínico en la consulta especializada / The new scenario of primary immunodeficiencies and the role of the clinical immunologist in the specialised clinic

No disponible

Tuberculosis en el adolescente; reto y oportunidad de evitar el contagio a la comunidad / Adolescent tuberculosis; a challenge and opportunity to prevent community transmission

INTRODUCCIÓN: La tuberculosis (TB) en el adolescente puede presentar formas radiológicas cavitadas en los lóbulos superiores, con esputos bacilíferos, en lo que se ha llamado TB pulmonar tipo adulto, que implica un importante riesgo de contagio en el entorno social y familiar del paciente. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo (2007-2012) en una serie pediátrica (< 18 años) con TB en un hospital pediátrico de referencia en Barcelona. Se compara a los pacientes ≤ 12 y > 12 años. RESULTADOS: Se incluyeron 124 pacientes (56,5% hombres, edad mediana: 4,0 años). En la mitad, la TB afectó a pacientes de origen inmigrante y se diagnosticó por sospecha clínico-radiológica. La TB intratorácica fue la forma clínica predominante (91,9%), los cultivos fueron positivos en un tercio de los casos (37,9%) y sensibles a los fármacos orales de primera línea en su totalidad. El tiempo mediano (rango intercuartil) de tratamiento fue de 6 (6-9) meses; solo 10 pacientes precisaron tratamiento directamente observado y la evolución fue satisfactoria en la mayoría (98,4%). Entre los adolescentes, la TB fue más prevalente en mujeres (63,2%) e inmigrantes (68,4%), la comorbilidad al diagnóstico y las formas pulmonares cavitadas fueron más comunes y se identificó el caso índice solo en el 21,1% de los pacientes. CONCLUSIÓN: En el adolescente, la TB pulmonar tipo adulto es común, y a menudo asocia comorbilidad y se diagnostica más tarde, implicando un mayor riesgo de contagio a la comunidad

INTRODUCTION: Adolescents may present with adult-type pulmonary tuberculosis (TB), including cavity disease in upper lobes and smear-positive sputum, which involves a significant transmission risk for social and family contacts. PATIENTS AND METHODS: A retrospective (2007-2012) observational study of a case series of TB was conducted in children and adolescents (< 18 years) in a paediatric referral centre in Barcelona. Patients aged ≤ 12 and > 12 years at diagnosis are compared. RESULTS: The series consisted of 124 patients (56.5% males, median age: 4.0 years). In half of the cases, the patient was of immigrant origina and TB was diagnosed after clinical-radiological suspicion, intra-thoracic disease being the most common (91.9%). Cultures yielded positive results in one third of cases (37.9%) and isolates were sensitive to oral first-line anti-TB agents in 100%. Median (interquartile range) duration of treatment was 6 (6-9) months, directly observed therapy was needed in 10 patients, and there was a satisfactory outcome after treatment in 98.4%. Among adolescents, TB was more prevalent in females (63.2%) and immigrant patients (68.4%), comorbidity at diagnosis and lung cavity forms were more common, and the source case was identified only in 21.1% of the patients. CONCLUSION: Adult-type pulmonary TB is common among adolescents, may be associated with underlying medical conditions, and is often diagnosed late, posing a significant transmission risk to the community

¿Se debe ser más intervencionista en urgencias con las convulsiones febriles atípicas? Experiencia en un hospital terciario durante tres años / Should a more interventionist approach be taken in A&E departments with atypical febrile seizures? Three years’ experience in a tertiary hospital

Introducción. Se han relacionado las convulsiones febriles atípicas (CFA) con una mayor incidencia de patología grave del sistema nervioso central (SNC). Estudios recientes muestran una disminución de la prevalencia de algunas de estas enfermedades, hecho que podría modificar su manejo. Objetivos. Determinar la prevalencia de patología grave del SNC en pacientes atendidos en urgencias por CFA y detectar diferencias con los pacientes con CFA no asociada a patología grave. Pacientes y métodos. Estudio retrospectivo mediante revisión de historias clínicas de los pacientes con diagnóstico de CFA entre noviembre de 2008 y noviembre de 2011. Resultados. Se incluyen 231 episodios de CFA (223 pacientes), con una edad media de 1,7 años (p25-75 = 1,2-2,3 años), 133 (57,6%) de los cuales eran varones. Doce pacientes (5,2%; IC 95% = 2,7-8,9) recibieron el diagnóstico de patología grave del SNC. En los pacientes con patología grave del SNC, la CFA es en la mayoría de las ocasiones el primer episodio (91,7% frente a 63%; p = 0,036), presenta más de un criterio diagnóstico (50% frente a 15,1%; p = 0,007), es más frecuente la convulsión focal (50% frente a 12,8%; p = 0,003) o el estado epiléptico (25% frente a 5,9%; p = 0,041) y los pacientes presentan alteración de la consciencia persistente posterior al episodio (66,7% frente a 31,5%; p = 0,002). Conclusiones. Dado que la prevalencia de patología grave del SNC en pacientes con CFA es baja, no se recomienda la realización rutinaria de pruebas complementarias ni el ingreso. Determinadas características del episodio aumentan la probabilidad de que la CFA sea la manifestación de una patología grave del SNC (ser un primer episodio, presentar más de un criterio diagnóstico de CFA y tratarse de una convulsión focal o estado epiléptico), por lo que deberían tenerse en cuenta en el manejo del paciente (AU)

Introduction. Atypical febrile seizures (AFS) have been related with a higher incidence of severe pathologies of the central nervous system (CNS). Recent studies show a reduction in the prevalence of some of these diseases, a fact that could affect their management. Aims. To determine the prevalence of severe pathologies of the CNS in patients treated for AFS in A&E departments and to detect any differences between these and patients suffering from AFS that is not associated to any severe pathology. Patients and methods. A retrospective study was conducted by reviewing the medical records of patients diagnosed with AFS between November 2008 and November 2011. Results. Altogether, the sample consisted of 231 episodes of AFS (223 patients), with an average age of 1.7 years (p25-75 = 1.2-2.3 years), 133 (57.6%) of whom were males. Twelve patients (5.2%; 95% CI = 2.7-8.9) were diagnosed with a severe pathology of the CNS. In patients with a severe pathology of the CNS, AFS is on most occasions the first episode (91.7% versus 63%; p = 0.036) and more than one diagnostic criterion is present (50% versus 15.1%; p = 0.007). Moreover, focal seizures (50% versus 12.8%; p = 0.003) or epileptic status (25% versus 5.9%; p = 0.041) are more common, and patients present altered levels of awareness that persist after the episode (66.7% versus 31.5%; p = 0.002). Conclusions. Given the fact that the prevalence of severe pathology of the CNS in patients with AFS is low, carrying out complementary tests or admission to hospital on a routine basis are not recommended. Certain characteristics of the episode increase the likelihood of AFS being the manifestation of a severe pathology of the CNS (being a first episode, presenting more than one diagnostic criterion for AFS and being a focal seizure or epileptic status), and should therefore be taken into account in the management of the patient (AU)

Utilización de un marcapasos encocavitario por bloqueo cardíaco completo debido a miocarditis por mycoplasma pneumoniae / Use of an encocavitary pacemaker in a patient with complete atrioventricular block due to myocarditis secondary to mycoplasma pneumoniae

Introducción. El bloqueo cardíaco auriculoventricular (BAV) completo en la infancia es una entidad poco frecuente pero potencialmente grave. La etiología más frecuente es la congénita, aunque también se puede presentar de forma adquirida. Hay pocos casos en la literatura de pacientes en edad pediátrica afectos de BAV como primera manifestación de una miocarditis aguda y en la cual se encuentre Mycoplasma pneumoniae como agente etiológico. También son escasas las publicaciones de pacientes pediátricos con esta patología tratados con marcapasos endocavitario. Caso clínico. Niño de 8 años de edad que presenta un episodio comicial e inestabilidad hemodinámica. El paciente es diagnosticado de BAV completo secundario a miocarditis aguda por Mycoplasma pneumoniae. Recibió tratamiento con corticoides, gammaglobulina intravenosa e infusión continua de isoproterenol endovenoso sin obtener respuesta, requiriendo la colocación de un marcapasos endocavitario temporal hasta la recuperación del ritmo sinusal. Comentarios. Determinados autoanticuerpos parece que tienen un papel fundamental en la fisiopatología de la miocarditis aguda. La infección por distintos gérmenes parece actuar como desencadenante de la respuesta autoinmune. De esta forma, parece coherente utilizar un tratamiento inmunosupresor o con gammaglobulinas, aunque no se puede recomendar su uso de forma rutinaria. En cuanto al BAV, puede ser necesario implantar un marcapasos endocavitario en espera de la restitución del ritmo sinusal(AU)

Introduction. Complete atriventricular block (CAB) is a rare but serious condition in children. It is usually congenital, but an acquired form is also well described. The literature on pediatric patients with CAB secondary to Mycoplasma pneumoniae myocarditis is scarce. Moreover, information on the use of an endocavitary pacemaker for children with CAB is very limited. Case Report. An 8-yo boy presented with a generalized tonic-clonic seizure and hemodynamic instability. He was diagnosed with CAB secondary to myocarditis caused by Mycoplasma pneumoniae. He was initially treated with steroids, intravenous immunoglobulins, and continuous infusion isoproterenol with no response, and required the placement of a temporary endocavitary pacemaker until sinus rhythm was recovered. Comments. Specific antibodies play a major role in the pathophysiology of acute myocarditis; infection by different agents could be the trigger of that immune response. The administration of intravenous immunoglobulin therapy for immunomodulation may have a role, although its routine use cannot be recommended. The use of an endocavitary pacemaker may be required until recovery of sinus rhythm(AU)