RESUMEN
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30). METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect. CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.
Asunto(s)
Efecto Fundador , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Subunidad p40 de la Interleucina-12/genética , Mutación , Infecciones por Mycobacterium/etiología , Preescolar , Análisis Mutacional de ADN , Exoma , Femenino , Humanos , Lactante , Masculino , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/terapia , Linaje , Arabia Saudita , Secuenciación del ExomaRESUMEN
The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.
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Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Interferón Tipo I/farmacología , Interferón gamma/farmacología , Transactivadores/deficiencia , Transactivadores/genética , Virosis/etiología , Sustitución de Aminoácidos , Antivirales/farmacología , Secuencia de Bases , Consanguinidad , ADN/genética , Femenino , Humanos , Técnicas In Vitro , Lactante , Masculino , Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/etiología , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/fisiopatología , Linaje , Proteínas Recombinantes , Factor de Transcripción STAT1 , Eliminación de Secuencia , Transducción de Señal , Virosis/tratamiento farmacológico , Virosis/genética , Virosis/fisiopatologíaRESUMEN
The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.
Asunto(s)
Inmunidad Innata , Receptores de Interleucina/deficiencia , Adolescente , Adulto , Células Cultivadas , Niño , Preescolar , Humanos , Mutación , Infecciones por Mycobacterium/inmunología , Infecciones Oportunistas/inmunología , Polimorfismo Conformacional Retorcido-Simple , Receptores de Interleucina/genética , Receptores de Interleucina/fisiología , Receptores de Interleucina-12 , Infecciones por Salmonella/inmunologíaRESUMEN
Natural killer (NK) cells have been originally defined by their "naturally occurring" effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-gamma (IFN-gamma) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rbeta1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-gamma production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rbeta1- and IL-12p40-deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56(+) effector memory T cells. The susceptibility of IL-12/23 axis-deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56(+) T cells in the control of these infections in humans.
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Antígeno CD56 , Interleucina-12/fisiología , Interleucina-23/fisiología , Células Asesinas Naturales/inmunología , Adolescente , Adulto , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Memoria Inmunológica , Subunidad p40 de la Interleucina-12/deficiencia , Masculino , Mutación , Infecciones por Mycobacterium/inmunología , Receptores de Interleucina-12/deficiencia , Receptores de Interleucina-12/genética , Infecciones por Salmonella/inmunología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: The main study aim was to track infections, evaluate performance, and identify opportunities for improved practice since infections, especially those associated with multidrug-resistant organisms, are the second most common cause of death among end-stage renal disease patients. METHODS: This study describes the establishment of baseline dialysis event surveillance at a large dialysis center. Every month, the dialysis center staff reported the total number of maintenance hemodialysis patients to the department of infection control and hospital epidemiology. The surveillance system for dialysis events included monthly monitoring of hemodialysis patients in outpatient settings for positive blood cultures, intravenous antimicrobial initiation, and local vascular access infections. RESULTS: We calculated the pooled mean rates of positive blood cultures, intravenous antimicrobial initiation, and local vascular access infections during the period from June 1, 2014 to September 30, 2017. Results indicated more dialysis events were attributed to the CVC than any other dialysis vascular access. Regardless of vascular access type, intravenous antimicrobial initiation was the most commonly reported dialysis-associated event. CONCLUSIONS: Dialysis events surveillance can be used to produce a decrease in both morbidity and mortality rates in hemodialysis patients.
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Fístula Arteriovenosa/microbiología , Bacteriemia/microbiología , Infecciones Bacterianas/microbiología , Infecciones Relacionadas con Catéteres/microbiología , Fallo Renal Crónico/terapia , Diálisis Renal , Administración Intravenosa , Adulto , Anciano , Antibacterianos/uso terapéutico , Fístula Arteriovenosa/tratamiento farmacológico , Fístula Arteriovenosa/etiología , Fístula Arteriovenosa/prevención & control , Bacteriemia/tratamiento farmacológico , Bacteriemia/etiología , Bacteriemia/prevención & control , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/etiología , Infecciones Bacterianas/prevención & control , Cultivo de Sangre , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/etiología , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres Venosos Centrales/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Pacientes Ambulatorios , Estudios Retrospectivos , Vancomicina/uso terapéuticoRESUMEN
Basidiobolomycosisis an unusual fungal infection that manifests in the skin and rarely involves other systems including the gastrointestinal tract. We retrospectively reviewed records of six pediatric patients (< or =14 years of age) diagnosed with gastrointestinal basidiobolomycosis from March 2000 to March 2002. Four patients came from the same region, suggesting environmental exposure. Basidiobolomycosis should be considered in the differential diagnosis in pediatric patients presenting with abdominal mass and eosinophilia.
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Entomophthorales , Enfermedades Gastrointestinales/diagnóstico , Cigomicosis/diagnóstico , Niño , Preescolar , Enfermedades Gastrointestinales/epidemiología , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/terapia , Humanos , Masculino , Estudios Retrospectivos , Arabia Saudita/epidemiología , Cigomicosis/epidemiología , Cigomicosis/terapiaRESUMEN
OBJECTIVE: The proportion of penicillin and ceftriaxone resistant Streptococcus pneumoniae isolates and associated risk factors varies by geographic areas in the world. We conducted a retrospective study to determine the extent of penicillin and ceftriaxone non-susceptible Streptococcus pneumoniae bacteremia in a tertiary care medical center in the city of Riyadh, Kingdom of Saudi Arabia. METHODS: We reviewed 172 episodes of Streptrococcus pneumoniae bacteremic diseases involving 160 hospitalized patients at King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, over a 5 year period between January 1995 through to December 1999. Patients' characteristics and underlying illnesses of those patients with bacteremias and meningitis caused by Streptococccus pneumoniae as well as antimicrobial susceptibility were examined. RESULTS: The majority of patients affected with Streptococcus pneumoniae bacteremia were children <5 years of age (number=91, 53%). Malignant diseases were the main underlying diagnosis in our patient population affected with pneumoncoccal bacteremia (number=46, 27%). Overall (51%) of the isolates were penicillin non-susceptible; of these (7%) were highly resistant. The overall resistance rate to ceftriaxone was 7%. CONCLUSION: With the high prevalence in Streptococcus pneumoniae antimicrobial resistance to penicillin and ceftriaxone, it is important to continue surveillance of infections caused by Streptococcus pneumoniae, and also we recommend that guidelines for treatment and prevention of pneumococcal infection must be addressed by health care and public health agencies.
Asunto(s)
Bacteriemia/tratamiento farmacológico , Ceftriaxona/farmacología , Cefalosporinas/farmacología , Penicilinas/farmacología , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus pneumoniae/efectos de los fármacos , Adolescente , Bacteriemia/microbiología , Ceftriaxona/uso terapéutico , Cefalosporinas/uso terapéutico , Niño , Preescolar , Farmacorresistencia Microbiana , Femenino , Humanos , Lactante , Masculino , Penicilinas/uso terapéutico , Estudios Retrospectivos , Arabia SauditaRESUMEN
BACKGROUND AND OBJECTIVES: Tuberculosis (TB) remains a global health problem. There is limited data on pediatric central nervous system tuberculosis (CNSTB) in Saudi Arabia on diagnosis and therapy. DESIGN AND SETTING: Retrospective review of health record of pediatric patients < 14 years old who were diagnosed as having CNSTB or spinal TB and admitted to a tertiary care center. PATIENTS AND METHODS: Health records and microbiology data of pediatric patients diagnosed with CNSTB were over 20-year period were reviewed. Data on demographics, clinical presentation, surgical interventions, neuroimaging, mycobacterial cultures and susceptibility and treatment were collected. RESULTS: Thirteen children were diagnosed with CNSTB or spinal TB. Tuberculoma was the most frequent in 8 cases (62%), followed by TB of the spine in 4 cases (31%), and one case of meningitis. Six patients had a history of TB contact (46%) and 8 (62%) patients had a positive tuberculin skin test (TST). Seizure and weakness was the most frequent symptoms (38% each), while fever was less frequently encountered (23%). Tissue cultures (brain tissues/spinal tissues) showed a high yield (92%) of Mycobacterium tuberculosis with positive cultures for 11 surgical specimens out of 12 for whom cultures were done. There were no surgical complications from biopsies. All of MTB isolates were sensitive to first-line agents. CONCLUSIONS: Brain or spinal biopsy is safe and has a high culture yield for MTB so it is advisable to perform a biopsy for any child in whom CNSTB is suspected and when there is no other less risky involved site for biopsy. All MTB isolates in this series were sensitive to first-line anti-tubercular agents.
Asunto(s)
Tuberculosis del Sistema Nervioso Central/epidemiología , Tuberculosis Meníngea/epidemiología , Tuberculosis de la Columna Vertebral/epidemiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mycobacterium tuberculosis/aislamiento & purificación , Estudios Retrospectivos , Arabia Saudita/epidemiología , Centros de Atención Terciaria , Prueba de Tuberculina , Tuberculosis del Sistema Nervioso Central/diagnóstico , Tuberculosis Meníngea/diagnóstico , Tuberculosis de la Columna Vertebral/diagnósticoRESUMEN
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
Asunto(s)
Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/genética , Infecciones por Mycobacterium no Tuberculosas/genética , Infecciones por Salmonella/genética , Adolescente , Adulto , Edad de Inicio , Asia Occidental/epidemiología , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Penetrancia , Análisis de Supervivencia , Túnez/epidemiología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown. To our knowledge, there are no reports of CRMO from Saudi Arabia. We describe the clinical and laboratory features and treatment of a cohort of children with CRMO. DESIGN AND SETTING: Retrospective, patients referred to pediatric rheumatology clinic at a tertiary care center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: The diagnosis of CRMO was based on evidence of recurrent osteomyelitis with radiographic evidence of chronic osteomyelitis involving at least two sites in the absence of infectious cause in a child less than 14 years old. RESULTS: Ten patients (9 female, 1 male) with CRMO; 2 patients presented in infancy. The referral diagnosis was inaccurate in all patients. All of them presented with pain and 8 of them had associated swelling and were found to have multifocal lesions. Imaging studies showed findings consistent with chronic osteomyelitis. Histopathological and microbiological examination confirmed the diagnosis in 9 patients. Cyclic pamidronate infusions induced good improvement in 6 patients. CONCLUSION: This report indicates that CRMO may be overlooked in our community. Early diagnosis and treatment are required to avoid potential complications.
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Diagnóstico por Imagen/métodos , Diagnóstico Precoz , Osteomielitis/diagnóstico , Adolescente , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Masculino , Osteomielitis/epidemiología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Arabia Saudita/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVE: Published data from Saudi Arabia regarding autoinflammatory diseases are scarce. In this study, we describe the clinical and laboratory features of autoinflammatory diseases in Saudi children. DESIGN AND SETTING: Restrospective, hospital-based study conducted from January 2010 until June 2010. PATIENTS AND METHODS: Patients with autoinflammatory disease treated at the Pediatric Rheumatology Clinic at King Faisal Specialist Hospital and Research Center, Riyadh, over the past 10 years were included. Autoinflammatory diseases included the following: familial Mediterranean fever (FMF); chronic recurrent multifocal osteomyelitis (CRMO); early-onset sarcoidosis (EOS); periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA); chronic infantile neurologic cutaneous and articular syndrome (CINCA); and Muckle-Wells syndrome (MWS). Demographic characteristics, diagnosis, age at onset, disease duration, follow-up duration, clinical and laboratory variables, and outcome data were compiled. Gathered laboratory data were part of patients' usual medical care. RESULTS: Thirty-four patients (females, 53%) with autoinflammatory diseases were included (mean age, 151 months). Mean disease duration was 118 months; mean age at onset was 32 months; consanguinity was present in 40%. Patients were diagnosed as follows: FMF, 50%; CRMO, 23.5%; CINCA, 8.8%; EOS, 8.8%; MWS, 6%; and PFAPA, 2.9%. The referral diagnosis was inaccurate in all patients except for FMF patients. Gene study was informative in 9 of 14 FMF patients who had molecular analyses. None of our cohort had amyloidosis. All CRMO patients had a favorable response to treatment except 1 patient, who had refractory, progressive disease. All patients with EOS had multiorgan involvement, including uveitis. All CINCA patients had a favorable response to anakinra. CONCLUSION: Our report shows that autoinflammatory diseases other than FMF may be overlooked. Increased awareness among pediatricians about these conditions will help to provide better health care to patients in the form of early diagnosis and management.
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Síndromes Periódicos Asociados a Criopirina/diagnóstico , Fiebre Mediterránea Familiar/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Osteomielitis/diagnóstico , Reumatología/métodos , Sarcoidosis/diagnóstico , Adolescente , Antirreumáticos/uso terapéutico , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Diagnóstico Diferencial , Fiebre Mediterránea Familiar/tratamiento farmacológico , Femenino , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Humanos , Lactante , Masculino , Osteomielitis/tratamiento farmacológico , Estudios Retrospectivos , Sarcoidosis/tratamiento farmacológico , Arabia Saudita , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Stem cells from umbilical cord blood (CB) have increasingly become a viable alternate source of progenitor cells for hematopoietic cell transplantation (HSCT). Cytomegalovirus (CMV) is thought to contribute significantly to HSCT morbidity and mortality. DESIGN AND SETTING: Retrospective case-control study in patients at tertiary care center. PATIENTS AND METHODS: We determined the incidence, risk factors and outcomes for CMV infection and disease after unrelated cord blood transplantation (UCBT) in children. RESULTS: Between 2003 and 2007, 73 pediatric patients underwent UCBT and 68% of recipients were CMV seropositive. The overall incidence of CMV infection, early and late CMV infection was 58.9% (43/73), 62.8% (27/43), and 37.4% (16/43), respectively. in patients with early CMV infection, 6 of 27 (22%) patients progressed to develop CMV end-organ disease including pneumonitis and retinitis. High levels CMV antigenemia ≥70 infected cells by pp65 antigenemia assay + PMNs, P=.237) were associated with a higher risk of progression to CMV disease. The development of CMV infections was higher in CMV-seropositive recipients (P<.001) and in those who developed graft-versus-host-diseases (GVhD) (P<.001). other risk factors for CMV infection include the use of high-dose corticosteroids (P<.001) and older age of the recipient at the time of transplant (P<.002). Late CMV infection was strongly associated with a previous history of early CMV infection (P<.001). CONCLUSION: CMV infection is a significant complication in UCBT recipients in pediatric patients and is associated with an increase in transplant-related morbidity and mortality. Risk factors for CMV infections after UCBT include GvHD, use of corticosteroids, underlying diseases (hematologic malignancies) and older age. Late CMV infection was strongly associated with a previous history of CMV infection.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/etiología , Factores de Edad , Antiinflamatorios/uso terapéutico , Anticuerpos Antivirales/sangre , Estudios de Casos y Controles , Niño , Preescolar , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/patología , Humanos , Incidencia , Lactante , Masculino , Metilprednisolona/uso terapéutico , Fosfoproteínas/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Trasplante Homólogo , Resultado del Tratamiento , Proteínas de la Matriz Viral/metabolismo , Activación ViralRESUMEN
Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
Asunto(s)
Sudunidad beta 1 del Receptor de Interleucina-12/deficiencia , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Citocinas/sangre , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Sudunidad beta 1 del Receptor de Interleucina-12/genética , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/genética , Mycobacterium bovis/aislamiento & purificación , Mycobacterium tuberculosis/aislamiento & purificación , Micobacterias no Tuberculosas/aislamiento & purificación , Análisis de SupervivenciaRESUMEN
Group B Streptococcus can cause early onset neonatal disease. Beyond neonatal life, group B Streptococci are unusual pathogens. It can cause septicemia, epiglottis, fascitis, and endocarditis. A male Saudi child with group B endocarditis who has congenital heart disease is discussed.
Asunto(s)
Endocarditis Bacteriana/diagnóstico , Infecciones Estreptocócicas/diagnóstico , Streptococcus agalactiae , Preescolar , Endocarditis Bacteriana/complicaciones , Endocarditis Bacteriana/terapia , Cardiopatías Congénitas/complicaciones , Humanos , Masculino , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/terapiaRESUMEN
Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.