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We report a novel case of SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) mutation successfully treated with hematopoietic stem cell transplantation. The female patient presented delayed cord separation, chronic diarrhea, skin abscesses, skeletal dysmorphisms, and neutropenia with specific granule deficiency. Analysis of the transcriptomic profile of peripheral blood sorted mature and immature SMARCD2 neutrophils showed defective maturation process that associated with altered expression of genes related to specific, azurophilic, and gelatinase granules, such as LTF, CRISP3, PTX3, and CHI3L1. These abnormalities account for the prevalence of immature neutrophils in the peripheral blood, impaired function, and deregulated inflammatory responses.
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BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system. METHODS: this is a retrospective analysis of clinical data, biochemical parameters, and immune cell subsets in 40 MIS-C patients from hospital admission to outpatient long-term follow-up. RESULTS: MIS-C patients had elevated inflammatory markers, associated with T- and NK-cell lymphopenia, a profound depletion of dendritic cells, and altered monocyte phenotype at disease onset, while the subacute phase of the disease was characterized by a significant increase in T- and B-cell counts and a rapid decline in activated T cells and terminally differentiated B cells. Most of the immunological parameters returned to values close to the normal range during the remission phase (20-60 days after hospital admission). Nevertheless, we observed a significantly reduced ratio between recently generated and more differentiated CD8+ T- and B-cell subsets, which partially settled at longer-term follow-up determinations. CONCLUSIONS: The characterization of lymphocyte distribution in different phases of MIS-C may help to understand the course of diseases that are associated with dysregulated immune responses and to calibrate prompt and targeted treatments.
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Compared to adults, severe or fatal COVID-19 disease is much less common in children. However, a higher risk for progression has been reported in infants. Different pediatric COVID-19 severity scores are reported in the literature. Methods: Subjects under 90 days of age admitted to 35 Italian institutions for COVID-19 were included. The severity of COVID-19 was scored as mild/moderate or severe/critical following the classification reported in the literature by Venturini, Dong, Kanburoglu, and Gale. To assess the diagnostic accuracy of each classification system, we stratified all enrolled patients developing a posteriori severity score based on clinical presentation and outcomes and then compared all different scores analyzed. Results: We included 216 infants below 90 days of age. The most common symptom was fever, followed by coryza, poor feeding, cough, and gastrointestinal manifestations. According to Venturini, Dong, Kanburoglu, and Gale's severity scores, 18%, 6%, 4.2%, and 29.6% of infants presented with severe/critical disease, respectively. A correlation analysis between these four scores and the a posteriori severity score assigned to all enrolled subjects was performed, and a crescent strength of correlation from Gale (R = 0.355, p < 0.001) to Venturini (R = 0.425, p < 0.001), Dong (R = 0.734, p < 0.001), and Kanburoglu (R = 0.859, p < 0.001) was observed. Conclusions: The percentage of infants with severe COVID-19 varies widely according to the score systems. A unique clinical score should be designed for neonates and infants with COVID-19.
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COVID-19 , Lactante , Adulto , Recién Nacido , Humanos , Niño , COVID-19/diagnóstico , SARS-CoV-2 , Fiebre , TosRESUMEN
Importance: Severe gastrointestinal (GI) manifestations have been sporadically reported in children with COVID-19; however, their frequency and clinical outcome are unknown. Objective: To describe the clinical, radiological, and histopathologic characteristics of children with COVID-19 presenting with severe GI manifestations to identify factors associated with a severe outcome. Design, Setting, and Participants: A multicenter retrospective cohort study (February 25, 2020, to January 20, 2021) enrolled inpatient and outpatient children (aged <18 years) with acute SARS-CoV-2 infection, confirmed by positive real-time reverse-transcriptase-polymerase chain reaction on nasopharyngeal swab or fulfilling the US Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children (MIS-C). The study was conducted by pediatricians working in primary care or hospitals in Italy participating in the COVID-19 Registry of the Italian Society of Pediatric Infectious Diseases. Main Outcomes and Measures: The occurrence of severe GI manifestations, defined by a medical and/or radiological diagnosis of acute abdomen, appendicitis (complicated or not by perforation and/or peritonitis), intussusception, pancreatitis, abdominal fluid collection, and diffuse adenomesenteritis requiring surgical consultation, occurring during or within 4 to 6 weeks after infection with SARS-CoV-2 infection. Logistic regression was used to estimate odds ratios (ORs) with 95% CIs of factors potentially associated with severe outcomes. Results: Overall, 685 children (386 boys [56.4%]; median age, 7.3 [IQR, 1.6-12.4] years) were included. Of these children, 628 (91.7%) were diagnosed with acute SARS-CoV-2 infection and 57 (8.3%) with MIS-C. The presence of GI symptoms was associated with a higher chance of hospitalization (OR, 2.64; 95% CI, 1.89-3.69) and intensive care unit admission (OR, 3.90; 95% CI, 1.98-7.68). Overall, 65 children (9.5%) showed severe GI involvement, including disseminated adenomesenteritis (39.6%), appendicitis (33.5%), abdominal fluid collection (21.3%), pancreatitis (6.9%), or intussusception (4.6%). Twenty-seven of these 65 children (41.5%) underwent surgery. Severe GI manifestations were associated with the child's age (5-10 years: OR, 8.33; 95% CI, 2.62-26.5; >10 years: OR, 6.37; 95% CI, 2.12-19.1, compared with preschool-age), abdominal pain (adjusted OR [aOR], 34.5; 95% CI, 10.1-118), lymphopenia (aOR, 8.93; 95% CI, 3.03-26.3), or MIS-C (aOR, 6.28; 95% CI, 1.92-20.5). Diarrhea was associated with a higher chance of adenomesenteritis (aOR, 3.13; 95% CI, 1.08-9.12) or abdominal fluid collection (aOR, 3.22; 95% CI, 1.03-10.0). Conclusions and Relevance: In this multicenter cohort study of Italian children with SARS-CoV-2 infection or MIS-C, 9.5% of the children had severe GI involvement, frequently associated with MIS-C. These findings suggest that prompt identification may improve the management of serious complications.
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COVID-19/complicaciones , Enfermedades Gastrointestinales/virología , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Niño , Preescolar , Femenino , Enfermedades Gastrointestinales/diagnóstico por imagen , Enfermedades Gastrointestinales/patología , Humanos , Masculino , Pronóstico , Radiografía , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα. The mutation preserves IKKα kinase activity but abolishes the interaction of IKKα with its activator NF-κBinducing kinase and impairs lymphotoxin-ßdriven p100/NF-κB2 processing and VCAM1 expression. Homozygous IKKαY580C/Y580C mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVß repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.
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Autoinmunidad/inmunología , Quinasa I-kappa B/inmunología , Mutación Missense/genética , Animales , Células HEK293 , Humanos , Quinasa I-kappa B/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense/inmunologíaRESUMEN
BACKGROUND: Human Cytomegalovirus (HCMV) still represents a crucial concern in solid organ transplant recipients (SOTRs) and the use of antiviral therapy are limited by side effects and the selection of viral mutations conferring antiviral drug resistance. CASE PRESENTATION: Here we reported the case of an HCMV seronegative patient with common variable immunodeficiency (CVID), multiple hepatic adenomatosis, hepatopulmonary syndrome and portal hypertension who received a liver transplant from an HCMV seropositive donor. The patient was treated with Valganciclovir (vGCV) and then IV Ganciclovir (GCV) at 5 week post-transplant for uncontrolled HCMV DNAemia. However, since mutation A594V in UL97 gene conferring resistance to ganciclovir was reported, GCV therapy was interrupted. Due to the high toxicity of Foscarnet (FOS) and Cidofovir (CDV), Letermovir (LMV) monotherapy at the dosage of 480 mg per day was administered, with a gradual viral load reduction. However, a relapse of HCMV DNAemia revealed the presence of mutation C325Y in HCMV UL56 gene conferring resistance to LMV. CONCLUSIONS: In conclusion, even if LMV is an effective and favorable safety molecule it might have a lower genetic barrier to resistance. A warning on the use of LMV monotherapy as rescue treatments for HCMV GCV-resistant infections in transplant recipients is warranted.
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Infecciones por Citomegalovirus , Trasplante de Hígado , Acetatos , Antivirales/farmacología , Antivirales/uso terapéutico , Citomegalovirus/genética , Infecciones por Citomegalovirus/tratamiento farmacológico , Farmacorresistencia Viral , Ganciclovir/uso terapéutico , Humanos , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , QuinazolinasRESUMEN
Background: Coronavirus Disease 2019 (COVID-19) seems to affect children only marginally, as a result, there isless knowledge of its manifestations in childhood. The purpose of this retrospective cross-sectional study was toinvestigate the oral and cutaneous manifestations in children affected by COVID-19.Material and Methods: All the medical records of children with COVID-19 admitted to the Pediatric Clinic- ASSTSpedali Civili of Brescia from March to April 2020 were reviewed. The following data were recorded: age, tem-perature, clinical presentation, oral mucosa lesions, taste alteration and cutaneous lesions.Results: The medical records of twenty-seven pediatric patients (mean age 4,2 years + 1,7) were analyzed. Theclinical presentation of the disease mainly included elevated body temperature and cough. The following oral le-sions were recorded: oral pseudomembranous candidiasis (7.4 %), geographic tongue (3.7%), coated tongue (7.4%) and hyperaemic pharynx (37 %). Taste alteration was reported by 3 patients. Six patients presented cutaneousflat papular lesions.Conclusions: As for our paediatric sample, COVID-19 resulted to be associated with non-specific oral and cutane-ous manifestations.(AU)
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Humanos , Masculino , Femenino , Niño , Pandemias , Infecciones por Coronavirus/complicaciones , Registros Médicos , Mucosa Bucal , Gusto , Estudios Retrospectivos , Estudios Transversales , ChinaRESUMEN
The object of this study was to investigate the frequency of human adenovirus (HAdV) infections in hospitalized pediatric patients. Stool samples were collected during a 1-year period (February 2018 to January 2019). HAdV was detected by a broad-range PCR and genotyped by sequencing and phylogenetic analysis. Demographic characteristics and detailed clinical information were analyzed for each patient. HAdV was detected in 7.1% of stool samples (34/476). Among these patients, 23.5% were coinfected with other enteric viral or bacterial pathogens. The majority (85.2%) of HAdV positives were detected in children of <5 years of age. Two HAdV species (B and C) with three types were identified in this study population. HAdV species F was not detected. Genetic analysis shows that the isolates circulating in our region present high diversity and do not exhibit clonal expansion. The presence of nonenteric HAdV in subjects with gastrointestinal symptoms and in immunocompromised patients has already been reported by different studies and underlines the need to develop routine molecular assays that have wide reactivity for most types of adenovirus in order to obtain an optimal tool for their rapid and accurate diagnosis. IMPORTANCE Gastroenteritis is the second leading cause of death among infants and children worldwide. Our study shows that adenovirus types other than 40 and 41 might be related to acute gastroenteritis. Therefore, a novel approach using diagnostic methods able to detect all adenovirus types is desirable in order to overcome the limitations of the current techniques.
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Infecciones por Adenovirus Humanos/virología , Adenovirus Humanos/aislamiento & purificación , Gastroenteritis/virología , Infecciones por Adenovirus Humanos/terapia , Adenovirus Humanos/clasificación , Adenovirus Humanos/genética , Adenovirus Humanos/fisiología , Adolescente , Niño , Niño Hospitalizado/estadística & datos numéricos , Preescolar , Femenino , Gastroenteritis/terapia , Humanos , Lactante , Recién Nacido , Masculino , FilogeniaRESUMEN
Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic characteristics of pediatric SARS-CoV-2 infection, focusing on risk factors for complicated and critical disease. Methods: The present multicenter Italian study was promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled from March 2020. Results: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4; 12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19. Age was inversely related to hospital admission (p < 0.01) and linearly to length of stay (p = 0.014). One hundred forty-nine children (19.6%) developed complications. Comorbidities were risk factors for complications (p < 0.001). Viral coinfections, underlying clinical conditions, age 5-9 years and lymphopenia were statistically related to ICU admission (p < 0.05). Conclusions: Complications of COVID-19 in children are related to comorbidities and increase with age. Viral co-infections are additional risk factors for disease progression and multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) for ICU admission.
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BACKGROUND: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. METHODS: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. RESULTS: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. CONCLUSION: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.
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COVID-19/fisiopatología , Enfermedad de la Arteria Coronaria/fisiopatología , Hipotensión/fisiopatología , Linfopenia/fisiopatología , Síndrome Mucocutáneo Linfonodular/fisiopatología , Miocarditis/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Distribución por Edad , Antirreumáticos/uso terapéutico , Aspirina/uso terapéutico , Proteína C-Reactiva/metabolismo , COVID-19/epidemiología , COVID-19/metabolismo , COVID-19/terapia , Niño , Preescolar , Tos/fisiopatología , Diarrea/fisiopatología , Disnea/fisiopatología , Femenino , Glucocorticoides/uso terapéutico , Insuficiencia Cardíaca/fisiopatología , Humanos , Hiperferritinemia/metabolismo , Hiperferritinemia/fisiopatología , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Lactante , Unidades de Cuidado Intensivo Pediátrico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Italia/epidemiología , Masculino , Síndrome Mucocutáneo Linfonodular/epidemiología , Síndrome Mucocutáneo Linfonodular/metabolismo , Síndrome Mucocutáneo Linfonodular/terapia , Inhibidores de Agregación Plaquetaria/uso terapéutico , SARS-CoV-2 , Choque/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Taquipnea/fisiopatología , Troponina T/metabolismo , Vómitos/fisiopatologíaAsunto(s)
Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Tracto Gastrointestinal/virología , Interacciones Huésped-Patógeno , Sistema Respiratorio/virología , SARS-CoV-2/inmunología , Carga Viral , Factores de Edad , Anticuerpos Antivirales/sangre , COVID-19/epidemiología , Tracto Gastrointestinal/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Italia/epidemiología , Sistema Respiratorio/inmunologíaAsunto(s)
Anticuerpos Antibacterianos/sangre , COVID-19/complicaciones , Síndrome Mucocutáneo Linfonodular/complicaciones , Mycoplasma pneumoniae/patogenicidad , Neumonía por Mycoplasma/complicaciones , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/complicaciones , Adolescente , Western Blotting , COVID-19/diagnóstico , COVID-19/patología , COVID-19/virología , Prueba de COVID-19 , Niño , Preescolar , Coinfección , Conjuntivitis/diagnóstico , Conjuntivitis/fisiopatología , Edema/diagnóstico , Edema/fisiopatología , Exantema/diagnóstico , Exantema/fisiopatología , Femenino , Fiebre/diagnóstico , Fiebre/fisiopatología , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/patología , Síndrome Mucocutáneo Linfonodular/virología , Mycoplasma pneumoniae/crecimiento & desarrollo , Neumonía por Mycoplasma/diagnóstico , Neumonía por Mycoplasma/microbiología , Neumonía por Mycoplasma/patología , SARS-CoV-2/crecimiento & desarrollo , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/patología , Síndrome Respiratorio Agudo Grave/virología , Estomatitis/diagnóstico , Estomatitis/fisiopatologíaRESUMEN
Activated phosphoinositide 3-kinase delta syndrome 1 (APDS-1) is a recently described inborn error of immunity caused by monoallelic gain-of-function mutations in the PIK3CD gene. We reviewed for the first time medical records and laboratory data of eight Italian APDS-1 patients. Recurrent sinopulmonary infections were the most common clinical feature at onset of disease. Seven patients presented lymphoproliferative disease, at onset or during follow-up, one of which resembled hemophagocytic lymphohistiocytosis (HLH). Genetic analysis of the PIK3CD gene revealed three novel mutations: functional testing confirmed their activating nature. In the remaining patients, the previously reported variants p.E1021K (n = 4) and p.E525A (n = 1) were identified. Six patients were started on immunoglobulin replacement treatment (IgRT). One patient successfully underwent hematopoietic stem cell transplantation (HSCT), with good chimerism and no GVHD at 21 months post-HSCT. APDS-1 is a combined immune deficiency with a wide variety of clinical manifestations and a complex immunological presentation. Besides IgRT, specific therapies targeting the PI3Kδ pathway will most likely become a valid aid for the amelioration of patients' clinical management and their quality of life.
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Antígeno CTLA-4/genética , Deleción Cromosómica , Cromosomas Humanos Par 2 , Inmunodeficiencia Variable Común/terapia , Haploinsuficiencia , Trasplante de Células Madre Hematopoyéticas , Adulto , Alelos , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Femenino , Humanos , Adulto JovenRESUMEN
This study provides evidence for the first time for APDS-1 presenting as MAS/HLH, with evident clinical implications in patient's management and prognosis.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Linfohistiocitosis Hemofagocítica/diagnóstico , Síndrome de Activación Macrofágica/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Niño , Humanos , Linfohistiocitosis Hemofagocítica/genética , Síndrome de Activación Macrofágica/genética , Masculino , Mutación , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
Data on features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents are scarce. We report preliminary results of an Italian multicentre study comprising 168 laboratory-confirmed paediatric cases (median: 2.3 years, range: 1 day-17.7 years, 55.9% males), of which 67.9% were hospitalised and 19.6% had comorbidities. Fever was the most common symptom, gastrointestinal manifestations were frequent; two children required intensive care, five had seizures, 49 received experimental treatments and all recovered.
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Enfermedad Crónica/epidemiología , Coinfección/epidemiología , Infecciones por Coronavirus/diagnóstico , Coronavirus/aislamiento & purificación , Pandemias/prevención & control , Neumonía Viral/diagnóstico , Adolescente , Antivirales/uso terapéutico , Betacoronavirus , COVID-19 , Prueba de COVID-19 , Niño , Preescolar , Técnicas de Laboratorio Clínico , Coinfección/virología , Comorbilidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Diarrea/etiología , Brotes de Enfermedades , Heces/virología , Femenino , Fiebre/etiología , Hospitales Pediátricos , Humanos , Huésped Inmunocomprometido , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Ventilación no Invasiva/métodos , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Inhibidores de Proteasas/uso terapéutico , Estudios Retrospectivos , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/diagnóstico , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/terapia , Resultado del TratamientoRESUMEN
Objective: Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus pyogenes infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are emerging immune-mediated encephalopathies characterized by sudden onset of seemingly inexplicable complex neuropsychiatric symptoms, including obsessions, compulsions, and heterogeneous tics, which occur in children. Main goal of this study was to report our experience in a large cohort of Italian children affected by either PANDAS or PANS and treated long term with an antibiotic regimen similar to that used for acute rheumatic fever. Patients and Methods: The clinical charts of a cohort of 371 consecutive Italian children, 345 with PANDAS (93.0%) and 26 with PANS (7.0%), were retrospectively evaluated. Antistreptococcal, antinuclear antibodies, and serologic evaluation for a group of common autoantibodies and microbial agents were also assessed. A strict differential diagnosis with other autoimmune diseases displaying neuropsychiatric manifestations was performed. Results: Antistreptolysin O and anti-DNase B antibody titers were tested and were positive in all PANDAS subjects, but negative in PANS. Anti-Mycoplasma pneumoniae antibodies and anti-Epstein-Barr virus Nuclear Antigen antibodies were found positive in 11 (42.3%) and 5 (19.2%) patients with PANS, respectively. Among PANDAS cases, a clear streptococcal infection was clinically evident at the onset of neurological symptoms in only 74 patients (21.4%), whereas the relationship with Streptococcus pyogenes was confirmed by serologic tests in the other 271 (78.6%). All patients fulfilling the diagnostic criteria for PANDAS (n = 345) received amoxicillin/clavulanic acid for 10-21 days at diagnosis, while those who were diagnosed with PANS (n = 26) received treatment according to the causative agent. Thereafter, all PANDAS/PANS patients received prophylaxis with benzathine benzylpenicillin for an overall period of at least 5 years to prevent subsequent potential streptococcal infections. To date, 75.0% of PANDAS patients (n = 258) have shown an improvement of neurologic symptoms, mainly observed within 3-5 months of treatment for PANDAS cases, while 88.4% of PANS patients (n = 23) have improved after 6-12 months. Infection-related relapses of neurologic manifestations were observed in both PANDAS and PANS patients (n = 167 out of 371; 45% of the total cohort) in the long term. Conclusions: Our study has confirmed the usefulness of the preliminary diagnostic criteria for PANDAS and PANS, revealing also the importance of early diagnosis to reduce the risk of evolution toward disabling chronic neurologic sequelae. Long-term antibiotic prophylaxis has resulted in a substantial benefit to reduce neurological symptoms for the majority of PANDAS and PANS patients over a 7-year period.
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Enfermedades Autoinmunes/inmunología , Trastorno Obsesivo Compulsivo/inmunología , Pruebas Serológicas , Infecciones Estreptocócicas/inmunología , Adolescente , Antibacterianos/uso terapéutico , Antiestreptolisina/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/microbiología , Encefalopatías , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Italia , Masculino , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/microbiología , Recurrencia , Estudios Retrospectivos , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/aislamiento & purificaciónRESUMEN
PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.
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Deficiencia de IgA/epidemiología , Adolescente , Enfermedad Celíaca/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Hipersensibilidad/epidemiología , Deficiencia de IgA/diagnóstico , Italia , Estudios Longitudinales , Masculino , Infecciones del Sistema Respiratorio/epidemiologíaRESUMEN
Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutières Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and brain imaging best characterize tetraparesis due to an interferonopathy.Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, brain imaging review, peripheral blood interferon signature and AGS-related genes analysis.At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with brain calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene.AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, brain white-matter lesions with late calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Interferón Tipo I/biosíntesis , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/diagnóstico , Paresia/etiología , Adolescente , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Enfermedades Autoinmunes del Sistema Nervioso/genética , Biomarcadores , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Interferón Tipo I/sangre , Interferón Tipo I/genética , Imagen por Resonancia Magnética , Masculino , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/genética , Proyectos Piloto , Adulto JovenRESUMEN
The protective role of Sickle Cell Trait (SCT) in malaria endemic areas has been proved, and prevalence of HbS gene in malaria endemic areas is high. Splenic infarction is a well-known complication of SCT, while the association with malaria is considered rare. A Nigerian boy was admitted to our ward after returning from his country of origin, for P. falciparum malaria. He underwent abdominal ultrasound for upper right abdominal pain, showing cholecystitis and multiple splenic lesions suggestive of abscesses. Empiric antibiotic therapy was undertaken. Bartonella, Echinococcus, Entamoeba serologies, blood cultures, Quantiferon test, copro-parasitologic exam were negative; endocarditis was excluded. He underwent further blood exams and abdomen MRI, confirming the presence of signal alterations areas, with radiographic appearance of recent post-infarction outcomes. Hemoglobin electrophoresis showed a percentage of HbS of 40.6% and a diagnosis of SCT was then made. Splenic infarction should be taken into account in patients with malaria and localized abdominal pain. Moreover, diagnosis of SCT should be considered.